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Background Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation. Methods This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1R132X-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II. Results Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each). Conclusions Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population.

Overall sequencing CONSORT diagram. Flow diagram of study patients and analyzed biospecimens processed through and selected for central sequencing using MSK-IMPACT and Guardant360. cfDNA, cell-free DNA; FFPE, formalin-fixed paraffin-embedded; MSK-IMPACT, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets; QC, quality control.

HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib.Significance:HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.This article is highlighted in the In This Issue feature, p. 161

Supplementary data

Aim: To study the relation between burnout and resilience and to identify the profile of nurses presenting this quality. Background and Introduction: Healthcare professionals are subject to high rates of burnout. Resilience could be an important factor in preventing or alleviating this condition. Methods: The PubMed, ProQuest, Scopus and ScienceDirect databases were consulted in February 2022 using the equation ‘burnout AND resilience AND nurs*’. The inclusion criteria applied were that the texts should describe quantitative studies, be published in English or Spanish, in any year, and be directly related to the question considered. The meta-analysis was performed using StatsDirect statistical software. Results: Analysis of the 29 studies shows that among the dimensions of burnout, nurses are especially prone to emotional exhaustion, and are less affected by depersonalisation and low personal accomplishment. Those who score highly for resilience tend to have longer service experience, acceptable salaries and lesswork overload.Meta-analysis reveals an inverse correlation between resilience and burnout (r = −0.41; n = 2750), exhaustion (r=−0.27; n = 6966) and depersonalisation (r=−0.23; n = 6115). Conclusion: Many nurses present low levels of resilience and suffer from burnout syndrome. The application of programmes to enhance their resilience would help prevent burnout and optimise the potential to provide quality health care. Implications for nursing and health policy: Resilience is inversely correlated with burnout, depersonalisation and emotional exhaustion. Accordingly, healthcare organisations should develop and implement evidence-based programmes to foster nurses’ resilience and thus reduce their susceptibility to burnout., FEDER/Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía, Grant/Award Number: Project: P20_00627

During radiation therapy (RT) of glioblastoma, daily MRI with combination MRI–linear accelerator (MRI–Linac) systems has demonstrated significant anatomic changes, including evolving post-surgical cavity shrinkage. Cognitive function RT for brain tumors is correlated with radiation doses to healthy brain structures, especially the hippocampi. Therefore, this study investigates whether adaptive planning to the shrinking target could reduce normal brain RT dose with the goal of improving post-RT function. We evaluated 10 glioblastoma patients previously treated on a 0.35T MRI–Linac with a prescription of 60 Gy delivered in 30 fractions over six weeks without adaptation (“static plan”) with concurrent temozolomide chemotherapy. Six weekly plans were created per patient. Reductions in the radiation dose to uninvolved hippocampi (maximum and mean) and brain (mean) were observed for weekly adaptive plans. The dose (Gy) to the hippocampi for static vs. weekly adaptive plans were, respectively: max 21 ± 13.7 vs. 15.2 ± 8.2 (p = 0.003) and mean 12.5 ± 6.7 vs. 8.4 ± 4.0 (p = 0.036). The mean brain dose was 20.6 ± 6.0 for static planning vs. 18.7 ± 6.8 for weekly adaptive planning (p = 0.005). Weekly adaptive re-planning has the potential to spare the brain and hippocampi from high-dose radiation, possibly reducing the neurocognitive side effects of RT for eligible patients.

Background Glioblastoma (GBM) cellularity correlates with whole brain spectroscopic MRI (sMRI) generated relative choline to N-Acetyl-Aspartate ratio (rChoNAA) mapping. In recurrent GBM (rGBM), tumor volume (TV) delineation is challenging and rChoNAA maps may assist with re-RT targeting. Methods Fourteen rGBM patients underwent sMRI in a prospective study. Whole brain sMRI was performed to generate rChoNAA maps. TVs were delineated by the union of rChoNAA ratio over 2 (rChoNAA > 2) on sMRI and T1PC. rChoNAA > 2 volumes were compared with multiparametric MRI sequences including T1PC, T2/FLAIR, diffusion-restriction on apparent diffusion coefficient (ADC) maps, and perfusion relative cerebral blood volume (rCBV). Results rChoNAA > 2 (mean 27.6 cc, range 6.6–79.1 cc) was different from other imaging modalities (P ≤ 0.05). Mean T1PC volumes were 10.7 cc (range 1.2–31.4 cc). The mean non-overlapping volume of rChoNAA > 2 and T1PC was 29.2 cm3. rChoNAA > 2 was 287% larger (range 23% smaller–873% larger) than T1PC. T2/FLAIR volumes (mean 111.7 cc, range 19.0–232.7 cc) were much larger than other modalities. rCBV volumes (mean 6.2 cc, range 0.2–19.1 cc) and ADC volumes were tiny (mean 0.8 cc, range 0–3.7 cc). Eight in-field failures were observed. Three patients failed outside T1PC but within rChoNAA > 2. No grade 3 toxicities attributable to re-RT were observed. Median progression-free and overall survival for re-RT patients were 6.5 and 7.1 months, respectively. Conclusions Treatment of rGBM may be optimized by sMRI, and failure patterns suggest benefit for dose-escalation within sMRI-delineated volumes. Dose-escalation and radiologic-pathologic studies are underway to confirm the utility of sMRI in rGBM.

