tbuckley/cabot-search huggingface dataset:
Annexin A1 drives macrophage skewing to accelerate muscle regeneration through AMPK activation
Authors: Simon McArthur, Gaëtan Juban, Thomas Gobbetti, Thibaut Desgeorges, Marine Theret, Julien Gondin, Juliana E. Toller-Kawahisa, Chris P. Reutelingsperger, Bénédicte Chazaud, Mauro Perretti, Rémi Mounier
Journal: Journal of Clinical Investigation (2020)

Understanding the circuits that promote an efficient resolution of inflammation is crucial to deciphering the molecular and cellular processes required to promote tissue repair. Macrophages play a central role in the regulation of inflammation, resolution, and repair/regeneration. Using a model of skeletal muscle injury and repair, herein we identified annexin A1 (AnxA1) as the extracellular trigger of macrophage skewing toward a pro-reparative phenotype. Brought into the injured tissue initially by migrated neutrophils, and then overexpressed in infiltrating macrophages, AnxA1 activated FPR2/ALX receptors and the downstream AMPK signaling cascade, leading to macrophage skewing, dampening of inflammation, and regeneration of muscle fibers. Mice lacking AnxA1 in all cells or only in myeloid cells displayed a defect in this reparative process. In vitro experiments recapitulated these properties, with AMPK-null macrophages lacking AnxA1-mediated polarization. Collectively, these data identified the AnxA1/FPR2/AMPK axis as an important pathway in skeletal muscle injury regeneration.
An assessment of the total cost of pancreatic cancer using real-world evidence.
Authors: Vincent J. Picozzi, Victoria G. Manax, Kelly Feehan, Zachary Wintrob, Michele Korfin, Giuseppe Del Priore, Robert Goldberg
Journal: Journal of Clinical Oncology (2020)

773 Background: The aggregate health economic implications of pancreatic cancer are poorly understood, especially from the patient perspective. As a preliminary effort, we sought to better understand changes in type and quantity of medical expenditures over time, along with quality of life related costs, from this perspective. This preliminary research is part of a larger effort to understand how the introduction of new treatments affect both the outcome and costs of pancreatic cancer associated with care, patients, survivors, their families, and their communities. Methods: We analyzed patient-level data from the Medical Expenditure Panel Survey (MEPS, 1996- 2017). All analyses were performed using R version 3.6.1 on Ubuntu 19.04. Averages were computed for the total health care costs, including prescription drug costs. Average individual annual cost estimates for the second year excluded individuals that were identified as having died prior to the first round of data collection in the second year. The individual patient level ratios of prescription drug cost to other medical expenses was also computed. All expenditures are adjusted for inflation using 2017 US dollars. Included subjects, N= 80 had a diagnosis of pancreatic cancer and available prescription data. Individual age and employment status were accounted for as covariates. Results: Between 1997 and 2017 inflation adjusted first and second year non-medication spending on pancreatic cancer care averaged $66,999.96 and $105,308.60 respectively. However, inflation-adjusted first and second year charges for hospitalizations and emergency visits fell between 2007-2017. Prescription drug as a proportion of total spending prescription drugs increased during the same time period. Lost work/school days declined between 2007 and 2017. Conclusions: Total inflation adjusted pancreatic cancer care expenses declined over the past decade even as drug costs increased. Quality of life costs declined as well. Further analysis is needed to evaluate the relationship between drug spending, total cost of care and quality of life.
Real-world patterns of care among patients with metastatic pancreatic cancer (mPC).
Authors: Eileen Mary O'Reilly, Andy Surinach, Zheng Wu, Paul Cockrum
Journal: Journal of Clinical Oncology (2020)

