tbuckley/cabot-search huggingface dataset:
Chronic mTOR activation induces a degradative smooth muscle cell phenotype
Authors: Guangxin Li, Mo Wang, Alexander W. Caulk, Nicholas A. Cilfone, Sharvari Gujja, Lingfeng Qin, Pei-Yu Chen, Zehua Chen, Sameh Yousef, Yang Jiao, Changshun He, Bo Jiang, Arina Korneva, Matthew R. Bersi, Guilin Wang, Xinran Liu, Sameet Mehta, Arnar Geirsson, Jeffrey R. Gulcher, Thomas W. Chittenden, Michael Simons, Jay D. Humphrey, George Tellides
Journal: Journal of Clinical Investigation (2020)

Smooth muscle cell (SMC) proliferation has been thought to limit the progression of thoracic aortic aneurysm and dissection (TAAD) because loss of medial cells associates with advanced disease. We investigated effects of SMC proliferation in the aortic media by conditional disruption of Tsc1, which hyperactivates mTOR complex 1. Consequent SMC hyperplasia led to progressive medial degeneration and TAAD. In addition to diminished contractile and synthetic functions, fate-mapped SMCs displayed increased proteolysis, endocytosis, phagocytosis, and lysosomal clearance of extracellular matrix and apoptotic cells. SMCs acquired a limited repertoire of macrophage markers and functions via biogenesis of degradative organelles through an mTOR/β-catenin/MITF-dependent pathway, but were distinguishable from conventional macrophages by an absence of hematopoietic lineage markers and certain immune effectors even in the context of hyperlipidemia. Similar mTOR activation and induction of a degradative SMC phenotype in a model of mild TAAD due to Fbn1 mutation greatly worsened disease with near-uniform lethality. The finding of increased lysosomal markers in medial SMCs from clinical TAAD specimens with hyperplasia and matrix degradation further supports the concept that proliferation of degradative SMCs within the media causes aortic disease, thus identifying mTOR-dependent phenotypic modulation as a therapeutic target for combating TAAD.
Recent Advances in Nanotheranostics for Treat‐to‐Target of Rheumatoid Arthritis
Authors: Shasha Wang, Jing Lv, Shanshan Meng, Jianxin Tang, Liming Nie
Journal: Advanced Healthcare Materials (2020)

Early diagnosis, standardized treatment, and regular monitoring are the clinical treatment principle of rheumatoid arthritis (RA). The overarching principles and recommendations of treat-to-target (T2T) in RA advocate remission as the optimum aim, especially for patients with very early disease who are initiating therapy with anti-RA medications. However, traditional anti-RA drugs cannot selectively target the inflammatory areas and may cause serious side effects due to its short biological half-life and poor bioavailability. These limitations have significantly driven the research and application of nanomaterial-based drugs in theranostics of RA. Nanomedicines have appropriate sizes and easily modified surfaces which can enhance their biological compatibility and prolong circulation time of drug-loading systems in vivo. Traditional T2T regimens cannot evaluate the efficacy of drugs in real time, while clinical drug nanosizing can realize the integration of diagnosis and treatment of RA. This review bridges clinically proposed T2T concepts and nanomedicine in an integrated system for RA early-stage diagnosis and treatment. The most advanced progress in various nanodrug delivery systems for theranostics of RA is summarized, establishing a clear path and a new perspective for further optimization of T2T. Finally, the key facing challenges are discussed and prospects are addressed.
Sex difference in patients with biliary tract cancer receiving chemotherapy: Post hoc analysis of ABC-01, -02, -03, -04, BILCAP.
Authors: Eiichiro Suzuki, John A. Bridgewater, Juan W. Valle, John Neil Primrose, Anna Dorothea Wagner, Andre Lopes, Richard Fox
Journal: Journal of Clinical Oncology (2020)

