Procarbazine, lomustine and vincristine toxicity in low-grade gliomas.

BACKGROUND: Procarbazine, lomustine, and vincristine (pcv) significantly improve survival outcomes in lgg (low-grade gliomas). Administration of pcv to lgg patients increased tremendously over the past years as it went from 2 patients per year between 2005 and 2012 to 23 patients in 2015 only in our centre. However, serious hematological and non-hematological adverse events may occur. The purpose of this study was to evaluate the toxicity of pcv and its clinical relevance in our practice. METHODS: We retrospectively reviewed the charts of 57 patients with lgg who received pcv at the Centre hospitalier de l'Université de Montréal between 1 January 2005 and 27 July 2016. RESULTS: Procarbazine, lomustine, and vincristine were associated with severe hematological toxicity as clinically significant grade 3 anemia, neutropenia, and thrombocytopenia occurred in 7%, 10%, and 28% of patients, respectively. Other frequent adverse events such as the increase of liver enzymes, cutaneous rash, neurotoxicity, and vomiting occurred in 65%, 26%, 60%, and 40% of patients, respectively. Patients with prophylactic trimethoprim/sulfamethoxazole had more grade 3 hematological toxicity with pcv, especially anemia (p = 0.040) and thrombocytopenia (p = 0.003) but we found no increase in pcv toxicity in patients on concurrent anticonvulsants. Patients with grade 3 neutropenia had a significantly lower survival (median survival 44.0 months vs. 114.0 months, p = 0.001). Patients who were given pcv at diagnosis had more grade 3 anemia than those who received it at subsequent lines of treatment (p = 0.042). CONCLUSION: Procarbazine, lomustine, and vincristine increase survival in lgg but were also associated with major hematologic, hepatic, neurologic, and cutaneous toxicity. Anti-Pneumocystis jiroveci pneumonia (pjp) prophylaxis, but not anticonvulsants, enhances hematologic toxicity.

Trigeminal nerve haemangioma eroding the petrous carotid canal.

OBJECTIVE: To report the first case of mandibular branch haemangioma of the trigeminal nerve causing erosion of the petrous carotid canal. The radiological and histological findings in this case are reviewed. CASE REPORT: A 60-year-old woman presented with severe, right-sided facial pain and paraesthesia. There were no associated symptoms of facial weakness or diplopia. A magnetic resonance imaging scan with gadolinium enhancement was performed. This showed a lesion slightly compressing the right Meckel's cave and eroding the right petrous carotid canal, occupying the foramen ovale and extending to the pterygoid muscle. The lesion was removed via a subtemporal approach. CONCLUSION: Haemangiomas are usually found on the skin and in other soft tissues. However, this rare tumour should also be considered in the differential diagnosis of lesions occupying Meckel's cave and the foramen ovale.

Scalp nerve blocks decrease the severity of pain after craniotomy.

UNLABELLED: Up to 80% of patients report moderate to severe pain after craniotomy. In this study, we assessed the efficacy of scalp block for decreasing postoperative pain in brain surgery. Thirty patients scheduled for supratentorial craniotomy were enrolled. They were randomly divided into two groups: Ropivacaine (scalp block with 20 mL of ropivacaine 0.75%) and Saline (scalp block with 20 mL of saline 0.9%). Anesthesia was standardized. The scalp block was performed after skin closure and before awakening. Postoperative pain was assessed at 4, 8, 12, 16, 20, 24, and 48 h by using a 10-cm visual analog scale. Analgesia was provided with sub- cutaneous codeine as requested by the patient. Average visual analog scale scores were higher in the Saline group as compared with Ropivacaine (3.7 +/- 2.4 vs 2.0 +/- 1.6; P = 0.036). The total dose of codeine did not differ, nor did the duration of time before the first dose of codeine was required in the Ropivacaine (571 +/- 765 min) versus Saline (319 +/- 409 min; P = 0.17) group. In conclusion, we found that postoperative scalp block decreases the severity of pain after craniotomy and that this effect is long lasting, possibly through a preemptive mechanism. IMPLICATIONS: Up to 80% of patients report moderate to severe pain after craniotomy. This randomized double-blinded study demonstrated that ropivacaine scalp block decreases the severity of pain after supratentorial craniotomy.

