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For three years, COVID-19 has circulated among our communities and around the world, fundamentally changing social interactions, health care systems, and service delivery. For people living with (and receiving treatment for) cancer, pandemic conditions presented significant additional hurdles in an already unstable and shifting environment, including disrupted personal contact with care providers, interrupted access to clinical trials, distanced therapeutic encounters, multiple immune vulnerabilities, and new forms of financial precarity. In a 2020 perspective in this journal, we examined how COVID-19 was reshaping cancer care in the early stages of the pandemic and how these changes might endure into the future. Three years later, and in light of a series of interviews with patients and their caregivers from the United States and Australia conducted during the pandemic, we return to consider the potential legacy effects of the pandemic on cancer care. While some challenges to care provision and survivorship were unforeseen, others accentuated and amplified existing problems experienced by patients, caregivers, and health care providers. Both are likely to have enduring effects in the “post-pandemic” world, raising the importance of focusing on lessons that can be learned for the future.

Endocytosis requires a coordinated framework of molecular interactions that ultimately lead to the fission of nascent endosomes. How cytosolic proteins, such as dynamin, timely concentrate at discrete sites that are sparsely distributed across the plasma membrane remains poorly understood. Two dynamin 1 (Dyn1) major splice variants differ by the length of their C-terminal proline-rich region (short-tail and long-tail). Using sptPALM in PC12 cells, neurons and MEF cells, we demonstrate that short-tail Dyn1 isoforms Dyn1ab and Dyn1bb display an activity-dependent recruitment to the membrane, promptly followed by concentration into nanoclusters. These nanoclusters were sensitive to both Calcineurin and Dyn1 GTPase inhibitors, and were larger, denser, and more numerous than that of long-tail isoform Dyn1aa. Spatiotemporal modelling confirmed that Dyn1 isoforms perform distinct search patterns and undergo dimensional reduction to generate endocytic nanoclusters, with short-tail isoforms more robustly exploiting lateral trapping in the generation of nanoclusters compared to long-tail isoform Dyn1aa.

Context is a critical determinant of the effectiveness of quality improvement programs. We assessed the role of contextual factors in influencing the efforts of 5 diverse quality improvement projects as part of the Pediatric Quality Measure Program (PQMP) directed by the Agency for Health Care Research and Quality.We conducted a mixed methods study of 5 PQMP grantees involving semistructured interviews followed by structured worksheets to identify influential contextual factors. Semistructured interviews and worksheets were completed between August and October 2020. Participants were comprised of PQMP grantee teams (2-4 team members per team for a total of 15 participants). Coding and analysis was based on the Tailored Implementation for Chronic Diseases (TICD) framework.Despite heterogeneity in the process and outcome targets of the PQMP initiatives, professional interactions, incentives and resources, and capacity for organizational change were the domains most commonly identified as influential across the grantees. While social, political, and legal factors was not commonly referenced as an important domain, payer or funder policies (a factor within this domain) was highlighted as one of the most influential factors. Overall, the incentives and resources domain was identified as the most influential.We found that using a determinant framework, such as the TICD, is valuable in facilitating comparisons across heterogeneous projects, allowing us to identify key contextual factors influencing the implementation of pediatric quality measures across a diverse range of clinical topics and settings. Future quality improvement work should account for this and include resources to support infrastructure development in addition to program implementation.

Since its inception, the Pediatric Quality Measures Program has focused on the development and implementation of new and innovative pediatric quality measures (PQM) for both public and private use. Building the evidence base related to measure usability and feasibility is central to increasing measure uptake and, thereby, to increased performance monitoring and quality improvement (QI) for children in Medicaid or the Children's Health Insurance Program. This paper describes key stakeholder insights focused on measure implementation and increasing the uptake of PQM.The PQMP Learning Collaborative conducted semistructured interviews with 9 key informants (KIs) representing states, health plans, and other potential end users of the measures. The interviews focused on gaining KIs' perspectives on 6 research questions focused on assessing the feasibility and usability of PQM and strengthening the connection between measurement and improvement.Our synthesis identified insights that highlight facilitators and barriers from the KIs' experience and the strategies they employ when using measures to drive improvement "on-the-ground." Importantly, while the KIs agreed on how essential the research questions are to measure implementation and uptake, they uniformly acknowledged the complexity of the issues raised and pinpointed multiple unresolved issues.The views expressed by these stakeholders point to several key issues - including incorporation of socio-economic status into quality measures and performance comparisons, use of benchmark data, and criteria for QI versus accountability - for developing a real-world research agenda to guide the future direction of quality measurement and implementation to improve children's health care.

