Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma.

BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas. METHODS: In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed. RESULTS: A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo. CONCLUSIONS: In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).

Development and testing of patient-centered education about hormone replacement therapy for women at high genetic risk of breast and ovarian cancer.

OBJECTIVE: In this study, we aimed to develop education to assist BRCA mutation carriers in making informed decisions about HRT in the context of risk-reducing surgery, while simultaneously clarifying their treatment-specific values and reducing decisional conflict. METHODS: We enrolled premenopausal BRCA mutation carriers ages 19-49 without prior cancer or risk-reducing salpingo-oophorectomy to structured interviews in which they reviewed education about the risks and benefits of HRT. Materials included literature-derived data demonstrating associations between HRT and commonly considered health outcomes (breast cancer, vasomotor symptoms, sexual functioning, cardiovascular disease, osteoporosis, and blood clots). Participants completed the 16-item Decisional Conflict Scale (DCS) before and after education, communicated their preferences by rating and ranking the six outcomes, and provided feedback to inform iterative revisions of the educational content. RESULTS: 25 participants completed interviews. DCS scores decreased significantly from 54.6 to 22.8 following education (p < 0.001); sub-scores for uncertainty (71.7 to 37.3), informed (71.7 to 15.3), values clarity (53.7 to 17.0), effective decision (44.2 to 25.5), and support (35.0 to 17.7) also decreased significantly. Participants ranked cardiovascular disease as the most important outcome to consider, followed by breast cancer, osteoporosis, blood clots, decline in sexual function, and hot flashes. Participants with prior mastectomy (N = 10) ranked breast cancer as the most important outcome 25% of the time, compared to 80% in participants without mastectomy (N = 15). CONCLUSION: Following education, BRCA mutation carriers had significantly less decisional conflict regarding the choice to use HRT. This pilot study was successful in generating a prototype educational aid for further testing.

Patient perspectives on considerations, tradeoffs, and experiences with multiple myeloma treatment selection: a qualitative descriptive study.

BACKGROUND: Advances in multiple myeloma treatment and a proliferation of treatment options have resulted in improved survival rates and periods of symptom-free remission for many multiple myeloma patients. As a result, health-related quality of life (HRQoL) concerns related to myeloma treatments have become increasingly salient for this patient population and represent an important consideration guiding patients' treatment choices. To gain an understanding of patients' experiences with choosing myeloma therapies and explore the HRQoL concerns that are most important to them, we interviewed a diverse sample of US-based multiple myeloma patients about their treatment considerations. METHODS: We conducted a qualitative descriptive study using in-depth interviews. Participants reflected on (1) the factors that were most important to them when thinking about multiple myeloma treatment and how these have changed over time, (2) how they might weigh the importance of treatment efficacy vs. side effects, (3) trade-offs they would be willing to make regarding efficacy vs. HRQoL, and (4) treatment changes they had experienced. Interviews were audio-recorded and transcribed, and narratives were analyzed using applied thematic analysis. RESULTS: We interviewed 21 patients, heterogeneous in their disease trajectory and treatment experience. Participants were 36 to 78 years, 52% female, and 38% Black. Efficacy was named as the most important treatment consideration by almost two-thirds of participants, and over half also valued HRQoL aspects such as the ability to maintain daily functioning and enjoyment of life. Participants expressed concern about potential treatment side effects and preferred more convenient treatment options. Although participants stated largely trusting their clinicians' treatment recommendations, many said they would stop a clinician-recommended treatment if it negatively impacted their HRQoL. Participants also said that while they prioritized treatment efficacy, they would be willing to change to a less efficacious treatment if side effects became intolerable. CONCLUSIONS: Our findings link to other reports reflecting considerations that are important to multiple myeloma patients, including the importance placed on increasing life expectancy and progression-free survival, but also the tension between treatment efficacy and quality of life. Our results extend these findings to a racially diverse US-based patient population at different stages in the disease trajectory.

The relationship between central and mid-peripheral motion perception and the hazard perception test in younger and older adults.

