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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.

Real-World Assessment of Health Care Costs for Patients with Metastatic Pancreatic Cancer Following Initiation of First-Line Chemotherapy

J Manag Care Spec Pharm

2020 Elena Chiorean

BACKGROUND: Management of metastatic pancreatic ductal adenocarcinoma (mPDA) places a significant financial burden on the U.S. health care system because of such factors as treatment with multidrug chemotherapy regimens, management of chemotherapy-related adverse events, and disease- or treatment-related hospitalizations. Depending on functional status, first-line chemotherapy regimens that are guideline recommended include nab-paclitaxel with gemcitabine (AG) and FOLFIRINOX (FFX), the combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin. However, few previous studies have examined overall health care costs associated with mPDA management. OBJECTIVE: To describe health care costs following initiation of first-line treatment with AG or FFX among patients with mPDA. METHODS: Retrospective cohorts of first-line AG and FFX initiators were constructed from the MarketScan database (2014-2017). The index date was the date of first-line AG or FFX initiation. Included patients had insurance enrollment for 6 months before the index date. Total cumulative health care costs and costs from outpatient services, inpatient admissions, emergency department visits, chemotherapy administrations, and pharmacy dispensing were assessed within 12 months after the index date (i.e., 0-1, 0-2, , 0-12 months). Patient-level cost data began accruing from the first paid claim and continued accruing until the censoring date. RESULTS: A total of 2,199 patients with mPDA initiated first-line AG (n = 1,352) or FFX (n = 847). Compared with AG initiators, FFX patients were younger (mean age 59 vs. 63 years) and had better baseline health status, with fewer having diabetes (43% vs. 57%) or coronary artery disease (12% vs. 22%). Median follow-up was 5.4 and 7.2 months for AG and FFX, respectively. Median first-line treatment duration was 2.1 months with AG and 2.3 months with FFX. Six months following first-line treatment initiation, total cumulative health care costs (median) were $85,714 (95% CI = $79,683-$91,788) and $114,116 (95% CI = $105,816-$119,591) for AG and FFX initiators, respectively. Outpatient services contributed the largest fractional cost for both groups. CONCLUSIONS: Total health care costs for patients with mPDA who initiated FFX or AG are driven mostly by outpatient rather than inpatient costs. Further research, using comparative methodology, is warranted to fully understand cost drivers and whether higher costs for FFX patients relate primarily to use of FFX or higher underlying use of outpatient care among FFX patients. DISCLOSURES: This study was funded by Halozyme Therapeutics. Oestreicher and Yeganegi were employees of Halozyme Therapeutics at the time of the study and were involved in study design, data interpretation, and the decision to submit the data for publication. Bullock reports advisory board fees from Eisai, Exelixis, Bayer, and Taiho and consulting fees from Halozyme Therapeutics, outside the submitted work. Rowan reports consulting fees from Halozyme Therapeutics, during the conduct of the study. Chiorean reports grants and consulting fees from Celgene and Halozyme Therapeutics; grants from Lilly, Stemline, Ignyta, Roche, Merck, Boehringer-Ingelheim, Bristol Meyer Squibb, Incyte, Macrogenics, Rafael, and AADi; and consulting fees from Astra Zeneca, Array, Eisai, Ipsen, Five Prime Therapeutics, Seattle Genetics, Vicus, and Legend, outside the submitted work.

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.

Mailed fecal immunochemical test outreach for colorectal cancer screening: Summary of a Centers for Disease Control and Prevention-sponsored summit