517 Background: The relationship between toxicity from chemotherapy and clinical outcome in biliary tract cancer (BTC) is uncertain. Aim: This post hoc analysis evaluated differences by sex in the frequency of adverse events (AEs) and overall survival (OS) and its impact on progression-free survival (PFS)/recurrence-free survival (RFS) for BTC patients. Methods: Individual patient data were retrieved from ABC -01, -02, -03, -04, and BILCAP study. AEs were graded according to National Cancer Institute's Common Toxicity Criteria v 4.02 and odds ratios along with 95%CI and p-values derived from logistic regression were used to assess the effect of sex on the risk of AEs. Time to event outcomes were evaluated using Cox regression and plotted using Kaplan-Meier plots. All statistical tests were two-sided. Results: Overall 994 patients-data were examined: 86 in ABC-01, 324 in-02, 124 in -03, 13 in -04 and 447 in BILCAP. A total of 484 (49%) were males (M) and 510 (51%) were females (F). 770 patients were evaluable for AEs because a total of 224 patients in BILCAP study belonged to the observation group. Urinary tract infection (M, 1.6%; F, 5.5%), nausea (M, 50.7%; F, 69.9%), vomiting (M, 29.1%; F, 46.1%), alopecia (M, 11.3%; F, 27.3%), are dominant in F, hyperbilirubinaemia (M, 36.7%; F, 29.1%) and thrombocytopenia (M, 43.1%; F, 34.3%) and hiccups (M, 2.4%; F, 0.5%) are dominant in M at any grade. Vomiting (M, 3.5%; F, 7.0%) and fatigue (M, 4.0%; F, 8.5%) are higher in F than in M for grade 3-5. The median OS (M, 16.2 months (Mo); F, 17.5 Mo), PFS (M, 6.4 Mo; F, 6.5 Mo) and RFS (M, 20.8 Mo; F 19.4 Mo) were similar. Amongst the subgroup of patients with gallbladder, F achieved longer OS (M, 11.5 Mo; F 13.3 Mo, 0.73 (95%CI:0.54,0.99), p = 0.041) and RFS than M (M, 20.8 Mo; median PFS for F not reached, HR:0.52 (95%CI:0.27,1.02), p = 0.057). Conclusions: Females with BTC have tended to have more AEs, especially grade 3+. Although no difference was observed in OS, PFS, and RFS between males and females for the overall cohort of patients, females with gallbladder cancer had an improved OS and RFS compared with males. These findings suggest, in BTC, sex may play a role when designing clinical trials as well as in making treatment decisions.
Regorafenib with TAS-102 (REGOTAS) in metastatic colorectal cancer patients who progressed after at least two standard therapies: Efficacy and safety results of a multicenter phase I study (REMETY).
Authors: Markus H. Moehler, Alexander Stein, Jorg Trojan, Jens Uwe Marquardt, Julia Quidde, Oliver Waidmann, Arndt Weinmann, Marcus Woerns, Helge Schroeder, Martin Maenz, Aysun Karatas, Friedrich Foerster
Journal: Journal of Clinical Oncology (2020)

158 Background: The multi-kinase inhibitor regorafenib (REGO) and oral fluoropyrimidine TAS-102 (TAS) show efficacies as single agents in treatment of refractory metastatic CRC patients (pts). We conducted a conventional 3+3 dose finding to determine a recommended phase II dose (RP2D) of its combination REGOTAS and efficacy in 3-4.-line. Methods: Eligible patients with ECOG 0-1, measurable mCRC, not amenable to surgery had at least 3rd-line treatments. Prior fluoropyrimidine-based and anti-VEGF (R) combinations were mandatory, and anti-EGFR for RAS WT tumors. TAS was given on days 1-5 and 8-12 (28-days cycle); REGO on days 2-22 (dose levels see table below). The following major AE categories were used to define DLTs if they occurred during the first 2 treatment cycles: any grade ≥3 non-hematologic toxicity (except vomiting, nausea, non-significant lab abnormalities), grade ≥3 hematological toxicities, grade ≥3 bleeding. Tumor response was assessed Q8W as per RECIST1.1. EudraCT 2016-001968-11; NCT03305913. Results: All observed toxicities were consistent with safety profile of individual IMPs. 6 pts were enrolled into each DL1 and DL2 (n=12 in total). One DLT was observed in 1/6 pts in DL1; 2 DLTs in 2/6 pts in DL2. All DLTs were only grade 3 hypertension was well manageable, causality was attributed to REGO. No DLT resulted in treatment discontinuation. Results indicate a RP2D of 25mg/m² TAS-102 BID + 120mg REGO daily. No remissions were observed. Overall disease control rate (DCR) after 8 weeks was promising with 58.3% (DCR of 33.3% for DL1 and 83.3% in DL2) and remarkably better as historical data with 41/44% for REGO/TAS102 alone, respectively (Lancet 2013/NEJM 2015). Conclusions: Toxicities of REGOTAS were consistent with safety profiles of REGO and TAS alone. No additional DLTs were attributed to REGOTAS. Thus, the risk-benefit assessment of REGOTAS was positive. DCR was clinically quite meaningful. Mature PFS and OS will be presented at the meeting. Clinical trial information: NCT03305913. [Table: see text]
Continuous fluropyrimidine (FP) with platinum (P) based chemotherapy (CT) versus maintenance FP after induction therapy in advanced gastric (G) and gastroesophageal (GE) cancer.
Authors: Daniel Walden, Mohamad Bassam Sonbol, Skye Buckner Petty, Mitesh J. Borad, Tanios S. Bekaii-Saab, Daniel H. Ahn
Journal: Journal of Clinical Oncology (2020)