INTRODUCTION: Vision standards for driving are typically based on visual acuity, despite evidence that it is a poor predictor of driving safety and performance. However, visual motion perception is potentially relevant for driving, as the vehicle and surroundings are in motion. This study explored whether tests of central and mid-peripheral motion perception better predict performance on a hazard perception test (HPT), which is related to driving performance and crash risk, than visual acuity. Additionally, we explored whether age influences these associations, as healthy ageing impairs performance on some motion sensitivity tests. METHODS: Sixty-five visually healthy drivers (35 younger, mean age: 25.5; SD 4.3 years; 30 older adults, mean age: 71.0; SD 5.4 years) underwent a computer-based HPT, plus four different motion sensitivity tests both centrally and at 15° eccentricity. Motion tests included minimum displacement to identify motion direction (Dmin ), contrast detection threshold for a drifting Gabor (motion contrast), coherence threshold for a translational global motion stimulus and direction discrimination for a biological motion stimulus in the presence of noise. RESULTS: Overall, HPT reaction times were not significantly different between age groups (p = 0.40) nor were maximum HPT reaction times (p = 0.34). HPT response time was associated with motion contrast and Dmin centrally (r = 0.30, p = 0.02 and r = 0.28, p = 0.02, respectively) and with Dmin peripherally (r = 0.34, p = 0.005); these associations were not affected by age group. There was no significant association between binocular visual acuity and HPT response times (r = 0.02, p = 0.29). CONCLUSIONS: Some measures of motion sensitivity in central and mid-peripheral vision were associated with HPT response times, whereas binocular visual acuity was not. Peripheral testing did not show an advantage over central testing for visually healthy older drivers. Our findings add to the growing body of evidence that the ability to detect small motion changes may have potential to identify unsafe road users.

[Intercultural competences achieved by health sciences students during the clinical practice]. / Nivel de Competencia Intercultural en estudiantes de Ciencias de la Salud desarrollada en práctica clínica.

BACKGROUND: During their clinical practice, health Sciences students get acquainted with the cultural diversity of patients and learn to deal with this reality in a model of social learning. AIM: To determine the level of Intercultural Competence in Health Sciences students based on the Confrontation, Resistance, and Cultural Openness (CRAC) model, specific for health professionals. MATERIAL AND METHODS: Semi-structured interviews were conducted with 106 Health Sciences students from three universities in Chile. Content analysis was supported by the software ATLAS.ti version 9. RESULTS: The students progressed through the CRAC model and were able to configure a new level called Cultural Understanding, in which the participants innovated care models and offered new therapeutic schemes with cultural relevance. In addition, a fifth level called Cultural Inclusion was proposed. However, a training process with a marked theoretical/scientific emphasis can overshadow the learning process resulting from reflexive practical experience, reducing its real value such as traditional/ancestral medicine. CONCLUSIONS: The students were able to update the Confrontation, Resistance, Openness, Understanding and Intercultural Inclusion Model. The features of those participants who achieve the highest levels of intercultural competences should be explored and used for the training process.

Impact on daily clinical practice of the latest evidence on percutaneous closure of patent foramen ovale after cryptogenic stroke: a single-center experience.

INTRODUCTION AND OBJECTIVES: At the end of 2017, three clinical trials demonstrated that, in selected patients, percutaneous closure of patent foramen ovale (PFO) after cryptogenic stroke (CS) reduces the risk of recurrence. Our aim was to determine the impact of these findings on routine clinical practice in a tertiary hospital. METHODS: Patients with CS and percutaneous closure of PFO during 2001-2020 were included. The clinical characteristics of the patient and the anatomical characteristics of the foramen were analyzed. Based on both, the closure indications were classified into three groups according to the latest European recommendations and were analyzed in two periods, before and after the publication date of the clinical trials. RESULTS: A total of 293 patients were included. The mean age was 49 ± 11 years, and 15% were older than 60 years. The median RoPE score was 6 [p25-75, 5-7] and 75% had complex anatomy (CA). After the publication of the studies, the frequency of CA and the mean age of the patients were significantly higher (89% vs. 69% p < 0.0005 and 51 ± 11 vs. 48 ± 11 years, p = 0.02, respectively), and the RoPE score, significantly lower (5 [5-7] versus 6 [5-7], p = 0.02). Inadequate closure indications were significantly reduced (8% vs. 18%, p = 0.02). CONCLUSION: After the publication of clinical trials that have shown benefit of PFO closure after CS, the number of inappropriate indications for closure has decreased significantly in our institution, with a higher percentage of CA, despite a clinical profile suggestive of lower causal probability of PFO.

Mutational spectrum of GNAL, THAP1 and TOR1A genes in isolated dystonia: study in a population from Spain and systematic literature review.

