Long-term Outcomes in Primary CNS Lymphoma After R-MVP and High-Dose Chemotherapy With Autologous Hematopoietic Stem Cell Transplant.

BACKGROUND AND OBJECTIVES: Primary CNS lymphoma (PCNSL), a rare CNS malignancy, is usually treated with high-dose methotrexate in the first-line setting, typically followed by consolidation therapy. Due to the broad range of currently available treatments for PCNSL, comparability in long-term follow-up studies is limited, and data are scattered across small studies. METHODS: In this study, we report the long-term survival of patients with newly diagnosed immunocompetent PCNSL, enrolled in a phase II trial from June 2005 to September 2011. Patients were treated using rituximab, methotrexate, vincristine, and procarbazine (R-MVP) chemotherapy followed by high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) in those with partial or complete response to R-MVP. In a post hoc analysis, clinical and imaging features were evaluated in those still alive. RESULTS: 26 of 32 patients underwent HDC-ASCT consolidation. Of them, 3 patients died of treatment-related toxicity and 2 due to disease progression within 1 year of ASCT. None of the remaining 21 patients had disease progression with a median follow-up of 12.1 years and were included in the analysis. Compared with the post-HDC-ASCT assessment, at the last follow-up, there was no significant difference in the median Karnofsky Performance Status (80 [range: 60-100] vs 90 [range: 70-100]), the median Neurologic Assessment in Neuro-Oncology score (1 [range: 0-4] vs 1 [range: 0-5]), and leukoencephalopathy score (1 [range: 0-3] vs 1 [range: 1-4]). DISCUSSION: Long-term follow-up demonstrated that treatment was well tolerated in most patients enrolled in this study, with stable leukoencephalopathy on imaging and stable clinical performance status. Disease recurrence was not observed beyond 2 years after HDC-ASCT consolidation.

Accuracy of Buffy Coat in the Diagnosis of Disseminated Histoplasmosis in AIDS-Patients in an Endemic Area of Brazil.

The buffy coat is obtained routinely for disseminated histoplamosis (DH) diagnosis in Ceará, Brazil. The aim of this study is to describe the accuracy of staining smears for Histoplasma in the buffy coat of AIDS-patients with DH. From 2012-2013, all results of stained buffy coat smears and culture for fungi performed at São José Hospital were recorded. In total, 489 buffy coats of 361 patients were studied; 19/361 (5.3%; 95%CI = 2.9-7.6%) had positive direct examination stained smears for Histoplasma and 61/361 (16.9%; 95%CI = 13.0-20.8%) had growth in culture. For those with positive Histoplasma cultures, the CD4 count was significantly lower (139.3 vs. 191.7cells/µL; p = 0.014) than others, and death was 18%. The sensitivity and specificity of stained smears was 25.9% and 100%, respectively. A second test, performed up to 36 days from the first one, increased the sensitivity of stained smears to 32.2%. Stained smears of buffy coat have low accuracy; nonetheless, they are easy to perform and can give a quick diagnosis in low-resource endemic areas. Despite the decrease in mortality, it is not yet to the low levels observed in areas that have better and more efficient methods.

Effectiveness of an intervention in multicomponent exercise in primary care to improve frailty parameters in patients over 70 years of age (MEFAP-project), a randomised clinical trial: rationale and study design.