375 Background: Combination FP with P CT have become the standard of care for advanced G/GEJ cancer. Clinical trials in conjunction with practice, have adopted induction FP and P CT for 3-4 months (mos). In other GI malignancies, induction CT followed by maintenance CT (MTC) has been shown to improve patient (pt) outcomes compared to observation, with a decrease in treatment (trmt) related toxicities with induction therapy. However a maintenance approach in G/GEJ cancer has not been investigated in clinical trials. We investigated pt outcomes with metastatic G/GEJ cancer who received continuous induction (CTX) versus induction followed by MTC. Methods: A retrospective analysis of pts with metastatic G/GEJ adenocarcinoma treated with (FP+ P)-based CT between 2007 to 2017 from three centers of a single institution was performed. Metastatic G/GEJ cancer pts who achieved at least stable disease after initial induction trmt were included. Pts were categorized into the CTX group if they received greater than 16 weeks or 8 cycles of combined CT and assigned to the MTC group if they received maintenance FP monotherapy after 8 or less cycles of combined induction CT. Data was extracted from the medical record to determine progression free survival (PFS), overall survival (OS), and toxicities. Results: Sixty-four pts that met criteria and were evaluated, thirty-four received CTX and thirty received MTC. No significant difference in PFS (12.1 vs 8.0 mos p = .72, HR=1.10 95%CI .66-1.83) was observed between the CTX and MTC groups, additionally there was no significant difference in OS. A significant decrease in trmt related toxicities were observed, with a higher proportion of thrombocytopenia (84.8% vs 50.0% p = .004), and grade 3 neuropathy (39.4% vs 13.8% p =.024) in CTX pts (Table). Conclusions: MTC following induction FP/P CT is associated with an improved toxicity profile and appears to be effective compared to CTX in metastatic G/GEJ cancer. Prospective randomized studies confirming its potential benefits compared with continuous induction CT are warranted. [Table: see text]
Effect of age on swallowing dysfunction after esophagectomy.
Authors: Della Mann, Vishwa Raj, Madison Colcord, Michael D Watson, Sally Jeanne Trufan, Jennifer H Benbow, Nicole Lee Gower, Joshua Hill, Jonathan C. Salo
Journal: Journal of Clinical Oncology (2020)

455 Background: Patients undergoing esophagectomy frequently experience malnutrition, which in combination with the catabolic effects of surgery can result in loss of muscle mass and function. Safe swallowing requires the preservation of muscle mass. Modified barium swallow (MBS) enables assessment of postoperative swallowing impairments. We assessed the incidence and risk factors of swallowing dysfunction post-esophagectomy. Methods: Patients with a MBS post-esophagectomy were identified between January 2015-June 2019 at Levine Cancer Institute at Carolinas Medical Center. Swallowing was evaluated with the Penetration Aspiration Scale. Muscle loss was evaluated with pre-operative hand-grip strength (HGS) and skeletal muscle index (SMI) and skeletal muscle density (SMD) from axial CT images. Uni- and multivariable GLM analyses were performed. Results: 91 patients (79 men, 12 women) underwent esophagectomy with an average age of 64.0 + 10.1. Pre-operative HGS, SMI, and SMD all decreased with age. Significant differences existed between sexes in HGS, SMI, and SMD, so the cohort was stratified by sex for analysis. Univariate analysis of male patients revealed older age, lower body mass index (BMI), smoking history, prior feeding tube, and lower pre-operative HGS and SMI were associated with aspiration or penetration on MBS. Among women, no factors analyzed were significantly associated with swallowing dysfunction. Conclusions: Swallowing dysfunction after esophagectomy is correlated with increased age and lower BMI. The role of muscle loss in the risk of aspiration after esophagectomy is not clear. Further research is needed to determine the relationship between these factors with the goal of enabling preoperative physiologic optimization and patient selection. [Table: see text]
Surgery for stage IV gastric cancer: An Italian perspective.
Authors: Maria Bencivenga, Silvia Ministrini, Leonardo Solaini, Elisabetta Marino, Alessia d’Ignazio, Gianni Mura, Silvia Sofia, Silvia Sofia, Chiara Cipollari, Daniele Marrelli, Maurizio Degiuli, Annibale Donini, Franco Roviello, Paolo Morgagni, Giovanni De Manzoni, Guido Tiberio
Journal: Journal of Clinical Oncology (2020)

