Search

Glioblastoma multiforme is an aggressive malignant brain tumor. The monoclonal antibody, bevacizumab, is active in recurrent disease via inhibition of angiogenesis. Proteinuria and renal thrombotic microangiopathy are known complications. We report a case of a patient developing acute renal failure with biopsy-proven interstitial nephritis while receiving bevacizumab for recurrent disease. The patient was otherwise well with a history of controlled hypertension. Renal function improved with discontinuation of bevacizumab and the administration of corticosteroid therapy. [ABSTRACT FROM PUBLISHER]

Objective: To build a descriptive literature base of investigated and identified gender differences in the psychosocial experience of parents of children with cancer, in order to guide future research in this area. Methods: An extensive literature search was conducted using Medline, PsycINFO, CINAHL and EMBASE databases. Thirty papers were included in the review. Themes from these papers were identified, and on this basis, the review findings were grouped according to five main outcome categories: role perceptions, illness beliefs, psychological distress, coping strategies and perceptions of marital, family and child functioning. Results: Few gender differences were found in perceptions of marital, family and child functioning. There was a tendency toward traditional gender roles in the division of parental tasks. Findings in relation to parent psychological distress and preferred coping strategies were mixed, with trends toward increased distress, more emotion-focused coping and greater social support-seeking in mothers. Conclusions: Further studies using longitudinal designs with solid theoretical groundings will provide valuable information on the unique psychosocial experiences of mothers and fathers throughout the child's illness, which may in turn guide the development of evidence-based interventions. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

SMARCB1 is deleted in rhabdoid tumor, an aggressive paediatric malignancy affecting the kidney and CNS. We hypothesized that the oncogenic pathway in rhabdoid tumors involved epigenetic silencing of key cell cycle regulators as a consequence of altered chromatin-remodelling, attributable to loss of SMARCB1, and that this hypothesis if proven could provide a biological rationale for testing epigenetic therapies in this disease. We used an inducible expression system to show that the imprinted cell cycle inhibitor CDKN1C is a downstream target for SMARCB1 and is transcriptionally activated by increased histone H3 and H4 acetylation at the promoter. We also show that CDKN1C expression induces cell cycle arrest, CDKN1C knockdown with siRNA is associated with increased proliferation, and is able to compete against the anti-proliferative effect of restored SMARCB1 expression. The histone deacetylase inhibitor (HDACi), Romidepsin, specifically restored CDKN1C expression in rhabdoid tumor cells through promoter histone H3 and H4 acetylation, recapitulating the effect of SMARCB1 on CDKNIC allelic expression, and induced cell cycle arrest in G401 and STM91-01 rhabdoid tumor cell lines. CDKN1C expression was also shown to be generally absent in clinical specimens of rhabdoid tumor, however CDKN1A and CDKN1B expression persisted. Our observations suggest that maintenance of CDKN1C expression plays a critical role in preventing rhabdoid tumor growth. Significantly, we report for the first time, parallels between the molecular pathways of SMARCB1 restoration and Romidepsin treatment, and demonstrate a biological basis for the further exploration of histone deacetylase inhibitors as relevant therapeutic reagents in the treatment of rhabdoid tumor. [ABSTRACT FROM AUTHOR]

Aim: This study describes the management of and outcomes for adult patients with newly diagnosed intramedullary spinal cord tumors during 1998–2000 in Victoria. Methods: The adult patients were identified in a retrospective cohort study conducted by surveying doctors involved in managing incident glioma cases identified from the population-based Victorian Cancer Registry. Results: Sixteen patients were considered eligible for this review. Of these 15 (94%) had a histological diagnosis: an ependymoma was diagnosed in 13 patients (81%). A complete macroscopic resection was achieved in eight patients (50%). A variety of tumor types and grades were observed with surgery and radiotherapy the mainstays of therapy. One patient received chemotherapy (7%). One patient died from disease within six months of diagnosis. Of the remaining 15 patients, all were alive at 5 years and 10 (63%) remain disease free. Conclusion: This review documents characteristics of a rare condition and suggests that, overall, prognosis is excellent. [ABSTRACT FROM AUTHOR]