OBJECTIVE: We aimed to investigate the prevalence of TOR1A, GNAL and THAP1 variants as the cause of dystonia in a cohort of Spanish patients with isolated dystonia and in the literature. METHODS: A population of 2028 subjects (including 1053 patients with different subtypes of isolated dystonia and 975 healthy controls) from southern and central Spain was included. The genes TOR1A, THAP1 and GNAL were screened using a combination of high-resolution melting analysis and direct DNA resequencing. In addition, an extensive literature search to identify original articles (published before 10 August 2020) reporting mutations in TOR1A, THAP1 or GNAL associated to dystonia was performed. RESULTS: Pathogenic or likely pathogenic variants in TOR1A, THAP1 and GNAL were identified in 0.48%, 0.57% and 0.29% of our patients, respectively. Five patients carried the variation p.Glu303del in TOR1A. A very rare variant in GNAL (p.Ser238Asn) was found as a putative risk factor for dystonia. In the literature, variations in TOR1A, THAP1 and GNAL accounted for about 6%, 1.8% and 1.1% of published dystonia patients, respectively. CONCLUSIONS: There is a different genetic contribution to dystonia of these three genes in our patients (about 1.3% of patients) and in the literature (about 3.6% of patients), probably due the high proportion of adult-onset cases in our cohort. As regards age at onset, site of dystonia onset, and final distribution, in our population there is a clear differentiation between DYT-TOR1A and DYT-GNAL, with DYT-THAP1 likely to be an intermediate phenotype.

Incomplete information and irrelevant attributes in stated-preference values for health interventions.

Violations of the assumptions of complete information [CI] and independence of irrelevant alternatives (IIA) in discrete-choice experiment (DCE) data imply sensitivity of preference estimates to the decision context and the alternatives evaluated. There is a paucity of evidence on how these two assumptions affect health-preference results and whether the usual specifications of random-parameters logit models are sufficient to address these violations. We assessed the appropriateness of these assumptions in a DCE valuating interventions to prevent long-term health problems that could be identified through whole genome sequencing. A DCE survey was administered to members of a nationally representative consumer panel to elicit their preferences for options to reduce the risk of health problems. The treatment options presented (surgery, medication, and watchful waiting) and the context for the decisions elicited (severity and likelihood of the health problem) were varied experimentally to evaluate the sensitivity of preference results to such changes. We find evidence of IIA violations as the options presented to prevent health changed. Our results also are consistent with the expectation that additional substitutes decrease the monetized value of alternatives. We also find some evidence that the decision context can moderate such effects, which constitutes a new finding.

Motion perception at mesopic light levels: effects of physiological ageing and eccentricity.

PURPOSE: To explore the differential effects of age and eccentricity on the perception of motion at photopic and mesopic light levels. METHODS: Thirty-six visually normal participants (18 younger; mean age 25 years, range: 20-31) and (18 older; mean age 70 years, range: 60-79) underwent two testing sessions, one at photopic and one at mesopic light levels. In each session, motion perception was tested binocularly at two eccentricities (centrally, and peripherally at 15° rightwards and 5° superior to the horizontal) for four motion tasks: minimum contrast of a drifting Gabor to identify motion direction (motion contrast); translational global motion coherence; biological motion embedded in noise and the minimum duration of a high-contrast Gabor to determine the direction of motion, using two Gabor sizes to measure spatial surround suppression of motion. RESULTS: There was a significant main effect of light condition (higher thresholds in mesopic) for motion contrast (p < 0.001), translational global motion (p = 0.001) and biological motion (p < 0.001); a significant main effect of age (higher thresholds in older adults) for motion contrast (p < 0.001) and biological motion (p = 0.04) and a significant main effect of eccentricity (higher thresholds peripherally) for motion contrast (p < 0.001) and biological motion (p < 0.001). Additionally, we found a significant three-way interaction between light levels, age and eccentricity for translational global motion (similar increase in mesopic thresholds centrally for both groups, but a much larger deterioration in older adult's peripheral mesopic thresholds, p = 0.02). Finally, we found a two-way interaction between light condition and eccentricity for translational global motion (higher values in central mesopic relative to peripheral photopic, p = 0.001) and for biological motion (higher values in peripheral mesopic relative to central photopic, p < 0.001). CONCLUSIONS: For the majority of tasks assessed, motion perception was reduced in mesopic relative to photopic conditions, to a similar extent in both age groups. However, because some older adults exhibited elevated thresholds even under photopic conditions, particularly in the periphery, the ability to detect mesopic moving stimuli even at high contrast was markedly impaired in some individuals. Our results imply age-related differences in the detection of peripheral moving stimuli at night that might impact hazard avoidance and night driving ability.