Context Critically ill patients with brain metastases (BM) face significant uncertainty regarding prognosis and survival and can benefit from Palliative care (PC). However, research regarding the role of PC in this population is lacking. Objectives We sought to compare BM patients admitted to an intensive care unit who received an inpatient PC consult (PC cohort) to those who did not (Usual Care, UC cohort). Methods We performed a single-institution retrospective cohort analysis. Our outcome variables were mortality, time from intensive care unit admission to death, disposition, and change in code status. We also evaluated PC's role in complex medical decision making, symptom management and hospice education. Results PC consult was placed in 31 of 118 (28%) of patients. The overall mortality rates were not statistically different (78.8% vs. 90.3%, P= 0.15, UC vs. PC cohort). Patients in the PC cohort had a shorter time to death, higher rate of death within 30 days of admission, increased rate of discharge to hospice, and increase percentage of code status change to “do not attempt resuscitation” during the admission. The primary services provided by PC were symptom management (n = 21, 67.7%) and assistance in complex medical decision making (n = 20, 64.5%). Conclusion In our patient cohort, PC is an underutilized service that can assist in complex medical decision making and symptom management of critically ill BM patients. Further prospective studies surveying patient, family and provider experiences could better inform the qualitative impact of PC in this unique patient population.

People living with HIV (PLWH) on suppressive antiretroviral therapy (ART) can have residual immune dysfunction and often display poorer responses to vaccination. We assessed in a cohort of PLWH (n=110) and HIV negative controls (n=64) the humoral and spike-specific B-cell responses following 1, 2 or 3 SARS-CoV-2 vaccine doses. PLWH had significantly lower neutralizing antibody (nAb) titers than HIV-negative controls at all studied timepoints. Moreover, their neutralization breadth was reduced with fewer individuals developing a neutralizing response against the Omicron variant (BA.1) relative to controls. We also observed a delayed development of neutralization in PLWH that was underpinned by a reduced frequency of spike-specific memory B cells (MBCs) and pronounced B cell dysfunction. Improved neutralization breadth was seen after the third vaccine dose in PLWH but lower nAb responses persisted and were associated with global, but not spike-specific, MBC dysfunction. In contrast to the inferior antibody responses, SARS-CoV-2 vaccination induced robust T cell responses that cross-recognized variants in PLWH. Strikingly, a subset of PLWH with low or absent neutralization had detectable functional T cell responses. These individuals had reduced numbers of circulating T follicular helper cells and an enriched population of CXCR3+CD127+CD8+T cells after two doses of SARS-CoV-2 vaccination, which may compensate for sub-optimal serological responses in the event of infection. Therefore, normalisation of B cell homeostasis could improve serological responses to vaccines in PLWH and evaluating T cell immunity could provide a more comprehensive immune status profile in these individuals and others with B cell imbalances.

We assessed a cohort of people living with human immunodeficiency virus (PLWH) (n = 110) and HIV negative controls (n = 64) after 1, 2 or 3 SARS-CoV-2 vaccine doses. At all timepoints, PLWH had significantly lower neutralizing antibody (nAb) titers than HIV-negative controls. We also observed a delayed development of neutralization in PLWH that was underpinned by a reduced frequency of spike-specific memory B cells (MBCs). Improved neutralization breadth was seen against the Omicron variant (BA.1) after the third vaccine dose in PLWH but lower nAb responses persisted and were associated with global MBC dysfunction. In contrast, SARS-CoV-2 vaccination induced robust T cell responses that cross-recognized variants in PLWH. Strikingly, individuals with low or absent neutralization had detectable functional T cell responses. These PLWH had reduced numbers of circulating T follicular helper cells and an enriched population of CXCR3+CD127+CD8+T cells after two doses of SARS-CoV-2 vaccination.

