EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force

The objectives have been to establish evidence-based guidelines and identify controversies regarding the management of patients with brain metastases. The collection of scientific data was obtained by consulting the Cochrane Library, bibliographic databases, overview papers and previous guidelines from scientific societies and organizations. A tissue diagnosis is necessary when the primary tumor is unknown or the aspect on computed tomography/magnetic resonance imaging is atypical. Dexamethasone is the corticosteroid of choice for cerebral edema. Anticonvulsants should not be prescribed prophylactically. Surgery should be considered in patients with up to three brain metastases, being effective in prolonging survival when the systemic disease is absent/controlled and the performance status is high. Stereotactic radiosurgery should be considered in patients with metastases of 3–3.5 cm of maximum diameter. Whole-brain radiotherapy (WBRT) after surgery or radiosurgery is debated: in case of absent/controlled systemic cancer and Karnofsky Performance score of 70 or more, one can either withhold initial WBRT or deliver early WBRT with conventional fractionation to avoid late neurotoxicity. WBRT alone is the treatment of choice for patients with single or multiple brain metastases not amenable to surgery or radiosurgery. Chemotherapy may be the initial treatment for patients with brain metastases from chemosensitive tumors.     

Clinical characteristics of severe peripheral neuropathy induced by docetaxel (Taxotere)

Background: Docetaxel, a semi-synthetic taxane may cause a usuallymild sensory neuropathy. We describe the clinical characteristics of fivepatients who developed a more severe neuropathy following treatment withdocetaxel.Patients and methods: All patients were treated in phase II studieswith 100 mg/m² docetaxel in three weekly cycles, withoutsteroid administration.Results: The clinical picture in these patients was dominated by asensory neuropathy, but in one case severe weakness was present. Anotherpatient developed Lhermitte's sign. Signs and symptoms are usually reversibleafter discontinuation of docetaxel administration, but in three patientssymptoms worsened for some time after the end of treatment before improvementoccurred.Conclusion: Severe docetaxel neuropathy may especially occurfollowing treatment with cumulative dosage over 600 mg/m²; inpatients treated with this dosage a moderate or severe neuropathy may not berare.     

Platelet aggregability in relation to impaired consciousness after head injury.

ADP-induced platelet aggregation was studied for up to six weeks in 34 patients with head injuries. The patients were divided into three groups according to the degree of impaired consciousness assessed by a clinical coma scale, and change in platelet aggregation was related to the coma score. Platelet aggregation was markedly reduced in all eight patients dying within 24 hours of injury. All 17 patients who remained unconscious for four days or more showed decreased platelet aggregation up to nine days after admission, the most marked effect being on the second day. Platelet function in this group returned to normal within 16 days. Nine patients with only slightly impaired consciousness also showed subnormal platelet aggregation during the first few days with a return to normal by the fourth day. Platelet counts remained within normal limits in all groups. We suggest that during coma following head injury brainstem dysfunction induces neurohumoral changes in the blood which are responsible for a decrease in platelet function.     

Virulence of Streptococcus suis type 2 strains in newborn germfree pigs depends on phenotype.

To determine whether the virulence of Streptococcus suis type 2 is associated with the phenotype of the strain, we infected newborn germfree pigs with 10 strains of S. suis type 2 categorized by three phenotypes. In an earlier study, the phenotypes were distinguished by the presence or absence of the muramidase-released protein (MRP) and an extracellular factor (EF) and were designated MRP+ EF+, MRP+ EF- and MRP- EF-. Pigs were first inoculated with Bordetella bronchiseptica to predispose them to infection and were then intranasally inoculated with the streptococci. Strains of the MRP+ EF+ phenotype induced fever and increased the number of polymorphonuclear leukocytes in blood. Specific clinical signs of disease such as nervous disorders and lameness were also observed. At necropsy bacteriologic and pathologic examination disclosed meningoencephalitis, polyserositis, and polyarthritis. Strains of the MRP+ EF- phenotype induced only nonspecific clinical signs of disease such as recumbency, lack of appetite, and fever; only slight pathologic changes were detected in the serosae. The four strains of the MRP- EF- phenotype induced no signs of disease. These findings indicate that the 110-kDa EF and, to a lesser degree, the 136-kDa MRP may be associated with the virulence of the bacterium. The results demonstrated that S. suis type 2 strains producing both MRP and EF are pathogenic for pigs.     

Identification of two proteins associated with virulence of Streptococcus suis type 2.

