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ONC201 (dordaviprone), an oral, blood-brain barrier penetrant, small molecule ClpP agonist and DRD2 antagonist, has demonstrated efficacy in patients with recurrent H3 K27M-mutant diffuse midline glioma (DMG). This analysis evaluated the efficacy of ONC201 in these patients by front-line radiotherapy (RT). This analysis was conducted as part of an integrated analysis of five previously conducted studies of single-agent ONC201; primary outcomes, including safety endpoints, were previously reported (Arrillaga-Romany, et al, 2024, JCO). Eligible patients had measurable H3 K27M-mutant DMG by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria, performance score ≥60, and were ≥90 days from radiation. Pontine and spinal tumors were not eligible. The first 50 eligible patients were evaluated. Radiographic endpoints were assessed by dual-reader, blinded independent central review. Among patients with RT dose reported (84%, 42/50), most patients received 54-60 Gy (92.8%, 39/42); two patients received <54 Gy and one received >60 Gy. Most patients received RT with concurrent chemotherapy or targeted therapy followed by adjuvant (CRT+Adj, 70.0%, 35/50). Other regimens included RT with concurrent chemotherapy or targeted therapy without adjuvant (CRT, 16%, 8/50), RT followed by adjuvant (RT+Adj, 8%, 4/50), and RT alone (6%, 3/50) Of these, pediatric patients (age <18 years, n = 4) received CRT+Adj (n = 1), RT+Adj (n = 1), or RT alone (n = 2). The majority of patients administered CRT and/or Adj had received temozolomide (91.2%, 43/47). Among 10 patients with radiographic responses by RANO-HGG criteria, seven had received between 54-60 Gy of RT and two received <50 Gy; one responder did not have RT dose reported. By regimen, seven responders had received CRT+Adj, two had received CRT, and one had received RT+Adj. One responder previously treated with RT+Adj had received proton therapy. ONC201 was well tolerated with treatment-related treatment-emergent adverse events (TR-TEAEs) occurring in 20% of patients, the most common of which was fatigue (n = 5; 10%). No grade 4 TR-TEAEs, deaths, or discontinuations occurred. Radiographic responses to ONC201 in patients with H3 K27M-mutant DMG were observed irrespective of prior standard RT dosing modality. Additionally, responses to ONC201 were observed both in patients receiving prior photon and proton radiation therapy. The phase 3 ACTION trial (NCT05580562) is currently evaluating ONC201 in newly diagnosed H3 K27M-mutant diffuse glioma following standard front-line RT. [ABSTRACT FROM AUTHOR]

A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification., Competing Interests: Declaration of interests M.L.S. is equity holders, scientific co-founder and advisory board member of Immunitas Therapeutics. I.T. is advisory board member of Immunitas Therapeutics. D.P.C. has consulted for Lilly, Incephalo, Boston Pharmaceuticals, Servier, Boston Scientific and Pyramid Biosciences (equity interest), and has received honoraria and travel reimbursement from Merck for invited lectures. J.J.M. received consulting fees from Servier. The authors declare that such activities have no relationship to the present study. M.T. reports consulting or advisory role for Servier, Novocure, Resilience, Agios Pharmaceutical, Integragen, and Taiho Oncology, honoraria for Ono, and research funding from Sanofi. P.Y.W. reports research support from Astra Zeneca, Black Diamond, Bristol Meyers Squibb, Chimerix, Eli Lily, Erasca, Global Coalition For Adaptive Research, Kazia, MediciNova, Merck, Novartis, Quadriga, Servier, VBI Vaccines and consulting or advisory role for Anheart, Astra Zeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, Glaxo Smith Kline, Kintara, Merck, Mundipharma, Novartis, Novocure, Prelude Therapeutics, Sagimet, Sapience, Servier, Symbio, Tango, Telix, VBI Vaccines. K.L.L is equity holder, consultant, and co-founder of Travera, is a consultant for BMS, Blaze Biosciences and Integragen, and has grant research funding through DFCI from BMS and Lilly. L.N.G.C. has received research support from Merck & Co, and consulting fees from BMJ Best Practice and Oakstone Publishing., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: H3 K27M-mutant diffuse glioma primarily affects children and young adults, is associated with a poor prognosis, and no effective systemic therapy is currently available. ONC201 (dordaviprone) has previously demonstrated efficacy in patients with recurrent disease. This phase 3 trial evaluates ONC201 in patients with newly diagnosed H3 K27M-mutant glioma., Methods: ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international phase 3 study of ONC201 in newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy are randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on 2 consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS); PFS is assessed by response assessment in neuro-oncology high-grade glioma criteria (RANO-HGG) by blind independent central review. Secondary objectives include safety, additional efficacy endpoints, clinical benefit, and quality of life. Eligible patients have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility is not restricted by age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in multiple international sites., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Diffuse midline glioma, H3 K27-altered (H3 K27M-altered DMG) are invariably lethal, disproportionately affecting the young and without effective treatment besides radiotherapy. The 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumors Classification defined H3 K27M mutations as pathognomonic but restricted diagnosis to diffuse gliomas involving midline structures by 2018. Dordaviprone (ONC201) is an oral investigational small molecule, DRD2 antagonist, and ClpP agonist associated with durable responses in recurrent H3 K27M-mutant DMG. Activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas has not been reported., Methods: Patients with recurrent non-midline H3 K27M-mutant diffuse gliomas treated with ONC201 were enrolled in 5 trials. Eligibility included measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma, Karnofsky/Lansky performance score ≥60, and ≥90 days from radiation. The primary endpoint was overall response rate (ORR)., Results: Five patients with cerebral gliomas (3 frontal, 1 temporal, and 1 parietal) met inclusion. One complete and one partial response were reported by investigators. Blinded independent central review confirmed ORR by RANO criteria for 2, however, 1 deemed nonmeasurable and another stable. A responding patient also noted improved mobility and alertness., Conclusions: H3 K27M-mutant diffuse gliomas occasionally occur in non-midline cerebrum. ONC201 exhibits activity in H3 K27M-mutant gliomas irrespective of CNS location., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Purpose: Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG., Methods: Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review., Results: The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred., Conclusion: ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.