La perspectiva demográfica en España pone de manifiesto la necesidad de incorporar nuevas alternativas que permitan la sostenibilidad del estado de bienestar. Claramente, una de las principales soluciones será la hipoteca inversa, que permite hacer líquido el importante ahorro inmobiliario de los mayores y, así, procurar ingresos complementarios a las pensiones públicas. El presente artículo analiza, desde el punto de vista del riesgo de longevidad, el impacto entre la utilización de tablas de mortalidad diferenciadas o tablas conjuntas, poniéndose de manifiesto la importancia de la gestión global de la cartera por parte de la entidad financiera.

The COVID pandemic has 0drastically changed the functioning of universities in Spain and may have altered individuals’ behaviours and emotions, the way they engage in the learning process and their psychological well-being. Burnout syndrome is a psychological problem that arises from persistent confrontation with emotional and interpersonal stressors. COVID-related burnout among Spanish students has received little research attention. For this study, a pre-post cohort study design was used. Data were collected using the Maslach Burnout Inventory—Student Survey, the Granada Burnout Questionnaire for university students, the UtrechtWork Engagement Scale and the Fear of CoronaVirus-19 scale. The population was composed of two samples of 190 and 226 students from Spanish universities. According to the results obtained, significant differences were observed between the pre- and post-test samples. Levels of burnout were higher after the COVID-19 pandemic and students’ levels of engagement have dropped significantly following their experiences of the COVID pandemic. This study shows the impact that the covid pandemic has had on Spanish university students, impacts which may have had important consequences for their mental and physical health. It is necessary to implement intervention programs to enable students to recover, at least, the levels of burnout and engagement prevailing before the outbreak of the pandemic., Junta de Andalucia P20_00627

Somatic point mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) are a defining feature of the majority of WHO grade 2-3 diffuse glioma and the most powerful positive prognostic factor for survival in gliomas. The purpose is to review experimental therapeutic approaches targeting IDH mutations in gliomas including small-molecule inhibitors, immunotherapies, and agents targeting mutant IDH-induced epigenetic and metabolic vulnerabilities.Extensive preclinical work supports targeting mutant IDH (mIDH) in glioma. In heavily pretreated patients with mIDH glioma, enzyme inhibitors demonstrated to be well tolerated with preliminary evidence of clinical activity in nonenhancing tumors and enhancing tumors when used as single agents. In patients with newly diagnosed WHO grade 3 or 4 astrocytomas, a phase 1 study of a vaccine-targeting IDH1 R132H showed to be well tolerated and demonstrated immunogenicity with a 3-year progression-free and overall survival rates of 0.63 and 0.84, respectively. A variety of ongoing trials aim to target mIDH, including treatments with single agents or combinatory approaches in the upfront or recurrent setting.mIDH are commonly found in gliomas and play a key role in gliomagenesis. This has led to studies using agents to directly inhibit them, immunotherapies, and epigenetic/metabolic drugs with varying and promising results. Ongoing studies may elucidate the precise role of these therapies and the best timing for treatment within the disease course.

Background Neuro-oncology has grown tremendously since 2010, marked by increasing society membership, specialized clinical expertise, and new journals. Yet, modest improvement in racial/ethnic diversity amongst clinical trial participants, researchers, and clinicians led us to conduct a survey to identify opportunities to enhance diversity and inclusiveness amongst neuro-oncology professionals. Methods In summer 2020, the Women and Diversity Committee of the Society for Neuro-Oncology (SNO) distributed an anonymous online survey to members and affiliates including the European Association of Neuro-Oncology (EANO), Asian Society for Neuro-Oncology (ASNO), Society for Neuro-Oncology Latin America (SNOLA) and Society for Neuro-Oncology Sub-Saharan Africa (SNOSSA). The survey captured personal and professional characteristics, biases, effective mentorship qualities, career service metrics, and suggested field/society changes. Results were analyzed by geography, profession, age, racial/ethnic, and sexual identity. Standard descriptive statistics characterized the study population. Results The 386 respondents were predominantly female (58%) with a median age range of 40–49 years (31%), White (65%), and SNO members (97%). Most worked in North America (77%) in a research profession (67%). A majority of White respondents reported never experiencing biases (64%), while the majority of non-White respondents reported unconscious biases/microaggressions, followed by a lack of/limited mentorship. Qualitative assessments showcased that personal/professional success metrics were linked to needed improvements in diversity and inclusion efforts within the neuro-oncology field. Conclusions The prevalence of racial/ethnic biases and poor mentorship rates amongst underrepresented groups in neuro-oncology is high and potentially linked to the limited diverse representation amongst members and affiliates. These findings warrant a swift implementation of equity and inclusion practices within the neuro-oncology field.