Objectives There is increasing evidence to suggest that people living with HIV (PLWH) have significant morbidity from alcohol, recreational drug use and cigarette smoking. Our aim was to report associations of these factors with antiretroviral therapy (ART) non-adherence, viral non-suppression and subsequent viral rebound in PLWH. Methods The Antiretroviral Sexual Transmission Risk and Attitudes (ASTRA) study recruited PLWH attending eight outpatient clinics in England between February 2011 and December 2012. Data included self-reported excessive drinking (estimated consumption of > 20 units of alcohol/week), alcohol dependency (CAGE score ≥ 2 with current alcohol consumption), recreational drug use (including injection drug use in the past 3 months), and smoking status. Among participants established on ART, cross-sectional associations with ART non-adherence [missing ≥2 consecutive days of ART on ≥2 occasions in the past three months] and viral-non suppression [viral load (VL) > 50 copies/mL] were assessed using logistic regression. In participants from one centre, longitudinal associations with subsequent viral rebound (first VL > 200 copies/mL) in those on ART with VL ≤ 50 copies/mL at baseline were assessed using Cox regression during a 7-year follow-up. Results Among 3258 PLWH, 2248 (69.0%) were men who have sex with men, 373 (11.4%) were heterosexual men, and 637 (19.6%) were women. A CAGE score ≥ 2 was found in 568 (17.6%) participants, 325 (10.1%) drank > 20 units/week, 1011 (31.5%) currently smoked, 1242 (38.1%) used recreational drugs and 74 (2.3%) reported injection drug use. In each case, prevalence was much more common among men than among women. Among 2459 people on ART who started at least 6 months previously, a CAGE score ≥ 2, drinking > 20 units per week, current smoking, injection and non-injection drug use were all associated with ART non-adherence. After adjusting for demographic and socioeconomic factors, CAGE score ≥ 2 [adjusted odds ratio (aOR) = 1.52, 95% confidence interval (CI): 1.09-2.13], current smoking (aOR = 1.58, 95% CI: 1.10-2.17) and injection drug use (aOR = 2.11, 95% CI: 1.00-4.47) were associated with viral non-suppression. During follow-up of a subset of 592 people virally suppressed at recruitment, a CAGE score ≥ 2 [adjusted hazard ratio (aHR) = 1.66, 95% CI: 1.03-2.74], use of 3 or more non-injection drugs (aHR = 1.82, 95% CI: 1.12-3.57) and injection drug use (aHR = 2.73, 95% CI: 1.08-6.89) were associated with viral rebound. Conclusions Screening and treatment for alcohol, cigarette and drug use should be integrated into HIV outpatient clinics, while clinicians should be alert to the potential for poorer virological outcomes.

Background Published literature on health care administration, management, and leadership and its impacts on health systems' programs to address health care inequities is limited, as is information about how organizations integrate health equity in their cultures, missions, and strategic plans. Purpose The aims of this study were to identify the key components necessary for health systems to implement systematic organizational change to promote health equity and to describe approaches organizations have implemented. Methodology/approach We conducted an environmental scan to identify central principles for implementing lasting change in health systems and experts working to advance health equity through organizational change. We interviewed 19 experts in health equity and hospital executives in 2020. Using iterative thematic analysis, we identified common themes. Results Consistent with the literature on organizational change, interviewees described a variety of systematic approaches to change, all of which involve the following core components: (a) committed and engaged leadership; (b) integrated organizational structure; (c) commitment to quality improvement and patient safety; (d) ongoing training and education; (e) effective data collection and analytics; and (f) stakeholder communication, engagement, and collaboration. Conclusion and practice implications There is no "one-size-fits-all" approach to advancing health equity. Decisions about which components require the most attention vary depending on an organization's internal and external environment. Understanding those environments and identifying which levers will be most effective are essential. As provider organizations strive to develop more strategic and systematic approaches to addressing disparities, long-term vision and commitment are necessary to achieve sustainable organizational change.

The production and use of the highly addictive stimulant methamphetamine are a serious public health problem in the USA and globally. Because of its increased popularity with recreational drug users, accidental or intentional poisoning incidents in companion animals have become an unavoidable scenario in veterinary medicine. We describe a case of methamphetamine poisoning in a 4-year-old female German Shepherd, with postmortem analytical quantitation of methamphetamine and its metabolite, amphetamine, in bodily tissues and fluids. Many tissues and bodily fluids can be tested to confirm methamphetamine exposure. More importantly, the higher concentrations found in stomach contents and liver, kidney and heart tissues suggest these are the most useful diagnostic specimens for postmortem confirmation of toxicosis in pets, especially in cases in which the source material is not available for testing or in cases with no postmortem evaluation.

