CBTRUS Statistical Report: American Brain Tumor Association & NCI Neuro-Oncology Branch Adolescent and Young Adult Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2016-2020.

Recent analyses have shown that, whereas cancer survival overall has been improving, it has not improved for adolescents and young adults ages 15-39 years (AYA). The clinical care of AYA with primary brain and other central nervous system (CNS) tumors (BT) is complicated by the fact that the histopathologies of such tumors in AYA differ from their histopathologies in either children (ages 0-14 years) or older adults (ages 40+ years). The present report, as an update to a 2016 publication from the Central Brain Tumor Registry of the United States and the American Brain Tumor Association, provides in-depth analyses of the epidemiology of primary BT in AYA in the United States and is the first to provide biomolecular marker-specific statistics and prevalence by histopathology for both primary malignant and non-malignant BT in AYA. Between 2016 and 2020, the annual average age-specific incidence rate (AASIR) of primary malignant and non-malignant BT in AYA was 12.00 per 100,000 population, an average of 12,848 newly diagnosed cases per year. During the same period, an average of 1,018 AYA deaths per year were caused by primary malignant BT, representing an annual average age-specific mortality rate of 0.96 per 100,000 population. When primary BT were categorized by histopathology, pituitary tumors were the most common (36.6%), with an AASIR of 4.34 per 100,000 population. Total incidence increased with age overall; when stratified by sex, the incidence was higher in females than males at all ages. Incidence rates for all primary BT combined and for non-malignant tumors only were highest for non-Hispanic American Indian/Alaska Native individuals, whereas malignant tumors were more frequent in non-Hispanic White individuals, compared with other racial/ethnic groups. On the basis of histopathology, the most common molecularly defined tumor was diffuse glioma (an AASIR of 1.51 per 100,000). Primary malignant BT are the second most common cause of cancer death in the AYA population. Incidence rates of primary BT overall, as well as specific histopathologies, vary significantly by age. Accordingly, an accurate statistical assessment of primary BT in the AYA population is vital for better understanding the impact of these tumors on the US population and to serve as a reference for afflicted individuals, for researchers investigating new therapies, and for clinicians treating these patients.

Perspectives on digital testing services for sexually transmitted and blood-borne infections from Two-Spirit, gay, bisexual, transgender, and other queer Black, Indigenous, people of colour living in Ontario, Canada.

OBJECTIVES: Increased sexually transmitted and blood-borne infections (STBBI) testing can reduce the burden of disease among Two-Spirit, gay, bisexual, transgender, and other queer Black, Indigenous, people of colour (2SGBTQ+ BIPOC). However, this population encounters barriers, such as discrimination, when accessing in-person STBBI testing services. Digital STBBI testing, such as self-testing/collection kits ordered online and digital requisitions, may address some of these barriers. Our aim was to understand acceptability of free digital STBBI testing among 2SGBTQ+ BIPOC living in Ontario, Canada. DESIGN: We approached this analysis using Implementation Science and Critical Race Theory. We conducted interviews and focus groups with 21 2SGBTQ + BIPOC individuals from 2020-2021. Participants were asked about their perceptions of the benefits and drawbacks of digital STBBI testing, populations that would benefit from using these services, and recommendations for how these services may be implemented in Ontario. Interviews and focus groups were transcribed verbatim and analyzed using reflexive thematic analysis. RESULTS: Six themes emerged. Digital STBBI testing services: (1) May reduce oppression experienced by 2SGBTQ + BIPOC when testing in-person; (2) Should address the unique needs that 2SGBTQ + BIPOC experience due to other intersecting identities they possess; (3) Should adapt their services to suit the varying cultural contexts and living circumstances of 2SGBTQ + BIPOC; (4) Should be accessible to 2SGBTQ + BIPOC who hold diverse or no documentation; (5) Should be offered in multiple languages; (6) May be inaccessible to those without Internet access or devices. CONCLUSION: Digital STBBI testing is one strategy that may reduce discrimination experienced by 2SGBTQ + BIPOC when getting tested in-person. However, digital STBBI testing services may not address all the needs of 2SGBTQ + BIPOC. Racism and other forms of oppression embedded into in-person and digital testing services will need to be addressed to meet the needs of this diverse population.

Reach of GetCheckedOnline among gay, bisexual, transgender and queer men and Two-Spirit people and correlates of use 5 years after program launch in British Columbia, Canada.