Purpose: Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes. Patients and Methods: We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154. Results: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2–40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8–6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients. Conclusions: Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG.

Introduction Burnout refers to a constellation of feelings of exhaustion, depersonalization, and low sense of personal accomplishment that develops secondary to long-term occupational stress. Several studies have identified that health care professionals are a high-risk occupational group for burnout, but knowledge about this syndrome among midwives has not been fully explored. The purpose of this study was to perform a systematic review of the prevalence and levels of burnout among midwives and analyze the related factors. Methods The following databases were searched: CINAHL, LILACS, MEDLINE, ProQuest, PsycINFO, SciELO, and Scopus. Any date of publication was acceptable. Literature from different countries was included. Studies were appraised for quality following the recommendations of the Oxford Centre for Evidence-Based Medicine. Results The literature review identified 27 studies with a total of N = 5612 midwives. The main factors related to burnout were working conditions such as work overload, lack of autonomy, and professional recognition. Midwives who had less than 10 years of experience were more vulnerable to burnout than those who had more than 10 years' experience. With regard to the subcategories of burnout (emotional exhaustion, depersonalization and perceived personal achievement), midwives who did not live with a partner were more vulnerable low levels of personal accomplishment when compared with midwives who were living with a partner. The most significant protective factors against burnout were good leadership and the use of continuity models of care. Discussion Midwives had moderate levels of emotional exhaustion and low levels of personal accomplishment. Working conditions were identified as the main modifiable factors related to burnout syndrome. Intervention programs for midwives should be aimed at reducing emotional exhaustion and enhancing personal accomplishment.

PURPOSE Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 ( IDH1) gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors. METHODS We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with m IDH1 solid tumors. Ivosidenib was administered orally daily in 28-day cycles. RESULTS In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors. CONCLUSION In patients with m IDH1 advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.

Background: The treatment associated with non-Hodgkin lymphoma patients may cause adverse effects on their physical and psychological condition. The aim of this study is to detect the response to an eight-week, 16-session, 60-min presential Qigong program in anxiety, depression and vagal nerve activity alongside a control group. Methods: A randomized controlled clinical trial was managed. Randomization was carried out by generating a numerical sequence of three cycles through the software EPIDAT 4.1. Numbers were placed in sealed opaque envelopes for assignment to the different groups. Results: Anxiety levels were substantially decreased in the experimental group, with a large effect size (F = 30.38, p < 0.00). Depression levels had an improvement in the experimental group in contrast to the control group, reaching statistical significance (F = 19.19, p < 0.00). Heart Rate Variability unveiled significant results in terms of between-group differences, with a large effect size in the HRV Index (F = 15.80, p < 0.00), SDNN (F = 8.82, p < 0.00), and RMSSD (F = 6.72, p < 0.01) in the time domain, and a medium effect size in the HF (F = 9.78, p < 0.003), LF (F = 9.78, p < 0.00), and LF/HF Ratio (F = 18.44, p < 0.00) in the frequency domain, which were all bettered in the experimental group, after the Qigong program. Conclusions: Qigong therapy can be an effective therapeutic activity in consonance with traditional medicine to improve psychological health and autonomic nervous system balance in non-Hodgkin lymphoma survivors., Education Ministry, Madrid, Spanish Government FPU16/01437

Background: GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 Response Adaptive Randomization platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. GBM AGILE is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed and recurrent GBM. Methods: The primary objective of GBM AGILE is to identify therapies that improve the overall survival in patients with newly diagnosed or recurrent GBM. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different pharmaceutical/biotech companies to be evaluated simultaneously and/or over time against a common control. New experimental therapies are added as new information about promising new drugs is identified while other therapies are removed as they complete their evaluation. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. GBM AGILE has screened over 1300 patients and enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/site/month. There are 41 active sites in the US, 4 active sites in Canada and 3 active sites in Europe with 12 more sites anticipated to open across 3 countries in Europe. Expansion to Australia is in progress. Stratification of the newly diagnosed patients is based on methylation status per the MGMT assay provided by a central CLIA lab. Maintaining reasonable timelines for MGMT read out to support eligibility and screening requires ongoing operational oversight. In order to continue to improve MGMT testing times, the percentage discordance between results from central testing and local lab testing is being evaluated to assess if local lab testing can be utilized for randomization within GBM AGILE. Exploratory analyses are ongoing to expand knowledge of GBM. For example, information from imaging and clinical assessments will be used to build a longitudinal model, which may inform randomization by providing earlier and continuous information regarding how a given experimental arm is performing. Citation Format: Ingo K. Mellinghoff, Brian Alexander, Donald Berry, Nicholas Blondin, Meredith Buxton, Webster Cavenee, Howard Colman, John de Groot, Macarena I. de la Fuente, Benjamin Ellingson, Gary Gordon, Emma M.V. Hyddmark, Mustafa Khasraw, Andrew Lassman, Eudocia Lee, Wenbin Li, Michael Lim, Tom Mikkelsen, Apoorva Nelli, James Perry, Erik Sulman, Kirk Tanner, Michael Weller, Patrick Y. Wen, Timothy Cloughesy. GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT062.