Expression of multidrug-resistance P-glycoprotein (MDR1) in human brain tumors.

Multidrug resistance (MDR) is associated with the expression of P-glycoprotein (P-gp), an ATP-dependent transporter which expels anti-cancer drugs from cells. In the present study, MDR1 P-gp was immunodetected by Western blot analysis in 60 human brain tumors, including meningiomas, schwannomas, low-grade gliomas (astrocytomas, pilocytic astrocytomas) and high-grade gliomas (anaplastic astrocytomas, glioblastomas and anaplastic oligodendrogliomas). Most samples from primary tumors expressed P-gp at the same levels as normal brain tissue except for schwannomas, in which levels were reduced by 65%, and meningiomas, in which levels were more than 10-fold higher in 7 of 10 samples. P-gp levels were 70% and 95% lower in brain metastases from melanomas and lung adenocarcinomas, respectively, than in normal brain tissue. These results indicate that the majority of primary brain tumors express MDR1 P-gp and that its high expression levels in meningiomas may be a marker for this type of brain tumor.

Expression of matrix metalloproteinases and their inhibitors in human brain tumors.

Sixty human brain tumors, classified according to the New World Health Organization (WHO) classification including, grade I schwannomas, meningiomas and pilocytic astrocytomas, grade II astrocytomas, grade III anaplastic astrocytomas, grade IV glioblastomas, grade III anaplastic oligodendrogliomas and grade IV glioblastomas and lung and melanoma metastases were analyzed for the expression of three matrix metalloproteinases (MMPs), two tissue inhibitors of MMPs (TIMPs) and for MMP activity. Some correlation was found between MMP expression and the degree of malignancy. Western blotting analysis revealed a more uniform pattern of distribution of MMP-2 (gelatinase A) than of MMP-9 (gelatinase B) and MMP-12 (metalloelastase) among tumors. MMP-9 levels were found to be significantly higher in grade III anaplastic astrocytomas and anaplastic oligodendrogliomas than those in grade I schwannomas and meningiomas. Anaplastic astrocytomas and Grade IV glioblastomas expressed significantly higher levels MMP-12 than grade I meningiomas. All sixty tumors showed a similar pattern of activity in zymography, proMMP-9 being the major species detected. Interestingly, TIMP-1 and TIMP-2 expression levels were especially low in tumors of grade II and grade III but significantly higher in tumors of grade I, particularly in schwannomas. Taken together, these data suggest that: 1) a balance between MMPs and TIMPs has an important role to play in human brain tumors; 2) TIMP expression may be valuable markers for tumor malignancy.

Expression of matrix metalloproteinases and their inhibitors in human brain tumors.

Sixty human brain tumors, including grade I meningiomas, schwannomas, and pilocytic astrocytomas, grade II astrocytomas, grade III anaplastic astrocytomas and oligodendrogliomas, and grade IV glioblastomas and lung and melanoma metastases were analyzed for expression of four matrix metalloproteinases (MMPs), two tissue inhibitors of MMPs (TIMPs), and MMP activity. No marked correlation was found between MMP expression and the degree of malignancy. Western blotting analysis revealed a more uniform pattern of distribution of MMP-2 (gelatinase A) than of MMP-9 (gelatinase B) and MMP-12 (metalloelastase) among tumors. All 60 tumors showed a similar pattern of activity in zymography, MMP-2 being the major species detected. Interestingly, TIMP-1 and TIMP-2 expression levels were low in tumors of grade III but significantly higher in tumors of grade I, particularly schwannomas. Altogether, these data suggest that: (1) the balance between MMP-2 and TIMP-2 is important in human brain tumors; and (2) TIMP expression may be a valuable marker for tumor malignancy.

Endovascular treatment of ophthalmic segment aneurysms with Guglielmi detachable coils.

