Is a pretreatment radiological staging system feasible for suggesting the optimal extent of resection and predicting prognosis in glioblastoma? An observational study.

To assess the value of resection in glioblastoma based on pre-surgical tumor characteristics and a subsequent staging system. The lack of a staging system for glioblastoma hinders the analysis of treatment outcome. We classified 292 uniformly treated glioblastoma patients as stage I, II, or III based on tumor size, location, and eloquence and then analyzed the impact of the extent of resection. We classified 62% of patients as stage I, 25.3% as stage II, and 12.7% as stage III. Gross total resection (GTR) was performed mainly in stage I rather than stage II or III patients (79.2% vs. 14.6% vs. 6.3%; P < 0.001). Overall survival (OS) was 17.7, 14.6, and 10.8 months for stage I, II, and III patients, respectively (P = 0.005). Longer OS was significantly associated with greater extent of resection, younger age, KPS ≥ 70%, MGMT methylation, lower stage, and tumor ≤ 5 cm. In the subgroups of stage I (P = 0.04) and stage II (P < 0.001)-but not stage III-patients, GTR and partial resection (PR) were associated with longer OS. We constructed several multivariable models including different variables, and greater extent of resection, smaller tumor size, and MGMT methylation consistently emerged as independent markers of longer OS. This staging system provides a feasible tool for comparison of results. We confirmed the value of partial resection in stage I and II patients, in contrast to some reports suggesting that biopsy only is sufficient when gross total resection cannot be safely achieved.

IDH mutation status trumps the Pignatti risk score as a prognostic marker in low-grade gliomas.

Management of low-grade gliomas (LGG) is based on clinical and radiologic features, including the Pignatti prognostic scoring system, which classifies patients as low- or high-risk. To determine whether molecular data can offer advantages over these features, we have examined the prognostic impact of several molecular alterations in LGG. In a cohort of 58 patients with LGG, we have retrospectively analyzed clinical and molecular characteristics, including the Pignatti criteria, IDH mutations, TP53 mutations, the 1p/19q deletion, and MGMT methylation, and correlated our findings with progression-free survival (PFS) and overall survival (OS). Mean age of patients was 45 years; 71% were classified as low-risk by the Pignatti system. IDH mutations were detected in 62%, p53 mutations in 17%, the 1p/19q codeletion in 46%, and MGMT methylation in 40% of patients. Survival analyses were performed in the 49 patients without contrast enhancement. In the univariate analysis, IDH mutations, the 1p/19q codeletion, and the combination of IDH mutations with the 1p/19q codeletion were associated with both longer PFS (P = 0.006, P = 0.037, and P = 0.003, respectively) and longer OS (P < 0.001, P = 0.02, and P < 0.001, respectively). The multivariate analysis identified absence of IDH mutations as a factor for greater risk of progression [hazard ratio (HR) = 3.1; P = 0.007]and death (HR = 6.4; P < 0.001). We suggest that IDH mutations may be more effective than the Pignatti score in discriminating low- and high-risk patients with LGG.

Comparison of elevated intracranial pressure pulse amplitude and disproportionately enlarged subarachnoid space (DESH) for prediction of surgical results in suspected idiopathic normal pressure hydrocephalus.

