The role of the neurologist in the diagnosis and treatment of brain metastases and carcinomatous meningitis.

Traditionally, in the past, most of central nervous system metastases from solid tumors were associated with an advanced phase of the disease needing palliation only, while to date they increasingly develop as an early and/or solitary relapse in patients with the systemic disease under control. This review will cover all the aspects of a modern management of brain and leptomeningeal metastases from diagnosis to the different therapeutic options, either local (surgery, stereotactic radiosurgery, whole-brain radiotherapy with hippocampal avoidance) or systemic. Particular emphasis is reserved to the new-targeted drugs, that allow to target specifically driver molecular alterations. These new compounds pose new problems in terms of monitoring efficacy and adverse events, but increasingly they allow improvement of outcome in comparison to historical controls.

Lacosamide in monotherapy in BTRE (brain tumor-related epilepsy): results from an Italian multicenter retrospective study.

PURPOSE: Lacosamide (LCM) is a third-generation anti-seizure medication (ASM) approved for focal onset epilepsy in patients aged ≥ 4.378 Previous studies have reported an efficacy of LCM as add-on treatment in brain tumor-related epilepsy (BTRE). To date, there are no studies in the literature focusing on lacosamide used in monotherapy to treat BTRE. In our retrospective study we investigated efficacy and tolerability of LCM in monotherapy in a multicenter national cohort of primary brain tumor patients. METHODS: We collected from 12 Italian Centers 132 patients with primary brain tumors who were treated with LCM in monotherapy. For each patient we evaluated seizure freedom at 3 and 6 months (primary endpoints), side effects and drop-out rate (secondary endpoints). RESULTS: Overall, LCM led to seizure freedom in 64.4% of patients at 3 months and 55% at 6 months. Patients who used two or more ASMs before LCM had a worse seizure control than patients in monotherapy with LCM as first choice. In 14 patients, we observed seizure control despite tumor progression on magnetic resonance (MRI). Multivariate analysis showed that gross-total resection at diagnosis was significantly associated with higher seizure freedom rate at 6 months. Side effects were mainly mild (grade 1-2 according to CTCAE classification) and drop-out rate was low (1.5%). Main side effects were dizziness and somnolence. CONCLUSIONS: This is the first study showing a good efficacy and tolerability of LCM when used in monotherapy in BTRE. Further prospective studies are needed to confirm these preliminary data, investigating also quality of life and neurocognitive functions.

Review: Peering through a keyhole: liquid biopsy in primary and metastatic central nervous system tumours.

Tumour molecular profiling by liquid biopsy is being investigated for a wide range of research and clinical purposes. The possibility of repeatedly interrogating the tumour profile using minimally invasive procedures is helping to understand spatial and temporal tumour heterogeneity, and to shed a light on mechanisms of resistance to targeted therapies. Moreover, this approach has been already implemented in clinical practice to address specific decisions regarding patients' follow-up and therapeutic management. For central nervous system (CNS) tumours, molecular profiling is particularly relevant for the proper characterization of primary neoplasms, while CNS metastases can significantly diverge from primary disease or extra-CNS metastases, thus compelling a dedicated assessment. Based on these considerations, effective liquid biopsy tools for CNS tumours are highly warranted and a significant amount of data have been accrued over the last few years. These results have shown that liquid biopsy can provide clinically meaningful information about both primary and metastatic CNS tumours, but specific considerations must be taken into account, for example, when choosing the source of liquid biopsy. Nevertheless, this approach is especially attractive for CNS tumours, as repeated tumour sampling is not feasible. The aim of our review was to thoroughly report the state-of-the-art regarding the opportunities and challenges posed by liquid biopsy in both primary and secondary CNS tumours.

Digital PCR quantification of MGMT methylation refines prediction of clinical benefit from alkylating agents in glioblastoma and metastatic colorectal cancer.