BACKGROUND Older age is a poor prognostic factor for glioblastoma (GBM) patients. We tested whether the intrinsic molecular landscape of the tumor may contribute to this poor prognosis. METHODS In accordance with the 2021 WHO classification scheme, we included only isocitrate dehydrogenase (IDH) wild type GBM. Based on published literature, we defined older as age > 65. RNA expression, gene amplification, tumor mutational burden (TMB) and mutational profiles were analyzed in three unique datasets: Tempus (n = 1,410), Caris (n = 1,432), and TCGA (n = 557). Comparison were made between < 65 and ³ 65 year olds using Pearson’s Chi-squared tests, Fisher’s exact tests, or Wilcoxon rank-sum where appropriate. RESULTS From our evaluable gene sets, TERT promoter mutations were more prevalent in patients ³ 65 years old (Caris 82.64 vs 77.27%, p = 0.016; Tempus 58.0 vs 49.0%, p = 0.002). There were no significant differences in PDCD1, CD274, CD3E, TNFRSF18, CD40, CD8A, TNFRSF4, CTLA4, HAVCR2, TNFSF9, CD274, or CDKN2A; PDL-1 (by IHC); dMMR/MSI-H, TMB; CDK6 amplification, EGFR amplification, EGFR, EGFRvIII, EGFR fusions, MET fusions, PTEN, TP53, or NF-1. MGMT promoter methylation (Caris data) was more common in the older group (49.73 v 34.14%, p < 0.001). TGCA data demonstrated that gene expression, TMB, and methylation did not change significantly with age. Additionally, PCOLCE2 and SLC10A4 were differentially methylated, and missense mutations, of any type, were more common in the older group (p=0.006). CONCLUSION Despite worse survival outcomes for older patients with IDHwt GBM as compared to younger counterparts, the molecular landscape is similar at the genomic, transcriptomic and epigenomic levels. The key exception is TERT promoter mutations that are more common in older GBM patients. Poorer survival is therefore not likely to be attributable solely to intratumoral factors.

BACKGROUND COVID-19 radically changed neuro-oncology care. In this retrospective study, we examine the impact of COVID-19 infection on neuro-oncological care and clinical outcomes in two geographically separate populations. METHODS Descriptive statistics compared demographic and clinical history extracted from the medical records of COVID-19 positive patients with primary brain tumors treated between 3/1/2020 and 3/31/2021. All subjects were unvaccinated given our cohort pre-dates the ubiquitous availability of vaccines. Patients were treated at Washington University (WashU) in St. Louis, MO and Duke University in Durham, NC. Each site’s respective institutional review board approved the study, with a data transfer agreement in place. RESULTS We identified 62 total (WashU=13; Duke=49) subjects with positive COVID-19 infection. Patients were predominantly white (85.5%), male (56.5%), with KPS >=70 (82.3%) and never smoked (69.4%). WashU patients tended to be older with grade 4 tumors, but this was not significant. At the time of COVID infection 35.5% of patients were receiving cancer-directed therapy. Notably, 37.1% experienced delayed care due to a COVID-19 diagnosis, most often for scheduled systemic treatment or radiation treatment. A further 37.1% had an ER visit, hospitalization, or ICU stay attributed to COVID-19. Of the 17 patients who died during the study period, 4 deaths were attributed directly to COVID-19 and not to their underlying brain tumor or other cause. Finally, telehealth use differed between sites (84.6% at WashU vs 14.3% at Duke). However, this difference could not be attributed to patient age, performance status, or distance from treating institution. CONCLUSION COVID-19 infection led to treatment delays and death for a subset, but not the majority of neuro-oncology patients. Telehealth use varied between sites and was not associated with commonly held assumptions about patient distance or performance status, suggesting evolving practice norms following telehealth’s introduction. Study limitations include a small sample size

Objective: We investigated differences in all-cause hospitalization between key demographic groups among people with HIV in the UK in the current antiretroviral therapy (ART) era. Design/Methods: We used data from the Royal Free HIV Cohort study between 2007 and 2018. Individuals were classified into five groups: MSM, Black African men who have sex with women (MSW), MSW of other ethnicity, Black African women and women of other ethnicity. We studied hospitalizations during the first year after HIV diagnosis (Analysis-A) separately from those more than one year after diagnosis (Analysis-B). In Analysis-A, time to first hospitalization was assessed using Cox regression adjusted for age and diagnosis date. In Analysis-B, subsequent hospitalization rate was assessed using Poisson regression, accounting for repeated hospitalization within individuals, adjusted for age, calendar year, time since diagnosis. Results: The hospitalization rate was 30.7/100 person-years in the first year after diagnosis and 2.7/100 person-years subsequently; 52% and 13% hospitalizations, respectively, were AIDS-related. Compared with MSM, MSW and women were at much higher risk of hospitalization during the first year [aHR (95% confidence interval, 95% CI): 2.7 (1.7–4.3), 3.0 (2.0–4.4), 2.0 (1.3–2.9), 3.0 (2.0–4.5) for Black African MSW; other ethnicity MSW; Black African women; other ethnicity women respectively, Analysis-A] and remained at increased risk subsequently [corresponding aIRR (95% CI): 1.7 (1.2–2.4), 2.1 (1.5–2.8), 1.5 (1.1–1.9), 1.7 (1.2–2.3), Analysis-B]. Conclusion: In this setting with universal healthcare, substantial variation exists in hospitalization risk across demographic groups, both in early and subsequent periods after HIV diagnosis, highlighting the need for targeted interventions.