CA Cancer J Clin

2020 Jason Dominitz; Rachel Issaka

Uptake of colorectal cancer screening remains suboptimal. Mailed fecal immunochemical testing (FIT) offers promise for increasing screening rates, but optimal strategies for implementation have not been well synthesized. In June 2019, the Centers for Disease Control and Prevention convened a meeting of subject matter experts and stakeholders to answer key questions regarding mailed FIT implementation in the United States. Points of agreement included: 1) primers, such as texts, telephone calls, and printed mailings before mailed FIT, appear to contribute to effectiveness; 2) invitation letters should be brief and easy to read, and the signatory should be tailored based on setting; 3) instructions for FIT completion should be simple and address challenges that may lead to failed laboratory processing, such as notation of collection date; 4) reminders delivered to initial noncompleters should be used to increase the FIT return rate; 5) data infrastructure should identify eligible patients and track each step in the outreach process, from primer delivery through abnormal FIT follow-up; 6) protocols and procedures such as navigation should be in place to promote colonoscopy after abnormal FIT; 7) a high-quality, 1-sample FIT should be used; 8) sustainability requires a program champion and organizational support for the work, including sufficient funding and external policies (such as quality reporting requirements) to drive commitment to program investment; and 9) the cost effectiveness of mailed FIT has been established. Participants concluded that mailed FIT is an effective and efficient strategy with great potential for increasing colorectal cancer screening in diverse health care settings if more widely implemented.

We understand our community: implementation of the Healthy Eating Healthy Aging program among community-based organizations

Transl Behav Med

2020 Sonia Bishop; Linda Ko

Cardiovascular disease is the second leading cause of death in the USA among Asian Americans and Pacific Islanders (AAPIs) over the age of 65. Healthy Eating Healthy Aging (HEHA), an evidence-based heart health program, can provide culturally appropriate nutrition education to decrease the risk of cardiovascular disease. Community-based organizations (CBOs) are optimal settings to implement community-based programs. However, there is inadequate research on how evidence-based interventions like HEHA are implemented in CBOs. This study examined processes that facilitated the implementation of HEHA among CBOs serving older AAPIs. Twelve representatives from CBOs that implemented the HEHA program were recruited to participate in a semistructured interview. All the participants were CBO directors or senior managers. A semistructured interview guide was created and informed by the Consolidated Framework for Implementation Research (CFIR) to capture how HEHA played into the five domains of CFIR: (a) intervention characteristics, (b) outer setting, (c) inner setting, (d) characteristics of the individuals, and (e) process. Data analysis captured themes under the CFIR domains. All five CFIR domains emerged from the interviews. Under intervention characteristics, three constructs emerged as facilitating the implementation of HEHA: (a) the participant's beliefs around the quality of the HEHA program and its ability to promote healthy eating, (b) HEHA's adaptability to different AAPI subgroups, and (c) perceptions of how successfully HEHA was bundled and assembled. Under outer setting, the participants described the community's need for healthy eating programs and how the HEHA program meets that need. Four constructs emerged under inner setting: (a) the CBO's structural characteristics and social standing in the community; (b) resources dedicated to the implementation and ongoing operations, including funding, training, education, physical space, and time; (c) the culture of the CBO; and (d) the participant's commitment and involvement in marketing, promotion, and implementation of HEHA. Under characteristics of individuals, participants' described their desire to learn the content of HEHA and deliver them successfully. Under process, participants described strategies to engage relevant individuals to facilitate HEHA implementation. The interviews with CBO representatives provided insights into CFIR domain constructs that facilitated the implementation of HEHA. CBOs are key settings for community health education. Understanding processes that lead to the successful implementation of evidence-based interventions among CBOs is critical for accelerating the dissemination and implementation of best practices.

How we prevent infections in patients receiving CD19-targeted chimeric antigen receptor T-cells for B-cell malignancies


2020 Joshua Hill

Adoptive immunotherapy using B cell-targeted chimeric antigen receptor-modified T (CAR-T) cells to treat hematologic malignancies is transforming cancer care for patients with refractory or relapsed diseases. Recent and anticipated regulatory approval for products targeting acute lymphoblastic leukemia, lymphomas, and multiple myeloma have led to global implementation of these novel treatments. The rapidity of commercial utilization of CAR-T cell therapy has created a largely unexplored gap in patient supportive care approaches. Such approaches are critical in these complex patients given their high net-state of immunosuppression prior to CAR-T cell infusion coupled with unique acute and persistent insults to their immune function after CAR-T cell infusion. In this "How I Treat", we focus on key questions that arise during three phases of management for patients receiving CD19-targeted CAR-T cells: pre-CAR-T cell infusion, immediate post-CAR-T cell infusion, and long-term follow up. A longitudinal patient case is presented for each phase to highlight fundamental issues including infectious diseases screening, antimicrobial prophylaxis, immunoglobulin supplementation, risk factors for infection, and vaccination. We hope this discussion will provide a framework for institutions and healthcare providers to formulate their own approach to preventing infections in light of the paucity of data specific to this treatment modality.

