Long-term survival in patients with recurrent glioblastoma treated with bevacizumab: a multicentric retrospective study.

PURPOSE: Recurrence of glioblastoma (GB) occurs in most patients after standard concomitant temozolomide-based radiochemotherapy (CTRC). Bevacizumab (BV), an anti-VEGF antibody, has an effect on progression-free survival (PFS) but not on overall survival (OS). However, a small part of the patients experience a survival, longer than expected. This retrospective study aims to characterize long responder (LR) patients treated with BV for a first or second GBM recurrence. METHODS: Medical records from patients (814) who received BV for a first or second recurrence of primary glioblastoma between September 2010 and September 2015, and initially treated by CTRC were analyzed. Patients, who had at least a stable disease according to RANO criteria at 12 months from the start of BV, were included. Patients who had, a secondary GB, or received BV in neoadjuvant or adjuvant setting were excluded. RESULTS: We focused on 65 LR patients without progression 12 months after the first injection of BV (8%). Median PFS was 21.7 months [95% CI (19.3; 27.2)] and median OS was 31.1 months [95% CI (24.3; 37.5)] from the start of BV. No prognostic factor was associated with OS in multivariate analysis. Karnofsky performance status, neurological status and corticosteroid dose were stable at 12 months. CONCLUSIONS: Our results highlight that among patients receiving bevacizumab in first or second recurrence, one patient out of twelve could be classified as LR. A median OS of 31.1 months from the start of BV could be expected in this subpopulation. These findings reinforce the potential benefit of the use of BV in the situation of recurrence. 256 words.

Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma: Final analysis of the phase II 'proof-of-concept' iLOC study by the Lymphoma study association (LYSA) and the French oculo-cerebral lymphoma (LOC) network.

BACKGROUND: Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal centre B-cell subtype, with unmet medical needs. This study aimed to evaluate the efficacy and toxicity of ibrutinib in DLBCL-PCNSL PATIENTS AND METHODS: This prospective, multicentre, phase II study involved patients with relapse or refractory(R/R) DLBCL-PCNSL or primary vitreoretinal lymphoma. The treatment consisted of ibrutinib (560 mg/day) until disease progression or unacceptable toxicity occurred. The primary outcome was the disease control (DC) rate after two months of treatment (P0 < 10%; P1 > 30%). RESULTS: Fifty-two patients were recruited. Forty-four patients were evaluable for response. After 2 months of treatment, the DC was 70% in evaluable patients and 62% in the intent-to-treat analysis, including 10 complete responses (19%), 17 partial responses (33%) and 5 stable diseases (10%). With a median follow-up of 25.7 months (range, 0.7-30.5), the median progression-free and overall survivals were 4.8 months (95% confidence interval [CI]; 2.8-12.7) and 19.2 months (95% CI; 7.2-NR), respectively. Thirteen patients received ibrutinib for more than 12 months. Two patients experienced pulmonary aspergillosis with a favourable (n = 1) or fatal outcome (n = 1). Ibrutinib was detectable in the cerebrospinal fluid (CSF). The clinical response to ibrutinib seemed independent of the gene mutations in the BCR pathway. CONCLUSION: Ibrutinib showed clinical activity in the brain, the CSF and the intraocular compartment and was tolerated in R/R PCNSL. The addition of ibrutinib to standard methotrexate-base induction chemotherapy will be further evaluated in the first-line treatment. CLINICAL TRIAL NUMBER: NCT02542514.

[Supportive care, cognition and quality of life in brain metastases]. / Soins de support, cognition, qualité de vie et métastases cérébrales.

Brain metastases impact on the survival of the patients, but on their quality of life as well. The objective of the management of these patients is then double. Currently, due to medical advances, survivals tend to improve, especially for some tumor subtypes. During the course of the disease, different neurological signs and symptoms can be observed according to the location, the number and the volume of the metastase(s). Patients and caregivers are especially worried about the loss of autonomy and cognitive impairments. A permanent dialogue, during the course of the disease, is mandatory, in order to adapt the management to the objectives determined by the patients and the medical team. These objectives may vary according to the objective response rates of the disease to anticancer therapies, according to the impact of the disease and its management in daily living. Anticancer therapies and supportive care must be appreciated according to their impact on the survival, on the preservation of the functional independence and the quality of life of the patient, on their abilities to preserve the neurological status and delay the apparition of new neurological signs and symptoms, and their adverse events. Supportive care, cognition and quality of life should be regularly evaluated and adapted according to the objectives of the management of brain metastases patients. Different approaches are described in this paper.

Pigments analysis and gold layer thickness evaluation of polychromy on wood objects by PXRF.