BACKGROUND: Physical activity may reverse frailty in the elderly, but we encounter barriers to the implementation of exercise programs in this population. Our main aim is to evaluate the effect of a multicomponent physical activity program, versus regular medical practice, on reverting pre-frailty status among the elderly, 12 months post-intervention. METHODS: Randomized parallel group multicenter clinical trial located in primary care setting, among non-dependent and pre-frail patients > 70 years old, including 190 patients (95 intervention, 95 control group). INTERVENTION: Multicomponent physical activity program (MEFAP, for its acronym in Spanish) with twelve 1.5 h-weekly sessions comprised of: 1. Informative session; 2. Exercises for improving aerobic resistance, muscle strength, propioception-balance and flexibility; and 3. Handing out of at-home exercise chart (twice/week). Main variable: pre-frailty according to the Fried phenotype. Secondary variables: sociodemographic, clinical and functional variables; exercise program adherence, patient satisfaction with the program and quality of life. We will perform an intention-to-treat analysis by comparing the retrogression from pre-frailty (1 or 2 Fried criteria) to robust status (0 Fried criteria) by the end of the intervention, 6 months and 12 months post-intervention. The accumulated incidence in each group will be calculated, as well as the relative risk (RR) and the number needed to treat (NNT) with their corresponding 95% confidence intervals. Protocol was approved by the Ethics Committee Hospital la Paz. DISCUSSION: Within the context of regular clinical practice, our results will provide evidence regarding the effects of exercise interventions on frailty among pre-frail older adults, a key population given their significant potential for functional, physical, and mental health improvement. TRIAL REGISTRATION: NCT03568084 . Registered 26 June 2018. Date of enrollment of the first participant to the trial: July 2nd 2018.

Identification of microplastics using Raman spectroscopy: Latest developments and future prospects.

Widespread microplastic pollution is raising growing concerns as to its detrimental effects upon living organisms. A realistic risk assessment must stand on representative data on the abundance, size distribution and chemical composition of microplastics. Raman microscopy is an indispensable tool for the analysis of very small microplastics (<20 µm). Still, its use is far from widespread, in part due to drawbacks such as long measurement time and proneness to spectral distortion induced by fluorescence. This review discusses each drawback followed by a showcase of interesting and easily available solutions that contribute to faster and better identification of microplastics using Raman spectroscopy. Among discussed topics are: enhanced signal quality with better detectors and spectrum processing; automated particle selection for faster Raman mapping; comprehensive reference libraries for successful spectral matching. A last section introduces non-conventional Raman techniques (non-linear Raman, hyperspectral imaging, standoff Raman) which permit more advanced applications such as real-time Raman detection and imaging of microplastics.

Overall survival in patients with glioblastoma before and after bevacizumab approval.

OBJECTIVE: Glioblastoma (GBM) is an aggressive disease with limited therapeutic options. While bevacizumab was approved in 2009 for the treatment of patients with progressive GBM, its impact on overall survival (OS) remains unclear. Using US population-based cancer registry data (SEER), this study compared OS of patients diagnosed with GBM before and after bevacizumab approval. METHODS: Adult patients from SEER with a GBM diagnosis were divided into two cohorts: patients diagnosed in 2006-2008 (pre-bevacizumab cohort, n = 6,120) and patients diagnosed in 2010-2012 (post-bevacizumab cohort, n = 6,753). Patients were included irrespective of the treatments received. OS post-diagnosis was compared between the study cohorts utilizing Kaplan-Meier analyses and multivariate Cox proportional hazards regression. RESULTS: Among 12,873 patients with GBM, the median age was 62 years, 41% were women, 31% underwent gross total resection, and 75% received radiation therapy. Survival was stable within the 2006-2008 period (median survival = 9 months for each year), but increased after year 2009 (median survival = 10 and 11 months for years 2010/2011 and 2012, respectively). The adjusted hazard of death was significantly lower in the post-bevacizumab approval cohort (hazard ratio = 0.91, p < .01). CONCLUSIONS: The results of this large population-based study suggested an improvement in OS among patients with a GBM diagnosis in 2010-2012 compared to 2006-2008. While the cause of this improvement cannot be proven in a retrospective analysis, the timing of the survival increase coincides with the approval of bevacizumab for the treatment of patients with progressive GBM, indicating a possible benefit of bevacizumab in this population.

Total Facial Discrimination of 1,3-Dipolar Cycloadditions in a d-Erythrose 1,3-Dioxane Template: Computational Studies of a Concerted Mechanism.