The aims of the study were to describe the prevalence of obesity in the Pharmacokinetic and Clinical Observations in People over Fifty (POPPY) cohort, to identify demographic, clinical and HIV-specific factors associated with obesity, and to characterize the association between obesity and sociodemographic, clinical and HIV-specific factors and quality of life (QoL).A cross-sectional analysis was carried out of baseline data from the three groups ["older" people with HIV infection (PWH) aged ≥ 50 years, "younger" PWH aged50 years and HIV-negative controls aged ≥ 50 years] within the POPPY cohort. Obesity was defined as a body mass index (BMI) 30 kg/mA total of 1361 subjects were included in the study, of whom 335 (24.6%) were obese. The prevalence of obesity was higher in controls (22.3%) than in older (16.8%) and younger (14.2%) PWH, with no differences between the two groups of PWH. Factors associated with obesity were older age, female gender, black African ethnicity and alcohol consumption. Recreational drug use and a higher current CD4 T-cell count (in PWH) were associated with lower and higher odds of being obese, respectively. The presence of obesity was associated with worse physical health QoL scores, higher odds of having cardiovascular disease, type 2 diabetes and hypertension, but lower odds of having osteopenia/osteoporosis, irrespective of HIV status.Despite a lower prevalence of obesity in PWH, specific subgroups (women, people of black African origin and older people) were more likely to be obese, and negative health consequences of obesity were evident, regardless of HIV status. Whether targeted preventive strategies can reduce the burden of obesity and its complications in PWH remains to be determined.

Primary central nervous system lymphoma (PCNSL) is a subtype of non-Hodgkin’s lymphoma that involves the brain, spinal cord, or leptomeninges, without evidence of systemic disease. This rare disease accounts for ~ 3% of all primary central nervous system (CNS) tumors. Methotrexate-based regimens are the standard of care for this disease with overall survival rates ranging from 14 to 55 months. Relapse after apparent complete remission can occur. We sought to understand the outcomes of patients who relapsed. This is an IRB-approved investigation of patients treated at our institution between 12/31/2004 and 10/12/2016. We retrospectively identified all cases of PCNSL as part of a database registry and evaluated these cases for demographic information, absence or presence of relapse, location of relapse, treatment regimens, and median relapse-free survival. This analysis identified 44 patients with a pathologically confirmed diagnosis of PCNSL. Mean age at diagnosis was 63.1 years (range 20–86, SD = 13.2 years). Of the 44 patients, 28 patients successfully completed an initial treatment regimen without recurrence or toxicity that required a change in therapy. Relapse occurred in 11 patients with the location of relapse being in the CNS only (n = 5), vitreous fluid only (n = 1), outside CNS only (n = 3), or a combination of CNS and outside of the CNS (n = 2). Sites of relapse outside of the CNS included testes (n = 1), lung (n = 1), adrenal gland (n = 1), kidney/adrenal gland (n = 1), and retroperitoneum (n = 1). Median relapse-free survival after successful completion of therapy was 6.7 years (95% CI 1.1, 12.6). After successful initial treatment, PCNSL has a propensity to relapse, and this relapse can occur both inside and outside of the CNS. Vigilant monitoring of off-treatment patients with a history of PCNSL is necessary to guide early diagnosis of relapse and to initiate aggressive treatment.

In the NEAT022 trial, virologically suppressed persons with HIV at high cardiovascular risk switching from protease inhibitors to dolutegravir either immediately (DTG-I) or after 48 weeks (DTG-D) showed non-inferior virological suppression and significant lipid and CVD risk reductions on switching to dolutegravir relative to continuing protease inhibitors.Post-hoc analysis. Major endpoints were 48-week and 96-week weight and body mass index (BMI) changes. Factors associated with weight/BMI changes within the first 48 weeks of DTG exposure, proportion of participants by category of percent weight change, proportions of BMI categories over time, and impact on metabolic outcomes were also assessed.Between May/2014 and November/2015, 204 (DTG-I) and 208 (DTG-D) participants were included. Weight significantly increased (mean +0.810 kg DTG-I arm, and +0.979 kg DTG-D arm) in the first 48 weeks post-switch, but remained stable from 48 to 96 weeks in DTG-I arm. Switching from darunavir, white race, total-to-HDL cholesterol ratio3.7, and normal/underweight BMI were independently associated with higher weight/BMI gains. The proportion of participants with ≥5% weight change increased similarly in both arms over time. The proportions of BMI categories, use of lipid-lowering drugs, diabetes and/or use of antidiabetic agents, and hypertension and/or use of antihypertensive agents did not change within or between arms at 48 and 96 weeks.Switching from protease inhibitors to dolutegravir in persons with HIV with high cardiovascular risk led to modest weight gain limited to the first 48 weeks which involved preferentially normal-weight or underweight persons and was not associated with negative metabolic outcomes.