Abstract: This study describes the management of and outcomes for adult and paediatric patients with newly diagnosed brain stem gliomas during 1998–2000 in Victoria. Adult patients were identified in a retrospective cohort study conducted by surveying doctors involved in managing incident brainstem glioma cases identified from the population-based Victorian Cancer Registry. Paediatric cases were identified from a retrospective analysis of the Victorian Paediatric Brain tumour database for the same period. Ten adult and 14 paediatric patients were considered eligible for this study. Nine (38%) did not have a histologic diagnosis but were diagnosed on the basis of radiological appearance. Complete macroscopic resection was performed in two patients (8%). A variety of tumour types and grades were observed with surgery and radiotherapy the mainstays of therapy. No adult patients and only eight (57%) paediatric patients received chemotherapy. The median survivals for adult patients, paediatric patients with pontine lesions and paediatric patients with non-pontine lesions were: 57, 10 and 60+ months respectively. [Copyright &y& Elsevier]

The cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway is a critical driver of type I interferon (IFN-I) and antitumor CD8+ T cell responses after radiotherapy (RT). In this issue of the JCI, two reports describe mechanisms that restrained STING signaling and abrogated antitumor immunity after RT. Wen, Wang, and colleagues discovered that IFN-I mediated the induction of YTHDF1, an RNA N6- methyladenosine-binding protein, in DCs after RT promoted cathepsimmediated STING degradation. Zhang, Deng, Wu, and colleagues discovered that hemeoxygenase 1 (HO-1) was induced and proteolytically cleaved after RT to suppress cGAS cytoplasmic export as well as STING oligomerization at the ER. Blocking the STING-suppressive functions of YTHDF1 and HO-1, respectively, improved antitumor T cell immunity and tumor control after RT. Together, these studies support the development of clinical avenues to sustain STING signaling during RT, a standard treatment for approximately 50% of malignancies. [ABSTRACT FROM AUTHOR]

Simple Summary: Atypical teratoid rhabdoid tumour (ATRT) is an aggressive undifferentiated malignancy of the central nervous system in children. A defining feature of ATRT is the loss of the SMARCB1 gene that is essential for regulating gene expression required for normal developmental processes. We show that treatment of human ATRT cell models with the histone deacetylate inhibitor, panobinostat, inhibits tumour growth, reactivates the expression of developmental genes, and drives neuronal differentiation. These results demonstrate the therapeutic potential of panobinostat for the treatment of ATRT. Atypical teratoid rhabdoid tumour (ATRT) is a rare but highly aggressive undifferentiated solid tumour arising in the central nervous system and predominantly affecting infants and young children. ATRT is exclusively characterized by the inactivation of SMARCB1, a member of the SWI/SNF chromatin remodelling complex that is essential for the regulation of large sets of genes required for normal development and differentiation. Histone deacetylase inhibitors (HDACi) are a promising anticancer therapy and are able to mimic the normal acetylation functions of SMARCB1 in SMARCB1-deficient cells and drive multilineage differentiation in extracranial rhabdoid tumours. However, the potential efficacy of HDACi in ATRT is unknown. Here, we show that human ATRT cells are highly responsive to the HDACi panobinostat and that sustained treatment leads to growth arrest, increased cell senescence, decreased clonogenicity and induction of a neurogenesis gene-expression profile. Furthermore, in an orthotopic ATRT xenograft model, continuous panobinostat treatment inhibits tumour growth, increases survival and drives neuronal differentiation as shown by the expression of the neuronal marker, TUJ1. Collectively, this preclinical study supports the therapeutic potential of panobinostat-mediated differentiation therapy for ATRT. [ABSTRACT FROM AUTHOR]

