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Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells

J Exp Med

2020 Philip Greenberg; Kristin Anderson; Breanna Bates

CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by the tumor microenvironment (TME) can dampen their ability to control tumor progression. We describe lipid accumulation in the TME areas of pancreatic ductal adenocarcinoma (PDA) populated by CD8+ T cells infiltrating both murine and human tumors. In this lipid-rich but otherwise nutrient-poor TME, access to using lipid metabolism becomes particularly valuable for sustaining cell functions. Here, we found that intrapancreatic CD8+ T cells progressively accumulate specific long-chain fatty acids (LCFAs), which, rather than provide a fuel source, impair their mitochondrial function and trigger major transcriptional reprogramming of pathways involved in lipid metabolism, with the subsequent reduction of fatty acid catabolism. In particular, intrapancreatic CD8+ T cells specifically exhibit down-regulation of the very-long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, which exacerbates accumulation of LCFAs and very-long-chain fatty acids (VLCFAs) that mediate lipotoxicity. Metabolic reprogramming of tumor-specific T cells through enforced expression of ACADVL enabled enhanced intratumoral T cell survival and persistence in an engineered mouse model of PDA, overcoming one of the major hurdles to immunotherapy for PDA.

Endolymphatic exclusion for the treatment of pediatric chylous ascites secondary to neuroblastoma resection: report of two cases

Radiol Case Rep

2020 Jay Sarthy

Chylous ascites is a rare, but highly morbid complication of oncologic resection, often associated with retroperitoneal lymphadenectomy. Conservative measures with total parenteral nutrition or lipid-reduced formulas constitute the initial mainstay therapy, but not without risks and failures. This report describes 2 endolymphatic treatment strategies for iatrogenic chylous ascites following neuroblastoma resection. Lymphatic leaks were identified using intranodal lymphangiography, targeted with cone-beam computed tomographic guidance, and embolized with n-butyl cyanoacrylate. There were no adverse outcomes, with complete resolution of chylous ascites and a mean follow-up of 26 months.

Prevalence of COVID-19 Infection and Outcomes Among Symptomatic Healthcare Workers in Seattle, Washington

Clin Infect Dis

2020 Noah Hoffman; Catherine Liu; Sara Marquis; Keith Jerome; Alex Greninger; Steven Pergam

BACKGROUND: Healthcare workers (HCW) serving on the front lines of the coronavirus disease 2019 (COVID-19) pandemic have been at increased risk for infection due to SARS-CoV-2 in some settings. Healthcare-acquired infection has been reported in similar epidemics, but there are limited data on the prevalence of COVID-19 among HCWs and their associated clinical outcomes in the United States. METHODS: We established two high-throughput employee testing centers in Seattle, Washington with drive-through and walk-through options for symptomatic employees in the University of Washington Medicine system and its affiliated organizations. Using data from these testing centers, we report the prevalence of SARS-CoV-2 infection among symptomatic employees and describe the clinical characteristics and outcomes among employees with COVID-19. RESULTS: Between March 12 and April 23, a total of 3,477 symptomatic employees were tested for COVID-19 at two employee testing centers; 185 (5.3%) employees tested positive for COVID-19. The prevalence of SARS-CoV-2 was similar when comparing frontline HCWs (5.2%) to non-frontline staff (5.5%). Among 174 positive employees reached for follow-up at least 14 days after diagnosis, 6 reported COVID-related hospitalization; all recovered. CONCLUSIONS: During the study period, we observed that the prevalence of positive SARS-CoV-2 tests among symptomatic HCWs was comparable to that of symptomatic non-frontline staff. Reliable and rapid access to testing for employees is essential to preserve the health, safety, and availability of the healthcare workforce during this pandemic and to facilitate the rapid return of SARS-CoV-2 negative employees to work.

Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer

J Med Genet

2020 Mary Anne Rossing; Holly Harris

PURPOSE: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. METHODS: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14135 EOC cases and 28655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. RESULTS: The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95%CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95%CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95%CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95%CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. CONCLUSIONS: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

Genome-wide gene-diabetes and gene-obesity interaction scan in 8,255 cases and 11,900 controls from the PanScan and PanC4 Consortia

Cancer Epidemiol Biomarkers Prev

2020 Phyllis Goodman; J White; Charles Kooperberg; Ulrike Peters

BACKGROUND: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. METHODS: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer GWAS datasets (PanScan I-III and PanC4). Obesity (BMI=30 kg/m2) and diabetes (duration = 3 years) were the environmental variables of interest. Approximately 870,000 SNPs were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual-GWAS summary statistics. RESULTS: No genome-wide significant interactions with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P<1.25E-6) was observed in the meta-analysis (PGxE= 1.2E-6, PJoint= 4.2E-7). CONCLUSIONS: Our current analyses did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. IMPACT: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

Clinical Development of BRAF plus MEK Inhibitor Combinations

Trends Cancer

2020 Christina Baik

Genomic profiling shows that many solid tumors are characterized by specific driver aberrations, and this has expanded the therapeutic options for many patients. The mitogen-activated protein kinase (MAPK) pathway is a key cell signaling pathway involved in regulating cellular growth, proliferation, and survival. Driver mutations in the BRAF gene, a key player in the MAPK pathway, are described in multiple tumor types, including subsets of melanoma, non-small cell lung cancer (NSCLC), and anaplastic thyroid cancer (ATC), making BRAF a desirable target for inhibition. BRAF inhibitors have shown efficacy in several cancers; however, most patients eventually develop resistance. To delay or prevent resistance, combination therapy targeting BRAF and MEK, a downstream signaling target of BRAF in the MAPK pathway, was evaluated and demonstrated synergistic benefit. BRAF and MEK inhibitor combinations have been approved for use in various cancers by the US FDA. We review the clinical data for various BRAF plus MEK combination regimens in three cancer types with underlying BRAF driver mutations: melanoma, NSCLC, and ATC. We also discuss practical treatment considerations and management of selected combination therapy toxicities.

