Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. Significance: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo or immunotherapy. See related article by Ye et al., p. 1302.

A ketogenic diet enhances fluconazole efficacy in murine models of systemic fungal infection.

Invasive fungal infections are a significant public health concern, with mortality rates ranging from 20% to 85% despite current treatments. Therefore, we examined whether a ketogenic diet could serve as a successful treatment intervention in murine models of Cryptococcus neoformans and Candida albicans infection in combination with fluconazole-a low-cost, readily available antifungal therapy. The ketogenic diet is a high-fat, low-carbohydrate diet that promotes fatty acid oxidation as an alternative to glycolysis through the production of ketone bodies. In this series of experiments, mice fed a ketogenic diet prior to infection with C. neoformans and treated with fluconazole had a significant decrease in fungal burden in both the brain (mean 2.66 ± 0.289 log10 reduction) and lung (mean 1.72 ± 0.399 log10 reduction) compared to fluconazole treatment on a conventional diet. During C. albicans infection, kidney fungal burden of mice in the keto-fluconazole combination group was significantly decreased compared to fluconazole alone (2.37 ± 0.770 log10-reduction). Along with higher concentrations of fluconazole in the plasma and brain tissue, fluconazole efficacy was maximized at a significantly lower concentration on a keto diet compared to a conventional diet, indicating a dramatic effect on fluconazole pharmacodynamics. Our findings indicate that a ketogenic diet potentiates the effect of fluconazole at multiple body sites during both C. neoformans and C. albicans infection and could have practical and promising treatment implications.IMPORTANCEInvasive fungal infections cause over 2.5 million deaths per year around the world. Treatments for fungal infections are limited, and there is a significant need to develop strategies to enhance antifungal efficacy, combat antifungal resistance, and mitigate treatment side effects. We determined that a high-fat, low-carbohydrate ketogenic diet significantly potentiated the therapeutic effect of fluconazole, which resulted in a substantial decrease in tissue fungal burden of both C. neoformans and C. albicans in experimental animal models. We believe this work is the first of its kind to demonstrate that diet can dramatically influence the treatment of fungal infections. These results highlight a novel strategy of antifungal drug enhancement and emphasize the need for future investigation into dietary effects on antifungal drug activity.

Immunoprofiles and Oncologic Outcomes of 15 Patients with Androgen Receptor-Positive Salivary Duct Carcinoma.

BACKGROUND: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland neoplasm. They can present with distinct immunoprofiles, such as androgen receptor (AR) and HER-2/Neu-positivity. To date, no consensus exists on how to best manage this entity. METHODS: All patients diagnosed with nonmetastatic AR+ SDC of the parotid from 2013 to 2019 treated with curative intent were included. Immunologic tumor profiling was conducted using 24 distinct markers. Kaplan-Meier analyses were used to estimate locoregional recurrence (LRR), distant control, and overall survival (OS). RESULTS: Fifteen patients were included. Nine (60%) patients presented with T4 disease and eight (53%) had positive ipsilateral cervical lymphadenopathy. Ten (67%) patients underwent trimodality therapy, including surgery followed by adjuvant radiation and concurrent systemic therapy. The median follow-up was 5.5 years (interquartile range, 4.8-6.1). The estimated 5-year rates of LRR, distant progression, and OS were 6%, 13%, and 87%, respectively. CONCLUSION: Despite only including AR+ SDC of the parotid, immunoprofiles, such as expression of HER-2, were highly variable, highlighting the potential to tailor systemic regimens based on individual histologic profiles in the future. Studies with larger patient numbers using tumor-specific molecular profiling and tumor heterogeneity analyses are justified to better understand the biology of these tumors. Molecularly informed treatment approaches, including the potential use of AR- and HER-2/Neu-directed therapies upfront in the definitive setting, may hold future promise to further improve outcomes for these patients.

"RIPping" off Pancreas Cancer's Blockage of Immune Surveillance.

SUMMARY: MHC-I downregulation is correlated with immunotherapy resistance in PDAC, but efficient strategies to increase cell-surface MHC-I are still lacking. This study by Sang, Zhou, Chen, Yu, and colleagues identified inhibition of tumor-intrinsic RIPK2 as a pharmacologic target to block the degradation of MHC-I on tumor cells and improved PDAC responses to anti-PD-1 immunotherapy. See related article by Sang et al., p. 326 (1) .

Intensive Versus Traditional Cardiac Rehabilitation: Mortality and Cardiovascular Outcomes in a 2016-2020 Retrospective Medicare Cohort.