OBJECTIVES: Understanding who uses internet-based sexually transmitted and blood-borne infection (STBBI) services can inform programme implementation, particularly among those most impacted by STBBIs, including gender and sexual minority (GSM) men. GetCheckedOnline, an internet-based STBBI testing service in British Columbia, Canada, launched in 2014. Our objectives were to assess reach, identify factors associated with use of GetCheckedOnline 5 years into implementation and describe reasons for using and not using GetCheckedOnline among GSM men. METHODS: The Sex Now 2019 Survey was an online, cross-sectional survey of GSM men in Canada administered from November 2019 to February 2020. Participants were asked a subset of questions related to use of GetCheckedOnline. Multivariable binary logistic regression modelling was used to estimate associations between correlates and use of GetCheckedOnline. RESULTS: Of 431 British Columbia (BC) participants aware of GetCheckedOnline, 27.6% had tested using the service. Lower odds of having used GetCheckedOnline were found among participants with non-white race/ethnicity (adjusted OR (aOR)=0.41 (95% CI 0.21 to 0.74)) and those living with HIV (aOR=0.23 (95% CI 0.05 to 0.76)). Those who usually tested at a walk-in clinic, relative to a sexual health clinic, had greater odds of using GetCheckedOnline (aOR=3.91 (95% CI 1.36 to 11.61)). The most commonly reported reason for using and not using GetCheckedOnline was convenience (78%) and only accessing the website to see how the service worked (48%), respectively. CONCLUSION: Over a quarter of GSM men in BC aware of GetCheckedOnline had used it. Findings demonstrate the importance of social/structural factors related to use of GetCheckedOnline. Service promotion strategies could highlight its convenience and privacy benefits to enhance uptake.

Haploinsufficiency of phosphodiesterase 10A activates PI3K/AKT signaling independent of PTEN to induce an aggressive glioma phenotype.

Glioblastoma is universally fatal and characterized by frequent chromosomal copy number alterations harboring oncogenes and tumor suppressors. In this study, we analyzed exome-wide human glioblastoma copy number data and found that cytoband 6q27 is an independent poor prognostic marker in multiple data sets. We then combined CRISPR-Cas9 data, human spatial transcriptomic data, and human and mouse RNA sequencing data to nominate PDE10A as a potential haploinsufficient tumor suppressor in the 6q27 region. Mouse glioblastoma modeling using the RCAS/tv-a system confirmed that Pde10a suppression induced an aggressive glioma phenotype in vivo and resistance to temozolomide and radiation therapy in vitro. Cell culture analysis showed that decreased Pde10a expression led to increased PI3K/AKT signaling in a Pten-independent manner, a response blocked by selective PI3K inhibitors. Single-nucleus RNA sequencing from our mouse gliomas in vivo, in combination with cell culture validation, further showed that Pde10a suppression was associated with a proneural-to-mesenchymal transition that exhibited increased cell adhesion and decreased cell migration. Our results indicate that glioblastoma patients harboring PDE10A loss have worse outcomes and potentially increased sensitivity to PI3K inhibition.

Patterns of Socioeconomic Marginalization among People Who Use Drugs: A Gender-Stratified Repeated Measures Latent Class Analysis.

Socioeconomic factors are important correlates of drug use behaviors and health-related outcomes in people who use drugs (PWUD) residing in urban areas. However, less is known about the complex overlapping nature of socioeconomic conditions and their association with a range of individual, drug use, and health-related factors in men and women who use drugs. Data were obtained from two community-recruited prospective cohorts of PWUD. Using a gender-stratified approach, we conducted repeated measures latent class analyses (RMLCA) to identify discrete latent socioeconomic subgroups. Multivariable generalized estimating equations were then used to identify correlates of class membership. Between June 2014 and December 2018, RMLCA of 9844 observations from 1654 participants revealed five distinct patterns of socioeconomic status for both men and women. These patterns were primarily distinguished by variations in income, material and housing security, income generation activity, exposure to violence, criminal justice involvement, and police contact. Across gender, progressive increases in exposure to multiple dimensions of socioeconomic disadvantage were found to be associated with frequent use of opioids and stimulants, accessing social services, and being hepatitis C virus antibody-positive. Similar but less congruent trends across gender were observed for age, binge drug use, engagement with opioid agonist therapy, and living with HIV. Gendered patterns of multiple and overlapping dimensions of socioeconomic adversity aligned with patterns of frequent drug use and health-related concerns, highlighting priority areas for gender-inclusive, multilevel responses to mitigate health disparities and meet the diverse socioeconomic needs of urban-dwelling men and women who use drugs.