Effective Multi-lineage Engraftment in a Mouse Model of Fanconi Anemia Using Non-genotoxic Antibody-Based Conditioning

Mol Ther Methods Clin Dev

2020 Olivier Humbert; Yogendra Rajawat; Kevin Haworth; Christina Ironside; Hans-Peter Kiem; Meera Srikanthan

Conditioning chemotherapy is used to deplete hematopoietic stem cells in the recipient's marrow, facilitating donor cell engraftment. Although effective, a major issue with chemotherapy is the systemic genotoxicity that increases the risk for secondary malignancies. Antibody conjugates targeting hematopoietic cells are an emerging non-genotoxic method of opening the marrow niche and promoting engraftment of transplanted cells while maintaining intact marrow cellularity. Specifically, this platform would be useful in diseases associated with DNA damage or cancer predisposition, such as dyskeratosis congenita, Schwachman-Diamond syndrome, and Fanconi anemia (FA). Our approach utilizes antibody-drug conjugates (ADC) as an alternative conditioning regimen in an FA mouse model of autologous transplantation. Antibodies targeting either CD45 or CD117 were conjugated to saporin (SAP), a ribosomal toxin. FANCA knockout mice were conditioned with either CD45-SAP or CD117-SAP prior to receiving whole marrow from a heterozygous healthy donor. Bone marrow and peripheral blood analysis revealed equivalent levels of donor engraftment, with minimal toxicity in ADC-treated groups as compared with cyclophosphamide-treated controls. Our findings suggest ADCs may be an effective conditioning strategy in stem cell transplantation not only for diseases where traditional chemotherapy is not tolerated, but also more broadly for the field of blood and marrow transplantation.

DNA Barcoding in Nonhuman Primates Reveals Important Limitations in Retrovirus Integration Site Analysis

Mol Ther Methods Clin Dev

2020 Jennifer Adair; Daniel Humphrys; Hans-Peter Kiem; Lauren Schefter; Kevin Haworth; Reza Shahbazi; Mark Enstrom

In vivo tracking of retrovirus-tagged blood stem and progenitor cells is used to study hematopoiesis. Two techniques are used most frequently: sequencing the locus of retrovirus insertion, termed integration site analysis, or retrovirus DNA barcode sequencing. Of these, integration site analysis is currently the only available technique for monitoring clonal pools in patients treated with retrovirus-modified blood cells. A key question is how these two techniques compare in their ability to detect and quantify clonal contributions. In this study, we assessed both methods simultaneously in a clinically relevant nonhuman primate model of autologous, myeloablative transplantation. Our data demonstrate that both methods track abundant clones; however, DNA barcode sequencing is at least 5-fold more efficient than integration site analysis. Using computational simulation to identify the sources of low efficiency, we identify sampling depth as the major factor. We show that the sampling required for integration site analysis to achieve minimal coverage of the true clonal pool is likely prohibitive, especially in cases of low gene-modified cell engraftment. We also show that early subsampling of different blood cell lineages adds value to clone tracking information in terms of safety and hematopoietic biology. Our analysis demonstrates DNA barcode sequencing as a useful guide to maximize integration site analysis interpretation in gene therapy patients.

Hyperprogressive Disease After Treatment With Checkpoint Inhibitors: Time for Prospective Studies

JAMA Oncol

2020 Rafael Santana-Davila


Outcomes Among Homeless Patients With Non-Small-Cell Lung Cancer: A County Hospital Experience

JCO Oncol Pract

2020 Christina Baik; Qian (Vicky) Wu; Isaac Jenkins; Hannah Linden

PURPOSE: Lung cancer remains the leading cause of cancer death in the United States, with outcomes likely worsened by the presence of poorer outcomes among vulnerable populations such as the homeless. We hypothesized that homeless patients experience delays in biopsy, decreased appointment adherence, and increased overall mortality rates. METHODS: We conducted a retrospective electronic medical record-based review of all patients with non-small-cell lung cancer (NSCLC; N = 133) between September 2012 and September 2018 at an academic county hospital in Seattle, Washington. RESULTS: Of the 133 patients treated for NSCLC, 22 (17%) were homeless at the time of their treatment. Among homeless patients with localized lung cancer, the mean time from radiographic finding to biopsy was 248 days, compared with 116 days among housed patients (P = .37). Homeless patients with advanced disease missed a mean of 26% of appointments in the year after diagnosis, compared with 16% among housed patients (P = .03). Homeless patients with advanced NSCLC had a median survival of 0.58 years, versus 1.30 years in housed patients (P = .48). CONCLUSION: To our knowledge, this is the first US study comparing outcomes among homeless and housed patients with NSCLC within the same institution; we found homeless patients had longer delays to biopsy, increased rates of missed appointments, and a trend toward decreased survival. This study shows potential areas where interventions could be implemented to improve lung cancer outcomes in this patient population.

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