BACKGROUND Nivolumab is a PD-1 inhibitor with known safety profile. An increase in mutations as we age is well documented in glioblastoma and other cancers. Higher mutational load is associated with increased response to nivolumab in extracranial malignancies. NUTMEG examined the activity of nivolumab added to temozolomide in glioblastoma patients aged ≥ 65 years. METHODS NUTMEG was an international multicenter phase II trial for newly diagnosed glioblastoma patients aged ≥ 65 years, randomized 2:1 to experimental (40Gy/15 fractions with temozolomide 75mg/m2, then 6 cycles of temozolomide 150-200mg/m2 D1-5 Q28D + nivolumab 240mg D1,15 Q28D C1-4 and 480mg D1 Q28D C5-6) versus standard arm (40Gy/15 fractions with temozolomide 75mg/m2, then 6 cycles of temozolomide alone 150-200mg/m2 D1-5 Q28D), stratified by age, ECOG status, MGMT status and resection extent. RESULTS 103 patients were enrolled (69 in experimental arm, 34 in standard arm). Median age was 73 years, 36% ECOG 0, 57% MGMT-unmethylated and 51% gross macroscopic resection. Median follow-up is 31 months to date, with 77 deaths (surviving patients to continue follow-up and final results will be presented). Median overall survival was 11.8 months in the experimental arm versus 12.0 months in the standard arm (HR 0.95 95%CI 0.59-1.53 for experimental relative to control). Six-month progression-free survival rate using mRANO was 64% in the experimental arm versus 49% in the standard arm (HR 0.81 95%CI 0.51-1.26). Grade 3/4 adverse events were reported in 46% of experimental arm (7% lung infection, 7% thromboembolic events, 6% fatigue, 6% muscle weakness) and in 29% of control arm (9% fatigue, 6% seizure, 6% thromboembolic events). CONCLUSIONS There was insufficient evidence of clinical benefit with nivolumab in this population. No new safety signals were identified. Central imaging review is underway and correlative studies will characterize the immune landscape, including mutational load, neoantigen and other immune markers. NCT04195139.

BACKGROUND D2C7-IT, a novel immunotoxin-based cytotoxic therapy, targets epidermal growth factor receptor (EGFR) and mutant EGFR variant III. In preclinical studies, D2C7-IT kills tumor cells and prolongs survival, but is unable to generate cures in all animals. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. Eliminating glioblastoma immunosuppression via CD40 co-stimulation is anticipated to enhance D2C7-IT-induced antitumor responses. In murine glioma models, CED of D2C7-IT+αCD40 generated cures and long-term tumor-specific adaptive immunity. Hence, we are conducting a phase 1 trial of D2C7-IT+2141-V11 (αhuman-CD40) administered via CED in rMG patients. METHODS Eligibility includes adult patients with solitary supratentorial rMG (WHO grade 3/4); ≥ 4 weeks after chemotherapy, bevacizumab, or study drug; adequate organ function; and KPS ≥ 70%. Cohorts of 3 patients are treated with increasing doses of 2141-V11 to determine the maximum tolerated dose when administered sequentially following D2C7-IT (166,075 ng) via CED at 0.5 mL/hr. Five dose levels (DLs) are evaluated (2141-V11 at: #1: 0.70 mg; #2: 2.0 mg; #2**: 3.0 mg #2*: 4.0 mg; #3: 7.0 mg). RESULTS As of May 29, 2022, 13 patients were treated (3 patients on DL1, DL2, and DL2**; 2 patients on DL3 and DL2*). No dose-limiting toxicities were observed; however, lower DLs were added due to higher frequency of adverse events (AEs) expected with D2C7-IT+2141-V11 with DL3 and DL2* (fever, neurologic symptoms). All patients remain alive 0.7-10.6 months after therapy. Grade ≥ 2 AEs due to D2C7-IT+2141-V11 include: headache (grade 3, n = 1; grade 2, n = 4); pyramidal tract disorder (grade 3, n = 1; grade 2, n = 2); paresthesia (grade 3, n = 1); dysphasia (grade 3, n = 1); seizures (grade 2; n = 2); fever (grade 2; n = 2); and one each of grade 2 depressed level of consciousness, fatigue, and concentration impairment. Enrollment is ongoing. CONCLUSIONS Intratumoral administration of D2C7-IT+2141-V11 via CED is safe, encouraging efficacy results are observed.