A new d-erythrose 1,3-dioxane derivative was synthesized from d-glucose and found to be a highly stereoselective template as a dipolarophile. Different 1,3-dipoles of allenyl-type were employed, giving different regioselectivities, depending on its nature; the regioselectivity is complete with alkyl azides and phenyldiazomethane, but is inexistence with nitrile oxides. Computational studies were performed to understand the mechanisms of cycloadditions. All the studied cycloadditions were found to be concerted involving small free activation energies and are all exoenergonic. The stereoselectivity is due to a combined result of the steric effect H-8a and the hyperconjugative effect of the *C-O to the incoming 1,3-dipole. The regioselectivity observed in alkyl azides and phenyldiazomethane is mostly dependent on the distortion effect during the cycloaddition process. This distortion effect is however higher in the alkyl azide compounds than in phenyldiazomethane.

Detection and characterisation of frauds in bovine meat in natura by non-meat ingredient additions using data fusion of chemical parameters and ATR-FTIR spectroscopy.

Concerns about meat authenticity are increasing recently, due to great fraud scandals. This paper analysed real samples (43 adulterated and 12 controls) originated from criminal networks dismantled by the Brazilian Police. This fraud consisted of injecting solutions of non-meat ingredients (NaCl, phosphates, carrageenan, maltodextrin) in bovine meat, aiming to increase its water holding capacity. Five physico-chemical variables were determined, protein, ash, chloride, sodium, phosphate. Additionally, infrared spectra were recorded. Supervised classification PLS-DA models were built with each data set individually, but the best model was obtained with data fusion, correctly detecting 91% of the adulterated samples. From this model, a variable selection based on the highest VIPscores was performed and a new data fusion model was built with only one chemical variable, providing slightly lower predictions, but a good cost/performance ratio. Finally, some of the selected infrared bands were specifically associated to the presence of adulterants NaCl, tripolyphosphate and carrageenan.

Effect of polymeric substrate on sludge settleability.

The study aims to evaluate the role of a polymeric substrate (starch) on sludge settleability. Despite being an important COD component of the wastewater, the relationship between polymeric substrates and bulking sludge has been hardly studied. The polymers are hydrolysed at a rate smaller than the consumption rate of monomers. This means that the soluble substrate resulting from hydrolysis is likely to be present at growth rate limiting concentrations. According to the kinetic selection theory this leads to bulking sludge. However, a recently postulated theory suggests that, strong diffusion limited micro-gradients of substrate concentration inside flocs lead to bulking sludge, and not a low substrate concentration as such. If the polymeric COD is first incorporated in the sludge floc and afterwards hydrolysed in the sludge floc then there is essentially no substrate gradient inside the biological flocs. The experiments showed that conditions leading to bulking sludge with monomers (glucose) did not lead to bulking when starch was used. A bulking sludge event was even cured just by substituting the monomer with starch. These results are clearly in line with a diffusion gradient--based theory for bulking sludge. Nevertheless, flocs growing on starch are more open, fluffy and porous than flocs formed on maltose or glucose, most likely because the starch needs to be hydrolysed at the surface of the micro-colonies forming the flocculated sludge. Some additional observations on occurrence of filamentous bacteria in oxygen diffusion limited systems are also discussed in this manuscript.

Temozolomide and methotrexate for primary central nervous system lymphoma in the elderly.

BACKGROUND: Treatment for primary CNS lymphoma (PCNSL) in the elderly is associated with lower response rates and higher risks of acute and late delayed toxicity as compared to younger patients. Temozolomide has emerged as a new alternative treatment for PCNSL and constitutes an attractive option for the elderly because of its favorable toxicity profile. In this study we report outcomes of a consecutive series of PCNSL elderly patients initially treated with an innovative regimen combining methotrexate and temozolomide without radiotherapy or intra-thecal chemotherapy. METHODS: Histologically confirmed newly-diagnosed PCNSL patients older than 60 years were included. An induction chemotherapy was initially given (methotrexate 3 g /m(2) on days 1, 10, and 20, and temozolomide 100 mg/m(2) on days 1-5). Patients achieving a partial or complete response proceeded to a maintenance phase (up to 5 monthly cycles of methotrexate 3 g/m(2) on day 1, and temozolomide 100 mg/m(2 )days 1-5). Non-responders were treated on an individual basis. RESULTS: Among the 23 included patients, a complete response was observed in 55%, and disease progressed in the other 45%. Median event-free survival was 8 months, and median overall survival was 35 months. Grades 3 or 4 toxicities included nephrotoxicity in three patients, and hematotoxicity in five; no neurotoxicity has been observed to date. One patient died while on treatment from complications of intestinal obstruction. CONCLUSION: Our efficacy results are comparable to other reported regimens, with the advantages of a favorable toxicity profile, and absence of intra-thecal chemotherapy. Prospective, controlled studies are warranted to confirm such results.