Patients with brain tumours are motivated to participate in clinical trials involving repeat tissue sampling. Normalising the use of neoadjuvant and staged surgical trials necessitates collaboration among patients, regulatory agencies, and researchers. Initial and repetitive tissue sampling plays a crucial role in enhancing our understanding of resistance mechanisms and vulnerabilities in brain tumour therapy. Standardising biopsy techniques and ensuring technical uniformity across institutions are vital for effective interinstitutional collaboration. Although liquid biopsy technologies hold promise, they are not yet ready to replace tissue analysis. Clear communication about the risks and benefits of biopsies is essential, particularly regarding potential postoperative deficits. Changes in mindset and neurosurgical culture are imperative to achieve much needed breakthroughs in the development of new, effective therapies for brain tumours. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) remains an untreatable malignant tumor with poor patient outcomes, characterized by palisading necrosis and microvascular proliferation. While single-cell technology made it possible to characterize different lineage of glioma cells into neural progenitor-like (NPC-like), oligodendrocyte-progenitor-like (OPC-like), astrocyte-like (AC-like) and mesenchymal like (MES-like) states, it does not capture the spatial localization of these tumor cell states. Spatial transcriptomics empowers the study of the spatial organization of different cell types and tumor cell states and allows for the selection of regions of interest to investigate region-specific and cell-type-specific pathways. Here, we obtained paired 10x Chromium single-nuclei RNA-sequencing (snRNA-seq) and 10x Visium spatial transcriptomics data from three GBM patients to interrogate the GBM microenvironment. Integration of the snRNA-seq and spatial transcriptomics data reveals patterns of segregation of tumor cell states. For instance, OPC-like tumor and NPC-like tumor significantly segregate in two of the three samples. Our differentially expressed gene and pathway analyses uncovered significant pathways in functionally relevant niches. Specifically, perinecrotic regions were more immunosuppressive than the endogenous GBM microenvironment, and perivascular regions were more pro-inflammatory. Our gradient analysis suggests that OPC-like tumor cells tend to reside in areas closer to the tumor vasculature compared to tumor necrosis, which may reflect increased oxygen requirements for OPC-like cells. In summary, we characterized the localization of cell types and tumor cell states, the gene expression patterns, and pathways in different niches within the GBM microenvironment. Our results provide further evidence of the segregation of tumor cell states and highlight the immunosuppressive nature of the necrotic and perinecrotic niches in GBM. [ABSTRACT FROM AUTHOR]

Background Isocitrate dehydrogenase (IDH) is commonly mutated (mIDH) in gliomas, and this mutant enzyme produces the oncometabolite 2-hydroxyglutarate (2HG). 2HG promotes gliomagenesis and is implicated in epileptogenesis. Ivosidenib (IVO), a small molecule oral mIDH1 inhibitor, is FDA-approved for mIDH1 newly diagnosed and relapsed/refractory acute myeloid leukemia. Moreover, IVO has efficacy in clinical trials for recurrent mIDH1 gliomas. Given the lack of targeted treatments for gliomas, we initiated off-label IVO for mIDH glioma patients in October 2020. Methods Retrospectively, we sought to assess early outcomes in our patients and describe their experience on IVO from October 2020 through February 2022. Our objective was to report on the following variables of off-label use of IVO: radiographic response, seizure control, tolerability, and access to the medication. All patients initially received single-agent IVO dosed at 500 mg orally once daily. Results The cohort age range was 21–74 years. Tumor types included astrocytoma (n = 14) and oligodendroglioma (n = 16), with most being grade 2 (n = 21). The best radiographic response in nonenhancing disease (n = 22) was 12 stable diseases, 5 minor responses, 3 partial responses, and 2 progressive diseases. Seizure frequency was stable to improved for most patients (70%, n = 21). IVO was well-tolerated, with the most common toxicities being diarrhea, elevated creatine kinase, and QTc interval prolongation. Most patients (66.7%, n = 20) received drugs via the patient assistance program, with insurance initially covering a third of patients and with ongoing use, later covering 60%. Conclusions Targeted therapies like IVO are options for mIDH glioma patients and can provide positive oncologic and neurological outcomes. [ABSTRACT FROM AUTHOR]