BACKGROUND: O(6)-methyl-guanine-methyl-transferase (MGMT) silencing by promoter methylation may identify cancer patients responding to the alkylating agents dacarbazine or temozolomide. PATIENTS AND METHODS: We evaluated the prognostic and predictive value of MGMT methylation testing both in tumor and cell-free circulating DNA (cfDNA) from plasma samples using an ultra-sensitive two-step digital PCR technique (methyl-BEAMing). Results were compared with two established techniques, methylation-specific PCR (MSP) and Bs-pyrosequencing. RESULTS: Thresholds for MGMT methylated status for each technique were established in a training set of 98 glioblastoma (GBM) patients. The prognostic and the predictive value of MGMT methylated status was validated in a second cohort of 66 GBM patients treated with temozolomide in which methyl-BEAMing displayed a better specificity than the other techniques. Cutoff values of MGMT methylation specific for metastatic colorectal cancer (mCRC) tissue samples were established in a cohort of 60 patients treated with dacarbazine. In mCRC, both quantitative assays methyl-BEAMing and Bs-pyrosequencing outperformed MSP, providing better prediction of treatment response and improvement in progression-free survival (PFS) (P < 0.001). Ability of methyl-BEAMing to identify responding patients was validated in a cohort of 23 mCRC patients treated with temozolomide and preselected for MGMT methylated status according to MSP. In mCRC patients treated with dacarbazine, exploratory analysis of cfDNA by methyl-BEAMing showed that MGMT methylation was associated with better response and improved median PFS (P = 0.008). CONCLUSIONS: Methyl-BEAMing showed high reproducibility, specificity and sensitivity and was applicable to formalin-fixed paraffin-embedded tissues and cfDNA. This study supports the quantitative assessment of MGMT methylation for clinical purposes since it could refine prediction of response to alkylating agents.

An Italian multicenter retrospective real-life analysis of patients with brain metastases from renal cell carcinoma: the BMRCC study.

BACKGROUND: The treatment of patients with brain-spread renal cell carcinoma (RCC) is an unmet clinical need, although more recent therapeutic strategies have significantly improved RCC patients' life expectancy. Our multicenter, retrospective, observational study investigated a real-world cohort of patients with brain metastases (BM) from RCC (BMRCC). PATIENTS AND METHODS: A total of 226 patients with histological diagnosis of RCC and radiological evidence of BM from 22 Italian institutions were enrolled. Univariate and multivariate models were performed to investigate the impact of clinicopathological features and multimodal treatments on both overall survival (OS) from the BM diagnosis and intracranial progression-free survival (iPFS). RESULTS: The median OS from the BM diagnosis was 18.8 months (interquartile range: 6.2-43 months). Multivariate analysis confirmed the following as positive independent prognostic factors: a Karnofsky Performance Status >70% [hazard ratio (HR) = 0.49, 95% confidence interval (CI) 0.26-0.92, P = 0.0026] and a single BM (HR = 0.51, 95% CI 0.31-0.86, P = 0. 0310); in contrast, the following were confirmed as worse prognosis factors: progressive extracranial disease (HR = 1.66, 95% CI 1.003-2.74, P = 0.00181) and only one line of systemic therapy after the BM occurrence (HR = 2.98, 95% CI 1.62-5.49, P = 0.029). Subgroup analyses showed no difference in iPFS according to the type of the first systemic treatment [immunotherapy (IT) or targeted therapy (TT)] carried out after the BM diagnosis (HR = 1.033, 95% CI 0.565-1.889, P = 0.16), and revealed that external radiation therapy (eRT) significantly prolonged iPFS when combined with IT (10.7 months, 95% CI 4.9-48 months, P = 0.0321) and not when combined with TT (9.01 months, 95% CI 2.7-21.2 months, P = 0.59). CONCLUSIONS: Our results suggest a potential additive effect in terms of iPFS for eRT combined with IT and encourage a more intensive multimodal therapeutic strategy in a multidisciplinary context to improve the survival of BMRCC patients.

Cerebral venous thrombosis: role of CT, MRI and MRA in the emergency setting.

PURPOSE: It is often difficult to diagnose cerebral venous thrombosis (CVT), an uncommon condition that more frequently affects young subjects, is responsible for 1%-2% of strokes in adults and has a subtle clinic onset. The aim of this study was to evaluate the role of computed tomography (CT), magnetic resonance imaging (MRI) and MR venography in the emergency setting and to discuss the risk factors, clinical presentation, outcome and follow-up of this disease. MATERIALS AND METHODS: We retrospectively studied 40 patients with CVT admitted to the emergency department between 1996 and 2006 and examined with unenhanced CT, MRI and MR venography. Fourteen patients also underwent digital subtraction angiography (DSA). RESULTS: Headache was the most common presenting feature (60%). Unenhanced CT showed typical signs (cord or empty delta sign) in 11 cases and nonspecific signs in the other cases. The diagnosis was achieved with MRI and MR venography in 38/40 cases (95%) and with DSA in 2/40 cases. All patients were treated with heparin. Five patients died, and only one of the remaining patients developed serious disability. CONCLUSIONS: Knowledge of the CT, MRI and MR-venography signs of CVT is crucial and enables an early diagnosis and timely treatment with heparin in the majority of cases. DSA should be reserved for doubtful cases only.