Purpose: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design., Patients and Methods: Patients with newly diagnosed O 6 -methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780)., Results: Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit ( P > .05)., Conclusion: The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.

Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction., Significance: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Planar and single-photon emission computed tomography (SPECT) nuclear imaging techniques with bone seeking radiotracers have been increasingly adopted for diagnosis of ATTR cardiac amyloidosis. However, inherent limitations of these techniques due to lack of anatomical landmarks have been recognized, with consequent high numbers of equivocal or false positive cases. SPECT/computed tomography (CT) fusion imaging offers a significant advantage to overcome these limitations by substantially reducing inaccurate interpretations. The authors present the results of a 3-year imaging quality improvement project that focused on reducing the high number of equivocal studies that were noted in the first two years of the amyloidosis program, comparing SPECT only to SPECT/CT fusion technique., Methods: A retrospective, systematic analysis of 176 patient records was performed to test the premise that SPECT/CT fusion imaging has the potential to reduce equivocal and false positive results., Results: Of a total of 176 patients, 35 equivocal (19.8%), 32 (18.18%) strongly suggestive, and 109 (61.93%) not suggestive cases were identified. Recognizing that this was not consistent with the international data, the authors set out on a comprehensive quality assessment project to reduce the number of equivocal and false positive cases. In patients who initially underwent SPECT only (Group A; n = 78), the addition of SPECT/CT fusion resulted in the net reclassification of 73% of cases: 100% of equivocal cases (n = 35) were reclassified to not suggestive (n = 34) or strongly suggestive (n = 1). 73% of strongly suggestive cases (n = 30) were reclassified to not suggestive (n = 22) while 8 strongly suggestive cases were confirmed as true positives. 13 not suggestive cases remained negative after SPECT/CT fusion. In cases where SPECT/CT fusion was utilized from the beginning (Group B; n = 98), there were no reclassification of any of the cases when these cases were reprocessed as a control group., Conclusion: Addition of SPECT/CT imaging reduces the false positive or equivocal studies and increases the diagnostic accuracy of the test. All false positive and equivocal studies were eliminated using the fusion technique. Utilizing the fusion imaging technique increases the spatial resolution, with the ability to localize myocardial uptake and accurately differentiate from blood pool, which is a major source of error., (© 2023. The Author(s).)

Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of 'proneural' and 'stemness' gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Medulloblastoma (MB) is a rare central nervous system malignancy of adults, with limited contemporary studies to define treatment guidelines and expected late toxicity., Methods: A single-center, retrospective study was conducted of patients age ≥18 years from 1997-2019 with MB and who were treated with postoperative radiotherapy. Late toxicity was defined as a minimum of 18 months from diagnosis. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analyses., Results: Fifty-nine patients met criteria, with median age of 25 years (range 18-62 y) and median follow-up of 6.5 years (range 0.7-23.1 y). At diagnosis, 68% were standard-risk, 88% Chang M0, and 22% with anaplastic histology. Gross total resection was achieved in 75%; median craniospinal irradiation dose was 30.6 Gy (relative biological effectiveness [RBE]), median total dose was 54.0 Gy (RBE), 80% received proton radiotherapy; 81% received chemotherapy. 5 year PFS and OS were 86.5% and 95.8%, respectively; 10 year PFS and OS were 83.9% and 90.7%, respectively. Anaplastic histology was associated with worse PFS (P = .04). Among eight recurrences, 25% presented after 5 years. Most common grade ≥2 late toxicities were anxiety/depressive symptoms (30%), motor dysfunction (25%), and ototoxicity (22%). Higher posterior fossa radiation dose was associated with increased risk of late toxicity, including worse cognitive dysfunction (P = .05)., Conclusions: Adults with MB have favorable survival outcomes, but late failures and toxicity are not uncommon. Better understanding of prognostic factors, possibly from molecular subtyping, may help to define more personalized treatments for patients with high risk of recurrence and long-term treatment sequelae., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels of maturation dependent on location. We reveal a previously underappreciated relationship between mesenchymal cancer cell states and age, linked to age-dependent differences in the immune microenvironment. Further, we resolve the spatial organization of H3-K27M DMG cell populations and identify a mitotic oligodendroglial-lineage niche. Collectively, our study provides a powerful framework for rational modeling and therapeutic interventions., (© 2022. The Author(s).)

We define cancer equity as all people having as the same opportunity for cancer prevention, treatment, and survivorship care. However, marginalized populations continue to experience avoidable and unjust disparities in cancer care, access to clinical trials, and cancer survival. Racial and ethnic minorities, and individuals with low socioeconomic status, Medicaid insurance, limited health literacy, disabilities, and mental health disorders are more likely to experience delays to cancer diagnosis and less likely to receive guideline-concordant cancer care. These disparities are impacted by the social determinants of health including structural discrimination, racism, poverty, and inequities in access to healthcare and clinical trials. There is an urgent need to develop and adapt evidence-based interventions in collaboration with community partners that have potential to address the social determinants of health and build capacity for cancer care for underserved populations. We established the Virtual Equity Hub by developing a collaborative network connecting a comprehensive cancer center, academic safety net hospital, and community health centers and affiliates. The Virtual Equity Hub utilizes a virtual tumor board, an evidence-based approach that increases access to multi-specialty cancer care and oncology subspecialty expertise. We adapted the tumor board model by engaging person-centered teams of multi-disciplinary specialists across health systems, addressing the social determinants of health, and applying community-based research principles with a focus on populations with poor cancer survival. The virtual tumor board included monthly videoconferences, case discussion, sharing of expertise, and a focus on addressing barriers to care and trial participation. Specifically, we piloted virtual tumor boards for breast oncology, neuro-oncology, and individuals with cancer and serious mental illness. The Virtual Equity Hub demonstrated promise at building capacity for clinicians to care for patients with complex needs and addressing barriers to care. Research is needed to measure the impact, reach, and sustainability of virtual equity models for patients with cancer., (© The Author(s) 2022. Published by Oxford University Press.)

Background Patients with recurrent glioblastoma (GBM) are often treated with antiangiogenic agents, such as bevacizumab (BEV). Despite therapeutic promise, conventional MRI methods fail to help determine which patients may not benefit from this treatment. Purpose To use MR spectroscopic imaging (MRSI) with intermediate and short echo time to measure corrected myo-inositol (mI)normalized by contralateral creatine (hereafter, mI/c-Cr) in participants with recurrent GBM treated with BEV and to investigate whether such measurements can help predict survivorship before BEV initiation (baseline) and at 1 day, 4 weeks, and 8 weeks thereafter. Materials and Methods In this prospective longitudinal study (2016-2020), spectroscopic data on mI-a glial marker and osmoregulator within the brain-normalized by contralateral creatine in the intratumoral, contralateral, and peritumoral volumes of patients with recurrent GBM were evaluated. Area under the receiver operating characteristic curve (AUC) was calculated for all volumes at baseline and 1 day, 4 weeks, and 8 weeks after treatment to determine the ability of mI/c-Cr to help predict survivorship. Results Twenty-one participants (median age ± standard deviation, 62 years ± 12; 15 men) were evaluated. Lower mI/c-Cr in the tumor before and during BEV treatment was predictive of poor survivorship, with receiver operating characteristic analyses showing an AUC of 0.75 at baseline, 0.87 at 1 day after treatment, and 1 at 8 weeks after. A similar result was observed in contralateral normal-appearing tissue and the peritumoral volume, with shorter-term survivors having lower levels of mI/c-Cr. In the contralateral volume, a lower ratio of mI to creatine (hereafter, mI/Cr) predicted shorter-term survival at baseline and all other time points. Within the peritumoral volume, lower mI/c-Cr levels were predictive of shorter-term survival at baseline (AUC, 0.80), at 1 day after treatment (AUC, 0.93), and at 4 weeks after treatment (AUC, 0.68). Conclusion Lower levels of myo-inositol normalized by contralateral creatine within intratumoral, contralateral, and peritumoral volumes were predictive of poor survivorship and antiangiogenic treatment failure as early as before bevacizumab treatment. Adapting MR spectroscopic imaging alongside conventional MRI modalities conveys critical information regarding the biologic characteristics of tumors to help better treat individuals with recurrent glioblastoma. Clinical trial registration no. NCT02843230 © RSNA, 2021 Online supplemental material is available for this article .