"Tumor Treating Fields" delivered via electromagnetic induction have varied effects across glioma cell lines and electric field amplitudes.

Previous studies reported that alternating electric fields (EFs) in the intermediate frequency (100-300 kHz) and low intensity (1-3 V/cm) regime - termed "Tumor Treating Fields" (TTFields) - have a specific, anti-proliferative effect on glioblastoma multiforme (GBM) cells. However, the mechanism(s) of action remain(s) incompletely understood, hindering the clinical adoption of treatments based on TTFields. To advance the study of such treatment in vitro, we developed an inductive device to deliver EFs to cell cultures which improves thermal and osmolar regulation compared to prior devices. Using this inductive device, we applied continuous, 200 kHz electromagnetic fields (EMFs) with a radial EF amplitude profile spanning 0-6.5 V/cm to cultures of primary rat astrocytes and several human GBM cell lines - U87, U118, GSC827, and GSC923 - for a duration of 72 hours. Cell density was assessed via segmented pixel densities from GFP expression (U87, U118) or from staining (astrocytes, GSC827, GSC923). Further RNA-Seq analyses were performed on GSC827 and GSC923 cells. Treated cultures of all cell lines exhibited little to no change in proliferation at lower EF amplitudes (0-3 V/cm). At higher amplitudes (> 4 V/cm), different effects were observed. Apparent cell densities increased (U87), decreased (GSC827, GSC923), or showed little change (U118, astrocytes). RNA-Seq analyses on treated and untreated GSC827 and GSC923 cells revealed differentially expressed gene sets of interest, such as those related to cell cycle control. Up- and down-regulation, however, was not consistent across cell lines nor EF amplitudes. Our results indicate no consistent, anti-proliferative effect of 200 kHz EMFs across GBM cell lines and thus contradict previous in vitro findings. Rather, effects varied across different cell lines and EF amplitude regimes, highlighting the need to assess the effect(s) of TTFields and similar treatments on a per cell line basis.

Virtual multi-institutional tumor board: a strategy for personalized diagnoses and management of rare CNS tumors.

PURPOSE: Multidisciplinary tumor boards (MTBs) integrate clinical, molecular, and radiological information and facilitate coordination of neuro-oncology care. During the COVID-19 pandemic, our MTB transitioned to a virtual and multi-institutional format. We hypothesized that this expansion would allow expert review of challenging neuro-oncology cases and contribute to the care of patients with limited access to specialized centers. METHODS: We retrospectively reviewed records from virtual MTBs held between 04/2020-03/2021. Data collected included measures of potential clinical impact, including referrals to observational or therapeutic studies, referrals for specialized neuropathology analysis, and whether molecular findings led to a change in diagnosis and/or guided management suggestions. RESULTS: During 25 meetings, 32 presenters discussed 44 cases. Approximately half (n = 20; 48%) involved a rare central nervous system (CNS) tumor. In 21% (n = 9) the diagnosis was changed or refined based on molecular profiling obtained at the NIH and in 36% (n = 15) molecular findings guided management. Clinical trial suggestions were offered to 31% (n = 13), enrollment in the observational NCI Natural History Study to 21% (n = 9), neuropathology review and molecular testing at the NIH to 17% (n = 7), and all received management suggestions. CONCLUSION: Virtual multi-institutional MTBs enable remote expert review of CNS tumors. We propose them as a strategy to facilitate expert opinions from specialized centers, especially for rare CNS tumors, helping mitigate geographic barriers to patient care and serving as a pre-screening tool for studies. Advanced molecular testing is key to obtaining a precise diagnosis, discovering potentially actionable targets, and guiding management.

Defining the role of digital public health in the evolving digital health landscape: policy and practice implications in Canada. / Définition du rôle de la santé publique numérique dans le paysage changeant de la santé numérique : répercussions sur les politiques et les pratiques au Canada.