The X-ray fluorescence technique by energy dispersion (EDXRF), being a multi elemental and non-destructive technique, has been widely used in the analysis of artworks and archeometry. An X-ray fluorescence portable equipment from the Laboratory of Applied Nuclear Physics of the State University of Londrina (LFNA/UEL) was used for the measurement of pigments in golden parts of a Gilding Preparation Standard Plaque and also pigments measurement on the Wood Adornment of the High Altar Column of the Side Pulpit of the Immaculate Conception Church Parish Sao Paulo-SP. The portable X-ray fluorescence PXRF-LFNA-02 consists of an X-ray tube with Ag anode, a Si-PIN detector (FWHM=221 eV for Mn line at 5.9 keV), a chain of electronics nuclear standard of X-ray spectrometer, a multichannel 8K, a notebook and a mechanical system designed for the positioning of detector and X-ray tube, which allows movements with two degrees of freedom from the system of excitation-detection. The excitation-detection time of each measurement was 100 and 500 s, respectively. The presence of elements Ti, Cr, Fe, Cu, Zn and Au was found in the golden area of the Altar Column ornament. On the other hand, analysis of the ratios for the intensities of Kα/Kß lines measured in the areas made it possible to explore the possibility of measuring the stratigraphies of the layers of pigments and to estimate the thickness of the same.

Simulation techniques in the anatomy curriculum: review of literature.

Modern medical education faces a problem of combining the latest technology, procedures and information with classic teaching methods. Simulation is a technique, which replaces or amplifies doctor-patient experiences in controlled conditions and therefore evokes or replicates substantial aspects of the real world in a fully interactive manner. The basic course of anatomy in medical education could be recognised as the best example of implementing new educational techniques such as simulation, into the traditional medical curriculum. The PubMed database was searched using specific key words. Finally 72 articles were accepted and were divided into 3 basic categories of teaching methods: Category 1 - cadaveric dissection, Category 2 - simulator based education and Category 3 - other. A state of the art anatomical curriculum offers numerous possibilities and solutions including the oldest like cadaveric dissection and newest like simulators. Different simulation techniques are used with different intensity; however cadaveric dissection is still the most popular method. The second most frequent method is simulation-based training, in which North America is the leading country. The identification of anatomical structures during virtual surgical procedures or laparoscopic robotic procedures can be integrated into the traditional anatomy course. New technologies are supportive and beneficial in anatomy teaching however each excitement of new technologies sometimes should be tempered and evaluated for its usefulness in making the learning process constructive for students and their future practice.

Response to intrathecal infusions of Depocyt® in secondary diffuse leptomeningeal gliomatosis. A case report.

UNLABELLED: Secondary diffuse leptomeningeal gliomatosis, in which a glioma of the brain or spinal cord infiltrates the leptomeninges, is an uncommon clinical metastatic complication of malignant glioma, for which there is no consensus regarding treatment. In an ante mortem series in which the diagnosis of leptomeningeal gliomatosis was based on neuroradiological results, an incidence of 2% was reported. The appearance of leptomeningeal gliomatosis is a pre-terminal event. CASE REPORT: A 44 year-old woman rapidly developed intracranial pressure and impairment of cognitive function. A huge right temporal tumor was diagnosed and an incomplete resection performed. Histology showed it was a glioblastoma and a concurrent radiation therapy with temozolomide was administered. Her clinical status was subnormal. A first course of adjuvant chemotherapy, temozolomide, was administered, and her neurological status suddenly worsened in days: deterioration of cognitive function status, inability to walk, and aphasia were reported. The cerebrospinal fluid showed an elevated protein content of 2 g/l, and glucose concentration was low. Cytology of cerebrospinal fluid showed no malignant cells. Systemic nitrosourea chemotherapy (fotemustine) was administered. Intrathecal sustained-release cytarabine, Depocyt®, was initiated (an induction cycle followed by a consolidation). After a second intrathecal infusion, her clinical status significantly improved, and she was discharged to a medical unit. The duration of response was approximately 6 months. CONCLUSION: Intrathecal infusions of Depocyt®, recommended for the treatment of lymphoma neoplastic meningitis, seems to be effective in treatment of secondary diffuse leptomeningeal gliomatosis.

Supportive care in neurooncology.

The quality of life of patients treated for brain tumor is, in all cases, deeply altered by the tumor and the treatments. Optimizing the symptomatic management is a key objective for all care givers. We present in this paper a very pragmatic focus concerning the management of intracranial hypertension (and/or neurological deficits), venous thromboembolism, confusion, epilepsy and symptoms more directly associated with the end of life.

[Medulloblastomas: review]. / Les médulloblastomes: revue générale.