Background: Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder which leads to progressive muscle degeneration and weakness. Most patients die from cardiac or respiratory failure. Gene transfer therapy offers a promising approach to treating this disorder., Objective: Given the genetic disease burden, family size, and the high consanguinity rates in the Middle East, our objective is to address current practices and challenges of DMD patient care within two countries in this region, namely the United Arab Emirates and Kuwait, and to outline readiness for gene therapy., Methods: An expert panel meeting was held to discuss the DMD patient journey, disease awareness, current management of DMD, challenges faced and recommendations for improvement. Opportunities and challenges for gene therapy in both countries were also deliberated. A pre-meeting survey was conducted, and the results were used to guide the discussion during the meeting., Results: DMD awareness is poor resulting in a delay in referral and diagnosis of patients. Awareness and education initiatives, along with an interconnected referral system could improve early diagnosis. Genetic testing is available in both countries although coverage varies. Corticosteroid therapy is the standard of care however there is often a delay in treatment initiation. Patients with DMD should be diagnosed and managed by a multi-disciplinary team in centers of excellence for neuromuscular disorders. Key success factors to support the introduction of gene therapy include education and training, timely and accessible genetic testing and resolution of reimbursement and cost issues., Conclusion: There are many challenges facing the management of DMD patients in the United Arab Emirates and Kuwait and most likely other countries within the Middle East. Successful introduction of gene therapy to treat DMD will require careful planning, education, capacity building and prioritization of core initiatives.

Background: Antimicrobial resistance is a significant global issue that presents an increasing threat to patients' wellbeing. Although a global concern, the emergence of multi-drug resistant organisms is of particular significance in the Middle East. In recent years, this region has seen an alarming increase in antimicrobial resistance presenting a major challenge to physicians managing various infectious diseases., Methods: A Working Group comprising experts in infectious diseases from Arab countries of Middle East assembled to review similarities and differences in antimicrobial practices and management of multi-drug resistant organisms across the region and assess the barriers to achieving cross-regional collaboration. The Working Group conducted an anonymous online survey to evaluate current practice and understanding of management of multi-drug resistant organisms across the region., Results: A total of 122 physicians from Arab countries of the Middle East responded to the survey. Their responses demonstrated heterogeneity between countries in awareness of local epidemiology, management of multi-drug resistant organisms and antimicrobial stewardship practices. The Working Group recognized similarities and differences in the management of multi-drug resistant organisms across the region, and these were validated by the data collected in the survey. Overall, the similarities across the region reflect several key issues that can have an impact on the management of multi-drug resistant organisms and the prevention of antimicrobial resistance., Conclusions: This paper highlights the urgency of addressing antimicrobial resistance in Arab countries of the Middle East. The Working Group identified key barriers to effective management which may guide the development of future coherent strategies to promote effective antimicrobial stewardship in the region. Here, we outline a call to action for the region, with a need to focus on training and education, capacity building, infrastructure, regional research, and regional surveillance., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cardiac amyloidosis is frequently misdiagnosed, denying patients the opportunity for timely and appropriate management of the disease. The purpose of this review and case studies is to raise awareness of the diagnostic "red flags" associated with cardiac amyloidosis and the currently available non-invasive strategies for diagnosis. The review focuses on the identification of one of the two main types of cardiac amyloidosis, transthyretin amyloid cardiomyopathy, and non-invasive tools to distinguish this from light-chain amyloidosis. A diagnostic algorithm centered around the use of non-invasive imaging and laboratory analysis is presented. The algorithm generates four differential diagnoses for patients presenting with signs and symptoms consistent with cardiac amyloidosis. Case examples are presented, representing the four potential outcomes of diagnosis using the algorithm. The review provides a guide on how to recognize the often-overlooked presentations of this disease in clinical practice. Non-invasive imaging techniques and diagnostic tools that do not require the involvement of a specialty center have allowed for the improved diagnosis of cardiac amyloidosis. Timely diagnosis of this life-threatening disease is essential for optimal management and it is imperative that clinicians have a high index of suspicion for patients presenting with "red flag" symptoms., Competing Interests: HS, HA, and FA reports personal fees from Pfizer Gulf FZ LLC, outside the submitted work. IR was a full-time employee of Pfizer Gulf LLC. This work was supported by Pfizer Gulf FZ LLC. Pfizer provided funding for the editorial assistance in the development of the manuscript. Neither honoraria nor payments were made for authorship. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sabbour, Hasan, Al Badarin, Alibazoglu, Rivard, Romany and Perlini.)