OBJECTIVE The median age of onset for glioblastoma (GBM; IDHwt) is 68-70 years. Age is a strong prognostic factor for GBM patient outcomes such that overall survival in older adults is less than their younger counterparts – even after adjustment for MGMT promoter methylation status. Aging is associated with increased levels of senescence in the brain. Several age-related neurological disorders have been shown to improve with senolytic treatments. Here, we explored the effects and therapeutic neutralization of syngeneic brain tumors on increasing senescence levels in the extratumoral brain (ie. outside of the brain tumor) of young and old mice. METHODS General RNA-sequencing, as well as single-cell (sc) RNA-sequencing was performed on extratumoral tissue from young (8-12 weeks) and older adult (80-90 weeks) C57BL/6 mice with or without GL261 and key markers were validated with RT-PCR. The combined effects of the senolytics, dasatinib and quercetin, with radiation, anti-PD-1 mAb, and IDO enzyme inhibitor treatment, was also investigated. RESULTS General- and sc-RNA sequencing revealed a distinct gene expression profile in the extratumoral brain of older mice with syngeneic GL261 as compared to all other groups. RT-PCR results confirmed that the brain tumor increased gene expression for senescence levels, p53, and NFkB signaling in the older adult extratumoral brain. Expression of the senescence marker p16INK4A was primarily localized to oligodendrocyte progenitor cells in the older adult brain. The combinatorial treatment of senolytics with RT, anti-PD-1 mAb, and IDO enzyme inhibitor led to a synergistic survival benefit in older adult mice with GL261 as compared to the treatment with senolytics, or immunotherapy, alone. CONCLUSIONS The data suggest that the extratumoral brain may be responsible in-part for the poorer outcomes of older adults with GBM and that treatment approaches that target senescent cells may provide clinical benefit.

BACKGROUND Nausea and vomiting remain the most feared cancer treatment-related side effects. Trials establishing antiemetic guidelines exclude malignant glioma (MG) patients. In MG patients receiving radiation with concurrent temozolomide, chemoradiation-induced nausea and vomiting (cRINV) rates are 35 and 26%, respectively, which reduce quality of life, treatment adherence, and potentially cancer control.OBJECTIVES: In a randomized phase II open label trial, we compared patient satisfaction and efficacy of ondansetron monotherapy (short-acting 5HT3-RA; 3h half-life) vs. rolapitant (long-acting NK1-RA; 180h half-life) plus ondansetron in preventing cRINV during 6-weeks of daily temozolomide (75 mg/m2/dX42d) with radiation. METHODS Fifty-three eligible patients receiving chemoradiation were randomized to Arm-A (ondansetron 8mg Days 1-42, rolapitant 180mg on Day 21) or Arm-B (rolapitant on Day 1 plus daily ondansetron). Primary endpoint included the percentage achieving cRINV-complete response (CR; no vomiting or antiemetic rescue) during the first 2-weeks of radiation. Secondary endpoints included cRIN/cRIV rates, preference for rolapitant plus ondansetron, and toxicity. RESULTS Forty-eight initiated protocol treatment. Mean age=53, 58% male, median KPS 90%, 71% low alcohol N/V risk factor, 73% glioblastoma. During the first 2-weeks of radiation, cRINV-CR was 60% for 25 evaluable patients receiving ondansetron monotherapy and 65% for 23 receiving rolapitant/ondansetron (p< 0.71). Patient-reported cRINV-CR was 61% and 74%, respectively (p< 0.41); cRIN rates (44% Arm-A; 53% Arm-B) were more than cRIV rates (28% Arm-A; 11% Arm-B). More patients receiving ondansetron alone vomited the first 2-weeks (22%) than with rolapitant/ondansetron (0%); p< 0.05. Among 32 patients who completed the study, patients preferred ondansetron (63%) over rolapitant/ondansetron (19%); p< 0.0039; 19% had no preference. Adverse events attributable to antiemetic treatment (fatigue/constipation) were all grade 1-2. CONCLUSIONS While patients prefer ondansetron monotherapy, there was no difference in cRINV-CR between the first 2-week treatments and some had less vomiting with rolapitant plus ondansetron. We will present overall N/V results.