In this article, we argue that current digital health strategies across Canada do not appropriately consider the implications of digital technologies (DTs) for public health functions because they adopt a primarily clinical focus. We highlight differences between clinical medicine and public health, suggesting that conceptualizing digital public health (DPH) as a field distinct from, but related to, digital health is essential for the development of DTs in public health. Focussing on DPH may allow for DTs that deeply consider fundamental public health principles of health equity, social justice and action on the social and ecological determinants of health. Moreover, the digital transformation of health services catalyzed by the COVID-19 pandemic and changing public expectations about the speed and convenience of public health services necessitate a specific DPH focus. This imperative is reinforced by the need to address the growing role of DTs as determinants of health that influence health behaviours and outcomes. Making the distinction between DPH and digital health will require more specific DPH strategies that are aligned with emergent digital strategies across Canada, development of intersectoral transdisciplinary partnerships and updated competencies of the public health workforce to ensure that DTs in public health can improve health outcomes for all Canadians.

Dans cet article, nous soutenons que les stratégies actuelles en matière de santé numérique à l'échelle du Canada ne tiennent pas adéquatement compte des répercussions des technologies numériques sur les fonctions de santé publique, car elles ont une orientation principalement clinique. Nous soulignons les différences entre médecine clinique et santé publique et nous suggérons qu'il est essentiel, pour le développement des technologies numériques dans le domaine de la santé publique, de concevoir la santé publique numérique comme un domaine distinct de la santé numérique tout en étant lié à celle-ci. Si l'accent était mis sur la santé publique numérique, les technologies numériques pourraient tenir compte en profondeur des principes fondamentaux de la santé publique que sont l'équité en santé, la justice sociale et l'action sur les déterminants sociaux et environnementaux de la santé. De plus, la transformation numérique des services de santé, catalysée par la pandémie de COVID-19, et l'évolution des attentes du public à l'égard de la rapidité et de la commodité des services de santé publique exigent que l'on mette l'accent sur la santé publique numérique. Cet impératif est renforcé par la nécessité de prendre en compte le rôle croissant des technologies numériques en tant que déterminants de la santé ayant une influence sur les comportements et les résultats en matière de santé.

rWTC-MBTA Vaccine Induces Potent Adaptive Immune Responses Against Glioblastomas via Dynamic Activation of Dendritic Cells.

Despite strides in immunotherapy, glioblastoma multiforme (GBM) remains challenging due to low inherent immunogenicity and suppressive tumor microenvironment. Converting "cold" GBMs to "hot" is crucial for immune activation and improved outcomes. This study comprehensively characterized a therapeutic vaccination strategy for preclinical GBM models. The vaccine consists of Mannan-BAM-anchored irradiated whole tumor cells, Toll-like receptor ligands [lipoteichoic acid (LTA), polyinosinic-polycytidylic acid (Poly (I:C)), and resiquimod (R-848)], and anti-CD40 agonistic antibody (rWTC-MBTA). Intracranial GBM models (GL261, SB28 cells) are used to evaluate the vaccine efficacy. A substantial number of vaccinated mice exhibited complete regression of GBM tumors in a T-cell-dependent manner, with no significant toxicity. Long-term tumor-specific immune memory is confirmed upon tumor rechallenge. In the vaccine-draining lymph nodes of the SB28 model, rWTC-MBTA vaccination triggered a major rise in conventional dendritic cell type 1 (cDC1) 12 h post-treatment, followed by an increase in conventional dendritic cell type 2 (cDC2), monocyte-derived dendritic cell (moDC), and plasmacytoid dendritic cell (pDC) on Day 5 and Day 13. Enhanced cytotoxicity of CD4+ and CD8+ T cells in vaccinated mice is verified in co-culture with tumor cells. Analyses of immunosuppressive signals (T-cell exhaustion, myeloid-derived suppressor cells (MDSC), M2 macrophages) in the GBM microenvironment suggest potential combinations with other immunotherapies for enhanced efficacy. In conclusion, the authors findings demonstrate that rWTC-MBTA induces potent and long-term adaptive immune responses against GBM.

The Resurgence of Lymphogranuloma Venereum: Changing Presentation of Lymphogranuloma Venereum in the Era of HIV Preexposure Prophylaxis, 2004 to 2022.