666 Background: Pancreatic cancer is the third deadliest cancer in the US and mPC has a 2.9% 5-year survival. The analyses herein describe treatment patterns, trends in usage, and overall survival (OS) in mPC. Methods: Using the Flatiron Health EHR-derived database, data were extracted and analyzed for patients with mPC (pts) between Jan 1, 2014 and Jun 30, 2019. The database includes de-identified data from over 280 cancer clinics (~800 sites of care) representing more than 2.2 million U.S. cancer patients available for analysis, with 80% of pts from community centers and 20% from academic centers. Lines of therapy in the metastatic setting are derived from structured medication records. OS from metastatic diagnosis was reported using the Kaplan-Meier method. Results: 7,666 pts with mPC were identified. 5,687 (74.2%) received therapy in the metastatic setting. Pts who didn’t receive therapy in the metastatic setting were more likely to be older (p &lt; 0.0001) and less likely to have been diagnosed initially with stage IV disease (p &lt; 0.0001) than pts who were treated. The frequency of (1L) regimens were gemcitabine plus nab-paclitaxel (GnP) 46.8%, FOLFIRINOX (FFX) 24.1%, gemcitabine monotherapy 9.3%, and FOLFOX 3.8%. Gemcitabine monotherapy use was 12.9% in 2014 and 7.3% in 2018. GnP (31.4%), FFX (12.3%), FOLFOX (11.4%), and liposomal irinotecan (nal-IRI) + 5-FU/LV (10.2%) were the most frequent second line (2L) regimens. Between 2015 and 2018 nal-IRI based regimens increased from 6% to 17.6% in 2L. In the third line (3L) setting nal-IRI + 5FU/LV (19.3%), GnP (12.1%), FOLFOX (11.4%), and FFX (9.1%) were the most common treatments. Aggregate median OS (mOS) for treated pts was 8.1 mos (95% CI 7.8 – 8.4), and mOS for untreated pts was 2.8 mos (2.6 – 3.0), p &lt; 0.0001. Conclusions: Survival for mPC is improving and practice patterns are changing. GnP is the most commonly used 1L regimen, followed increasingly by nal-IRI + 5-FU/LV in 2L and 3L. Further studies are necessary to understand the treatment gaps for pts with mPC. [Table: see text]
Infective endocarditis in patients who have undergone transcatheter aortic valve implantation: a review
Authors: L. Østergaard, T. Kiilerich Lauridsen, K. Iversen, H. Bundgaard, L. Søndergaard, N. Ihlemann, C. Moser, E. Fosbøl
Journal: Clinical Microbiology and Infection (2020)
Association of neutrophil, platelet, and lymphocyte ratios with prognosis in metastatic pancreatic cancer.
Authors: Jessica Allen, Colin Cernik, Suhaib Bajwa, Anwaar Saeed, Anup Kasi
Journal: Journal of Clinical Oncology (2020)

767 Background: High mortality associated with pancreatic ductal adenocarcinoma (PDA) warrants research into prognostic factors. We examined the relationship between the daily rate of change of CA19-9 over the first 90 days of treatment (DRC90) and pretreatment levels of neutrophils, lymphocytes, and platelets with overall survival (OS) and progression free survival (PFS) in patients with stage IV PDA that received chemotherapy. Methods: We retrospectively evaluated 102 locally advanced and metastatic PDA patients treated at KU Cancer Center between Jan 2011 and Sep 2019. We compared the ratio of pretreatment absolute neutrophil count to pretreatment absolute lymphocyte count (NLR) and the ratio between pretreatment platelet count to pretreatment absolute lymphocyte count (PLR) with OS and PFS. We also compared DRC90 to OS and PFS. Log-rank trend test using the mean of NLR, PLR, and DRC90 as the threshold for two groups within each variable. Results: Baseline demographics are shown in the table. Pts with ≥ mean NLR (4.6) had significantly lower OS [p = 0.0444] and PFS [p = 0.0483] than Pts below the mean. Pts with PLR ≥ mean (3.9) did not have significantly different OS [p = 0.507] or PFS [p = 0.643] than Pts below the mean. Pts with DRC90 ≥ mean (-1%) did not have significantly different OS [p = 0.342] or PFS [p = 0.313] than Pts below the mean. Conclusions: Pts with NLR ≥ mean (4.6) had significantly lower OS and PFS than Pts with NLR below the mean. This implies the possibility of NLR as a prognostic marker in PDA that could guide treatment approach but needs validation in a larger cohort. [Table: see text]
The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer
Authors: Lei Zhang, Yidong Li, Qianchao Wang, Zhuo Chen, Xiaoyun Li, Zhuoxun Wu, Chaohua Hu, Dan Liao, Wei Zhang, Zhe-Sheng Chen
Journal: Molecular Cancer (2020)