Targeting endolysosomes is a strategy extensively pursued for treating cancers, including glioblastomas (GBMs), on the basis that the intact function of these subcellular organelles is key to tumor cell autophagy and survival. Through gene expression analyses and cell type abundance estimation in GBMs, we showed that genes associated with the endolysosomal machinery are more prominently featured in non-tumor cells in GBMs than in tumor cells, and that tumor-associated macrophages represent the primary immune cell type that contributes to this trend. Further analyses found an enrichment of endolysosomal pathway genes in immunosuppressive (pro-tumorigenic) macrophages, such as M2-like macrophages or those associated with worse prognosis in glioma patients, but not in those linked to inflammation (anti-tumorigenic). Specifically, genes critical to the hydrolysis function of endolysosomes, including progranulin and cathepsins, were among the most positively correlated with immunosuppressive macrophages, and elevated expression of these genes is associated with worse patient survival in GBMs. Together, these results implicate the hydrolysis function of endolysosomes in shaping the immunosuppressive microenvironment of GBM. We propose that targeting endolysosomes, in addition to its detrimental effects on tumor cells, can be leveraged for modulating immunosuppression to render GBMs more amenable to immunotherapies. [ABSTRACT FROM AUTHOR]

Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to understand and therapeutically target the STING pathway in cancer have ensued. Relative to other cancer types, the glioma immune microenvironment harbors few infiltrating T cells, but abundant tumor-associated myeloid cells, possibly explaining disappointing responses to immune checkpoint blockade therapies in cohorts of patients with glioblastoma. Notably, unlike most extracranial tumors, STING expression is absent in the malignant compartment of gliomas, likely due to methylation of the STING promoter. Nonetheless, several preclinical studies suggest that inducing cGAS/STING signaling in the glioma immune microenvironment could be therapeutically beneficial, and cGAS/STING signaling has been shown to mediate inflammatory and antitumor effects of other modalities either in use or being developed for glioblastoma therapy, including radiation, tumor-treating fields, and oncolytic virotherapy. In this Review, we discuss cGAS/STING signaling in gliomas, its implications for glioma immunobiology, compartment-specific roles for STING signaling in influencing immune surveillance, and efforts to target STING signaling -- either directly or indirectly -- for antiglioma therapy. [ABSTRACT FROM AUTHOR]

Purpose: This was an open label, phase I (3 + 3 design), multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumors.Methods: Primary endpoints were to establish MTD, define and describe associated toxicities, including dose limiting toxicities (DLT) and to characterize its pharmacokinetics (PK). Secondary endpoints included assessing the anti-tumour activity of panobinostat, and its biologic activity, by measuring acetylation of histones in peripheral blood mononuclear cells.Results: Nine patients were enrolled and treated with intravenous panobinostat at a dosing level of 15 mg/m2 which was tolerated. Six were evaluable for adverse events. Two (33%) patients experienced Grade 3-4 thrombocytopenia, 1 (17%) experienced Grade 3 anemia, and 2 (33%) experienced Grade 3 neutropenia. Grade 4 drug related pain occurred in 2 (33%) of the patients studied. Two (33%) patients experienced a Grade 2 QTcF change (0.478 ± 0.006 ms). One cardiac DLT (T wave changes) was reported. PK values for 15 mg/m2 (n = 9) dosing were: Tmax 0.8 h, Cmax 235.2 ng/mL, AUC0-t 346.8 h ng/mL and t1/2 7.3 h. Panobinostat significantly induced acetylation of histone H3 and H4 at all time points measured when compared to pre-treatment samples (p < 0.05). Pooled quantitative Western blot data confirmed that panobinostat significantly induced acetylation of histone H4 at 6 h (p < 0.01), 24 h (p < 0.01) and 28-70 h (p < 0.01) post dose.Conclusion: A significant biological effect of panobinostat, measured by acetylation status of histone H3 and H4, was achieved at a dose of 15 mg/m2. PK data and drug tolerability at 15 mg/m2 was similar to that previously published. [ABSTRACT FROM AUTHOR]