Purpose: Although uncommon, detection of BRAF V600E mutations in adult patients with glioblastoma has become increasingly relevant given the widespread application of molecular diagnostics and encouraging therapeutic activity of BRAF/MEK inhibitors., Methods: We performed a retrospective study of adult glioblastoma patients treated at Dana-Farber Cancer Institute/Brigham and Women's Hospital or Massachusetts General Hospital from January 2011 to July 2019 with an identified BRAF V600E mutation by either immunohistochemistry or molecular testing. Patient characteristics, molecular genomics, and preoperative MRI were analyzed., Results: Nineteen glioblastoma patients were included, with median age at diagnosis of 41-years-old (range 22-69). Only 1/18 was IDH1/2-mutant; 10/17 had MGMT unmethylated tumors. The most common additional molecular alterations were CDKN2A/2B biallelic loss/loss-of-function (10/13, 76.9%), polysomy 7 (8/12, 66.7%), monosomy 10 (5/12, 41.7%), PTEN biallelic loss/loss-of-function (5/13, 38.5%) and TERT promoter mutations (5/15, 33.3%). Most tumors were well-circumscribed (11/14) and all were contrast-enhancing on MRI. Twelve patients eventually developed subependymal or leptomeningeal dissemination. Six patients were treated with BRAF/MEK inhibition following disease progression after standard of care therapy, with 4/6 patients showing partial response or stable disease as best response. Median time to progression after BRAF/MEK inhibition was 6.0 months (95% CI 1.2-11.8). Grade 1 skin rash was present in 2 patients, but no other adverse events were reported. Median OS for the entire cohort was 24.1 months (95% CI 15.7-38.9)., Conclusion: Understanding the natural history and features of BRAF V600E glioblastoma may help better identify patients for BRAF/MEK inhibition and select therapeutic strategies.