Natural history and management of brainstem gliomas in adults. A retrospective Italian study.

Brainstem gliomas in adults are rare tumors, with heterogeneous clinical course; only a few studies in the MRI era describe the features in consistent groups of patients. In this retrospective study, we report clinical features at onset, imaging characteristics and subsequent course in a group of 34 adult patients with either histologically proven or clinico-radiologically diagnosed brainstem gliomas followed at two centers in Northern Italy. Of the patients 18 were male, 14 female, with a median age of 31. In 21 of the patients histology was obtained and in 20 it was informative (2 pilocytic astrocytoma, 9 low-grade astrocytoma, 8 anaplastic astrocytoma and 1 glioblastoma). Contrast enhancement at MRI was present in 14 patients. In all of the 9 patients who were investigated with MR spectroscopy, the Cho/NAA ratio was elevated at diagnosis. In 8 of the patients, an initial watch and wait policy was adopted, while 24 were treated shortly after diagnosis with either radiotherapy alone [4] or radiotherapy and chemotherapy [20] (mostly temozolomide). Only minor radiological responses were observed after treatments; in a significant proportion of patients (9 out of 15) clinical improvement during therapy occurred in the context of radiologically (MRI) stable disease. Grade III or IV myelotoxicity was observed in 6 patients. After a follow-up ranging from 9 to 180 months, all but 2 patients have progressed and 14 have died (12 for disease progression, 2 for pulmonary embolism). Median overall survival time was of 59 months. Investigation of putative prognostically relevant parameters showed that a short time between disease onset and diagnosis was related to a shorter survival. Compared with literature data, our study confirms the clinical and radiological heterogeneity of adult brainstem gliomas and underscores the need for multicenter trials in order to assess the efficacy of treatments in these tumors.

Primary CNS Lymphomas: Challenges in Diagnosis and Monitoring.

Primary Central Nervous System Lymphoma (PCNSL) is a rare neoplasm that can involve brain, eye, leptomeninges, and rarely spinal cord. PCNSL lesions most typically enhance homogeneously on T1-weighted magnetic resonance imaging (MRI) and appear T2-hypointense, but high variability in MRI features is commonly encountered. Neurological symptoms and MRI findings may mimic high grade gliomas (HGGs), tumefactive demyelinating lesions (TDLs), or infectious and granulomatous diseases. Advanced MRI techniques (MR diffusion, spectroscopy, and perfusion) and metabolic imaging, such as Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) or amino acid PET (usually employing methionine), may be useful in distinguishing these different entities and monitoring the disease course. Moreover, emerging data suggest a role for cerebrospinal fluid (CSF) markers in predicting prognosis and response to treatments. In this review, we will address the challenges in PCNSL diagnosis, assessment of response to treatments, and evaluation of potential neurotoxicity related to chemotherapy and radiotherapy.

Endocrine dysfunction in patients operated on for non-pituitary intracranial tumors.

OBJECTIVE: Hypopituitarism frequently follows pituitary neurosurgery (NS) and/or irradiation. However, the frequency of hypothalamic-pituitary dysfunction after NS of non-pituitary intracranial tumors is unclear. The aim of this study was to assess the presence of endocrine alterations in patients operated on for intracranial tumors. DESIGN: This is a retrospective study. METHODS: We studied 68 consecutive adult patients (28 female, 40 male, age 45.0 +/- 1.8 years; body mass index (BMI): 26.5 +/- 0.6) with intracranial tumors who underwent NS only (n = 17) or in combination with radiotherapy (RT) and/or chemotherapy (CT) (n = 51). In all subjects, basal endocrine parameters and the GH response to GHRH + arginine test (using BMI-dependent cut offs) were evaluated. RESULTS: In 20.6% of the patients, peripheral endocrinopathy related to CT and/or RT was present. Hypopituitarism was found in 38.2% of the patients. Total pituitary hormone, multiple pituitary hormone, and isolated pituitary hormone deficits were present in 16.2, 5.8, and 16.2% respectively. The most common pituitary deficits were, in decreasing order: LH/FSH 29.4%, GH 27.9%, ACTH 19.1%, TSH 17.7%, and diabetes insipidus 4.4%. Hyperprolactinemia was present in 13.2%. The prevalence of hypopituitarism was higher in patients who underwent NS only and with tumors located closely to the sella turcica, but a substantial proportion of patients with tumors not directly neighboring the sella also showed hypopituitarism. CONCLUSIONS: Hypopituitarism frequently occurs after NS for intracranial tumors. Also, exposure of these patients to CT and/or RT is frequently associated with peripheral endocrinopathies. Thus, endocrine evaluation and follow-up of patients treated for intracranial tumors should be performed on a regular basis.