INTRODUCTION: The term of "medulloblastoma" refers to cerebellar tumors belonging to the family of primitive neuro-ectodermic tumors (PNET). Medulloblastomas represent 40% of cerebellar tumors, 15 to 20% of brain tumors and the first cause of malignant brain tumors in childhood. Seventy to 80% of cases are diagnosed in children versus 20 to 30% in adults. UPDATED KNOWLEDGE: Diagnosis is based on clinical and radiological exams, and proved on pathological analysis in association with molecular biology. Treatment comprises surgery, craniospinal radiotherapy except for children under five years of age and chemotherapy according to age and high-risk criteria. Medulloblastoma is a rare case of a central nervous system tumor which is radio- and chemo-sensitive. Treatment goals are, on one hand, to improve the survival rates and, on the other hand, to avoid late neurocognitive, neuroendocrine and orthopedic side effects related to radiation therapy, notably in children. The prognosis is relatively good, with a five year survival rate over 75% after complete resection of a localized tumor although sequelae may still compromise outcome. PERSPECTIVES AND CONCLUSION: Management of patients with medulloblastoma implies a multidisciplinary approach combining the contributions of neurosurgery, neuroradiology, pediatric oncology, neuro-oncology and radiotherapy teams.

The body constitution of patients and intubation scales as predictors of difficult intubation considered in relation to the experience of the intubator.

The aims of the study were to identify factors that may result in difficulties in intubation, and to compare the results obtained when an experienced and when a less experienced anaesthesiologist was involved. The 96 patients included in the study were evaluated for difficult intubation according to the following scales: Mallampati, upper lip bite test (ULBT) and Patil. The mobility of the cervical segments of the vertebral column, the distance between the jugular notch of the sternum and the chin and the anatomical constitution of the body were other factors that were taken into consideration. Statistical analysis was performed in order to identify factors that may result in difficulties in intubation for an experienced and for a less experienced anaesthesiologist.

The subcellular localization of cyclin dependent kinase 2 determines the fate of mesangial cells: role in apoptosis and proliferation.

Apoptosis is closely linked to proliferation. In this study we showed that inducing apoptosis in mouse mesangial cells with ultraviolet (UV) irradiation was associated with increased cyclin A-cyclin dependent kinase (CDK) 2 activity. Inhibiting CDK2 activity with Roscovitine or dominant negative mutant reduced apoptosis. Because apoptosis typically begins in the cytoplasm, we tested the hypothesis that the subcellular localization of CDK2 determines the proliferative or apoptotic fate of the cell. Our results showed that cyclin A-CDK2 was nuclear in proliferating cells. However, inducing apoptosis in proliferating cells with UV irradiation was associated with a decrease in nuclear cyclin A and CDK2 protein levels. This coincided with an increase in protein and kinase activity for cyclin A-CDK2 in the cytoplasm. Translocation of cyclin A-CDK2 also occurred in p53-/- mesangial cells. Finally, we showed that caspase-3 activity was significantly reduced by inhibiting CDK2 activity with Roscovitine. In summary, our results show that apoptosis is associated with an increase in cytoplasmic cyclin A-CDK2 activity, which is p53 independent and upstream of caspase-3. We propose that the subcellular localization of CDK2 determines the proliferative or apoptotic fate of the cell.

Axons regulate the expression of Shaker-like potassium channel genes in Schwann cells in peripheral nerve.

We examined potassium channel gene expression of two members of the Shaker subfamily, MK1 and MK2, in sciatic nerves from rats and mice. In Northern blot analysis, MK1 and MK2 probes detected single transcripts of approximately 8 kb and approximately 9.5 kb, respectively, in sciatic nerve and brain from both species. Polymerase chain reaction amplification of a cDNA library of cultured rat Schwann cells using MK1- and MK2- specific primers produced DNA fragments that were highly homologous to MK1 and MK2. To determine whether these channel genes were axonally regulated, we performed Northern blot analysis of developing, permanently transected, and crushed rat sciatic nerves. The mRNA levels for both MK1 and MK2 increased from P1 to P15 and then declined modestly. Permanent nerve transection in adult animals resulted in a dramatic and permanent reduction in the mRNA levels for both MK1 and MK2, whereas normal levels of MK1 and MK2 were restored when regeneration was allowed to occur following crush injury. In all cases, MK1 and MK2 mRNA levels paralleled that of the myelin gene P0. Elevating the cAMP in cultured Schwann cells by forskolin, which mimics axonal contact but not myelination, did not induce detectable levels of MK1 and MK2 mRNA by Northern blot analysis. Further, the level of MK1 mRNA in the vagus nerve, which contains relatively fewer myelinating Schwann cells and relatively more non-myelinating Schwann cells than the sciatic nerve, is reduced relative to the sciatic nerve. In conclusion, we have identified two Shaker-like potassium channel genes in sciatic nerves whose expressions are regulated by axons. We suggest that MK1 and MK2 mRNA are expressed in high levels only in myelinating Schwann cells and that these Shaker-like potassium channel genes have specialized roles in these cells.