Abstract Background PI3K/AKT is a vital signaling pathway in humans. Recently, several PI3K/AKT inhibitors were reported to have the ability to reverse cancer multidrug resistance (MDR); however, specific targets in the PI3K/AKT pathways and the mechanisms associated with MDR have not been found because many of the inhibitors have multiple targets within a large candidate protein pool. AKT activation is one presumed mechanism by which MDR develops during cancer treatment. Methods The effects of inhibiting PI3K 110α and 110β by BAY-1082439 treatment and CRISPR/Cas9 knockout were examined to determine the possible functions of BAY-1082439 and the roles of PI3K 110α and 110β in the reversal of MDR that is mediated by the downregulation of P-gp and BCRP. Inhibition of AKT with GSK-2110183 showed that the downregulation of P-gp and BCRP is independent of generalized AKT inactivation. Immunofluorescence, immunoprecipitation, MTT, flow cytometry and JC-1 staining analyses were conducted to study the reversal of MDR that is mediated by P-gp and BCRP in cancer cells. An ATPase assay and a structural analysis were also used to analyze the potential mechanisms by which BAY-1082439 specifically targets PI3K 110α and 110β and nonspecifically influences P-gp and BCRP. Results By inhibiting the activation of the PI3K 110α and 110β catalytic subunits through both the administration of BAY-1082439 and the CRISPR/Cas9 deletion of Pik3ca and Pik3cb , the ATP-binding cassette transporters P-gp/ABCB1 and BCRP/ABCG2 were downregulated, thereby reestablishing the drug sensitivity of human epidermoid carcinoma and non-small cell lung cancer (NSCLC) MDR cells. Inhibition of AKT did not reverse the MDR mediated by P-gp or BCRP. The ABC family proteins and AKT may play MDR-enhancing roles independently. Conclusions The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110α or 110β promises to improve current strategies based on combined drug treatments to overcome MDR challenges.
Autoantibody Reversion: Changing Risk Categories in Multiple-Autoantibody–Positive Individuals
Authors: Michelle So, Colin O’Rourke, Henry T. Bahnson, Carla J. Greenbaum, Cate Speake
Journal: Diabetes Care (2020)

Most individuals with two or more islet autoantibodies progress to clinical type 1 diabetes. However, in some individuals, autoantibodies are subsequently lost. Here, our objectives were to determine the frequency of autoantibody loss (reversion) in multiple-autoantibody-positive individuals and to determine the association between reversion and progression to clinical disease.We analyzed multiple-autoantibody-positive individuals participating in TrialNet's Pathway to Prevention Study for reversion and determined the effect of reversion on progression to clinical disease using a Cox regression analysis.Of 3,284 multiple-autoantibody-positive subjects, reversion occurred in 134 (4.1%) and was associated with reduced incidence of clinical disease. Reversion occurred more frequently with older age, lower autoantibody titers, and fewer positive autoantibodies.Although reversion of multiple-autoantibody positivity is rare, when it occurs, the risk of progressing to clinical disease is reduced. This suggests unknown mechanisms promoting immune remission in some individuals.
Pathological examination of CT findings of tumor infiltration to the periarterial plexus in pancreatic cancer.
Authors: Takashi Miyamoto, Yusuke Yamamoto, Teiichi Sugiura, Yukiyasu Okamura, Takaaki Ito, Ryo Ashida, Katsuhisa Ohgi, Katsuhiko Uesaka
Journal: Journal of Clinical Oncology (2020)