BACKGROUND: To compare the prognostic value of pulse amplitude on intracranial pressure (ICP) monitoring and disproportionately enlarged subarachnoid space hydrocephalus (DESH) on magnetic resonance imaging (MRI) for predicting surgical benefit after shunt placement in idiopathic normal pressure hydrocephalus (iNPH). METHOD: Patients with suspected iNPH were prospectively recruited from a single centre. All patients received preoperative MRI and ICP monitoring. Patients were classified as shunt responders if they had an improvement of one point or more on the NPH score at 1 year post-surgery. The sensitivity, specificity, Youden index, and positive and negative predictive values of the two diagnostic methods were calculated. RESULTS: Sixty-four of 89 patients clinically improved at 1 year post-surgery and were classed as shunt responders. Positive DESH findings had a sensitivity of 79.4 % and specificity of 80.8 % for predicting shunt responders. Fifty-five of 89 patients had positive DESH findings: 50 of these responded to VP shunt, giving a positive and negative predictive value of 90.9 % and 61.8 %, respectively. Fifty-seven of 89 patients had high ICP pulse amplitude. High ICP pulse amplitude had a sensitivity of 84.4 %, specificity of 88 %, positive predictive value of 94.7 % and negative predictive value of 61.8 % for predicting shunt responders. CONCLUSIONS: Both positive DESH findings and high ICP pulse amplitude support the diagnosis of iNPH and provide additional diagnostic value for predicting shunt-responsive patients; however, high ICP amplitude was more accurate than positive DESH findings, although it is an invasive test.

Measurement of 13C and 15N isotope labeling by gas chromatography/combustion/isotope ratio mass spectrometry to study amino acid fluxes in a plant-microbe symbiotic association.

We have developed a method based on a double labeling with stable isotopes and gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS) analyses to study amino acid exchange in a symbiotic plant-microbe association. Isotopic precision was studied for 21 standards including 15 amino acid derivatives, three N-protected amino acid methyl esters, three amines and one international standard. High correlations were observed between the δ(13)C and δ(15)N values obtained by GC/C/IRMS and those obtained by an elemental analyzer (EA) coupled to an isotope ratio mass spectrometer (R(2) = 0.9868 and 0.9992, respectively). The mean precision measured was 0.04‰ for δ(13)C and 0.28‰ for δ(15)N (n = 15). This method was applied in vivo to the symbiotic relationship between alfalfa (Medicago sativa L.) and N(2)-fixing bacteria. Plants were simultaneously labeled over 10 days with (13)C-depleted CO(2) ((12)CO(2)), which was assimilated through photosynthesis by leaves, and (15)N(2) fixed via nodules. Subsequently, the C and N isotope compositions (i.e. δ(13)C and δ(15)N) of free amino acids were analyzed in leaves and nodules by GC/C/IRMS. The method revealed the pattern of C and N exchange between leaves and nodules, highlighting that γ-aminobutanoic acid and glycine may represent an important form of C transport from leaves to the nodules. The results confirmed the validity, reliability and accuracy of the method for assessing C and N fluxes between plants and symbiotic bacteria and support the use of this technique in a broad range of metabolic and fluxomic studies.

Outdoor air monitoring: Performance evaluation of a gas sensor to assess episodic nuisance/odorous events using active multi-sorbent bed tube sampling coupled to TD-GC/MS analysis.

In order to evaluate the performance of a commercially available metal oxide semiconductor gas sensor (TGS 2602, Figaro Engineering Inc.) for activating a monitoring system when a nuisance/odorous pollution episode of volatile organic compounds (VOCs) occur, a widely used active sampling methodology based on multi-sorbent bed tubes (Carbotrap, Carbopack X and Carboxen 569) and analysis through automatic thermal desorption-gas chromatography/mass spectrometry was used. Daily 24 h samples of multi-sorbent bed tubes were taken over a period of 14 days using an air collector pump sampler specially designed in the LCMA-UPC laboratory. Simultaneously, daily episodic samples were taken according to the activation of another LCMA-UPC sampler by the metal oxide semiconductor gas sensor. Sampling was done throughout January-February 2019 at El Morell (Tarragona, Spain), near the petrochemical area. All episode samples present higher concentrations of VOCs than 24 h samples, with an average ratio of 3.5 times for Total VOCs. VOC familial distributions present very similar values in 24 h and episode samples (r2 = 0.7466), correlating significatively (F-Snedecor, p < 0.05). A higher level of VOCs in the atmosphere in general, not derived from a specific compound or a VOC/s family/ies, seems to be the trigger of the activation of the sampler by the sensor. On the other hand, no significant correlations are observed between alcohols concentrations and relative humidity (F-Snedecor, p < 0.05). Additionally, Total VOCs concentrations in episode samples are in agreement with higher percentages of NE-SSE wind directions, coming from the petrochemical complex. Hence, these aspects validate the use of the evaluated sensor for its application for the activation of samplers in air quality evaluations when episodic events occur, an interesting and innovative technique. Thus, this study is an important contribution to the understanding of the performance of gas sensors and proposes an expansion of their field of use.