Intro. Glioblastoma is the most common and aggressive adult brain cancer, with a 5-year survival of less than 15%. Treatment decisions are guided by imaging, which at early timepoints cannot distinguish tumor pseudoprogression from non-response. Our work seeks to identify circulating biomarkers that can classify response as an alternative or adjunct to imaging. Here we present preliminary data exploring the potential of circulating cytokines and tumor cells collected before, during, and after treatment with the goal to identify potential makers for treatment adaptation. Methods. After consent, patient blood was collected the week before initiating chemoradiotherapy, weekly during treatment, and three weeks after treatment. Serum was tested by multiplex bead-based immunoassay (Legendplex Human Inflammation Panel 1, Biolegend inc.) targeting 13 cytokines and ELISA targeting soluble Human GFAP (Glial fibrillary acidic protein) (Biovendor R&D). The Circulogix filtration system was also used to capture cells of size consistent with circulating tumor cells (CTCs). Initial efforts focused on cells co-staining for GFAP and Olig2 and negative for CD45 (hematopoietic marker). All patient tumor specimens and cell lines were verified for GFAP and Olig2 expression by IHC. We selected 13 patients for the current analysis: 5 with growth due to non-response (NR), 6 stable disease (S) and two pseudo progression (PP). These classifications were evaluated radiologically at the first follow up after chemoradiotherapy (S or no) and based on whether changes observed stabilized or resolved spontaneously within six months or continued to progress (NR or PP). Results. The immunoassays detected approximately 70% of the analytes in our samples. Among those, IL10 and IL33 were higher before treatment on patients later determined to have stable disease (IL10 p=0.09; IL33 p=0.043 KW test; IL10 median S=22.93 ng/mL, NR=13.415ng/mL; IL33 median S= 164.10ng/mL, NR=55.57ng/mL). Interestingly, IL33 is reduced on stable patients during week 5 of treatment (PRE vs. W5 p=0.033; median PRE=164.1ng/mL, W5=57.57ng/mL). GFAP presented a slightly lower level after treatment in stable patients (S vs. NR p=0.014; median S=0.441 ng/ml, NR=0.473 ng/ml). As proof of concept, 50 GBM cells from each of U87 adherent cells, or 0913 and 0821 neurosphere cells (CD45 negative) glioblastoma cell lines were mixed in separate vials with 106 hematopoietic cells (RAJI; CD45 positive) and filtered per the procedure to identify CTCs in patient blood. We separated GBM cells from hematopoietic cells on the filtration system. Conclusion. Our preliminary data suggest that blood obtained during chemoradiotherapy can identify biomarkers associated with response. For example, IL10, IL33, GFAP, and CTCs might be used to classify treatment response at very early timepoints. We continue to recruit additional patients for additional analyses. Citation Format: Paulo Roberto Del Valle, Jonathan B. Bell, Scott M. Welford, Kaylie Kullison, Alessandro Valderrama, Gregory A. Azzam, Jessica J. Meshman, Macarena I. De La Fuente, Eric A. Mellon. Preliminary analysis of circulating biomarkers of glioblastoma response during chemoradiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2162.

Aims: The aims of this study are to analyse the prevalence and levels of burnout syndrome in nurse managers and to evaluate the relationship between burnout and related sociodemographic, occupational and psychological factors. Background: Burnout syndrome, defined as an emotional response to chronic stress, is a major problem among nurse managers. Methods: The study was conducted using a cross-sectional survey design and data collected by the Maslach Burnout Inventory, the revised NEO Five Factor Inventory and the Educational-Clinical Questionnaire for Anxiety and Depression. The sample population consisted of 86 nurse managers from different hospitals from the Public Health Service of Andalusia, Spain. Results: A total of 22.4% of the participants presented high levels of emotional exhaustion, 21% experienced depersonalisation and 57.6% had little sense of personal accomplishment. Working long shifts was related to burnout. Emotional exhaustion and depersonalization were predicted by depression, while personal accomplishment was predicted by conscientiousness, agreeableness and openness. Conclusions: A total of 34.1% of the participants presented high levels of burnout, manifested by feelings of low personal accomplishment. Psychological and occupational factors play an important role in the development of this syndrome. Implications for Nursing Management: Nurse managers should seek to detect burnout among staff and colleagues matching the risk profile for this condition and promote interventions to prevent it.

Olutasidenib (FT2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1 R132X mutation.This was an open-label, multicenter, non-randomized, phase 1b/2 clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1 R132Xmutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase 1 and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase 2.Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase 2 dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each).Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1 R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population.

