Radiotherapy Plus Procarbazine,Lomustine, and Vincristine Versus Radiotherapy Plus Temozolomide for IDH-Mutant Anaplastic Astrocytoma: A Retrospective Multicenter Analysis of the French POLA Cohort

Background IDH‐mutant anaplastic astrocytomas (AAs) are chemosensitive tumors for which the best choice of adjuvant chemotherapy between procarbazine, lomustine, and vincristine (PCV) or temozolomide (TMZ) after radiotherapy (RT) remains unclear.MethodsIn a large cohort of patients with histologically proven 2016 World Health Organization classification AA with IDH1/2 mutations included in the French national POLA cohort (n = 355), the primary objective was to compare progression‐free survival (PFS) between the two treatment regimens (n = 311). Secondary endpoints were overall survival (OS), progression type, pseudoprogression rate, and toxicity.ResultsThe 4‐year PFS in the RT + PCV arm was 70.8% versus 53.5% in the RT + TMZ arm, with a hazard ratio (HR) of 0.58 (95% confidence interval [CI], 0.38–0.87; p = .0074) in univariable analysis and 0.63 (95% CI, 0.41–0.97; p = .0348) in multivariable analysis. The 4‐year OS in the RT + PCV arm was 84.3% versus 76.6% in the RT + TMZ arm, with an HR of 0.57 (95% CI, 0.30–1.05; p = .0675) in univariable analysis. Toxicity was significantly higher in the RT + PCV arm with more grade ≥3 toxicity (46.7% vs. 8.6%, p < .0001).ConclusionRT + PCV significantly improved PFS compared with RT + TMZ for IDH‐mutant AA. However, RT + TMZ was better tolerated.Implications for PracticeIn the absence of fully conducted randomized trials comparing procarbazine, lomustine, and vincristine (PCV) with temozolomide (TMZ) in adjuvant treatment after radiotherapy (RT) for the management of IDH‐mutant anaplastic astrocytoma (AA) and a similar level of evidence, these two chemotherapies are both equally recommended in international guidelines. This study in a national cohort of IDH‐mutant AA defined according the 2016 World Health Organization (WHO) classification shows for the first time that the RT + PCV regimen significantly improves progression‐free survival in comparison with the RT + TMZ regimen. Even if at the time of analysis the difference in overall survival was not significant, this result provides new evidence for the debate about the chemotherapy regimen to prescribe in adjuvant treatment to RT for WHO 2016 IDH‐mutant AA.     

Use of an Emergency Department in Saint-Laurent du Maroni,French Guiana: Does Being Undocumented Make a Difference?

Few data exist on the health status and heath care utilization of the undocumented migrants in France. Data are particularly scarce in French overseas territories where this population is numerous. We aimed to describe the characteristics of undocumented patients who use the emergency department of Saint-Laurent du Maroni Hospital (SLMH) in French Guiana, and to identify factors associated with their subsequent hospitalization. In a random sample of 177 patients, we used logistic regression models to test the mediational role of health-care system utilization and medical characteristics at admission in the association between residency status and hospitalization. More than a quarter of patients (27.7 %) were undocumented migrants, who were subsequently hospitalized more often than the others [OR 3.11, 95 % CI (1.32–7.34)]. More-severe symptoms at admission, a poorer access to health insurance, a greater distance between their home and SLMH, and poorer French language skills partially explained this higher hospitalization rate. Despite the fact that France has instituted a specific insurance program for the undocumented, an increasing number of barriers to accessing health care is being reported for these people. Our results suggest that these obstacles have some impacts in the utilization of hospital care.     

Performance Comparison of Various Maximum Likelihood Nonlinear Mixed-Effects Estimation Methods for Dose–Response Models