Background: Determining failure to anti-angiogenic therapy in recurrent glioblastoma (GBM) (rGBM) remains a challenge. The purpose of the study was to assess treatment response to bevacizumab-based therapy in patients with rGBM using MR spectroscopy (MRS)., Methods: We performed longitudinal MRI/MRS in 33 patients with rGBM to investigate whether changes in N-acetylaspartate (NAA)/Choline (Cho) and Lactate (Lac)/NAA from baseline to subsequent time points after treatment can predict early failures to bevacizumab-based therapies., Results: After stratifying based on 9-month survival, longer-term survivors had increased NAA/Cho and decreased Lac/NAA levels compared to shorter-term survivors. ROC analyses for intratumoral NAA/Cho correlated with survival at 1 day, 2 weeks, 8 weeks, and 16 weeks. Intratumoral Lac/NAA ROC analyses were predictive of survival at all time points tested. At the 8-week time point, 88% of patients with decreased NAA/Cho did not survive 9 months; furthermore, 90% of individuals with an increased Lac/NAA from baseline did not survive at 9 months. No other metabolic ratios tested significantly predicted survival., Conclusions: Changes in metabolic levels of tumoral NAA/Cho and Lac/NAA can serve as early biomarkers for predicting treatment failure to anti-angiogenic therapy as soon as 1 day after bevacizumab-based therapy. The addition of MRS to conventional MR methods can provide better insight into how anti-angiogenic therapy affects tumor microenvironment and predict patient outcomes., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Decitabine (DAC) is an FDA-approved DNA methyltransferase (DNMT) inhibitor that is used in the treatment of patients with myelodysplastic syndromes. Previously, we showed that DAC marks antitumor activity against gliomas with isocitrate dehydrogenase 1 (IDH1) mutations. Based on promising preclinical results, a clinical trial has been launched to determine the effect of DAC in IDH-mutant gliomas. The next step is to comprehensively assess the efficacy and potential determinants of response to DAC in malignant gliomas., Methods: The expression and activity of telomerase reverse transcriptase (TERT) and DNMT1 were manipulated in patient-derived IDH1-mutant and -wildtype glioma lines, followed by assessment of cell proliferation with DAC treatment alone or in combination with telomerase inhibitors. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and correlation analysis were performed., Results: IDH1-mutant glioma tumorspheres with hemizygous codeletion of chromosome arms 1p/19q were particularly sensitive to DAC and showed significant inhibition of DNA replication genes. Our transcriptome analysis revealed that DAC induced expression of cyclin-dependent kinase inhibitor 1A/p21 (CDKN1A), along with downregulation of TERT. These molecular changes were also observed following doxorubicin treatment, supporting the importance of DAC-induced DNA damage in contributing to this effect. We demonstrated that knockdown of p21 led to TERT upregulation. Strikingly, TERT overexpression increased DNMT1 levels and DAC sensitivity via a telomerase-independent mechanism. Furthermore, RNA inhibition (RNAi) targeting of DNMT1 abrogated DAC response in TERT-proficient glioma cells., Conclusions: DAC downregulates TERT through p21 induction. Our data point to TERT and DNMT1 levels as potential determinants of response to DAC treatment., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Antimicrobial resistance is an important global issue that impacts the efficacy of established antimicrobial therapy. This is true globally and within the Arab countries of the Middle East, where a range of key Gram-negative pathogens pose challenges to effective therapy. There is a need to establish effective treatment recommendations for this region given specific challenges to antimicrobial therapy, including variations in the availability of antimicrobials, infrastructure and specialist expertise. This consensus provides regional recommendations for the first-line treatment of hospitalized patients with serious infections caused by World Health Organization critical priority Gram-negative pathogens Acinetobacter baumannii and Pseudomonas aeruginosa resistant to carbapenems, and Enterobacteriaceae resistant to carbapenems and third-generation cephalosporins. A working group comprising experts in infectious disease across the region was assembled to review contemporary literature and provide additional consensus on the treatment of key pathogens. Detailed therapeutic recommendations are formulated for these pathogens with a focus on bacteraemia, nosocomial pneumonia, urinary tract infections, skin and soft tissue infections, and intra-abdominal infections. First-line treatment options are provided, along with alternative agents that may be used where variations in antimicrobial availability exist or where local preferences and resistance patterns should be considered. These recommendations take into consideration the diverse social and healthcare structures of the Arab countries of the Middle East, meeting a need that is not filled by international guidelines. There is a need for these recommendations to be updated continually to reflect changes in antimicrobial resistance in the region, as well as drug availability and emerging data from clinical trials., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: ONC201 is a dopamine receptor D2 (DRD2) antagonist that penetrates the blood-brain barrier. ONC201 efficacy has been shown in glioblastoma animal models and is inversely correlated with dopamine receptor DRD5 expression. ONC201 is well tolerated in adult recurrent glioblastoma patients with dosing every 3 weeks and has achieved an objective radiographic response in a patient harboring the H3 K27M mutation., Methods: In a window-of-opportunity arm, 6 adult subjects initiated ONC201 prior to re-resection of recurrent glioblastoma with intratumoral concentrations as the primary endpoint. An additional 20 adults with recurrent glioblastoma received single agent weekly oral ONC201 at 625 mg, with progression-free survival at 6 months (PFS6) by Response Assessment in Neuro-Oncology (RANO) criteria as the primary endpoint., Results: The window-of-opportunity arm achieved its primary endpoint with intratumoral ONC201 concentrations at ~24 hours following the second weekly dose ranging from 600 nM to 9.3 µM. Intratumoral pharmacodynamics assessed by activating transcriptional factor 4, death receptor 5, and apoptosis induction relative to archival samples were observed with the strongest intensity and uniformity among patients with low DRD5 tumor expression. The primary endpoint of PFS6 by RANO was not achieved at 5% in this molecularly unselected cohort; however, 1 of 3 patients enrolled with the H3 K27M mutation had a complete regression of enhancing multifocal lesions that remained durable for >1.5 years. No treatment modifications or discontinuations due to toxicity were observed, including in those who underwent re-resection., Conclusions: Weekly ONC201 is well tolerated, and meaningful intratumoral concentrations were achieved. ONC201 may be biologically active in a subset of adult patients with recurrent glioblastoma., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated., Methods: Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence., Findings: Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms., Interpretation: The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.