Fanconi anemia is primarily inherited as an autosomal recessive genetic disorder with common delays in diagnosis and challenging treatments. Fanconi anemia patients have a high risk of developing solid tumors, particularly in the head and neck or anogenital regions. The diagnosis of Fanconi anemia is primarily based on the chromosomal breakage but FA gene sequencing is recommended in all patients with a positive chromosome fragility test. Here, we present a 32-year-old man with advanced tonsil squamous cell carcinoma and fatal toxicity after the first cycle of chemotherapy. No anemia was present. A recent variant mutation if the FANCM gene was detected (c1511_1515delGAGTA (pArg504AsnfsTer29)). Homozygous or double heterozygous pathogenic variants have been reported in FANCM and linked to azoospermia and primary ovarian failure without anemia. Alterations in this gene have also been associated with a genetic predisposition for solid tumors (breast and ovarian cancer) and hematological malignancies (B-cell acute lymphoblastic leukemia). Due to the hypersensitivity of these patients to DNA-damaging agents such as chemotherapy and radiotherapy, surgery is the best treatment option for malignant solid tumors. Dose reductions or alternative regimens of chemotherapy and/or radiotherapy are recommended in FA patients who develop a malignant tumor.

Background The usefulness of therapeutic drug monitoring(TDM) of infliximab during induction and its relationship with clinical outcome in patients with inflammatory bowel disease(IBD) is well established. However, the optimal time of monitoring in terms of clinical outcomes remains unclear. The aim is to evaluate the TDM at various times during induction and its association with clinical remission. Methods An observational, retrospective and single-centre study of patients with active disease ,Crohn’s disease (CD) or ulcerative colitis(UC), was performed. Induction treatment with infliximab 0, 2, 6 weeks was conducted and if there was response, maintenance therapy was provided. Antibody levels were measured in serum samples at week 2 and week 14 by using an enzyme-linked immunosorbent assay, within the therapeutic range(3-8 µg/ml). Patients were followed at least for one year or until loss of response. The clinical response was assessed in week 14 and week 52 by Harvey-Bradshaw Index in CD and Mayo Partial Index in UC. Results Out of 93 patients that were evaluated, 23 with UC(24.73%) and 70 with CD(75.27%,), 65 (69.89%) and 58 patients(62.37%) achieved remission at week 14 and week 52 respectively. Infliximab levels at week 14 but not at week 2 were significantly higher in patients who achieved clinical remission in both week 14 (5.8 vs 2.1 µg/ml; p=0.0002) as in week 52 (6.4 vs 1.9 µg/ml; p=0.0001). The levels at week 14, but not at week 2 had predictive value of remission, in both week 14 [OR 1,4 (CI 1.14-1.76) p=0.001] and week 52 [OR 1.4 (CI 1.15-1.87); p=0.001]. The patients with immunosuppressants at week 14 presented the highest rate of remission in week 52 (77.78 vs 52.63; p=0.014). The intensification of treatment was a negative factor to achieve remission both in week 14 and at week 52. Conclusion The levels of infliximab in week 14 are higher and have predictive value of clinical remission both in early (week 14) and long-term (week 52). Levels of infliximab in week 2 did not provide significant predictive value of clinical response. The use of immunosuppressants could be a favourable factor of clinical outcome.

To analyse the effect of mindfulness training on levels of burnout among nurses.Burnout syndrome is a common occupational hazard for nursing staff. Mindfulness training has been proposed as a valid intervention for burnout.Systematic review and meta-analysis.The CINAHL, LILACS, Medline, ProQuest, PsycINFO, Scielo and Scopus databases were consulted, using the search equation 'Nurs * AND burnout AND mindfulness'. There was no restriction on the year of publication.Papers were selected for analysis in accordance with the PRISMA guidelines. The meta-analysis was carried out using Review Manager 5.3 software.The sample was of 17 articles including 632 nurses. Mindfulness training reduces levels of burnout, producing lower scores for emotional exhaustion and depersonalization and higher for personal accomplishment. The differences in the means were 1.32 (95% CI: -9.41-6.78), 1.91 (95% CI: -4.50-0.68) and 2.12 (95% CI: -9.91-14.14), respectively, between the intervention and control groups.Mindfulness training reduces the emotional burden and hence levels of burnout, among nurses. However, further randomized clinical trials are required.目的: 分析正念训练对护士职业倦怠程度的影响。 背景: 倦怠综合征对护理人员来说是一种常见的职业危害。而正念训练被认为是一种有效的职业倦怠干预措施。 设计: 系统评估与荟萃分析。 数据来源: 通过使用搜索方程‘Nurs*和倦怠与正念’在CINAHL、LILACS、Medline、ProQuest、Psychinfo、Scielo和Scopus数据库中进行检索(不限制文献出版年份)。 评估方法: 根据PRISMA指南选择论文进行分析。使用Review Manager 5.3软件进行荟萃分析。 结果: 共选取17篇文献,包括632名护士。结果显示,正念训练可降低职业倦怠程度,而情绪衰竭和人格解体得分较低,个人成就感得分较高。干预组和对照组之间的平均值差异分别为1.32(95%CI:-9.41-6.78)、1.91(95%CI:-4.50-0.68)和2.12(95%CI:-9.91-14.14)。 结论: 正念训练可减轻护士的情绪负担,从而降低其职业倦怠程度。然而,还需开展进一步的随机临床试验进行验证。.

HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. Significance: HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer. This article is highlighted in the In This Issue feature, p. 161

Neurological emergencies are frequently catastrophic events in the course of haematological malignancies (HM) that, if not promptly recognized and treated, may lead to lethal outcomes or chronic sequelae. They may occur at any time during the disease course, but are more frequently observed following relapse. Practice guidelines are lacking in the management of most central nervous system (CNS) complications in HM. Herein we review the pathophysiology, presentation and treatment of elevated intracranial pressure, spinal cord compression, status epilepticus, neurovascular complications, CNS infection, leucostasis and hyperviscosity. Further, we discuss the expanding spectrum of neurological complications of old and novel treatments in HM.

Among the types of blood cancers, non-Hodgkin lymphoma is the most common. The usual treatments for this type of cancer can cause heart failure. A descriptive observational study was conducted that included 16 non-Hodgkin lymphoma survivors and 16 healthy controls matched by age and sex. Vagal tone was evaluated in the short term with a three-channel Holter device, and the time and frequency domains were analyzed following a previously accepted methodology to evaluate cardiac autonomic balance. The results of the analysis revealed that the standard deviation of the NN interval (F = 6.25, p = 0.021) and the square root of the mean of the sum of the differences between NN intervals (F = 9.74, p = 0.004) were significantly higher in healthy subjects than in lymphoma survivors. In the heart rate variability (HRV) index, there were no significant differences between the groups (F = 0.03, p = 0.85), nor in the parameters of the frequency domains LF (F = 1.94, p = 0.17), HF (F = 0.35, p = 0.55), and the ratio LF/HF (F = 3.07, p = 0.09). HRV values were lower in non-Hodgkin lymphoma survivors in the first year after treatment, resulting in autonomic imbalance compared to healthy paired subjects., Education Ministry (Program FPU16/01437), Madrid, Spanish Government

Background For patients with recurrent glioblastoma (rGBM), there are few options following treatment failure with radiotherapy plus temozolomide. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 antibody blocking PD-L1. Methods In this phase I, open-label expansion cohort (NCT02517398), patients with rGBM that progressed after radiotherapy plus temozolomide received bintrafusp alfa 1200 mg Q2W until disease progression, unacceptable toxicity, or trial withdrawal. Response was assessed per RANO criteria. The primary endpoint was disease control rate (DCR); secondary endpoints included safety. Results As of August 24, 2018, 35 patients received bintrafusp alfa for a median of 1.8 (range, 0.5–20.7) months. Eight patients (22.9%) experienced disease control as assessed by an independent review committee: 2 had a partial response, 4 had stable disease, and 2 had non-complete response/non-progressive disease. Median progression-free survival (PFS) was 1.4 (95% confidence interval [CI], 1.2–1.6) months; 6- and 12-month PFS rates were 15.1% and 11.3%, respectively. Median overall survival (OS) was 5.3 (95% CI, 2.6–9.4) months; 6- and 12-month OS rates were 44.5% and 30.8%, respectively. The DCR (95% CI) was 66.7% (22.3–95.7%) for patients with IDH-mutant GBM (n = 6) and 13.8% (3.9–31.7%) for patients with IDH–wild-type GBM (n = 29). Disease control was seen regardless of PD-L1 expression. Twenty-five patients (71.4%) experienced treatment-related adverse events (grade ≥3; 17.1% [n = 6]). Conclusions The percentage of patients achieving disease control and the manageable safety profile may warrant further investigation of bintrafusp alfa in GBM.

2000 Background: Craniopharyngiomas, a rare brain tumor along the pituitary-hypothalamic axis, can cause significant clinical sequelae. Surgery and radiation, the only effective treatments, can cause significant morbidity. Genetic analysis of craniopharyngiomas revealed that 95% of papillary craniopharyngiomas (PCP) have BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). We evaluated the efficacy of BRAF/MEK inhibition in patients (pts) with previously untreated PCP. Methods: Eligible pts without prior radiation whose PCP screened positively for BRAF mutations were treated with oral vemurafenib/cobimetinib in 28-day cycles. The primary endpoint of response rate (RR) based on centrally determined volumetric data was evaluated in 16 pts, where a partial response was defined as >20% decrease in volume. This single arm, Simon two-stage phase 2 trial had 89% power to detect a true RR of at least 30% (vs. the null RR 5%; alpha=0.04). In this design, 3 or more observed volumetric responses in 16 evaluable pts would be considered promising activity. Results: In the 16 pts evaluated, 56% were female, and the median age was 49.5 years. Median follow-up was 22 months (95% CI: 16-26.5) and median number of treatment cycles was 8. Three patients progressed after therapy was discontinued and none have died. Based on volumetric response criteria, 14 of 15 pts with volumetric data available for central review had response to therapy (93%; 95% CI: 68% to 99.8%). Of 16 patients evaluable based on local review, 15 had response to therapy (93.75%; 95% CI: 70% to 99.8%). The median tumor reduction was -83% (range: -52% to -99%). The one nonresponder received 2 days of treatment before coming off therapy due to toxicity. Median progression-free survival was not reached. Grade 3 toxicities at least possibly related to treatment occurred in 12 pts (rash in 6 pts). Grade 4 toxicities were observed in two pts: hyperglycemia (n=1) and increased CPK (n=1). Three pts discontinued treatment for adverse events. Conclusions: Vemurafenib/cobimetinib resulted in an objective response in all pts who received 1 or more cycles of therapy. Our study indicates that BRAF/MEK inhibitors could be a powerful tool in the treatment of previously untreated PCP and warrants further evaluation in larger studies. A second arm of this study is enrolling pts with progressive PCP after prior radiotherapy. Support: U10CA180821, U10CA180882; U24CA196171, U10CA180868 (NRG); Genentech; https://acknowledgments.alliancefound.org. Clinical trial information: NCT03224767.