644 Background: The radiographic diagnosis of tumor infiltration into the periarterial plexus in pancreatic cancer is important because it is related to the classification, however, it is difficult to distinguish the abnormal shadow along the artery caused by inflammation or cancer infiltration. The aim of this study is to investigate CT values of the abnormal shadow along artery could distinguish between inflammation and tumor invasion. Methods: Study 1: Of 26 patients who underwent DP-CAR between 2009 and 2018, we analyzed 19 patients who had dynamic CT and obtained sagittal slice taken 120 seconds after injection with less than 2.5 mm slice thickness. At first, we measured CT values at upper and lower point of CeA and CHA each sagittal slice using CT. Next, we evaluated tumor invasion at the upper and lower plexus of CeA and CHA in each section of the pathological specimen, and evaluated the relationship between the tumor invasion and the CT value. Study 2: Using these 19 patients and 40 patients who underwent DP for PDAC between 2010 and 2014, we analyzed the relation between CT value and long-term states. Results: Study 1: CT value was totally measured at the 606 points using 19 patients who underwent DP-CAR. At the 490 points, we did not observe cancer infiltration and fibrosis. At the 70 points, we observed fibrosis without cancer cells. At the 46 points, we observed cancer infiltration. CT value was significantly higher in the tumor infiltration group than that in the without cancer infiltration and fibrosis group (P &lt; 0.01). Study 2: The best cut-off of CT value of the presence of cancer infiltration was 44.9 HU using ROC curve (AUC = 0.861). The median survival time of patients who had the points of CT value &gt; 44.9 HU around arteries was significantly shorter than that of patients who did not have the points of CT value &gt; 44.9 HU (2.17 vs. 4.55 years, p = 0.03). Conclusions: The CT value around the arteries was significantly higher in the points of pathological tumor infiltration than that in the points of fibrosis without cancer cells. The best cut-off CT value of the presence of cancer infiltration around arteries was 44.9 HU, and the presence of the point of CT value &gt; 44.9 HU around arteries was associated with poor survival.
Standard management options for rosacea: The 2019 update by the National Rosacea Society Expert Committee
Authors: Diane Thiboutot, Rox Anderson, Fran Cook-Bolden, Zoe Draelos, Richard L. Gallo, Richard D. Granstein, Sewon Kang, Marian Macsai, Linda Stein Gold, Jerry Tan
Journal: Journal of the American Academy of Dermatology (2020)
Etiological involvement of weak acid reflux in the development of esophageal carcinoma.
Authors: Toru Kono, Daichi Sadatomi, Naoki Fujitsuka, Tomoharu Miyashita, Atsushi Kaneko, Masahiro Yamamoto
Journal: Journal of Clinical Oncology (2020)

435 Background: Patients with gastroesophageal reflux disease (GERD) with mixed gastric acid–bile acid reflux are at a high risk of developing reflux-induced esophageal cancer. Increased local production of prostaglandin E2 (PGE2) is etiologically associated with reflux-induced esophageal cancer pathogenesis; however, the underlying mechanism remains unclear. Our aim was to investigate the relationship between PGE2 production in esophageal cells and reflux fluids, particularly gastric acid. The effect of the Kampo medicine Hangeshashinto (HST), which reduced the incidence of reflux-induced esophageal cancer in rats (Surgery 2018), on PGE2 production was also examined. Methods: Esophageal squamous cell carcinoma were treated for 2 h with acidic culture condition (pH 3.5 – 6.5) and chenodeoxycholic acid (CDCA; 200, 400 μmol/L), followed by measurement of PGE2 production in the culture medium for the additional 6 h by enzyme-linked immunosorbent assay. Results: CDCA induced PGE2 production and significantly increased cyclooxygenase-2 (cox-2) expression. However, in weak acidic conditions (pH 4–5), a pH-specific and significant increase in PGE2 production with no increase in cox-2 expression was observed. cPLA2 inhibitor decreased the effect of weak acid stimulation, indicating that the mechanism underlying PGE2 production differs between weak acid and CDCA. In addition, HST significantly inhibited both weak acid- and CDCA-induced PGE2 production. Conclusions: The synergistic effect of bile acid-induced cox-2 expression and weak acid-induced arachidonic acid production via cPLA2 can cause excessive PGE2 production. Therefore, mixed reflux showing pH 4–5 could contribute to the high incidence of esophageal cancer, which might be prevented by HST treatment. Weak acid reflux around pH 4–5 has been observed in PPI-treated patients, who could exhibit excessive PGE2 production as well as increased risk of reflux-induced esophageal cancer.
Clinical outcomes of hepatocellular carcinoma patients with Child-Pugh class B treated with stereotactic body radiation therapy.
Authors: J Richelcyn Baclay, Diego Augusto Santos Toesca, Rie von Eyben, Madeline Minneci, Erqi L. Pollom, Daniel Tandel Chang
Journal: Journal of Clinical Oncology (2020)