Estimation methods for nonlinear mixed-effects modelling have considerably improved over the last decades. Nowadays, several algorithms implemented in different software are used. The present study aimed at comparing their performance for dose-response models. Eight scenarios were considered using a sigmoid E(max) model, with varying sigmoidicity and residual error models. One hundred simulated datasets for each scenario were generated. One hundred individuals with observations at four doses constituted the rich design and at two doses, the sparse design. Nine parametric approaches for maximum likelihood estimation were studied: first-order conditional estimation (FOCE) in NONMEM and R, LAPLACE in NONMEM and SAS, adaptive Gaussian quadrature (AGQ) in SAS, and stochastic approximation expectation maximization (SAEM) in NONMEM and MONOLIX (both SAEM approaches with default and modified settings). All approaches started first from initial estimates set to the true values and second, using altered values. Results were examined through relative root mean squared error (RRMSE) of the estimates. With true initial conditions, full completion rate was obtained with all approaches except FOCE in R. Runtimes were shortest with FOCE and LAPLACE and longest with AGQ. Under the rich design, all approaches performed well except FOCE in R. When starting from altered initial conditions, AGQ, and then FOCE in NONMEM, LAPLACE in SAS, and SAEM in NONMEM and MONOLIX with tuned settings, consistently displayed lower RRMSE than the other approaches. For standard dose-response models analyzed through mixed-effects models, differences were identified in the performance of estimation methods available in current software, giving material to modellers to identify suitable approaches based on an accuracy-versus-runtime trade-off.     

Effects of an integrated poultry value chain,nutrition, gender and WASH intervention (SELEVER) on hygiene and child morbidity and anthropometry in Burkina Faso: A secondary outcome analysis of a cluster randomised trial

Nutrition-sensitive agriculture programmes have the potential to improve child nutrition outcomes, but livestock intensification may pose risks related to water, sanitation and hygiene (WASH) conditions. We assessed the impact of SELEVER, a nutrition- and gender-sensitive poultry intervention, with and without added WASH focus, on hygiene practices, morbidity and anthropometric indices of nutrition in children aged 2−4 years in Burkina Faso. A 3-year cluster randomised controlled trial was implemented in 120 villages in 60 communes (districts) supported by the SELEVER project. Communes were randomly assigned using restricted randomisation to one of three groups: (1) SELEVER intervention (n = 446 households); (2) SELEVER plus WASH intervention (n = 432 households); and (3) control without intervention (n = 899 households). The study population included women aged 15−49 years with an index child aged 2−4 years. We assessed the effects 1.5-years (WASH substudy) and 3-years (endline) post-intervention on child morbidity and child anthropometry secondary trial outcomes using mixed effects regression models. Participation in intervention activities was low in the SELEVER groups, ranging from 25% at 1.5 years and 10% at endline. At endline, households in the SELEVER groups had higher caregiver knowledge of WASH-livestock risks (∆ = 0.10, 95% confidence interval [CI] [0.04−0.16]) and were more likely to keep children separated from poultry (∆ = 0.09, 95% CI [0.03−0.15]) than in the control group. No differences were found for other hygiene practices, child morbidity symptoms or anthropometry indicators. Integrating livestock WASH interventions alongside poultry and nutrition interventions can increase knowledge of livestock-related risks and improve livestock-hygiene-related practices, yet may not be sufficient to improve the morbidity and nutritional status of young children.     

Essential role of Notch signaling in apoptosis of human pancreatic tumoral cells mediated by exosomal nanoparticles

We previously reported that exosomal nanoparticles secreted by human pancreatic tumoral cell lines decrease tumoral cell proliferation through the mitochondria‐dependent apoptotic pathway, because of activation of pro‐apoptotic phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and of glucose synthase kinase‐3β (GSK‐3β). Interactions between exosomal nanoparticles and cells are thought to involve membrane lipid rafts. However, the underlying mechanism is unknown. Here, we report that the interaction of exosomal nanoparticles with pancreatic cancer cells led to decreased expression of hairy and enhancer‐of‐split homolog‐1 (Hes‐1), the intranuclear target of Notch‐1 signaling pathway, and to activation of the apoptotic pathway after a cell cycle arrest in G₀G₁ phase. Strikingly, the expression level of Notch‐1 pathway components was critical, because exosomal nanoparticles decreased the proliferation of cells in which these partners are either weakly represented, in differentiated adenocarcinoma cells, or inhibited, in poorly differentiated carcinoma cells, by blocking presenilin in the γ‐secretase complex that regulates the Notch‐1 pathway. Overexpression of Notch‐1 intracellular domain resulted in the reversion of the cell proliferation inhibition promoted by exosomal nanoparticles. Blocking presenilin unexpectedly resulted in activation of PTEN and GSK‐3β. Conversely, inhibiting either PTEN or GSK‐3β increased Hes‐1 expression and partially counteracted the inhibition of proliferation promoted by exosomal nanoparticles, highlighting reciprocal regulations between Notch signaling and PTEN/GSK‐3β. We concluded that interactions of exosomal nanoparticles with target cells, at lipid rafts where Notch‐1 pathway partners are localized, hampered the functioning of the Notch‐1 survival pathway and activated the apoptotic pathway, which determines tumoral cell fate. © 2009 UICC     