403 Background: Surgical approach to gastric cancer with hepatic metastases is becoming more and more accepted but few information exist concerning the surgical management of gastric cancer with extra-hepatic metastases. With this retrospective study we evaluated if the prognosis is influenced by different metastatic sites and we looked for the presence of prognostic factors. Methods: We analysed 282 patients with gastric cancer and synchronous metastases treated at our Institutions from 2010 to January 2017. We investigated survival performances after surgery according to the site of metastases: peritoneal, haematogenous, hepatic, distant lymph nodes and more than one site. Furthermore, we investigated how survival was influenced by patient-, gastric cancer-, metastases- and treatment-related prognostic factors. Results: Median overall survival was 10.9 months. We found no survival differences according to the site of metastases: median survival was 11.2, 11.6, 9.8, 21.4, 7.0 months for peritoneal, hepatic, lymph-nodal, haematogenous and more than1 site of metastases, respectively (p = 0.797). In all subgroups we observed an interesting number of long-term survivors (peritoneal 14.3% ≥36 months, 7.6% ≥60 months; hepatic 13.0% ≥36 months, 2.2% ≥60 months; lymph nodes 12.5% ≥36 months, 3.1% ≥60 months; &gt; 1 site 18.7% ≥36 months, 1.6% ≥60 months). At multivariate analysis the factors that influenced survival were: number of resected lymph-nodes (p = 0.013), extension of lymphadenectomy (p &lt; 0.001), pN (p = 0.003), curativity (p = 0.032) and histology (p = 0.028). Conclusions: We showed that no differences in overall survival according to site of metastases exist and we suggest that patients in whom a curative resection is possible, should be treated by resection of both gastric cancer and metastases.
Understanding Patient- and Hospital-Level Factors Leading to Differences, and Disparities, in Critical Care
Authors: Ayah Nayfeh, Robert A. Fowler
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

already present at low levels of cumulative cigarette smoking (the mean exposure was just 4 pack-years).To truly reduce the burden of COPD, we will need to understand the complexities of its natural history, profile of risk factors, and phenotypic manifestations across the entire lifespan.The study by Çolak and colleagues is an important starting point to characterize COPD in the first 50 years of life.Although the importance of smoking cessation cannot be overemphasized, we argue that understanding the interplay among smoking, early life risk factors, and developmental processes in age spans that have been traditionally left out of COPD research will be key to fully advance prevention strategies for stages when the natural history of the disease can still be substantially modified.
Comparison of clinicopathological characteristics and prognosis of borderline resectable pancreatic cancer according to the location of the primary tumor.
Authors: Tsuyoshi Takeda, Takashi Sasaki, Takafumi Mie, Takaaki Furukawa, Ryo Kanata, Akiyoshi Kasuga, Masato Matsuyama, Masato Ozaka, Naoki Sasahira
Journal: Journal of Clinical Oncology (2020)