PURPOSE: To evaluate the safety and efficacy of endovascular treatment of ophthalmic segment aneurysms with Guglielmi detachable coils (GDCs), as well as the primary indications for such treatment. METHODS: We conducted a prospective study of 26 patients with 28 aneurysms of the ophthalmic segment in whom treatment with GDCs was attempted. Anatomic results were measured by statistical analysis of variance for such factors as age, sex, presence of subarachnoid hemorrhage, anatomic type (ophthalmic or superior hypophyseal), size of aneurysmal sac, and width of aneurysmal neck. Clinical evaluation and control angiography were performed at 6 and 18 months. RESULTS: Overall, complete occlusion was obtained in 14 aneurysms (50%) and small residual necks were left in 11 aneurysms (39%). Three treatment attempts failed (11%). Complete occlusion was obtained in 76% of small-necked aneurysms as opposed to 9% of aneurysms with a large neck. The best predictor of anatomic result was the size of the aneurysmal neck. Complete occlusion was obtained in 85% of superior hypophyseal aneurysms of the paraclinoid variant. One permanent complication was related to treatment. CONCLUSION: Endovascular treatment with GDCs appears to be a safe and efficient alternative approach for ophthalmic segment aneurysms, especially for paraclinoid variants of superior hypophyseal aneurysms, which tend to have a small neck.

Endovascular treatment of acutely ruptured and unruptured aneurysms of the basilar bifurcation.

The surgical treatment of basilar bifurcation aneurysms is difficult and the need for an alternative approach is frequently stated. To assess the efficacy and safety of endovascular treatment of aneurysms located at the basilar bifurcation, the authors prospectively studied angiographic results, clinical results, and complications in 31 patients treated with Guglielmi detachable coils (GDCs). Patients treated acutely after subarachnoid hemorrhage (SAH) were graded according to the Hunt and Hess classification and clinical outcome was determined at 1- and 6-month intervals according to the Glasgow Outcome Scale (GOS). There were 18 women and 13 men, ranging in age from 34 to 67 years (mean age 48 years). Twenty-three were treated acutely after SAH. Clinical Hunt and Hess grades at presentation were as follows: Grade I, six patients; Grade II, three; Grade III, 11; Grade IV, two; and Grade V, one. The GOS score for the group of patients treated acutely was: GOS I, 18 patients; GOS II, III, and IV, one patient each; and GOS V, two patients. There were seven technical complications in this group, most often asymptomatic, but one patient died after aneurysm rupture during treatment and one had residual diplopia at 4 months. Eight patients were treated for incidental basilar bifurcation aneurysms. One technical complication with no neurological deficit occurred in this group of patients with incidental aneurysms. Immediate angiographic results were considered to be satisfactory in 94% of patients, with complete obliteration in 42% and residual neck and dog ears in 52%. There was no bleeding episode after treatment during clinical follow-up periods ranging from 3 to 42 months (mean 15.5 months in 29 surviving patients). Angiographic results were available for 27 patients at 6 months and were as follows: 30% of the lesions were completely obliterated, 59% presented some residual neck, and 11% showed some opacification of the aneurysm sac. During the follow-up period of up to 42 months, a total of seven recurrences were noted, necessitating retreatment with GDCs in five patients. Endovascular treatment of basilar bifurcation aneurysms prevented rebleeding and could be performed without clinically significant complications in 94% of patients. Clinical results after SAH compared favorably with surgical series. Morphological results appear less satisfactory, and long-term angiographic follow-up review is mandatory to detect recurrences.

Cerebral arterial ectasia and tuberous sclerosis: case report.

OBJECTIVE AND IMPORTANCE: Tuberous sclerosis is associated with a wide variety of central nervous system abnormalities. Cerebrovascular anomalies are extremely rare, but a case of cerebral arterial ectasia and giant fusiform aneurysm formation in a young child is reported. CLINICAL PRESENTATION: A 5-month-old male patient with tuberous sclerosis presented with seizures, a subependymal tumor, and intraventricular hemorrhage. Cerebral angiography demonstrated a large fusiform aneurysm of the left cavernous internal carotid artery as well as arterial ectasia of the proximal left anterior cerebral and middle cerebral arteries. The patient developed hydrocephalus and died of infectious complications after repeated shunt procedures. CONCLUSION: Tuberous sclerosis is commonly associated with central nervous system lesions. Although rare, cerebrovascular anomalies and aneurysms should be considered in the differential diagnosis of mass lesions to avoid an ill-advised biopsy of a vascular lesion, which could have disastrous consequences.

Spinal metastases as a first presentation of malignant astrocytoma.