Genetic and isotope ratio mass spectrometric evidence for the occurrence of starch degradation and cycling in illuminated Arabidopsis leaves.

Although there is a great wealth of data supporting the occurrence of simultaneous synthesis and breakdown of storage carbohydrate in many organisms, previous 13CO2 pulse-chase based studies indicated that starch degradation does not operate in illuminated Arabidopsis leaves. Here we show that leaves of gwd, sex4, bam4, bam1/bam3 and amy3/isa3/lda starch breakdown mutants accumulate higher levels of starch than wild type (WT) leaves when cultured under continuous light (CL) conditions. We also show that leaves of CL grown dpe1 plants impaired in the plastidic disproportionating enzyme accumulate higher levels of maltotriose than WT leaves, the overall data providing evidence for the occurrence of extensive starch degradation in illuminated leaves. Moreover, we show that leaves of CL grown mex1/pglct plants impaired in the chloroplastic maltose and glucose transporters display a severe dwarf phenotype and accumulate high levels of maltose, strongly indicating that the MEX1 and pGlcT transporters are involved in the export of starch breakdown products to the cytosol to support growth during illumination. To investigate whether starch breakdown products can be recycled back to starch during illumination through a mechanism involving ADP-glucose pyrophosphorylase (AGP) we conducted kinetic analyses of the stable isotope carbon composition (δ13C) in starch of leaves of 13CO2 pulsed-chased WT and AGP lacking aps1 plants. Notably, the rate of increase of δ13C in starch of aps1 leaves during the pulse was exceedingly higher than that of WT leaves. Furthermore, δ13C decline in starch of aps1 leaves during the chase was much faster than that of WT leaves, which provides strong evidence for the occurrence of AGP-mediated cycling of starch breakdown products in illuminated Arabidopsis leaves.

Fractionated stereotactic radiotherapy in the treatment of exclusive cavernous sinus meningioma: functional outcome, local control, and tolerance.

BACKGROUND: Fractionated stereotactic radiotherapy (FSRT) combines the precision of stereotactic positioning with the radiobiologic advantage of dose fractionation. METHODS: From June 1997 to June 2001, 30 patients with cavernous sinus meningiomas were treated with FSRT using fixed noncoplanar conformal fields. Patient skull fixation was achieved using the BrainLAB mask (20 patients) or Beverly frame (10 patients). The Cosman-Roberts-Wells coordinate frame was used for stereotactic space definition. In selected cases before 1999, and in all cases afterward, gadolinium-enhanced MRI for image fusion was performed. The median radiation dose was 52 Gy, with a daily fraction of 2 Gy. Patients were regularly followed up analyzing symptoms, tumor progression, and side effects. Neurocognitive function was evaluated retrospectively for 26 patients using Mini-Mental State Examination. RESULTS: Median follow-up period was 50 months (range, 28.2-74.5 months). Preexisting neurologic symptoms improved in 50% of the patients and worsened in 2 patients. Only 2 patients progressed and the actuarial local progression free survival was 93% at 4 years. Tolerance was good with 2 cases of late radiation toxicity which consisted of moderate short-term memory loss and dysphasia in one case and neuropsychologic deficit with seizures in the other. Postradiotherapy Mini-Mental State Examination results showed a median score of 28 (range, 16-30). CONCLUSIONS: Fractionated stereotactic radiotherapy is a high-precision technique. It is safe and feasible in the primary and adjuvant treatment of cavernous sinus meningiomas. Fractionated stereotactic radiotherapy allowed local control in more than 90% of patients.

Safety and Efficacy of 5-Aminolevulinic Acid for High Grade Glioma in Usual Clinical Practice: A Prospective Cohort Study.