Recurrence of atypical pulmonary pneumocystosis treated with pentamidine aerosol

Two cases are reported of atypical relapses of pneumocystosis in AIDS patients treated with aerosol pentamidine for 14 and 22 months. These pneumopathies are unusual because of their pitted aspect and recurrent spontaneous pneumothoraxes in spite of repeated drainage. They are difficult to diagnose because bronchoalveolar lavage fluid is negative for Pneumocystis carinii, despite their presence in lung biopsies. Histological lesions vary, being granulomatous, necrotizing and invasive, with involvement of the pleura and lymph nodes. Although a highly effective therapy against P. carinii pneumonia, aerosol pentamidine may play a role in these atypical episodes: either by causing bronchial obstructions beyond which the pneumocytotic lesions cannot be reached by lavage and become necrotic, or by favoring the extrapulmonary spread of P. carinii.     

Spastic paraplegia 15: Linkage and clinical description of three Tunisian families

Hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower limbs. The locus designated spastic paraplegia 15 (SPG15), located in a 16‐Mb interval on chromosome 14q, is associated with a rare autosomal recessive complicated form of HSP known as Kjellin's syndrome. In this study, we describe three additional families, of Tunisian origin, linked to the SPG15 locus, one of which had a significant multipoint LOD score of 3.46. In accordance with previous reports, the phenotype of our patients consisted of early onset spastic paraparesis associated with mental impairment and severe progression. Retinal degeneration was not observed, however, but we extended the phenotype of this form to include peripheral neuropathy and white matter abnormalities on MRI. Interestingly, like retinal degeneration, thin corpus callosum is not a constant feature in this entity. © 2007 Movement Disorder Society     

SPECT low-field MRI system for small-animal imaging.

Localization of regions with increased uptake of radiotracer in small-animal SPECT is greatly facilitated when using coregistration with anatomic images of the same animal. As MRI has several advantages compared with CT (soft-tissue contrast and lack of ionizing radiation) we developed a SPECT/low-field MRI hybrid device for small-animal imaging. METHODS: A small-animal single-pinhole gamma-camera (pinhole, 1.5 mm in diameter and 12 cm in focal length) adjacent to a dedicated low-field (0.1 T) small MR imager (imaging volume, 10 x 10 x 6 cm(3)) was used. The animal was placed in a warmed nonmagnetic polymethyl methacrylate imaging cell for MR acquisition, which was followed immediately by SPECT after translation of the imaging cell from one modality to the other. 3-Dimensional T1-weighted sequences were used for MRI. Phantom studies enabled verification of a low attenuation (10%) for (99m)Tc and (201)Tl and a very slight increase in Compton scattering due to the radiofrequency coil and polymethyl methacrylate imaging cell. RESULTS: SPECT/MRI data acquisition and image coregistration of selected examples using different radiotracers for lungs, kidneys, and brain were obtained in 3 nude mice with isotropic spatial resolutions of 0.5 x 0.5 x 0.5 mm(3) for MRI and 1 x 1 x 1 mm(3) for SPECT. The total acquisition time for combined SPECT and MRI lasted 1 h 45 min. CONCLUSION: A low-magnetic-field strength of 0.1 T is a simple and useful solution for a small-animal dual-imaging device combining pinhole SPECT with the adjacent MR imager.     

Pulmonary toxoplasmosis in AIDS. Report of 3 cases

Pulmonary toxoplasmosis in AIDS is rare. Its frequency is estimated to be between 0.2 and 3.7% but is probably underestimated; however, it is lower than that of neurotoxoplasmosis and is rarely identified prior to autopsy. We describe herein 3 cases diagnosed in living patients. The clinical presentation is usually severe interstitial pneumonitis, occurring in profoundly immunodeficient patients. Toxoplasma gondii, the infectious agent, must always be sought in the bronchoalveolar lavage of such patients and is sometimes associated with other opportunistic infectious agents, such as Pneumocystis carinii.