This study received funding from the Junta deAndalucia Excellence project (no. P11HUM-7771)., Data Availability Statement: The data presented in this study are available on request from the corresponding author. The data are not publicly available due to ethical., This article forms part of the Doctoral Thesis of the corresponding author (Laura Pradas-Hernández) within the Psychology doctoral program offered at the University of Granada (Spain)., Background: Burnout syndrome is an increasingly prevalent problem, characterised by emotional exhaustion (EE), depersonalization (D), and low personal accomplishment (PA), feelings that appear with prolonged exposure to stress-inducing situations. The syndrome alters physical well-being and endangers the quality of services provided. Among nurses working in the paediatric area, the association between burnout and the corresponding risk profile has received little research attention, despite the highly stressful nature of this work. Materials and Methods: The study population was composed of 95 nurses working in four hospitals in the province of Granada. Data were collected using the Maslach Burnout Inventory, the NEO Personality Inventory, and the Educational-Clinical Questionnaire: Anxiety and Depression. Results: According to the results obtained, 22.0% of the nurses working in the paediatric area present high levels of EE, 18.5% present high levels of D, and 39.6% had feelings of low PA. These burnout levels do not depend on sociodemographic or labour variables, but the three domains of the syndrome are related to the psychological factors analysed. Conclusions: Among the nurses who participated in this study, 38.6% presented high levels of burnout, especially regarding feelings of low personal accomplishment. Personality factors play an important role in the development of this syndrome. This study shows the impact of burnout in paediatric nurses as well as the risk factors, providing information for the development of strategies to prevent it., Junta de Andalucia P11HUM-7771

The rapid evolving knowledge of glioblastoma molecular biomarkers and their association to prognosis and treatment calls for clinicians to keep abreast of the latest literature on the recommendations that have an impact on clinical practice. The presence or absence of IDH mutations and MGMT methylation continue to be essential molecular markers that indicate prognosis and response to treatment. New emerging data on the presence of other alterations such as TERT promoter mutation, EGFR amplification, and/or the combination of gain of entire chromosome 7 and loss of entire chromosome 10 (+7/−10) in the case of IDH-wildtype astrocytomas and the presence of CDKN2A/B in IDH-mutant astrocytomas have become significant as these mutations are associated with more aggressive tumor behavior. Other mutations such as EGFRvIII expression, FGFR-TACC gene fusions, PTEN deletion, PDGFRA and BRAF V 600E have elucidated important pathways for targeted therapies and aid in prognosis assessment.

Background: Caring for a loved one can be rewarding but is also associated with substantial caregiver burden, developing mental outcomes and affecting happiness. The aim of this study was to determine the effects of a four-week, 16-h presential meditation program on physiological and psychological parameters and vagal nerve activity in high-burden caregivers, as compared to a control group. Methods: A non-randomized repeated-measures controlled clinical trial was conducted. Results: According to the ANCOVA results, the global happiness score (F = 297.42, p &lt, 0.001) and the scores for all subscales were significantly higher in the experimental group than in the control group at 5 weeks. Anxiety levels were also significantly reduced in the experimental group (F = 24.92, p &lt, 0.001), systolic (F = 16.23, p &lt, 0.001) and diastolic blood (F = 34.39, p &lt, 0.001) pressures, and the resting heart rate (F = 17.90, p &lt, 0.05). HRV results revealed significant between-group differences in the HRV Index (F = 8.40, p &lt, 0.05), SDNN (F = 13.59, p &lt, 0.05), and RMSSD (F = 10.72, p &lt, 0.05) in the time domain, and HF (F = 4.82 p &lt, 0.05)) in the frequency domain, which were all improved in the experimental group after the meditation program. Conclusions: Meditation can be a useful therapy to enhance the mental health and autonomic nervous system balance of informal caregivers, improving symptoms of physical and mental overload.