Lessons learned in the development of targeted therapy for malignant gliomas.

The prognosis of patients with glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma remains poor despite standard treatment with radiotherapy and temozolomide. Molecular targeted therapy holds the promise of providing new, more effective treatment options with minimal toxicity. However, the development of targeted therapy for gliomas has been particularly challenging. The oncogenetic process in such tumors is driven by several signaling pathways that are differentially activated or silenced with both parallel and converging complex interactions. Therefore, it has been difficult to identify prevalent targets that act as key promoters of oncogenesis and that can be successfully addressed by novel agents. Several drugs have been tested, including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (gefitinib and erlotinib), mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus), and vascular endothelial growth factor receptor (VEGFR), protein kinase C-beta, and other angiogenesis pathways inhibitors (vatalanib, bevacizumab, and enzastaurin). Although preliminary efficacy results of most trials in recurrent disease have fallen short on expectations, substantial advances have been achieved by associated translational research. In this article, we seek to recapitulate the lessons learned in the development of targeted therapy for gliomas, including challenges and pitfalls in the interpretation of preclinical data, specific issues in glioma trial design, insights provided by translational research, changes in paradigms, and future perspectives.

Chemotherapy for primary central nervous system lymphoma.

Chemotherapy, with or without radiotherapy, is the mainstay of treatment for primary central nervous system lymphoma (PCNSL). High-dose methotrexate (MTX) is the most effective drug available to treat these lesions, and it is used in doses of 1 to 8 g/m(2), either as a single agent or in combination with other drugs such as corticosteroid agents, cytarabine, procarbazine, vincristine, carmustine, lomustine, thiotepa, cyclophosphamide, temozolomide, and rituximab. To date, an overwhelming number of different regimens in which high-dose MTX is used have been reported. Given the lack of randomized trials, however, the optimal treatment remains controversial. Varying methodology makes the comparison of available studies extremely difficult, yet some common themes can be found throughout the literature. Treatment paradigms vary considerably according to the patient's age. Most studies support the use of chemotherapy-only treatments for elderly patients (> 60 years), given the high risks of neurotoxicity associated with radiotherapy. Nevertheless, the prognosis remains poor regardless of the chemotherapy chosen, and less toxic regimens might be preferable for such elderly patients. Conversely, in younger patients (< 60 years), there is growing evidence that commonly used chemotherapy-only regimens are associated with increased relapse rates that may not justify deferral of radiotherapy. Thus, a significant focus of research has been the development of intensified chemotherapy regimens that could replace radiotherapy. In this article, the authors discuss the principles guiding the use of chemotherapy for PCNSL, and critically review the available literature, including the most recent trials.

Hypersexuality following bilateral thalamic infarction: case report.

Hypersexuality is a rare but well recognized condition following brain injury. It has been described secondarily to dysfunction in the hypothalamus, the temporal and frontal lobes. We report a 63 year-old man that developed neuropsychological disturbances with hypersexuality as a prominent feature, disinhibition and moderate memory loss, hypersomnia and irritability after a bilateral paramedian thalamic infarction. A SPECT showed frontal hypoperfusion. We believe that these findings are expression of frontal-subcortical circuits dysfunction, particularly the orbitofrontal circuit, secondary to dorso medial thalamic infarction which probably plays a role in the determination of human sexual behavior. This case favors a thalamic modulation of frontal function.