BACKGROUND: Before the early 2000s, the sexually transmitted infection lymphogranuloma venereum (LGV) was rare in high-income countries. Initially, most cases in these countries were among symptomatic men who have sex with men (MSM) living with HIV. In the context of widespread HIV preexposure prophylaxis (PrEP), LGV's epidemiology may be changing. We aimed to characterize the epidemiology and clinical presentation of LGV in the PrEP era. METHODS: A retrospective chart review was performed on all LGV cases occurring between November 2004 to October 2022 in British Columbia (BC), Canada. Cases were stratified by having occurred before (2004-2017) or after widespread PrEP availability in BC (2018-2022). Annual rates and test positivity percentages were calculated. Bivariate logistic regression was performed to identify drivers of asymptomatic infection in the PrEP era. RESULTS: Among 545 cases identified, 205 (37.6%) occurred pre-PrEP and 340 (62.4%) occurred during the PrEP era. Most cases were among MSM (97.2%). The estimated rate of LGV has doubled from 2018 to 2022, reaching 1535.2 cases per 100,000 PrEP users. Most PrEP-era cases were among HIV-negative individuals (65.3%), particularly those on PrEP (72.6%). Cases in the PrEP era were often asymptomatic compared with pre-PrEP (38.6% vs. 19.3%; P < 0.001). Users of PrEP were more likely to experience asymptomatic infection compared with HIV-negative PrEP nonusers (odds ratio, 2.07; 95% confidence interval, 1.07-3.99). CONCLUSIONS: In the context of increased asymptomatic testing, LGV may be increasing in BC. Most infections now occur among HIV-negative MSM. A high proportion of infections are asymptomatic.

Long-term survivors of glioblastoma: Tumor molecular, clinical, and imaging findings.

Background: Glioblastoma (GBM) is the most aggressive primary brain malignancy with <45% living a year beyond diagnosis. Previously published investigations of long-term survivors (LTS) provided clinical data but rarely incorporated a comprehensive clinical and molecular analysis. Herein, we identify clinical, imaging, molecular, and outcome features for 23 GBM-LTS patients and compare them with a matched cohort of short-term survivors (STS). Methods: Molecularly confirmed Isocitrate Dehydrogenase (IDH) wildtype GBM patients living ≥3 years post-diagnosis (NLTS = 23) or <3 years (NSTS = 75) were identified from our Natural History study. Clinical and demographic characteristics were compared. Tumor tissue was analyzed with targeted next generation sequencing (NGS) (NLTS = 23; NSTS = 74) and methylation analysis (NLTS = 18; NSTS = 28). Pre-surgical MRI scans for a subset of LTS (N = 14) and STS control (N = 28) matched on sex, age, and extent of resection were analyzed. Results: LTS tended to be younger. Diagnostic MRIs showed more LTS with T1 tumor hypointensity. LTS tumors were enriched for MGMTp methylation and tumor protein 53 (TP53) mutation. Three patients with classic GBM histology were reclassified based on NGS and methylation testing. Additionally, there were LTS with typical poor prognostic molecular markers. Conclusions: Our findings emphasize that generalized predictions of prognosis are inaccurate for individual patients and underscore the need for complete clinical evaluation including molecular work-up to confirm the diagnosis. Continued accrual of patients to LTS registries that containcomprehensive clinical, imaging, tumor molecular data, and outcomes measures may pro\vide important insights about individual patient prognosis.

Propofol Infusion Syndrome Following Endoscopic Tracheoplasty and Jet Ventilation: Case Report.

OBJECTIVE: We present a case of propofol infusion syndrome (PRIS) following jet ventilation. METHOD: Case report and review of literature. RESULTS: A 70-year-old man required CO2 laser endoscopic tracheoplasty for tracheal and subglottic stenosis due to A-frame deformity. Postoperatively, the patient was reintubated for respiratory distress and propofol was resumed. Over the next two days the patient developed acute kidney injury, leukocytosis, acute primary respiratory acidosis with high anion gap metabolic acidosis, multiple end organ damage, elevated cardiac markers, and worsening lactic acidosis. The patient was recognized as having propofol infusion syndrome and propofol was immediately discontinued and replaced with dexmedetomidine. Unfortunately the patient progressed to multi-organ failure complicated by rhabdomyolysis and distributive intravascular coagulopathy. CONCLUSIONS: Propofol is often used as an anesthetic for jet ventilation during otolaryngologic airway surgery. Propofol related infusion syndrome is an uncommon but life-threatening peri-operative complication that should be considered in any patient with an unusual post-operative recovery characterized by metabolic acidosis, ECG changes, end organ damage, and elevated lactate.

Challenges and limitations of clinical trials in the adolescent and young adult CNS cancer population: A systematic review.