Simple Summary: Brain tumor-initiating cells (BTICs) drive tumor progression and resistance to treatments, posing formidable challenges to advancing effective treatments against glioblastoma (GBM). We postulated that inducing BTIC differentiation can serve as a solution to diminishing their malignant features. In this study, we found that clemastine, an over-the-counter oral medication for allergy relief, attenuated the propagation and promoted the differentiation of BTICs, and we uncovered the indispensable role of EBP (Emopamil-binding protein) in maintaining the BTIC population. Taken together, our study implicates specific pathways in the perpetuation of BTICs, and identifies a non-oncology drug with a well-established safety profile that can be repurposed to mitigate the malignant properties of BTICs in GBM. Brain tumor-initiating cells (BTICs) and tumor cell plasticity promote glioblastoma (GBM) progression. Here, we demonstrate that clemastine, an over-the-counter drug for treating hay fever and allergy symptoms, effectively attenuated the stemness and suppressed the propagation of primary BTIC cultures bearing PDGFRA amplification. These effects on BTICs were accompanied by altered gene expression profiling indicative of their more differentiated states, resonating with the activity of clemastine in promoting the differentiation of normal oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes. Functional assays for pharmacological targets of clemastine revealed that the Emopamil Binding Protein (EBP), an enzyme in the cholesterol biosynthesis pathway, is essential for BTIC propagation and a target that mediates the suppressive effects of clemastine. Finally, we showed that a neural stem cell-derived mouse glioma model displaying predominantly proneural features was similarly susceptible to clemastine treatment. Collectively, these results identify pathways essential for maintaining the stemness and progenitor features of GBMs, uncover BTIC dependency on EBP, and suggest that non-oncology, low-toxicity drugs with OPC differentiation-promoting activity can be repurposed to target GBM stemness and aid in their treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: There are few established treatment options for recurrent glioblastoma (rGBM). Immunotherapy, which potentiates the immune system to counter tumor growth, offers new hope for treating GBM that has relapsed after conventional therapies. The aim of this literature review is to summarize recent clinical studies of immunotherapy for rGBM, including that of immune checkpoint blockade, oncolytic virotherapy, chimeric antigen receptor (CAR) T-cell therapy, cancer vaccine and antibody-conjugated toxin. The literature search was concluded in February 2023. This review of immunotherapies provides a comprehensive overview of treatment advances, limitations in each strategy, ongoing opportunities, and preliminary correlates to survival, in order to support clinical decision-making and guide future research endeavors. Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Despite standard therapies, including resection and chemoradiation, recurrence is virtually inevitable. Current treatment for recurrent glioblastoma (rGBM) is rapidly evolving, and emerging therapies aimed at targeting primary GBM are often first tested in rGBM to demonstrate safety and feasibility, which, in recent years, has primarily been in the form of immunotherapy. The purpose of this review is to highlight progress in clinical trials of immunotherapy for rGBM, including immune checkpoint blockade, oncolytic virotherapy, chimeric antigen receptor (CAR) T-cell therapy, cancer vaccine and immunotoxins. Three independent reviewers covered literature, published between the years 2000 and 2022, in various online databases. In general, the efficacy of immunotherapy in rGBM remains uncertain, and is limited to subsets/small cohorts of patients, despite demonstrating feasibility in early-stage clinical trials. However, considerable progress has been made in understanding the mechanisms that may preclude rGBM patients from responding to immunotherapy, as well as in developing new approaches/combination strategies that may inspire optimism for the utility of immunotherapy in this devastating disease. Continued trials are necessary to further assess the best therapeutic avenues and ascertain which treatments might benefit each patient individually. [ABSTRACT FROM AUTHOR]

Gangliogliomas are brain tumors composed of neuron-like and macroglia-like components that occur in children and young adults. Gangliogliomas are often characterized by a rare population of immature astrocyte-appearing cells expressing CD34, a marker expressed in the neuroectoderm (neural precursor cells) during embryogenesis. New insights are needed to refine tumor classification and to identify therapeutic approaches. We evaluated five gangliogliomas with single nucleus RNA-seq, cellular indexing of transcriptomes and epitopes by sequencing, and/or spatially-resolved RNA-seq. We uncovered a population of CD34+ neoplastic cells with mixed neuroectodermal, immature astrocyte, and neuronal markers. Gene regulatory network interrogation in these neuroectoderm-like cells revealed control of transcriptional programming by TCF7L2/MEIS1-PAX6 and SOX2, similar to that found during neuroectodermal/neural development. Developmental trajectory analyses place neuroectoderm-like tumor cells as precursor cells that give rise to neuron-like and macroglia-like neoplastic cells. Spatially-resolved transcriptomics revealed a neuroectoderm-like tumor cell niche with relative lack of vascular and immune cells. We used these high resolution results to deconvolute clinically-annotated transcriptomic data, confirming that CD34+ cell-associated gene programs associate with gangliogliomas compared to other glial brain tumors. Together, these deep transcriptomic approaches characterized a ganglioglioma cellular hierarchy—confirming CD34+ neuroectoderm-like tumor precursor cells, controlling transcription programs, cell signaling, and associated immune cell states. These findings may guide tumor classification, diagnosis, prognostication, and therapeutic investigations. [ABSTRACT FROM AUTHOR]