A SIR-type model describing the successive waves of COVID-19.

It is well-known that the classical SIR model is unable to make accurate predictions on the course of illnesses such as COVID-19. In this paper, we show that the official data released by the authorities of several countries (Italy, Spain and The USA) regarding the expansion of COVID-19 are compatible with a non-autonomous SIR type model with vital dynamics and non-constant population, calibrated according to exponentially decaying infection and death rates. Using this calibration we construct a model whose outcomes for most relevant epidemiological paramenters, such as the number of active cases, cumulative deaths, daily new deaths and daily new cases (among others) fit available real data about the first and successive waves of COVID-19. In addition to this, we also provide predictions on the evolution of this pandemic in Italy and the USA in several plausible scenarios.

A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma.

PURPOSE: To estimate the maximum tolerated dose (MTD) and/or identify the recommended Phase II dose (RP2D) for combined INC280 and buparlisib in patients with recurrent glioblastoma with homozygous phosphatase and tensin homolog (PTEN) deletion, mutation or protein loss. METHODS: This multicenter, open-label, Phase Ib/II study included adult patients with glioblastoma with mesenchymal-epithelial transcription factor (c-Met) amplification. In Phase Ib, patients received INC280 as capsules or tablets in combination with buparlisib. In Phase II, patients received INC280 only. Response was assessed centrally using Response Assessment in Neuro-Oncology response criteria for high-grade gliomas. All adverse events (AEs) were recorded and graded. RESULTS: 33 patients entered Phase Ib, 32 with altered PTEN. RP2D was not declared due to potential drug-drug interactions, which may have resulted in lack of efficacy; thus, Phase II, including 10 patients, was continued with INC280 monotherapy only. Best response was stable disease in 30% of patients. In the selected patient population, enrollment was halted due to limited activity with INC280 monotherapy. In Phase Ib, the most common treatment-related AEs were fatigue (36.4%), nausea (30.3%) and increased alanine aminotransferase (30.3%). MTD was identified at INC280 Tab 300 mg twice daily + buparlisib 80 mg once daily. In Phase II, the most common AEs were headache (40.0%), constipation (30.0%), fatigue (30.0%) and increased lipase (30.0%). CONCLUSION: The combination of INC280/buparlisib resulted in no clear activity in patients with recurrent PTEN-deficient glioblastoma. More stringent molecular selection strategies might produce better outcomes. TRIAL REGISTRATION: NCT01870726.

Computational design of improved standardized chemotherapy protocols for grade II oligodendrogliomas.

Here we put forward a mathematical model describing the response of low-grade (WHO grade II) oligodendrogliomas (LGO) to temozolomide (TMZ). The model describes the longitudinal volumetric dynamics of tumor response to TMZ of a cohort of 11 LGO patients treated with TMZ. After finding patient-specific parameters, different therapeutic strategies were tried computationally on the 'in-silico twins' of those patients. Chemotherapy schedules with larger-than-standard rest periods between consecutive cycles had either the same or better long-term efficacy than the standard 28-day cycles. The results were confirmed in a large trial of 2000 virtual patients. These long-cycle schemes would also have reduced toxicity and defer the appearance of resistances. On the basis of those results, a combination scheme consisting of five induction TMZ cycles given monthly plus 12 maintenance cycles given every three months was found to provide substantial survival benefits for the in-silico twins of the 11 LGO patients (median 5.69 years, range: 0.67 to 68.45 years) and in a large virtual trial including 2000 patients. We used 220 sets of experiments in-silico to show that a clinical trial incorporating 100 patients per arm (standard intensive treatment versus 5 + 12 scheme) could demonstrate the superiority of the novel scheme after a follow-up period of 10 years. Thus, the proposed treatment plan could be the basis for a standardized TMZ treatment for LGO patients with survival benefits.

Differential aging effects in motion perception tasks for central and peripheral vision.