Context Breakthrough pain (BTP) is common in cancer and other conditions yet there is a lack of validated BTP measurement tools. Objectives We aimed to identify all tools assessing or characterising BTP in patients of any age with any condition, and to critically appraise their psychometric properties. Methods The Cochrane Library, PROSPERO, Embase, CINAHL, Medline, PsycINFO, Web of Science, Google Scholar, ProQuest, Evidence Search and OpenGrey were searched to identify all available tools used to assess BTP. A second search identified studies that had evaluated psychometric properties of tools identified in Search 1. Databases were searched from inception to November 2020. Studies were assessed using COSMIN criteria and GRADE guidelines. Results Search 1 found 51 tools used to assess BTP. Search 2 found six tools that had a development study and/or a study evaluating a tool psychometric property. No tool had more than one study evaluating psychometric properties so a meta-analysis could not be conducted. Studies were of inadequate to very good quality. Only the Breakthrough Pain Assessment Tool (BAT) had sufficient content validity and at least low-quality evidence for sufficient internal consistency. Conclusion The BAT is recommended to characterise BTP in adults with cancer; its applicability to other conditions is unknown. The remaining tools need further evaluation. Only the Breakthrough Pain Questionnaire for Children was designed for children with cancer, but no psychometric properties were evaluated. There is a need for a tool to assess and characterise BTP in children with non-cancer diagnoses and those who cannot self-report.

Clathrin-coated structures must assemble on cell membranes to internalize receptors, with the clathrin protein only linked to the membrane via adaptor proteins. These structures can grow surprisingly large, containing over 20 clathrin, yet they often fail to form productive vesicles, instead aborting and disassembling. We show that clathrin structures of this size can both form and disassemble spontaneously when adaptor protein availability is low, despite high abundance of clathrin. Here, we combine recent in vitro kinetic measurements with microscopic reaction-diffusion simulations and theory to differentiate mechanisms of stable vs unstable clathrin assembly on membranes. While in vitro conditions drive assembly of robust, stable lattices, we show that concentrations, geometry, and dimensional reduction in physiologic-like conditions do not support nucleation if only the key adaptor AP-2 is included, due to its insufficient abundance. Nucleation requires a stoichiometry of adaptor to clathrin that exceeds 1:1, meaning additional adaptor types are necessary to form lattices successfully and efficiently. We show that the critical nucleus contains ~25 clathrin, remarkably similar to sizes of the transient and abortive structures observed in vivo. Lastly, we quantify the cost of bending the membrane under our curved clathrin lattices using a continuum membrane model. We find that the cost of bending the membrane could be largely offset by the energetic benefit of forming curved rather than flat structures, with numbers comparable to experiments. Our model predicts how adaptor density can tune clathrin-coated structures from the transient to the stable, showing that active energy consumption is therefore not required for lattice disassembly or remodeling during growth, which is a critical advance towards predicting productive vesicle formation.

Objective\udHIV-remission strategies including kick-and-kill could induce viral transcription and immune-activation in the central nervous system, potentially causing neuronal injury. We investigated the impact of kick-and-kill on plasma neurofilament light (NfL), a marker of neuro-axonal injury, in RIVER trial participants commencing antiretroviral treatment (ART) during primary infection and randomly allocated to ART-alone or kick-and-kill (ART + vaccination + vorinostat (ART + V + V)).\ud\udDesign\udSub-study measuring serial plasma NfL concentrations.\ud\udMethods\udPlasma NfL (using Simoa digital immunoassay), plasma HIV-1 RNA (using single-copy assay) and total HIV-1 DNA (using quantitative polymerase chain reaction in peripheral CD4+ T-cells) were measured at randomisation (following ≥22 weeks ART), week 12 (on final intervention day in ART + V + V) and week 18 post-randomisation. HIV-specific T-cells were quantified by intracellular cytokine staining at randomisation and week 12. Differences in plasma NfL longitudinally and by study arm were analysed using mixed models and Student's t-test. Associations with plasma NfL were assessed using linear regression and rank statistics.\ud\udResults\udAt randomisation, 58 male participants had median age 32 years and CD4+ count 696 cells/μL. No significant difference in plasma NfL was seen longitudinally and by study arm, with median plasma NfL (pg/mL) in ART-only vs ART + V + V: 7.4 vs 6.4, p = 0.16 (randomisation), 8.0 vs 6.9, p = 0.22 (week 12) and 7.1 vs 6.8, p = 0.74 (week 18). Plasma NfL did not significantly correlate with plasma HIV-1 RNA and total HIV-1 DNA concentration in peripheral CD4+ T-cells at any timepoint. While higher HIV-specific T-cell responses were seen at week 12 in ART + V + V, there were no significant correlations with plasma NfL. In multivariate analysis, higher plasma NfL was associated with older age, higher CD8+ count and lower body mass index.\ud\udConclusions\udDespite evidence of vaccine-induced HIV-specific T-cell responses, we observed no evidence of increased neuro-axonal injury using plasma NfL as a biomarker up to 18 weeks following kick-and-kill, compared with ART-only.