Background Spirituality can impact patients' attitudes and decisions about treatment and end-of-life care when coping with cancer. Previous studies documented health-related quality of life (HRQoL) and spiritual well-being (SWB) as positively correlated within a general cancer patient population, but little is known about their association in the primary brain tumor population. We sought to measure SWB in primary brain tumor patients and evaluate whether it was associated with HRQoL. Methods Six-hundred and six patients treated at The Preston Robert Tisch Brain Tumor Center at Duke between December 16, 2013 and February 28, 2014 with data in the PRoGREss registry are included in this retrospective analysis. Each patient completed the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being 12 (FACIT-Sp-12) and -Fatigue (FACIT-F), and the Functional Assessment of Cancer Therapy-General and -Brain (FACT-G and FACT-Br). Results Mean age was 49.1 years (SD = 13.5 years), male (N = 328, 54.1%), married (N = 404, 66.7%), at least college-educated (N = 381, 62.9%), and diagnosed with a high-grade glioma (N = 412, 68.0%). Multiple regression analyses were performed on both the FACT-G and the FACT-Br using the FACIT-Sp-12 sub-scales of Meaning/Peace and Faith, FACIT-F, belief in God or a higher power, prayer, gender, tumor grade, and Karnofsky Performance Status (KPS) as predictors. We found that greater SWB (measured by FACIT-Sp-12) was associated with better HRQoL (measured by FACT-G and FACT-Br; p <.0001). Conclusion The association between reported SWB and reported improved HRQoL emphasizes the importance of spirituality in primary brain tumor patients, suggesting SWB must be considered in strategies to improve HRQoL. [ABSTRACT FROM AUTHOR]

Objective This paper aims to describe cancer survival and examine association between survival and socio-demographic characteristics across Barwon South- Western region ( BSWR) in Victoria, Australia. Design This study is based on the retrospective cohort database of patients accessing oncology services across BSWR. Setting Six rural and three urban hospital settings across the BSWR. Participants The participants were patients who were diagnosed with cancer in 2009. Main outcome measures Overall survival (OS) of participants was the main outcome measure. Results Total of 1778 eligible patients had four-year OS for all cancers combined of 59.7% (95% CI, 57.4-62.0). Improved OS was observed for patients in the upper socio-economic tertile (64.2%; 95% CI, 60.9-67.5) compared to the middle (59.3%; 95% CI, 55.5-63.1) and lowest tertiles (49.6%; 95% CI, 44.2-54.9) ( P < 0.01). On multivariate analyses, higher socio-economic status remained a significant predictor of OS adjusting for gender, remoteness and age ( HR [hazard ratio] 0.81; 95% CI 0.74-0.89; P < 0.01). Remoteness was significantly associated with improved OS after adjusting for age, gender and socio-economic status ( HR 0.86; 95% CI, 0.77-0.97; P = 0.01). Older age ≥70 years compared to <70 years conferred inferior OS ( HR 3.08; 95% CI, 2.64-3.59; P < 0.01). Conclusions Our study confirmed improved survival outcomes for patients of higher socio-economic status and younger age. Future research to explain the unexpected survival benefit in patients who lived in more remote areas should examine factors including the correlation between geographical residence and eventual treatment facility as well as compare the BSWR care model to other regions' approaches. [ABSTRACT FROM AUTHOR]