The perception of motion is considered critical for performing everyday tasks, such as locomotion and driving, and relies on different levels of visual processing. However, it is unclear whether healthy aging differentially affects motion processing at specific levels of processing, or whether performance at central and peripheral spatial eccentricities is altered to the same extent. The aim of this study was to explore the effects of aging on hierarchically different components of motion processing: the minimum displacement of dots to perceive motion (Dmin), the minimum contrast and speed to determine the direction of motion, spatial surround suppression of motion, global motion coherence (translational and radial), and biological motion. We measured motion perception in both central vision and at 15° eccentricity, comparing performance in 20 older (60-79 years) and 20 younger (19-34 years) adults. Older adults had significantly elevated thresholds, relative to younger adults, for motion contrast, speed, Dmin, and biological motion. The differences between younger and older participants were of similar magnitude in central and peripheral vision, except for surround suppression of motion, which was weaker in central vision for the older group, but stronger in the periphery. Our findings demonstrate that the effects of aging are not uniform across all motion tasks. Whereas the performance of some tasks in the periphery can be predicted from the results in central vision, the effects of age on surround suppression of motion shows markedly different characteristics between central and peripheral vision.

A Pilot, Phase II, Randomized, Open-Label Clinical Trial Comparing the Neurotoxicity of Three Dose Regimens of Nab-Paclitaxel to That of Solvent-Based Paclitaxel as the First-Line Treatment for Patients with Human Epidermal Growth Factor Receptor Type 2-Negative Metastatic Breast Cancer.

BACKGROUND: This study aimed to characterize the neurotoxicity of three different regimens of nab-paclitaxel compared with a standard regimen of solvent-based (sb) paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer based on the Total Neurotoxicity Score (TNS), a tool specifically developed to assess chemotherapy-induced neurotoxicity. MATERIALS AND METHODS: This was a randomized, open-label study testing 4-week cycles of 80 mg/m2 sb-paclitaxel (PACL80/w) on days 1, 8, and 15; 100 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB100/w); 150 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB150/w); and 150 mg/m2 nab-paclitaxel on days 1 and 15 (NAB150/2w). In addition to the TNS, neuropathy was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Tumor response and quality of life were also evaluated. RESULTS: Neurotoxicity, as evaluated by the TNS, did not significantly differ between the sb-paclitaxel group and any of the nab-paclitaxel groups. The frequency of (any grade) polyneuropathy, as measured by the NCI-CTCAE, was lower in the PACL80/w (n = 7, 50%) and NAB150/2w (n = 10, 62.5%) groups than in the NAB100/w (n = 13, 81.3%) or NAB150/w (n = 11, 78.6%) group. Although the differences were not statistically significant, compared with the other groups, in the NAB150/w group, the time to occurrence of grade ≥2 polyneuropathy was shorter, and the median time to recovery from grade ≥2 polyneuropathy was longer. Dose delays and reductions due to neurotoxicity and impact of neurotoxicity on the patients' experience of symptoms and functional limitations was greater with NAB150/w. Among the seven polymorphisms selected for genotyping, the variant alleles of EPHA5-rs7349683, EPHA6-rs301927, and EPHA8-rs209709 were associated with an increased risk of paclitaxel-induced neuropathy. CONCLUSION: The results of this exploratory study showed that, regardless of the dose, nab-paclitaxel did not differ from sb-paclitaxel in terms of neurotoxicity as evaluated with the TNS. However, results from NCI-CTCAE, dose delays and reductions, and functional tools consistently indicate that NAB150/w regimen is associated with a greater risk of chemotherapy-induced neuropathy. Thus, our results question the superiority of the TNS over NCI-CTCAE for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and potentially supported by pharmacogenetic analysis. Registry: EudraCT, 2012-002361-36; NCT01763710 IMPLICATIONS FOR PRACTICE: The results of this study call into question the superiority of the Total Neurotoxicity Score over the National Cancer Institute Common Terminology Criteria for Adverse Events for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context and suggest that a regimen of 150 mg/m2 nab-paclitaxel administered on days 1, 8, and 15 is associated with a greater risk of chemotherapy-induced neuropathy and hematological toxicity compared with other lower-dose nab-paclitaxel regimens or a standard regimen of solvent-based paclitaxel. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and could benefit from pharmacogenetics analysis.

Tumor cell vanishing with radiological changes suggesting progression in IDH-mutated diffuse astrocytoma treated only with surgery.

The radiological diagnosis of glioma progression is still challenging. A 33-year-old woman diagnosed with a frontal tumor underwent awake craniotomy with total tumor resection. The diagnosis was IDH-mutated diffuse astrocytoma, WHO grade II. The patient did not receive additional radiotherapy or chemotherapy. Periodic MRI scans showed a T2/FLAIR nodular enlargement which appeared de novo and grew slowly and gradually until 4 years post surgery. The patient underwent a second craniotomy to completely resect the T2/FLAIR hyperintensity. In the histological and molecular study of the second resection, no tumor cells were identified. We could hypothesize that the reactive changes favored by surgery could explain the ongoing radiologic findings.
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Identification of epsilon toxin-producing Clostridium perfringens strains in American retail food.

