BackgroundCancer immunotherapy research is expanding to include a more robust understanding of the mechanisms of treatment response and resistance. Identification of drivers of pro-tumor and anti-tumor immunity during treatment offers new strategies for effective alternative or combination immunotherapies. Currently, tissue or blood samples are collected and analyzed, then dichotomized based on clinical end points that may occur months or years after tissue is collected. While overall survival is ultimately the desired clinical outcome, this dichotomization fails to incorporate the nuances that may occur during an anti-tumor response. By failing to directly measure immune activation at the time of sampling, tumors may be misclassified and potentially obscure important biological information. Non-invasive techniques, such as positron emission tomography (PET), allow for global and quantitative measurements of cancer specific processes and are widely used clinically to help manage disease.MethodsWe have previously developed a novel PET agent that can non-invasively quantify granzyme B release in tumors and have demonstrated its ability to predict response to checkpoint inhibitor therapy in multiple murine models of cancer. Here, we used the quantitative measurement of granzyme B release as a direct and time-matched marker of immune cell activation in order to determine immune cell types and cytokines that correlate with effective checkpoint inhibitor therapy in both tumors and tumor-draining lymph nodes.ResultsThrough PET imaging, we were able to successfully distinguish distinct microenvironments, based on tumor type, which influenced immune cell subpopulations and cytokine release. Although each tumor was marked by functionally distinct pathways of immune cell activation and inflammation, they also shared commonalities that ultimately resulted in granzyme B release and tumor killing.ConclusionsThese results suggest that discrete tumor immune microenvironments can be identified in both responsive and non-responsive tumors and offers strategic targets for intervention to overcome checkpoint inhibitor resistance.

Key Points Question How did surgical volumes change with respect to subspecialty and patient acuity during the COVID-19 pandemic, and did they recover after the peak and vaccine release periods? Findings In this cohort study, a retrospective analysis of 129 956 records of weekly surgical procedures from January 6, 2019, to December 31, 2021, revealed that the overall volume did not fully recover to pre–COVID-19 levels well into 2021. Recovery rates were inconsistent across surgical subspecialties and case classes. Meaning Further research and hospital-level changes are needed to address the backlog of surgical services and muted recovery of surgical procedures to pre–COVID-19 volumes.

No abstract

TBI causes cognitive impairment but it remains contested which cognitive domains are most affected. Further, moderate-severe TBI is known to be deleterious, but studies of mild TBI (mTBI) show a greater mix of negative and positive findings . This study examines the longerterm cognitive effects of TBI severity and number of mild TBI in later life. We examined a subset (n=15,764) of the PROTECT study, a cohort assessing risk factors for cognitive decline (ages between 50 and 90). Participants completed cognitive assessments annually for four years. Cognitive tests were grouped using a Principal Components Analysis (PCA) into working memory, episodic memory, attention, processing speed and executive function. Lifetime TBI severity and number were retrospectively recalled by participants using the Brain Injury Screening Questionnaire (BISQ). Linear Mixed Models examined the effect of severity of head injury (non-TBI head strike, mild TBI (mTBI) and moderate-severe TBI) and number of mTBI at baseline and over time. mTBI was considered as a continuous and categorical variable (groups: 0 mTBI, 1 mTBI, 2 mTBIs, 3 mTBIs and 4+ mTBIs). Of the participants 5,725 (36.3%) reported at least one mild TBI and 510 (3.2%) at least one moderate-severe TBI, while 3,711 (23.5%) had suffered at worst a non-TBI head strike and 5,818 (32.9%) reported no head injuries. The participants had suffered their last reported head injury an average (SD) of 29.6 (20.0) years prior to the study. Regarding outcomes, there was no worsening in longitudinal cognitive trajectories over the study duration but at baseline there were significant cognitive deficits associated with TBI. At baseline, compared to those without head injury, individuals reporting at least one moderate-severe TBI had significantly poorer attention (B=-0.163, p<0.001), executive scores (B=-0.151, p=0.004) and processing speed (B=-0.075, p=0.033). Those who had suffered at least a single mTBI also demonstrated significantly poorer attention scores at baseline compared to the no head injury group (B=-0.052, p=0.001). Compared to those with no mTBI, those in the 3 mTBI group manifested poorer baseline executive function (B=-0.149, p=0.025) and attention scores (B=-0.085, p=0.015). At baseline, those who had suffered 4 or more mild TBIs demonstrated poorer attention (B=-0.135, p<0.001), processing speed (B=-0.072, p=0.009) and working memory (B=-0.052, p=0.036), compared to those reporting no mTBI. TBI is associated with fixed, dose, and severitydependent cognitive deficits. The most sensitive cognitive domains are attention and executive function, with approximately double the effect compared to processing speed and working memory. Post-TBI cognitive rehabilitation should be targeted appropriately to domain-specific effects. Significant long-term cognitive deficits were associated with 3 lifetime mTBI, a critical consideration when counselling individuals post-TBI about continuing high-risk activities.

Effective, disease modifying therapies for Alzheimer’s disease (AD) remain a quandary, following a panoply of expensive failures in human clinical trials. Given the stagnation in therapeutics, alternative approaches are needed. Recent successes of genetic therapies in other neurodegenerative diseases may highlight the way forward. This scoping review explores suggested targets of genetic therapy in AD, with a focus on vector-based approaches in pre-clinical and clinical trials. Putative targets of genetic therapies tested in pre-clinical trials include amyloid pathway intermediates and enzymes modulation, tau protein downregulation, APOE4 downregulation and APOE2 upregulation, neurotrophin expression (nerve growth factor (NGF) and brain-derived neurotrophic factor), and inflammatory cytokine alteration, among several other approaches. There have been three completed human clinical trials for genetic therapy in AD patients, all of which upregulated NGF in AD patients, showing some mixed evidence of benefit. Several impediments remain to be surpassed before genetic therapies can be successfully applied to AD, including the challenge of delivering monogenic genetic therapies for complex polygenic disorders, risks in the dominant delivery method (intracranial injection), stability of genetic therapies in vivo, poor translatability of pre-clinical AD models, and the expense of genetic therapy production. Genetic therapies represent an exciting opportunity within the world of AD therapeutics, but clinical applications likely remain a long term, rather than short term, possibility.

No abstract

A normal functioning lymphatic pump mechanism and unimpaired venous drainage are required for the body to remove inflammatory mediators from the extracellular compartment. Impaired vascular perfusion and/or lymphatic drainage may result in the accumulation of inflammatory substances in the interstitium, creating continuous nociceptor activation and related pathophysiological states including central sensitization and neuroinflammation. We hypothesize that following trauma and/or immune responses, inflammatory mediators may become entrapped in the recently discovered interstitial, pre-lymphatic pathways and/or initial lymphatic vessels. The ensuing interstitial inflammatory stasis is a pathophysiological state, created by specific pro-inflammatory cytokine secretion including tumor necrosis factor alpha, interleukin 6, and interleukin 1b. These cytokines can disable the local lymphatic pump mechanism, impair vascular perfusion via sympathetic activation and, following transforming growth factor beta 1 expression, may lead to additional stasis through direct fascial compression of pre-lymphatic pathways. These mechanisms, when combined with other known pathophysiological processes, enable us to describe a persistent feed-forward loop capable of creating and maintaining chronic pain syndromes. The potential for concomitant visceral and/or vascular dysfunction, initiated and maintained by the same feed-forward inflammatory mechanism, is also described.

No abstract