Hypersexuality following bilateral thalamic infarction: case report

Hiperssexualidade é uma condição rara mas bem reconhecida após lesão do sistema nervoso central. A literatura medica registra casos secundários a disfunção do hipotálamo, do lobo temporal e do lobo frontal. Relatamos o caso de um homem de 63 anos de idade que desenvolveu alterações neuropsicológicas com hiperssexualidade como característica mais proeminente, desinibição, moderada perda de memória, hipersonia e irritabilidade após infarto talâmico paramediano bilateral. O SPECT evidenciou hipoperfusão frontal. Nós acreditamos que esses achados sejam expressão da disfunção de circuitos córtico-subcorticais frontais, particularmente do circuito órbito-frontal, secundária ao infarto dorsomedial do tálamo, que provavelmente desempenha papel relevante na determinação do comportamento sexual humano. Este caso favorece uma possível função moduladora do tálamo sobre os circuitos córtico-subcorticais frontais.

Salvage temozolomide for prior temozolomide responders.

BACKGROUND: Temozolomide (TMZ) often is used as adjuvant or first-line therapy for patients with glioma. Because of potential hematologic complications, it usually is discontinued after 12-18 cycles, even in responders. Subsequent salvage therapies are reported to have limited efficacy at the time of disease recurrence. In the current study, the authors assessed the outcome and complications of reusing TMZ at the time of disease recurrence in patients who previously responded to treatment. METHODS: A retrospective review of patients with recurrent/progressive glioma who had a history of response to TMZ and were treated with the same agent at the time of disease recurrence was conducted. RESULTS: Fourteen patients were identified (8 men and 6 women). The median age of the patients was 56 years (range, 25-67 yrs) at the time of diagnosis; 9 patients had glioblastoma, 3 had anaplastic astrocytoma, and 2 patients had low-grade oligodendroglioma. No patient developed disease progression while receiving the initial TMZ treatment. At the time of the initial disease recurrence, 13 patients were readministered TMZ. One patient received TMZ at the time of second disease recurrence. All patients were assessed for radiographic response. Objective response or stable disease was achieved in 6 patients (43%; 95% confidence interval [95% CI], 21-67%) and the 6-month progression-free survival was 36% (95% CI, 16-61%). CONCLUSIONS: TMZ was found to be well tolerated and effective in this setting, suggesting that repeat use of TMZ in previous responders warrants further investigation.

Delayed neurotoxicity in primary central nervous system lymphoma.

BACKGROUND: Treatment for primary central nervous lymphoma (PCNSL) with chemotherapy and radiotherapy has resulted in improved survival, but some patients develop neurologic deterioration that represents a treatment-related toxic effect. This delayed neurotoxicity has been poorly defined in the literature, and the underlying mechanisms are unknown. OBJECTIVE: To describe the clinical findings, time course, and pathophysiologic mechanisms associated with neurotoxicity in an attempt to generate hypotheses for future studies that address prevention and treatment of this complication of successful PCNSL therapy. DESIGN: Retrospective review. SETTING: Department of Neurology, Memorial Sloan-Kettering Cancer Center. PATIENTS: One hundred eighty-five patients treated for PCNSL, including 43 who developed neurotoxicity. MAIN OUTCOME MEASURES: Potential risk factors, clinical course, and neuropsychological, neuroimaging, and histologic findings. RESULTS: The 5-year cumulative incidence of neurotoxicity was 24%; this incidence increases over time. Neurotoxicity presented as a rapidly progressive subcortical dementia characterized by psychomotor slowing, executive and memory dysfunction, behavioral changes, gait ataxia, and incontinence. Imaging findings revealed diffuse white matter disease and cortical-subcortical atrophy. Available autopsy data showed white matter damage with gliosis, thickening of small vessels, and demyelination. Statistical analyses were performed, accounting for death as a competing risk. Older age (P = .01), mental status changes at diagnosis (P = .04), female sex (P = .05), and radiotherapy (P<.001) predicted neurotoxicity on univariate analysis, but only radiotherapy remained significant in the multivariate setting. CONCLUSION: These findings suggest that the core pathophysiologic mechanism is the interruption of frontal-subcortical circuits mediated by radiation damage, possibly caused by progressive microvascular alterations, loss of oligodendrocyte progenitors, or oxidative stress.