Food samples (n = 216) from New York city were tested for the presence of C. perfringens via PCR for specific toxin genes. Thirty-four (16%) samples were positive for C. perfringens. Of these 34, 31 (91.2%) were type A or E, one (2.9%) was type B, and two (5.9%) were type D.

Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial.

We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ + BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m(2), days 1-21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ + BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ + BEV arm were evaluable for response. Results favored the TMZ + BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ + BEV arm, though the difference did not reach statistical significance. MGMT methylation in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ + BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity.

Brain Network Organization and Social Executive Performance in Frontotemporal Dementia.

OBJECTIVES: Behavioral variant frontotemporal dementia (bvFTD) is characterized by early atrophy in the frontotemporoinsular regions. These regions overlap with networks that are engaged in social cognition-executive functions, two hallmarks deficits of bvFTD. We examine (i) whether Network Centrality (a graph theory metric that measures how important a node is in a brain network) in the frontotemporoinsular network is disrupted in bvFTD, and (ii) the level of involvement of this network in social-executive performance. METHODS: Patients with probable bvFTD, healthy controls, and frontoinsular stroke patients underwent functional MRI resting-state recordings and completed social-executive behavioral measures. RESULTS: Relative to the controls and the stroke group, the bvFTD patients presented decreased Network Centrality. In addition, this measure was associated with social cognition and executive functions. To test the specificity of these results for the Network Centrality of the frontotemporoinsular network, we assessed the main areas from six resting-state networks. No group differences or behavioral associations were found in these networks. Finally, Network Centrality and behavior distinguished bvFTD patients from the other groups with a high classification rate. CONCLUSIONS: bvFTD selectively affects Network Centrality in the frontotemporoinsular network, which is associated with high-level social and executive profile.

The Wide Experience of the Sequential Therapy for Patients with Metastatic Renal Cell Carcinoma.

Sequential targeted therapies are the standard of care for patients with metastatic renal cell carcinoma (mRCC). Several drugs are available for patients whose disease progresses while they receive initial tyrosine kinase inhibitor (TKI) therapy; these include nivolumab (an inhibitor of PD-1 receptor), everolimus (an inhibitor of the mechanistic target of rapamycin) or additional TKIs. Until now, there has been no clinical evidence to support the use of one strategy versus another, so investigators and physicians rely on experience, judgement and findings from molecular analyses to select the appropriate treatment. However, with the arrival of nivolumab and cabozantinib that provide an overall survival higher than other alternative treatments, therapeutic strategies may have changed. Here, we discuss findings from preclinical and clinical studies that might help clinicians to choose the optimal treatment approach for patients with mRCC who progress to initial therapy.

miR-335 correlates with senescence/aging in human mesenchymal stem cells and inhibits their therapeutic actions through inhibition of AP-1 activity.

MicroRNAs, small noncoding RNAs, regulate gene expression primarily at the posttranscriptional level. We previously found that miR-335 is critically involved in the regulation and differentiation capacity of human mesenchymal stem cells (hMSCs) in vitro. In this study, we investigated the significance of miR-335 for the therapeutic potential of hMSCs. Analysis of hMSCs in ex vivo culture demonstrated a significant and progressive increase in miR-335 that is prevented by telomerase. Expression levels of miR-335 were also positively correlated with donor age of hMSCs, and were increased by stimuli that induce cell senescence, such as γ-irradiation and standard O2 concentration. Forced expression of miR-335 resulted in early senescence-like alterations in hMSCs, including: increased SA-ß-gal activity and cell size, reduced cell proliferation capacity, augmented levels of p16 protein, and the development of a senescence-associated secretory phenotype. Furthermore, overexpression of miR-335 abolished the in vivo chondro-osseous potential of hMSCs, and disabled their immunomodulatory capacity in a murine experimental model of lethal endotoxemia. These effects were accompanied by a severely reduced capacity for cell migration in response to proinflammatory signals and a marked reduction in Protein Kinase D1 phosphorylation, resulting in a pronounced decrease of AP-1 activity. Our results demonstrate that miR-335 plays a key role in the regulation of reparative activities of hMSCs and suggests that it might be considered a marker for the therapeutic potency of these cells in clinical applications.