BACKGROUND: During the last decade, the use of 5-aminolevulinic acid (5-ALA) has been steadily increasing in neurosurgery. The study's main objectives were to prospectively evaluate the effectiveness and safety of 5-ALA when used in clinical practice setting on high-grade gliomas' patients. METHODS: National, multicenter and prospective observational study. INCLUSION CRITERIA: authorized conditions of use of 5-ALA. EXCLUSION CRITERIA: contraindication to 5-ALA, inoperable or partial resected tumors, pregnancy and children. Epidemiological, clinical, laboratory, radiological, and safety data were collected. Effectiveness was assessed using complete resection of the tumor, and progression-free and overall survival probabilities. RESULTS: Between May 2010 and September 2014, 85 patients treated with 5-ALA were included, and 77 were suitable for the effectiveness analysis. Complete resection was achieved in 41 patients (54%). Surgeons considered suboptimal the fluorescence of 5-ALA in 40% of the patients assessed. The median duration of follow-up was 12.3 months. The progression-free survival probability at 6 months was 58%. The median duration overall survival was 14.2 months. Progression tumor risk factors were grade of glioma, age and resection degree; and death risk factors were grade of glioma and gender. No severe adverse effects were reported. At one month after surgery, new or increased neurological morbidity was 6.5%. Hepatic enzymes were frequently increased within the first month after surgery; however, they subsequently normalized, and this was found to have no clinical significance. CONCLUSION: In clinical practice, the 5-ALA showed a good safety profile, but the benefits related to 5-ALA have not been yet clearly shown. The improved differentiation expected by fluorescence between normal and tumor cerebral tissue was suboptimal in a relevant number of patients; in addition, the expected higher degree of resection was lower than in clinical trials as well as incomplete resection was not identified as a prognostic factor risk for death. Because optimal fluorescence was correlated to higher complete resection rate, further research is needed to identify patients (or tumors) with more surgery benefits when using the 5-ALA.

Evolution of care for patients with relapsed glioblastoma.

Glioblastoma is the most common and aggressive form of brain tumor in adults and has a poor prognosis and a high recurrence rate despite optimal care. The management of patients with relapsed glioblastoma is challenging, with no widely agreed standard of care. Different chemotherapy and radiotherapy combination treatment strategies provide only modest benefits. Recently, several novel agents, including bevacizumab and XL-184, have demonstrated promising results in Phase II trials with their further evaluation ongoing in Phase III randomized trials. Interpreting the data from such trials is a key challenge in glioblastoma, highlighting the need for relevant and standardized patient assessment techniques. Data from ongoing and planned trials should help to define optimal treatment strategies for this disease.

Assessment of verbal working memory before and after surgery for low-grade glioma.

OBJECT: While scarcely reported in low-grade glioma (LGG), accurate assessment of higher functions is essential to evaluate then preserve the quality of life. We assessed verbal working memory (vWM) in patients with LGG in language areas, before and after surgery, to evaluate the effect of glioma and resection on cognition, respectively. METHODS: About 23 patients harboring a LGG in language areas underwent awake surgery. All patients had a vWM assessment, before and immediately after the resection, in addition to KPS. vWM was also evaluated 3 months after surgery in eight patients (KPS in all cases), who performed postoperative rehabilitation. RESULTS: Preoperatively, 91% of patients had vWM disorders (KPS > or =90 in 22 patients). Immediately after surgery, 96% of patients had vWM worsening (50% of KPS > or =90). At 3 months, among the eight patients examinated, five recovered their preoperative vWM score, and three significantly improved it (KPS > or =90 in 23 patients). CONCLUSION: In LGG, neuropsychological assessment is encouraged in addition to KPS. vWM evaluation before treatment showed that most patients had a cognitive deficit. Moreover, surgery induced a transient vWM worsening, which nevertheless recovers within 3 months. Specific rehabilitation might help to recover and even to improve the preoperative cognitive status.