Background: The adolescent and young adult (AYA) cancer population, aged 15-39, carries significant morbidity and mortality. Despite growing recognition of unique challenges with this age group, there has been little documentation of unmet needs in their care, trial participation, and quality of life, particularly in those with primary brain tumors. Methods: A systematic literature review of 4 databases was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. Studies included editorials, reviews, and practice guidelines on the challenges and limitations faced by the AYA population. Papers had to address CNS tumors. Results: Sixty-eight studies met the inclusion criteria. The challenges and limitations in clinical trials in the AYA population were synthesized into 11 categories: molecular heterogeneity, tumor biology, diagnostic delay, access to care, physician factors, patient factors, primary brain tumor (PBT) factors, accrual, limited trials, long term follow up, and trial design. The published papers' recommendations were categorized based on the target of the recommendation: providers, coordination of care, organizations, accrual, and trial design. The AYA cancer population was found to suffer from unique challenges and barriers to care and the construction of trials. Conclusions: The AYA CNS cancer population suffers from unique challenges and barriers to care and construction of trials that make it critical to acknowledge AYAs as a distinct patient population. In addition, AYAs with primary brain tumors are underrecognized and underreported in current literature. More studies in the AYA primary brain tumor patient population are needed to improve their care and participation in trials.

TGF-ß and BMP signaling are associated with the transformation of glioblastoma to gliosarcoma and then osteosarcoma.

Background: Gliosarcoma, an isocitrate dehydrogenase wildtype (IDH-WT) variant of glioblastoma, is defined by clonal biphasic differentiation into gliomatous and sarcomatous components. While the transformation from a glioblastoma to gliosarcoma is uncommon, the subsequent transformation to osteosarcoma is rare but may provide additional insights into the biology of these typically distinct cancers. We observed a patient initially diagnosed with glioblastoma, that differentiated into gliosarcoma at recurrence, and further evolved to osteosarcoma at the second relapse. Our objective was to characterize the molecular mechanisms of tumor progression associated with this phenotypic transformation. Methods: Tumor samples were collected at all 3 stages of disease and RNA sequencing was performed to capture their transcriptomic profiles. Sequential clonal evolution was confirmed by the maintenance of an identical PTEN mutation throughout the tumor differentiation using the TSO500 gene panel. Publicly available datasets and the Nanostring nCounter technology were used to validate the results. Results: The glioblastoma tumor from this patient possessed mixed features of all 3 TCGA-defined transcriptomic subtypes of an IDH-WT glioblastoma and a proportion of osteosarcoma signatures were upregulated in the original tumor. Analysis showed that enhanced transforming growth factor-ß (TGF-ß) and bone morphogenic protein signaling was associated with tumor transformation. Regulatory network analysis revealed that TGF-ß family signaling committed the lineage tumor to osteogenesis by stimulating the expression of runt-related transcription factor 2 (RUNX2), a master regulator of bone formation. Conclusions: This unusual clinical case provided an opportunity to explore the modulators of longitudinal sarcomatous transformation, potentially uncovering markers indicating predisposition to this change and identification of novel therapeutic targets.

Management of Idiopathic Vocal Process Granuloma: A Survey of Academic Laryngologists.

OBJECTIVES: Vocal process granulomas (VPGs) are benign laryngeal lesions that may manifest as ulcerated regions of the vocal fold or nodular polypoid lesions. Gold standard treatments for idiopathic VPG are yet to be established at this time. This study evaluated clinical decision-making and outcomes in the treatment of VPG patients based on experiences of academic laryngologists across the United States. METHODS: A 21-question survey was developed to evaluate each respondent's specific VPG patient population, clinical decision-making in treating VPG, and corresponding treatment outcomes. The survey was distributed to 168 laryngologists at academic institutions across the United States. Data were analyzed through the Qualtrics platform. RESULTS: A total of 106 responses were analyzed, with a completion rate of 63.1%. Etiology of VPG was most commonly attributed to phonotrauma (96.2%) and reflux (71.8%). Primary first-line treatment was most commonly antireflux medications (92%). Other common first line treatments included voice therapy (58.8%) and inhaled steroids (42.5%). With these treatments, the majority of laryngologists report that recurrence is uncommon (68.4%). Dysphonia was cited as the most frequent long-term sequelae at 27.8%. CONCLUSIONS: VPG treatment strategies continue to be controversial across the United States with many treatments described in the literature with variable application in the practice of academic laryngologists today. Based on survey results, antireflux medications and voice therapy may be the most widely used and most effective treatment options. Establishment of gold standard therapy for VPG as well as further research into recurrent or persistent VPG despite antireflux and voice therapy should be explored. LEVEL OF EVIDENCE: 5 Laryngoscope, 134:795-802, 2024.

Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib.

Isocitrate dehydrogenase (IDH)-mutant gliomas have distinctive metabolic and biological traits that may render them susceptible to targeted treatments. Here, by conducting a high-throughput drug screen, we pinpointed a specific susceptibility of IDH-mutant gliomas to zotiraciclib (ZTR). ZTR exhibited selective growth inhibition across multiple IDH-mutant glioma in vitro and in vivo models. Mechanistically, ZTR at low doses suppressed CDK9 and RNA Pol II phosphorylation in IDH-mutant cells, disrupting mitochondrial function and NAD+ production, causing oxidative stress. Integrated biochemical profiling of ZTR kinase targets and transcriptomics unveiled that ZTR-induced bioenergetic failure was linked to the suppression of PIM kinase activity. We posit that the combination of mitochondrial dysfunction and an inability to adapt to oxidative stress resulted in significant cell death upon ZTR treatment, ultimately increasing the therapeutic vulnerability of IDH-mutant gliomas. These findings prompted a clinical trial evaluating ZTR in IDH-mutant gliomas towards precision medicine ( NCT05588141 ). Highlights: Zotiraciclib (ZTR), a CDK9 inhibitor, hinders IDH-mutant glioma growth in vitro and in vivo . ZTR halts cell cycle, disrupts respiration, and induces oxidative stress in IDH-mutant cells.ZTR unexpectedly inhibits PIM kinases, impacting mitochondria and causing bioenergetic failure.These findings led to the clinical trial NCT05588141, evaluating ZTR for IDH-mutant gliomas.

Clinical impact of molecular profiling in rare brain tumors.

PURPOSE OF REVIEW: The purpose of this review is to describe the commonly used molecular diagnostics and illustrate the prognostic importance to the more accurate diagnosis that also may uncover therapeutic targets. RECENT FINDINGS: The most recent WHO Classification of Central Nervous System Tumours (2021) lists over 100 distinct tumor types. While traditional histology continues to be an important component, molecular testing is increasingly being incorporated as requisite diagnostic criteria. Specific molecular findings such as co-deletion of the short arm of chromosome 1 (1p) and long arm of chromosome 19 (19q) now define IDH-mutant gliomas as oligodendroglioma. In recent years, DNA methylation profiling has emerged as a dynamic tool with high diagnostic accuracy. The integration of specific genetic (mutations, fusions) and epigenetic (CpG methylation) alterations has led to diagnostic refinement and the discovery of rare brain tumor types with distinct clinical outcomes. Molecular profiling is anticipated to play an increasing role in routine surgical neuropathology, although costs, access, and logistical concerns remain challenging. SUMMARY: This review summarizes the current state of molecular testing in neuro-oncology highlighting commonly used and developing technologies, while also providing examples of new tumor types/subtypes that have emerged as a result of improved diagnostic precision.

Cost-effectiveness of internet-based HIV screening among gay, bisexual and other men who have sex with men (GBMSM) in Metro Vancouver, Canada.

BACKGROUND: GetCheckedOnline is an internet-based screening service aiming to increase HIV testing among gay, bisexual and other men who have sex with men (GBMSM). We assessed the cost-effectiveness of GetCheckedOnline in its first implementation phase at different uptake scenarios compared to clinic-based screening services alone in Metro Vancouver, Canada. METHODS: From a healthcare payer's perspective, our cost-utility analysis used an established dynamic GBMSM HIV compartmental model estimating the probability of acquiring HIV, progressing through diagnosis, disease stages and treatment over a 30-year time horizon. The base case scenario assumed 4.7% uptake of GetCheckedOnline in 2016 (remainder using clinic-based services), with 74% of high-risk and 44% of low-risk infrequent testers becoming regular testers in five years. Scenario analyses tested increased GetCheckedOnline uptake to 10% and 15%. RESULTS: The cost per test for GetCheckedOnline was $29.40 compared to clinic-based services $56.92. Compared with clinic-based screening services, the projected increase in testing frequency with 4.7% uptake of GetCheckedOnline increased the costs by $329,600 (95% Credible Interval: -$498,200, $571,000) and gained 4.53 (95%CrI: 0, 9.20) quality-adjusted life years (QALYs) in a 30-year time horizon. The probability of GetCheckedOnline being cost-effective was 34% at the threshold of $50,000 per QALY, and increased to 73% at the threshold of $100,000 per QALY. The results were consistent in the other uptake scenarios. The probability of GetCheckedOnline being cost-effective became 80% at the threshold of $50,000 per QALY if assuming 5-year time horizon. CONCLUSIONS: GetCheckedOnline is almost half the cost of clinic-based services on a per-test basis. However, increased access to testing should be balanced with risk profiles of patients to ensure the implementation can be a cost-effective strategy for increasing HIV screening among GBMSM in Metro Vancouver. Additional analyses are needed to understand the impact of internet-based screening including screening for other STIs and in other populations.