Background: Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct subtype, reflected in the World Health Organization (WHO) 2016 revised diagnostic criteria. To inform IDH-targeting trial design, we sought to characterize outcomes exclusively within IDH mutant gliomas., Methods: We retrospectively analyzed 275 IDH mutant glioma patients treated at our institution. Progression was determined using low-grade glioma criteria from Response Assessment in Neuro-Oncology. We calculated survival statistics with the Kaplan-Meier method, and survival proportions were correlated with molecular, histologic, and clinical factors., Results: During a median follow-up of 6.4 years, 44 deaths (7.6%) and 149 first progression (PFS1) events (54.1%) were observed. Median PFS1 was 5.7 years (95% CI: 4.7-6.4) and OS was 18.7 years (95% CI: 12.2 y-not reached). Consistent with prior studies, we observed an association of grade, molecular diagnosis, and treatment with PFS1. Following the first progressive episode, 79 second progression events occurred during a median follow-up period of 4.1 years. Median PFS following an initial progressive event (PFS2) was accelerated at 3.1 years (95% CI: 2.1-4.1). PFS2 was a surrogate prognostic marker, identifying patients with poorer overall survival., Conclusion: We report outcomes in a large cohort of IDH mutant glioma, providing a well-characterized historical control population for future clinical trial design. Notably, the interval between first and second recurrence (PFS2, 3.0 y) is shorter than time from diagnosis to first recurrence (PFS1, 5.7 y), evidence that these tumors clinically degenerate from an indolent course to an accelerated malignant phase. Thus, PFS2 represents a relevant outcome for trials investigating drug efficacy at recurrence., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anticancer small molecule in clinical trials for high-grade gliomas and other malignancies. DRD5 is a dopamine receptor family member that opposes DRD2 signaling. We investigated the expression of these dopamine receptors in cancer and their influence on tumor cell sensitivity to ONC201., Experimental Design: The Cancer Genome Atlas was used to determine DRD2/DRD5 expression broadly across human cancers. Cell viability assays were performed with ONC201 in >1,000 Genomic of Drug Sensitivity in Cancer and NCI60 cell lines. IHC staining of DRD2/DRD5 was performed on tissue microarrays and archival tumor tissues of glioblastoma patients treated with ONC201. Whole exome sequencing was performed in RKO cells with and without acquired ONC201 resistance. Wild-type and mutant DRD5 constructs were generated for overexpression studies., Results: DRD2 overexpression broadly occurs across tumor types and is associated with a poor prognosis. Whole exome sequencing of cancer cells with acquired resistance to ONC201 revealed a de novo Q366R mutation in the DRD5 gene. Expression of Q366R DRD5 was sufficient to induce tumor cell apoptosis, consistent with a gain-of-function. DRD5 overexpression in glioblastoma cells enhanced DRD2/DRD5 heterodimers and DRD5 expression was inversely correlated with innate tumor cell sensitivity to ONC201. Investigation of archival tumor samples from patients with recurrent glioblastoma treated with ONC201 revealed that low DRD5 expression was associated with relatively superior clinical outcomes., Conclusions: These results implicate DRD5 as a negative regulator of DRD2 signaling and tumor sensitivity to ONC201 DRD2 antagonism., (©2018 American Association for Cancer Research.)

Purpose:: To reduce care variation and improve the management of patients with newly identified single brain masses and no history of cancer, we implemented a dedicated admission protocol., Methods:: We reviewed records of 206 patients who presented to our emergency department between January 2010 and May 2016 with a new single brain mass but no history of cancer. Patients admitted before the protocol implementation were designated the pre-implementation group (PRE), and those admitted after implementation were designated the post-implementation group (POST)., Results:: Ninety-six patients were in the PRE group and 110 in the POST group. Length of stay for POST patients was significantly shorter than for PRE patients (6 v 7 days, respectively; P = .042), and this effect was more robust after excluding the 66 patients who were discharged to rehabilitation, skilled nursing, or hospice facilities (5 v 7 days, respectively; P = .001). Additional comparison of POST with PRE patients showed that time to surgery was significantly reduced (2.7 v 3.5 days, respectively; P = .006) and that computed tomography scans of the chest, abdomen, and pelvis were reduced (12% v 47%, respectively; P < .001). No difference was found in the 30-day readmission rates. For patients with GBM, there also was no significant difference in time to initiation of chemoradiation or in median overall survival., Conclusion:: Implementation of a specialized admission pathway for patients with a new single brain mass decreased average length of hospital stay and time to surgery and reduced unnecessary diagnostic imaging tests in patients with primary brain tumors.

Background: In the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS)., Methods: Data from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS., Results: A log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status., Conclusion: Postsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.