560 Background: Caution is usually employed in the treatment of patients with hepatocellular carcinoma (HCC) due to the inherent liver radiosensitivity, especially in patients with Child Pugh (CP) B and C classes. This study aims to review the outcomes of patients treated with SBRT for CP class B with HCC. Methods: Medical records of all patients with HCC and compromised liver function (CP class B) treated with SBRT between 2003 and 2018 were retrieved after institutional review board approval. Clinical, laboratory, and treatment-related data were collected and analyzed for their correlation to toxicity and survival. Liver function was assessed prior to SBRT and at 1, 3 and 6 months after treatment using the CP score classification. Patients were censored for toxicity after extensive tumor progression in the liver, new liver-directed therapies, or liver transplant. Time-to-events were calculated from date of SBRT. Results: A total of 22 patients were identified, but 3 were excluded for incomplete follow-up. Median follow-up time was 33 months (range: 11-95 months). At baseline, 13 (68%) patients had a CP score of 7, and 6 (32%) had a CP score of 8. The median PTV volume was 94 cc (range: 14-710 cc). The median prescribed dose was in 5 fractions (range: 35-45 Gy in 3-5 fractions). After SBRT, 8 (42%) patients presented with worsening in CP score, with a mean increase of 1.5 points (95% CI, 0.6-2.5; p = 0.005) at the first month of follow-up, but followed by recovery in liver function with change in CP score not statistically different from baseline at 3- or 6-month follow-up times (p = 0.35 and p = 0.13, respectively). Eight patients (42%) presented with acute hepatobiliary toxicity, with six of those presenting with ≥grade 2 toxicity. Patients with CP score change ≥2 points (n = 6) showed a significantly higher incidence of acute grade 2 or higher hepatobiliary toxicity (p = 0.001) with a trend toward worse overall survival (33 vs. 51 months, p = 0.45). Conclusions: In our cohort, SBRT demonstrated to be safe for patients with Child Pugh Class B liver function.
Molecular profiling of early-stage colorectal cancer (CRC) using targeted next generation sequencing (NGS) to predict signatures of recurrence.
Authors: Michael C. Burns, Kristen Carroll, Ryan Jones, Masha Kocherginsky, Kirsten Bell Burdett, Guang-Yu Yang, Al Bowen Benson, Deva Mahalingam
Journal: Journal of Clinical Oncology (2020)

242 Background: While the 5-year recurrence rate in early stage CRC is low (12%) and there is currently limited role of adjuvant chemotherapy in such cases, a unique subset of patients (pts) will have late recurrences. To identify molecular signatures predictive of late recurrence after pts undergo intended curative resection, we employed a 22 targeted gene NGS panel in pts with early CRC. Association between mutation status and recurrence free survival (RFS) was analyzed. Methods: Pts with stage I-II CRC had their tumor prospectively sequenced between 09/2015-12/2018 by an ion torrent targeted 22 gene hotspot NGS panel, including KRAS, EGFR, BRAF, PIK3CA, AKT1, ERBB2/4, PTEN, NRAS, STK11, MAP2K1, ALK, DDR2, CTNNB1, MET, TP53, SMAD4, FBX7, NOTCH1, and FGFR1/2/3. Associations were analyzed with unadjusted p-values (p) and Benjamini &amp; Hochberg adjusted (BHp) shown. Results: Clinical and pathologic data from 180 pts were analyzed: median age 66 (range 24-86), male (47%), stage I (41%), stage II (69%), left (54%) vs right (36%) sided primary tumors, and microsatellite stable (85%). 35 (19%) pts had adjuvant therapy (n = 21 rectal, n = 14 colon). Pathological mutations were found in 160 (89%) of pts, including TP53 (56%), KRAS (44%), PIK3CA (22%), BRAF (12%), SMAD4 (8%), MET (6%) and NRAS (3%). There was only 1 case of ERBB2 mutation. 33 pts (18%) had evidence of recurrence. 36 month RFS was 82%. Common sites of recurrence included liver (13 pts, 39%), lung (10 pts, 30%), and bone (2 pts, 6%). Alterations in MET cDNA and protein were associated with recurrence-free survival (RFS) (HR = 4.1; p =0.0026, BHp= 0.057). Interestingly, while TP53 mutations are typically associated with worse prognosis in metastatic colorectal cancers, it was not associated with RFS (HR = 0.8; p = 0.55, BHp= 0.98). There was also no association between the number of gene alterations and RFS (p = 0.45). Conclusions: These data highlight that targeted NGS tumor profiling of early stage CRC, including sequencing MET among other genes, may be utilized alongside known prognostic pathological factors to predict pts with a higher risk of recurrence and may facilitate tailored adjuvant chemotherapy to mitigate this risk.