Distinct functions of wild-type and R273H mutant Δ133p53α differentially regulate glioblastoma aggressiveness and therapy-induced senescence.

Mutations effects on p53 isoforms' activities remain largely unknown, although they are mutated in 92% of TP53 mutant cancers. Therefore, exploring the effect of mutations on p53 isoforms activities is a critical, albeit unexplored area in the p53 field. In this article, we report for the first time a mutant Δ133p53α-specific pathway which increases IL4I1 and IDO1 expression and activates AHR, a tumor-promoting mechanism. Accordingly, mutant Δ133p53α R273H increases glioblastoma cancer cells proliferation and invasion while the WT does not. Furthermore, while WT Δ133p53α reduces apoptosis to promote DNA repair, the mutant also reduces apoptosis but fails to maintain genomic stability.Furthermore, both WT and mutant Δ133p53α reduce cellular senescence in a senescence inducer-dependent manner (temozolomide or radiation) because they regulate different senescence-associated target genes. Hence, WT Δ133p53α rescues temozolomide-induced but not radiation-induced senescence, while mutant Δ133p53α R273H rescues radiation-induced but not temozolomide-induced senescence. Lastly, using TCGA data, we determined that IL4I1, IDO1 and AHR are significantly higher in GBMs compared to LGGs. IL4I1 expression is increased in mutant TP53 LGGs and GBMs, although only significantly in LGG. Importantly, high expression of all three genes in LGG and IL4I1 in GBM is significantly associated with poorer patients' survival. These data show that, compared to WT Δ133p53α, R273H mutation reorientates its activities toward carcinogenesis and activates the oncogenic IL4I1/IDO1/AHR pathway, a potential prognostic marker and therapeutic target in GBM by combining drugs specifically modulating Δ133p53α expression and IDO1/Il4I1/AHR inhibitors.

Capturing evolving definitions of 12 select rare CNS tumors: a timely report from CBTRUS and NCI-CONNECT.

PURPOSE: Incidence, prevalence, and survival are population-based statistics describing cancer burden. The National Cancer Institute's (NCI) Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) specializes in tumor biology and outcomes for 12 rare CNS tumor types selected for their importance in adults, research interest, or potential for targeted treatment. The aim of this study was to update incidence, prevalence, and survival statistics for these tumors. METHODS: The Central Brain Tumor Registry of the United States (CBTRUS) database, a combined dataset of Centers for Disease Control and Prevention's (CDC) National Program of Cancer Registries (NPCR) and NCI's Surveillance, Epidemiology and End Results (SEER) data, was used to calculate average annual age-adjusted incidence rates (AAAIR) per 100,000 population overall and by sex, race-ethnicity, and age for diagnosis years 2008-2019. Incidence time trends were calculated for diagnosis years 2004-2019. NPCR data were used to calculate relative survival rates. Point prevalence on December 31, 2019 was estimated using annual age-specific incidence and survival. RESULTS: AAAIR was 1.47 per 100,000 for these tumors combined, with highest incidence in ependymomas (AAAIR = 0.41/100,000). Most tumor types were more common in males, adults (ages 40 + years) or children (ages < 15 years), and non-Hispanic White individuals. Ependymomas were the most prevalent tumor type (19,320 cases) followed by oligodendrogliomas (14,900 cases). Ependymomas had the highest five-year survival (90.6%) and primary CNS sarcomas the lowest (7.7%). CONCLUSIONS: These data provide means to measure the impact of clinical care and evaluate new therapies and the evolving histopathology definitions in rare CNS tumor types.