Background For patients with recurrent glioblastoma (rGBM), there are few options following treatment failure with radiotherapy plus temozolomide. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 antibody blocking PD-L1. Methods In this phase I, open-label expansion cohort (NCT02517398), patients with rGBM that progressed after radiotherapy plus temozolomide received bintrafusp alfa 1200 mg Q2W until disease progression, unacceptable toxicity, or trial withdrawal. Response was assessed per RANO criteria. The primary endpoint was disease control rate (DCR); secondary endpoints included safety. Results As of August 24, 2018, 35 patients received bintrafusp alfa for a median of 1.8 (range, 0.5–20.7) months. Eight patients (22.9%) experienced disease control as assessed by an independent review committee: 2 had a partial response, 4 had stable disease, and 2 had non-complete response/non-progressive disease. Median progression-free survival (PFS) was 1.4 (95% confidence interval [CI], 1.2–1.6) months; 6- and 12-month PFS rates were 15.1% and 11.3%, respectively. Median overall survival (OS) was 5.3 (95% CI, 2.6–9.4) months; 6- and 12-month OS rates were 44.5% and 30.8%, respectively. The DCR (95% CI) was 66.7% (22.3–95.7%) for patients with IDH-mutant GBM (n = 6) and 13.8% (3.9–31.7%) for patients with IDH–wild-type GBM (n = 29). Disease control was seen regardless of PD-L1 expression. Twenty-five patients (71.4%) experienced treatment-related adverse events (grade ≥3; 17.1% [n = 6]). Conclusions The percentage of patients achieving disease control and the manageable safety profile may warrant further investigation of bintrafusp alfa in GBM.

BACKGROUND Novel T cell-enabling therapies, in combination with checkpoint inhibition, may improve OS in GBM. INO-5401 (synthetic DNA plasmids encoding hTERT, WT-1, PSMA) plus INO-9012 (synthetic DNA plasmid encoding IL-12), and the PD-1 immune checkpoint inhibitor cemiplimab, is given to patients with newly diagnosed GBM to evaluate tolerability, efficacy and immunogenicity. METHODS Phase I/II, single arm, 2 cohort study (A: MGMT unmethylated, B: MGMT methylated). Primary endpoint is safety; efficacy and immunogenicity are secondary. Nine mg INO-5401 plus 1 mg INO-9012 (every 3 weeks x 4 doses, then Q9W) is given IM with EP by CELLECTRA® 2000 with cemiplimab (350 mg IV Q3W). RT is given as 40 Gy over 3 weeks. TMZ is given with radiation (all patients), and adjuvantly (Cohort B only). RESULTS Fifty-two subjects enrolled: 32 in Cohort A; 20 in Cohort B. 35% women; median age 60 years (19–78 years). The adverse event profile is consistent with single-agent (INO-5401, INO-9012, EP and cemiplimab) reported events. OS at 12 months was 84.4% (Cohort A) and 85% (Cohort B). OS at 18 months in Cohort A is 50% (95% CI 31.9 - 68.1); median OS is 17.9 months (14.5 - NR); Cohort B OS18 and median OS will be presented. Tumor gene transcripts at diagnosis confirmed expression of INO-5401 antigens. Peripheral immune responses following INO-5401 revealed antigen-specific T cell responses by Interferon gamma ELISpot and flow cytometry, including cytokine production and expansion of antigen specific CD8+T cells with lytic potential. CONCLUSIONS INO-5401 + INO-9012, a novel DNA plasmid immunotherapy, demonstrates acceptable risk/benefit and generates robust systemic immune responses to encoded tumor antigens when administered with cemiplimab and RT/TMZ in newly diagnosed GBM patients. Overall survival is encouraging. Clinical trial information: NCT03491683.

PURPOSE: Extent of resection remains a paramount prognostic factor for long-term outcomes for glioblastoma. As such, supramaximal resection or anatomic lobectomy have been offered for non-eloquent glioblastoma in an attempt to improve overall survival. Here, we conduct a propensity-matched analysis of patients with non-eloquent glioblastoma who underwent either lobectomy or gross total resection of lesion to investigate the efficacy of supramaximal resection of glioblastoma. METHODS: Patients who underwent initial surgery for gross total resection or lobectomy for non-eloquent glioblastoma at our tertiary care referral center from 2010-2019 were included for this propensity-matched survival analysis. Propensity scores were generated with the following covariates: age, location, preoperative KPS, product of perpendicular maximal tumor diameters, and product of perpendicular FLAIR signal diameters. Inverse probability of treatment weighting (IPTW) with generated propensity scores was used to compare progression-free survival and overall survival. RESULTS: Sixty-nine patients were identified who underwent initial resection of glioblastoma for non-eloquent glioblastoma from 2010-2019 (GTR=37, lobectomy=32). Using IPTW, overall survival (30.7 vs. 14.1 months) and progression-free survival (17.2 vs. 8.1 months were significantly higher in the lobectomy cohort compared to the GTR group (p