BACKGROUND: Traditional cardiac rehabilitation (CR) improves cardiovascular outcomes and reduces mortality, but less is known about the relative benefit of intensive CR (ICR) which incorporates greater lifestyle education through 72 sessions (versus 36 in CR). Our objective was to determine whether ICR is associated with a mortality and cardiovascular benefit compared with CR. METHODS: Retrospective cohort study of Medicare Fee-For-Service beneficiaries in a 100% sample, claims data set. Qualifying events were captured from May 1, 2016 to December 31, 2019 and ICR/CR utilization captured from May 1, 2016 to December 31, 2020. Among patients attending at least 1 day of either CR or ICR, Cox proportional hazards models using a 1 to 5 propensity score match were used to compare utilization and the association of ICR versus CR participation with (1) all-cause mortality and (2) cardiovascular-related hospitalizations or nonfatal cardiac events. Dose-response was assessed by the number of days attended. RESULTS: From 2016 to 2019, 1 277 358 unique patients met at least one qualifying indication for ICR/CR from 2016 to 2019. Of these, 262 579 (20.6%) and 4452 (0.4%) attended at least one session of CR or ICR, respectively (mean [SD] age, 73.2 [7.8] years; 32.3% female). In the matched sample, including 26 659 total patients (median, 2.4-year follow-up), ICR was associated with 12% lower all-cause mortality (multivariable adjusted hazard ratio, 0.88 [95% CI, 0.78-0.99]; P=0.036) compared with CR but no significant difference for cardiovascular-related hospitalization or nonfatal cardiac events. The mortality benefit was seen for both ICR and CR per day strata, with each modality demonstrating a clear dose-response benefit. CONCLUSIONS: ICR is associated with lower mortality than traditional CR among Medicare beneficiaries but no difference in cardiovascular-related hospitalization or nonfatal cardiac events. Moreover, ICR and CR demonstrate a dose-response relationship for mortality. Additional studies are needed to confirm these observations and to better understand the mechanisms by which ICR may lead to a reduction in mortality.

Using mass spectrometry imaging to map fluxes quantitatively in the tumor ecosystem.

Tumors are comprised of a multitude of cell types spanning different microenvironments. Mass spectrometry imaging (MSI) has the potential to identify metabolic patterns within the tumor ecosystem and surrounding tissues, but conventional workflows have not yet fully integrated the breadth of experimental techniques in metabolomics. Here, we combine MSI, stable isotope labeling, and a spatial variant of Isotopologue Spectral Analysis to map distributions of metabolite abundances, nutrient contributions, and metabolic turnover fluxes across the brains of mice harboring GL261 glioma, a widely used model for glioblastoma. When integrated with MSI, the combination of ion mobility, desorption electrospray ionization, and matrix assisted laser desorption ionization reveals alterations in multiple anabolic pathways. De novo fatty acid synthesis flux is increased by approximately 3-fold in glioma relative to surrounding healthy tissue. Fatty acid elongation flux is elevated even higher at 8-fold relative to surrounding healthy tissue and highlights the importance of elongase activity in glioma.

The time is now: Student-driven implementation of social justice and anti-racism focused curricula in medical scientist training program education.

There exists a dearth of supplementary programs to educate physician-scientist trainees on anti-racism and topics surrounding social justice in medicine and science. Education on these topics is critical to prevent the perpetuation of systemic racism within the institutions of academia and medicine. Students in the Washington University School of Medicine Medical Scientist Training Program and the Tri-Institutional MD-PhD Program developed journal clubs with curricula focused on social justice and anti-racism for the summer of 2020. In this article, we describe the impact of the Washington University journal club on the education of first year MD-PhD students and summarize the progress to date. The role of the journal club in the midst of the "double pandemic" of COVID-19 and generational systemic racism is discussed, highlighting the need for such supplemental curricula in MD-PhD programs nation-wide.

Tumor Heterogeneity in Glioblastomas: From Light Microscopy to Molecular Pathology.

One of the main reasons for the aggressive behavior of glioblastoma (GBM) is its intrinsic intra-tumor heterogeneity, characterized by the presence of clonal and subclonal differentiated tumor cell populations, glioma stem cells, and components of the tumor microenvironment, which affect multiple hallmark cellular functions in cancer. "Tumor Heterogeneity" usually encompasses both inter-tumor heterogeneity (population-level differences); and intra-tumor heterogeneity (differences within individual tumors). Tumor heterogeneity may be assessed in a single time point (spatial heterogeneity) or along the clinical evolution of GBM (longitudinal heterogeneity). Molecular methods may detect clonal and subclonal alterations to describe tumor evolution, even when samples from multiple areas are collected in the same time point (spatial-temporal heterogeneity). In GBM, although the inter-tumor mutational landscape is relatively homogeneous, intra-tumor heterogeneity is a striking feature of this tumor. In this review, we will address briefly the inter-tumor heterogeneity of the CNS tumors that yielded the current glioma classification. Next, we will take a deeper dive in the intra-tumor heterogeneity of GBMs, which directly affects prognosis and response to treatment. Our approach aims to follow technological developments, allowing for characterization of intra-tumor heterogeneity, beginning with differences on histomorphology of GBM and ending with molecular alterations observed at single-cell level.

Pediatric Gliosarcoma With and Without Neurofibromatosis Type 1: A Whole-exome Comparison of 2 Patients.

Gliosarcoma is rare among pediatric patients and among individuals with Neurofibromatosis Type 1 (NF1). Here we compare 2 pediatric gliosarcoma patients, one of whom has NF1. We performed whole-exome sequencing, methylation, and copy number analysis on tumor and blood for both patients. Whole-exome sequencing showed higher mutational burden in the tumor of the patient without NF1. Copy number analysis showed differences in chromosomal losses/gains between the tumors. Neither tumor showed O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The NF1 patient survived without progression while the other expired. This is the first reported case of gliosarcoma in a child with NF1.