Brain metastases from unknown primary tumour: a prospective study.

The best management of patients with brain metastases from an unknown primary tumour is still unclear, as data are scarce and studies are retrospective. We report 33 patients with biopsy-proven brain metastases from a primary tumour not found at the first investigations, who were treated by surgery and/or radiotherapy and followed with serial CT until death. Median survival time for all patients was 10 months and survival rates at 6 months, 1 year and 2 years were 76 %, 42 % and 15 % respectively. Patients with single brain metastasis treated by gross total resection and whole-brain radiotherapy (WBRT) had a median survival of 13 months with 76% alive at 6 months, 57 % at 1 year and 19% at 2 years. Patients with multiple brain metastases who underwent either WBRT alone or WBRT preceded by gross total resection of the symptomatic lesions had a poorer prognosis: median survival of 6-8 months with 50-100% alive at 6 months, 17-20% at 1 year and none alive at 2 years. In 85% of patients with a single brain metastasis a significant improvement in neurological functions was observed after surgical resection; among patients with multiple brain metastases a neurological improvement was observed in all patients who had a resection of symptomatic lesions and only in a half of patients who had WBRT alone. During the follow-up the primary tumour was found in 27/33 patients (82 %) and was located in the lung in 78%. Between 1987 and 1991 (with limited screening for the primary tumour in the follow-up) the unknown tumours were 6/15 (40%); in the more recent period (1992-1996) (CT-based screening for the primary tumour in the follow-up) no primary tumour remained unknown but overall survival has not significantly improved. The number of brain metastases was the only significant factor affecting survival after both univariate and multivariate analysis. This study suggests that, in patients with both single and multiple brain metastases from an undetected primary site when first studied, surgery and/or WBRT enable the control of the brain disease, partly because the systemic disease may be silent for a prolonged time. Only a few asymptomatic patients may benefit from an early detection and treatment of the primary tumour during the follow-up.

PCV chemotherapy for recurrent oligodendrogliomas and oligoastrocytomas.

OBJECTIVE: The role of chemotherapy in the treatment of low-grade oligodendrogliomas and oligoastrocytomas is still unclear. A Phase II study was conducted to determine the benefits and toxicity of the procarbazine, lomustine, and vincristine (PCV) regimen in patients with low-grade oligodendrogliomas and oligoastrocytomas recurrent after surgery alone or surgery with radiotherapy. METHODS: Patients with both enhancing and nonenhancing tumors were treated with up to six cycles of standard PCV, and response was evaluated by conventional criteria based on computed tomography or magnetic resonance imaging. RESULTS: Sixteen of 26 patients (62%) responded to PCV: 3 (12%) experienced complete response, 13 (50%) experienced partial response, 8 (31%) had stable disease, and 2 (8%) had progressive disease. All symptomatic patients who responded and three with stable disease improved in seizure frequency, lateralizing signs, and symptoms of intracranial hypertension. The response rate for patients with enhancing lesions revealed by computed tomography or magnetic resonance imaging (74%) was significantly higher than that of patients with nonenhancing lesions (29%) (P < 0.05). Both oligodendrogliomas and oligoastrocytomas responded to PCV, with complete responses occurring in association with pure tumors only. The median time to tumor progression of all 26 patients was 24 months and was significantly longer for those with oligodendrogliomas compared with those with oligoastrocytomas (32 versus 12 mo) (P < 0.001). Chemotherapy was well tolerated, with mild hematological toxicity and rare skin rashes being the most frequent sequelae. CONCLUSION: These results suggest that chemotherapy with PCV is effective in the treatment of recurrent low-grade oligodendrogliomas and oligoastrocytomas.

Peroneal sheath reconstruction in the growing child.