Objective: To characterize dendritic cell (DC) numbers, subset distribution, phenotype, and costimulation molecule expression in a normal pediatric population and in a lymphoblastic malignant pretherapy pediatric population. DC are potent antigen-presenting cells and are crucial for initiating specific immune responses. Materials and Methods: We first analyzed peripheral blood samples of healthy pediatric controls (n = 72). Once a range of normal parameters was established, we compared these to newly diagnosed pediatric leukemia and lymphoma patients prior to receiving therapy (n = 69). Using flow cytometry, we examined blood DC cell-surface expression of CD80, CD86, CD40, CD18, CD50, CD83, CD123, CD58, CD54, and CD11c. Results: Expression of each of these molecules was significantly altered except for CD80, CD83, and CD58. When compared to healthy children, absolute blood DC were reduced in children with leukemia or lymphoblastic lymphoma (p < 0.0001) and children with Hodgkin''s disease (p = 0.0028). Additionally, lymphocyte function in vitro, was impaired (p = 0.0489) for children with lymphoblastic malignancies, while patients with Hodgkin''s disease had normal proliferative function. Conclusions: Our results show that peripheral blood DC from children with newly diagnosed leukemia or lymphoma are significantly altered in number, subset distribution, and costimulation molecule expression, and that lymphocyte function is impaired compared to healthy pediatric controls. [Copyright &y& Elsevier]

Our international team highlights issues with efficacy reports in several studies on DMG with the new drug ONC201.

Background: High-grade gliomas (HGGs) are the most aggressive type of gliomas and have the poorest outcomes. Chromatin remodeling (CR) genes have been implicated in multiple oncogenic pathways in numerous cancer types. In gliomagenesis, CR genes have been implicated in regulating the stemness of glioma cells, the tumor microenvironment (TME), and resistance to therapies., Methods: We performed molecular profiling of 4244 HGGs and evaluated associations of CR mutations with other cancer-related biomarkers, infiltration by immune cells, and immune gene expression. We also evaluated the association between CR mutations and survival in wild-type IDH HGG patients., Results: Nearly 10% of HGGs carry mutations in CR genes, with a higher prevalence (15%) in HGGs with IDH mutations. Analysis of cooccurrence with other biomarkers revealed that CR-mutated HGGs possess favorable genetic alterations which may have prognostic value. CR-mutated HGGs with wild-type IDH demonstrated colder TME and worse OS overall compared to the CR-wild-type HGGs., Conclusions: Our study reveals the prognostic effects of CR mutations in HGG and points to several biomarker candidates that could suggest sensitivity to emerging therapeutic strategies., Competing Interests: A.S. discloses a conflict of interest as a consultant with Tempus and speakers’ bureau for Novocure; J.X, A.H., and D.S. are employed at Caris Life Sciences; S.D. discloses honoraria from OncoLens, BostonGene and advisory role at Bayer; M.J.D. discloses advisory roles at Bayer, Loxo/Lilly, OnCusp Therapeutics, Orphagen Pharmaceuticals, Pfizer, TD2, Crinetics, and Theralink; S.S. discloses advisory roles at Novocure and Data and Safety Monitoring Board (DSMB) at Bexion; S.K. discloses stock and other ownership Interests in xcures; S.K. discloses honoraria from Jubilant Biosys and Pyramid Biosciences; S.K. discloses advisory roles at Biocept, iCAD, and xcures; S.K. discloses research funding from AIVITA Biomedical, Inc., Bayer, Biocept, Blue Earth Diagnostics, Boehringer Ingelheim, Boston Biomedical, Caris MPI, CNS pharmaceuticals, EpicentRx, Lilly, Oblato, and Orbus therapeutics; D.M.A. discloses stock and other ownership Interests in Diverse Biotech and MAIA Biotechnology; D.M.A. discloses advisory roles at Jackson Laboratory for Genomic Medicine and MAIA Biotechnology; D.M.A discloses patents, royalties, and other Intellectual Property - Methods for predicting tumor response to immunotherapy, U.S. Provisional application no. 62/787,508 filed January 2, 2019 Methods for predicting tumor response to immunotherapy, U.S. Provisional application no. 62/620,577 filed January 23, 2018; A.L.S. discloses stock and other ownership Interests in Novocure; A.L.S. discloses honoraria from Cardinal Health, Curio Science, and Gerson Lehrman Group; A.L.S. discloses advisory roles at Abbvie, Amgen, Athenex, Bayer, Exelixis, Merck, and Novocure; A.L.S. discloses speaker’s bureau at Abbvie; Bayer; Bristol-Myers Squibb; Exelixis; Merck; Novocure; Prime Oncology; A.L.S. discloses research funding from Bristol-Myers Squibb, Exelixis, Kura Oncology, Novocure, and Oncoceutics; A.L.S. discloses travel and accommodation expenses from American Association of Neurological Surgeons, Bristol-Myers Squibb, Novocure, and Xcenda; M.J.G. discloses advisory role at Biocept; M.J.G. discloses research funding from cns pharmaceuticals, Denovo Biopharma, European Organization for Research and Treatment of Cancer (EORTC), Five Prime Therapeutics, Genentech, ImmunoCellular Therapeutics, Ono Pharmaceutical, RTOG, Sunovion, Triphase Accelerator Corp, and Vascular Biogenics; The rest of the authors have no conflicts of interest to disclose., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. Tumors from 173 GBM patients are analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. All patients were treated within the scope of an individual healing attempt. Among all vaccinated patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis is 31.9 months (95% CI: 25.0-36.5). Adverse events are infrequent and are predominantly grade 1 or 2. A vaccine-induced immune response to at least one of the vaccinated peptides is detected in blood samples of 87 of 97 (90%) monitored patients. Vaccine-specific T-cell responses are durable in most patients. Significantly prolonged survival is observed for patients with multiple vaccine-induced T-cell responses (53 months) compared to those with no/low induced responses (27 months; P = 0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients., (© 2024. The Author(s).)

Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor group. The natural history, when curative resection is not possible, is one of a chronic disease with periods of tumor stability and episodes of tumor progression. While there is a high overall survival rate, many patients experience significant and potentially lifelong morbidities. The majority of pLGGs have an underlying activation of the RAS/MAPK pathway due to mutational events, leading to the use of molecularly targeted therapies in clinical trials, with recent regulatory approval for the combination of BRAF and MEK inhibition for BRAFV600E mutated pLGG. Despite encouraging activity, tumor regrowth can occur during therapy due to drug resistance, off treatment as tumor recurrence, or as reported in some patients as a rapid rebound growth within 3 months of discontinuing targeted therapy. Definitions of these patterns of regrowth have not been well described in pLGG. For this reason, the International Pediatric Low-Grade Glioma Coalition, a global group of physicians and scientists, formed the Resistance, Rebound, and Recurrence (R3) working group to study resistance, rebound, and recurrence. A modified Delphi approach was undertaken to produce consensus-based definitions and recommendations for regrowth patterns in pLGG with specific reference to targeted therapies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of CD8+ T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 and iNOS, while decreasing immunosuppressive CD206 and arginase. In humanized mice, where tumor cell STING is epigenetically silenced, 8803 therapeutic activity was maintained, further attesting to myeloid dependency and reprogramming. Although the combination with a STAT3 inhibitor did not further enhance STING agonist activity, the addition of anti-PD-1 antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade-responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation.

Identification of immunogenic cancer neoantigens as targets for therapy is challenging. Here, we integrate the whole-genome and long-read transcript sequencing of cancers to identify the collection of neo-open reading frame peptides (NOP) expressed in tumors. We termed this collection of NOPs the tumor framome. NOPs represent tumor-specific peptides that are different from wild-type proteins and may be strongly immunogenic. We describe a class of hidden NOPs that derive from structural genomic variants involving an upstream protein coding gene driving expression and translation of noncoding regions of the genome downstream of a rearrangement breakpoint, i.e., where no gene annotation or evidence for transcription exists. The entire collection of NOPs represents a vast number of possible neoantigens particularly in tumors with many structural genomic variants and a low number of missense mutations. We show that NOPs are immunogenic and epitopes derived from NOPs can bind to MHC class I molecules. Finally, we provide evidence for the presence of memory T cells specific for hidden NOPs in peripheral blood from a patient with lung cancer. This work highlights NOPs as a major source of possible neoantigens for personalized cancer immunotherapy and provides a rationale for analyzing the complete cancer genome and transcriptome as a basis for the detection of NOPs., (©2024 American Association for Cancer Research.)