The protein profiles of various cell fractions of 180 strains of Streptococcus suis type 2, which were isolated from diseased pigs, from healthy pigs when they were slaughtered, and from human patients, were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. The isolates from diseased pigs contained two proteins that were absent in most of the isolates from healthy pigs. One of these proteins was a 136-kDa protein that was previously identified as the muramidase-released protein (MRP). This protein was predominantly detected in protoplast supernatants and culture supernatants. The second protein was a 110-kDa protein that was detected only in culture supernatants and therefore was provisionally called extracellular factor (EF). Three phenotypes of S. suis type 2 strains were recognized. Isolates from organs of diseased pigs mainly belonged to the MRP+ EF+ phenotype (77%), while isolates from tonsils of healthy pigs mainly had the MRP- EF- phenotype (86%). Most of the isolates from human patients contained MRP (89%); 74% had the MRP+ EF- phenotype. These findings confirm the results of previous investigations which demonstrated that S. suis type 2 strains differ in virulence. Monoclonal antibodies raised against the 110-kDa EF recognized proteins with higher molecular weights in culture supernatants of all of the strains with the MRP+ EF- phenotype. However, none of the strains with the MRP+ EF+ phenotype produced these high-molecular-weight proteins. Our results demonstrate that MRP and EF are associated with virulence. This suggests that one or both of these proteins are virulence factors that play a role in the pathogenesis of S. suis type 2 infections in pigs and human patients.     

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.     

The effect of dexamethasone on the uptake of cisplatin in 9L glioma and the area of brain around tumor

The negative influence of dexamethasone (Dex) on the uptake of cisplatin in brain tumors was investigated in rats bearing 9L glioma. Dex or saline was given intraperitoneally prior to intravenous administration of cisplatin 5 mg/kg. Total Platinum (Pt) concentration was quantified with atomic absorption spectroscopy (AAS) in tumor, brain around tumor (BAT), normal brain and plasma. In the second experiment DNA-adducts of cisplatin were determined in tumor and BAT by AAS. In tumor, there was no difference in the Pt concentration and in the DNA-adduct level between the two treatment groups. In BAT, the Pt level in the Dex group was 0.20 µg/g (SD = 0.10 µg/g), which was significantly lower than in the controls (0.53 µg/g (SD=0.21 µg/g); p < 0.001). In addition, the DNA-adduct level in BAT was 23% lower in the Dex treated rats (p=0.05). In normal brain the Pt concentration was 10-fold lower than in tumor tissue. Thus, Dex did not significantly limit the uptake of cisplatin in brain tumor nor did it influence the uptake in normal brain parenchyma. In contrast, in BAT that has a partially disrupted BBB, the concentrations of Pt and DNA-adduct formation were significantly decreased following pretreatment with Dex. The influence of Dex on limiting the effects of chemotherapy for brain tumors needs further study.     

Tumour and surgery effects on cognitive functioning in high-grade glioma patients

Background

Many high-grade glioma (HGG) patients have cognitive impairments, which impact daily functioning. Cognitive impairments can be caused by tumour-, treatment-, and patient-related factors. The effect of the tumour and of surgical resection on cognition is, however, not well known. We investigated tumour and surgical effects on cognitive functioning in patients with HGG.

Methods

At baseline, preceding surgery, 62 patients with HGG underwent neuropsychological testing concerning seven cognitive domains: verbal and working memory, attention, executive functioning, psychomotor function, information processing speed, and visuoconstructive abilities. Thirty-nine patients were included in follow-up testing after surgery, but before subsequent treatment. Tumour size and site, use of anti-epileptic drugs and corticosteroids, and extent of resection were recorded.

Results

Compared to healthy controls, cognitive functioning of patients was significantly impaired in all domains. Prior to surgery 79 % (49 of 62) of patients had cognitive impairment in at least one domain. At median follow-up of 5 weeks after surgery, 59 % (23 of 39) of patients were cognitively impaired in at least one domain. At follow-up, 49 % showed improvement, while 23 % declined. Left hemisphere tumour localization was associated with worse verbal memory (P=0.004), and larger tumours in this hemisphere with poorer executive functioning (P?<?0.001). Changes in cognitive performance at follow-up relative to baseline were not related to tumour characteristics or extent of resection.

Conclusions

Tumour-related cognitive deficits are present in a majority of HGG patients preceding surgery. Surgery does not result in cognitive deterioration in the short term in most patients.