A 46-year-old man presented with low dorsal pain and paresthesia. Computed tomography showed an osteolytic lesion involving most of the vertebral body and the left pedicle of the 12th thoracic vertebra (T12). Contrast-enhanced magnetic resonance imaging (MRI) of the spine showed an enhancing soft-tissue mass that involved the T11 and T12 vertebral bodies, as well as that of the first lumbar vertebra; the mass caused cord compression. Another lesion was identified at T9. The findings of percutaneous needle aspiration biopsy of the lesion were consistent with metastatic astrocytoma, a diagnosis confirmed at surgery. MRI of the brain showed an asymptomatic lesion of the left temporal lobe; histologic confirmation of malignant astrocytoma was obtained by stereotactic biopsy. This report shows that metastatic bone disease secondary to malignant astrocytoma may manifest itself before the primary lesion becomes symptomatic. This presentation of astrocytoma was unusual because there were no symptoms of the intracranial tumour and because metastatic disease to the bones is less common than to the chest and the lymph nodes.

Gamma-interferon promotes proliferation of adult human astrocytes in vitro and reactive gliosis in the adult mouse brain in vivo.

Reactive gliosis is a characteristic response of astrocytes to inflammation and trauma of the central nervous system. To investigate whether soluble factors (cytokines) from inflammatory mononuclear cells that accumulate at lesion sites can provide the cellular signals to initiate gliosis and to identify such cytokines, we have tested and found that supernatants derived from subsets of activated human T lymphocytes (CD8+ or CD4+) are potent mitogens for cultured human adult astrocytes. This effect is blocked by a neutralizing antibody to gamma-interferon (IFN). Recombinant IFN alone can induce proliferation of human adult astrocytes in vitro and increase the extent of trauma-initiated gliosis in the adult mouse brain. The astrocyte proliferation-inducing activity of supernatants of glial cultures treated with IFN can be completely blocked with IFN-neutralizing antibody, suggesting that the proliferative effect does not require intermediary cytokines or cells. These results implicate IFN as an important mediator of the gliosis observed in pathologic conditions of the adult central nervous system associated with infiltrating lymphocytes.

Intracerebral gangliogliomas in patients with partial complex seizures: CT and MR imaging findings.

The clinical and radiologic findings in 19 patients with partial complex seizures and surgically proved intracerebral gangliogliomas were reviewed to characterize the radiologic features of these lesions. The CT and MR findings were not specific. On CT the gangliogliomas can be hypodense with no enhancement and they often have calcifications. On MR these tumors have a wide variety of signals. In five of our cases the tumor had a high-intensity signal with a cystlike component on proton density- and T2-weighted images. In five cases the lesion had an inhomogeneously intense signal on proton density-weighted images and high signal intensity on T2-weighted images. The tumor had high-intensity signal on both proton density- and T2-weighted images in four patients. Finally, in two cases the MR findings were normal. We recommend MR as the examination of choice for patients with partial complex seizures because it allows an artifact-free evaluation of the temporal region. However, CT should also be performed in order to recognize calcifications that may be missed on the MR examination.

Origin of contralateral reactive gliosis in surgically injured rat cerebral cortex.

While reactive gliosis is readily observed close to the site of cerebral injury, astrocyte reactivity can also occur in distant areas either ipsilateral or contralateral to the lesion site. The present experiments were designed to address the origin of contralateral gliosis in adult rats following a cortical stab wound injury. One-month-old rats were subjected to either left cortical stab wound alone, callosotomy alone, callosotomy plus left cortical stab wound, or no surgery; 7 days later, animals were sacrificed. Formalin-fixed, paraffin-embedded sections were obtained and immunostained for GFAP. While untreated controls showed no cortical gliosis, callosotomy alone induced mild bilateral cortical gliosis. Whether or not rats were subjected to a callosotomy, the left cortical stab wound produced identical results: severe ipsilateral cortical gliosis and moderate contralateral gliosis. In all lesion models, both the intensity of GFAP staining and the number of reactive astrocytes were most marked in cortical areas abutting the subarachnoid spaces and decreased gradually into the deeper cortical layers. Our results suggest that the origin of contralateral gliosis in cortical stab injury is more likely due to the release of soluble substance(s) which diffuse to distant areas, rather than the migration of astrocytes through the corpus callosum from the lesion site, or being subsequent to degeneration of neurons which fibers traverse the corpus callosum.