ONC201 is an oral, small molecule selective antagonist of the G protein-coupled receptor DRD2 that causes p53-independent apoptosis in tumor cells via integrated stress response activation and Akt/ERK inactivation. We performed a Phase II study that enrolled 17 patients with recurrent, bevacizumab-naïve, IDH1/2 WT glioblastoma who received 625mg ONC201 every three weeks. Median OS was 41.6 weeks with OS6 of 71% and OS9 of 53%. Seven of 17 patients are alive. PFS6 was 11.8% with two patients remaining on study who continue to receive ONC201 for >12 months. One of these patients had a durable objective response with a secondary glioblastoma possessing a H3.3 K27M mutation, exhibiting regression by 85% in one lesion and 76% in the second lesion. The second patient who continues to receive ONC201 for >12 months remains disease-free after enrolling on this trial following a re-resection. No drug-related SAEs or treatment discontinuation due to toxicity occurred. Plasma PK at 2 hours post-dose was 2.6 ug/mL, serum prolactin induction was observed as a surrogate marker of target engagement, and DRD2 was expressed in all evaluated archival tumor specimens. In summary, ONC201 is well tolerated and may have single agent activity in recurrent glioblastoma patients., Competing Interests: CONFLICTS OF INTEREST J.E.A. and W.O. are employees and shareholders of Oncoceutics.

Introduction: Glioblastoma (GBM), the most common primary malignant brain tumor in adults, lacks effective long-term treatment. The tumor is dependent on neovascularization for survival, making angiogenesis an attractive target for therapeutic intervention. The exact mechanism underlying the effects of antiangiogenic agents on GBM remains debatable, although it likely involves vascular endothelial growth factor (VEGF), and other proangiogenic growth factors. Early studies in the recurrent GBM setting were promising and prompted two multinational randomized phase three trials (AVAglio and RTOG 0825) investigating the effect of bevacizumab, an anti-VEGF monoclonal antibody, in newly diagnosed GBM., Areas Covered: In this article, the authors discuss the basic mechanisms of angiogenesis and antiangiogenic resistance. The authors additionally summarize the current state of clinical research and how it will impact both future research and the development antiangiogenic therapies., Expert Opinion: The ultimate utility of antiangiogenic therapy in the management of GBM remains unclear. In an effort to improve outcomes, there remains an urgent need to better understand the biology underlying angiogenesis and tumor survival, as well as mechanisms of antiangiogeneic resistance. Ultimately, combinatorial approaches using antiangiogenic agents, targeted molecular therapy, immunotherapy or cytotoxics may be needed to improve treatment outcomes.

Glioblastoma is the most prevalent malignant primary brain tumor in adults and to date effective durable treatments are lacking. Preclinical studies underscore the importance of neovascularization for tumor survival, making angiogenesis an important treatment target. Early clinical experience in recurrent glioblastoma suggested that antiangiogenic agents may provide clinical benefit by prolonging progression-free survival, improving quality of life and decreasing peritumoral edema. Two recent Phase III randomized trials of antiangiogenic therapy at initial diagnosis suggested improvement in progression-free survival, but failed to show an overall survival benefit. Ongoing preclinical research focuses on mechanisms of resistance and potential predictive biomarkers. Identification of targets to resistance pathways and of predictive biomarkers will hopefully improve efficacy of antiangiogenic therapies.

Social defeat stress is a salient stressor that induces neuroadaptive changes in the mesocorticolimbic dopaminergic system. Substantial evidence indicates that mu-opioid receptors (MORs) modulate dopamine transmission in the ventral tegmental area (VTA). FosB/DeltaFosB protein accumulation in dopaminergic projections during repeated treatments is thought to be involved in long-term neuroplasticity. In this study we characterize the magnitude and time-course of MOR mRNA expression and FosB/DeltaFosB immunoreactivity in mesocorticolimbic regions following repeated social defeat stress. Effects of brief repeated social defeat stress or control handling procedures were studied in rats either 2 h after the last exposure, or 3, 7, 14, 21 and 28 days later. We found that MOR mRNA expression in the VTA doubled after the last stress compared with handling, and remained 30-70% higher until day 21. The number of FosB/DeltaFosB-labeled neurons in regions of the frontal cortex, nucleus accumbens (NAc) shell and core, and in the medial, central and basolateral amygdala increased significantly immediately after the last stress episode, and remained enhanced for 21 days. Another group of rats received bilateral intra-VTA infusion of the MOR agonist, DAMGO, 7 days after the last stress. Prior social defeat stress augmented DAMGO-induced Fos expression in the NAc shell, suggesting that Fos expression in this region might be the direct result of MOR activity in the VTA. Social defeat stress leads to an increased capacity for MOR activation in the VTA, which may be relevant to enduring FosB/DeltaFosB expression in mesocorticolimbic areas and to the behaviorally sensitized response to psychostimulant drugs.