Use of Aspirin and Statins in Relation to Inflammation in Benign Prostate Tissue in the Placebo Arm of the Prostate Cancer Prevention Trial

Cancer Prev Res (Phila)

2020 Catherine Tangen; Phyllis Goodman; Kathryn Arnold

Aspirin and statin use may lower risk of advanced/fatal prostate cancer, possibly by reducing intraprostatic inflammation. To test this hypothesis, we investigated the association of aspirin and statin use with the presence and extent of intraprostatic inflammation, and the abundance of specific immune cell types, in benign prostate tissue from a subset of men from the placebo arm of the Prostate Cancer Prevention Trial. Men were classified as aspirin or statin users if they reported use at baseline or during the seven-year trial. Presence and extent of inflammation were assessed, and markers of specific immune cell types (CD4, CD8, FoxP3, CD68, c-KIT) were scored, in slides from end-of-study prostate biopsies taken irrespective of clinical indication, per trial protocol. Logistic regression was used to estimate associations between medication use and inflammation measures, adjusted for potential confounders. Of 357 men included, 61% reported aspirin use and 32% reported statin use. Prevalence and extent of inflammation were not associated with medication use. However, aspirin users were more likely to have low FoxP3, a T regulatory cell marker (OR: 5.60, 95% CI: 1.16-27.07), and statin users were more likely to have low CD68, a macrophage marker (OR: 1.63, 95% CI: 0.81-3.27). If confirmed, these results suggest that these medications may alter the immune milieu of the prostate, which could potentially mediate effects of these medications on advanced/fatal prostate cancer risk.

Expanding Use of CD33-Directed Immunotherapy

Expert Opin Biol Ther

2020 Roland Walter


Late morbidity and mortality in adult survivors of childhood glioma with neurofibromatosis type 1: report from the Childhood Cancer Survivor Study

Genet Med

2020 Wendy Leisenring

PURPOSE: Neurofibromatosis type 1 (NF1) is associated with tumor predisposition and nonmalignant health conditions. Whether survivors of childhood cancer with NF1 are at increased risk for poor long-term health outcomes is unknown. METHODS: One hundred forty-seven 5+ year survivors of childhood glioma with NF1 from the Childhood Cancer Survivor Study were compared with 2629 non-NF1 glioma survivors and 5051 siblings for late mortality, chronic health conditions, and psychosocial, neurocognitive, and socioeconomic outcomes. RESULTS: Survivors with NF1 (age at diagnosis: 6.84.8 years) had greater cumulative incidence of late mortality 30 years after diagnosis (46.3% [95% confidence interval: 23.9-62.2%]) compared with non-NF1 survivors (18.0% [16.1-20.0%]) and siblings (0.9% [0.6-1.2%]), largely due to subsequent neoplasms. Compared with survivors without NF1, those with NF1 had more severe/life-threatening chronic conditions at cohort entry (46.3% [38.1-54.4%] vs. 30.8% [29.1-32.6%]), but similar rates of new conditions during follow-up (rate ratio: 1.26 [0.90-1.77]). Survivors with NF1 were more likely to report psychosocial impairments, neurocognitive deficits, and socioeconomic difficulties compared with survivors without NF1. CONCLUSIONS: Late mortality among glioma survivors with NF1 is twice that of other survivors, due largely to subsequent malignancies. Screening, prevention, and early intervention for chronic health conditions and psychosocial and neurocognitive deficits may reduce long-term morbidity in this vulnerable population.

Reply to S. Boutayeb et al

JCO Oncol Pract

2020 Veena Shankaran


Last Modified, February 20, 2020