The authors recommend the procedure described above specifically for children with congenital or acquired subluxation or dislocation of the peroneal tendons, but they advise against using this procedure alone when calcaneovalgus deformity is present and anterior dislocation of the peroneal tendons occurs as a result of spasticity. It may, however, have a place as part of a combined procedure to correct the spastic deformity. Reconstruction of the superior peroneal retinaculum is accomplished with a strong ligamentous structure, appropriately oriented and directed, without loss of lateral ankle stability. The authors believe that the complication of partial or complete fibular physeal arrest can be avoided, and that redislocation of the peroneal tendons as the child grows out of the repair can be eliminated. Therefore, this procedure is suggested as the procedure of choice for a growing child with anterior luxation or dislocation of the peroneal tendons and an intact calcaneofibular ligament. Properly performed, it will enable these children to return to the vigorous physical activity they desire.

[Cerebral metastatis. Diagnostic and therapeutic features]. / Metastasi cerebrali. Aspetti diagnostici e terapeutici.

Brain metastases represent the most frequent intracranial neoplasms in adults: between 15 and 25% of patients with systemic tumors will face brain metastases along the clinical course of disease. Lung cancers, breast cancers and melanomas are the commonest causes of brain metastases (about 75%), while the primary site remains unknown inasmuch as 15% of cases. Headache, focal neurological deficits, epilepsy and intracranial hypertension are the most frequent initial symptoms and signs. Computerized Tomography and Magnetic Resonance represent the methods of choice for diagnosis. Supportive care is based on corticosteroids and antiepileptic drugs. Anticancer therapy planning must be based on prognostic factors: performance status, tumor activity and age. Surgical removal followed by external adjuvant radiotherapy is considered the best treatment in patients with single brain metastases and systemic disease under control or absent. Stereotactic radiosurgery is preferable in cases of unoperable metastatic lesions of the brain or progressive systemic disease. The usefulness of whole brain radiotherapy following surgery or radiosurgery is debated. In patients with multiple brain metastases, apart from radiotherapy, surgical excision of the symptomatic lesions, when feasible, seems advantageous. Chemotherapy is a valid option only in cases of metastases from chemosensitive neoplasms (small-cell lung tumors or breast tumors).

Anti-angiogenic approaches to malignant gliomas.

Despite advances in multidisciplinary approaches, the prognosis for most patients with malignant gliomas is poor. Malignant gliomas are highly vascularized tumors with elevated expression of vascular endothelial growth factor (VEGF), an important mediator of angiogenesis. Recent studies of bevacizumab, an anti-VEGF monoclonal antibody, alone or associated with chemotherapy, have demonstrated high response rates and prolongation of median and 6-month progression-free survival. Clinical evaluation of several multitarget small molecule tyrosine kinase inhibitors is ongoing. Other promising antiangiogenic compounds are cilengitide and continuous temozolomide. Toxicity is acceptable. Open issues are represented by patterns of tumor progression, resistance mechanisms and biomarkers.

Role of diffusion- and perfusion-weighted MR imaging for brain tumour characterisation.

PURPOSE: This study was undertaken to correlate apparent diffusion coefficient (ADC) and relative regional cerebral blood volume (rrCBV) to histological findings in a large series of patients with primary or secondary brain tumours to evaluate diffusion-weighted (DWI) and perfusion-weighted (PWI) imaging in the characterisation of cerebral tumors. MATERIALS AND METHODS: Ninety-eight patients with cerebral tumours, 46 of which were primary (seven grade 0-I, nine low-grade gliomas, two gliomatosis cerebri, nine lymphomas and 19 high-grade gliomas) and 52 secondary, underwent conventional magnetic resonance (MR) imaging completed with DWI and dynamic contrast susceptibility PWI. Both ADC and rrCBV were calculated on a workstation by using Functool 2 software. Student's t test was used to determine any statistically significant differences in the ADC and rrCBV values. RESULTS: Seventeen of 98 tumours were cystic or necrotic (12/17 hypointense and 5/17 hyperintense on DWI); the ADC value of hyperintense cystic areas was 0.97+/-0.23x10(-3) mm2/s. The ADC value of solid tumours varied between 0.64 and 3.5x10(-3) mm2/s. The rrCBV value was 1.4 (sigma 0.66) in low-grade gliomas; 1.22 (sigma 0.25) in lymphomas; 4.5 (sigma 0.85) in grade III gliomas; 3.18 (sigma 1.26) in grade IV gliomas and 2.53 (sigma 1.6) in metastases. CONCLUSIONS: DWI has an important role in the differential diagnosis of cystic cerebral masses but not in tumour characterisation. PWI is helpful in differentiating high-from low-grade gliomas and lymphomas from high-grade gliomas.