662 Background: Little is known about the clinicopathological and prognostic differences between borderline resectable (BR) pancreatic head (Ph) and pancreatic body/tail (Pbt) cancer. Therefore, we conducted this study to compare the clinicopathological features and prognosis of BR pancreatic cancer (PC) according to the location of the primary tumor. Methods: We retrospectively investigated consecutive patients with BR PC who initiated neoadjuvant chemotherapy (NAC) between March 2015 and April 2019. We compared clinicopathological characteristics and prognosis between Ph and Pbt cancer. Furthermore, multivariate survival analysis was performed using cox proportional hazard model. Results: A total of 104 patients with BR PC (median age 68, male 49%) were included in this study. The location of the tumor was Ph 72 and Pbt 32, respectively. The initial regimen of NAC was nab-paclitaxel/gemcitabine in 102 and gemcitabine in 2, respectively. The median cycle of NAC was 4. Median age, sex, primary tumor size, performance status, neutrophil to lymphocyte ratio, and serum level of carbohydrate antigen 19-9 at the time of the initiation of NAC were not significantly different between Ph and Pbt cancer, while the modified glasgow prognostic score (mGPS) was lower in Pbt cancer (mGPS = 0; 78% vs. 94%, p = 0.05). R0/R1 resection rate (81% vs. 69%, p = 0.21) and median survival time (928 days vs. NA, p = 0.13) were also not different between Ph and Pbt cancer. Multivariate survival analysis revealed that R0/R1 resection (HR, 0.11; p &lt; 0.01) and Ph (HR, 2.29; p = 0.03) were independent prognostic factors for survival in patients with BR PC. Conclusions: Although R0/R1 resection rate was similar between BR Ph and Pbt cancer, Pbt cancer had a higher rate of mGPS score of 0 compared to Ph cancer. Furthermore, R0/R1 resection (HR, 0.11) and Ph (HR, 2.29) were independent prognostic factors for survival in patients with BR PC.
Bimekizumab in patients with active psoriatic arthritis: results from a 48-week, randomised, double-blind, placebo-controlled, dose-ranging phase 2b trial
Authors: Christopher T Ritchlin, Arthur Kavanaugh, Joseph F Merola, Georg Schett, Jose U Scher, Richard B Warren, Alice B Gottlieb, Deepak Assudani, Kathy Bedford-Rice, Jason Coarse, Barbara Ink, Iain B McInnes
Journal: The Lancet (2020)
International Trends in the Incidence of Cancer Among Adolescents and Young Adults
Authors: Sumit Gupta, Andrew Harper, Yibing Ruan, Ronald Barr, A Lindsay Frazier, Jacques Ferlay, Eva Steliarova-Foucher, Miranda M Fidler-Benaoudia
Journal: JNCI Journal of the National Cancer Institute (2020)

Although adolescent and young adult (AYA) cancers represent a unique spectrum of malignancies, epidemiological studies of cancer incidence often group AYAs together with younger or older populations, obscuring patterns specific to this population.
Mouse Systems Genetics as a Prelude to Precision Medicine
Authors: Hao Li, Johan Auwerx
Journal: Trends in Genetics (2020)

Mouse models have been instrumental in understanding human disease biology and proposing possible new treatments. The precise control of the environment and genetic composition of mice allows more rigorous observations, but limits the generalizability and translatability of the results into human applications. In the era of precision medicine, strategies using mouse models have to be revisited to effectively emulate human populations. Systems genetics is one promising paradigm that may promote the transition to novel precision medicine strategies. Here, we review the state-of-the-art resources and discuss how mouse systems genetics helps to understand human diseases and to advance the development of precision medicine, with an emphasis on the existing resources and strategies.
Loss of body weight during neoadjuvant chemotherapy with docetaxel, cisplatin, and fluorouracil as predictive of poor survival of patients with esophageal squamous cell carcinoma.
Authors: Munehiro Ito, Ken Kato, Shun Yamamoto, Hiroshi Imazeki, Masahiko Aoki, Kotoe Oshima, Hidekazu Hirano, Natsuko Okita, Hirokazu Shoji, Yoshitaka Honma, Satoru Iwasa, Atsuo Takashima, Jun Kanamori, Junya Oguma, Hiroyuki Daiko, Narikazu Boku
Journal: Journal of Clinical Oncology (2020)

371 Background: Though neoadjuvant chemotherapy with docetaxel/cisplatin/5-fluorouracil (DCF) showed a promising efficacy in patients (pts) with resectable esophageal squamous cell carcinoma (ESCC), grade 3 anorexia during the course and body weight loss (BWL) were frequently experienced. BWL is considered as a factor for poor survival in operable cancer pts, however, there is rarely reported of the relationship of BWL during neoadjuvant therapy and survival. Methods: We retrospectively evaluated pts of ESCC withclinical stage II or III, excluding T4, who had received neoadjuvant DCF and esophagectomy (R0 resection) at our institution between April 2010 and December 2018. We define the cut-off level at more than 3% weight reduction (BWL3 group) between before and after of first cycle of DCF. Results: Among the 77 pts who were selected for this analysis, 13 patients showed BWL &gt; 3% (BWLS group), and other 64 pts did not (no-BWL group). The median age, proportions of performance status of 0, cT3 stage, cN2-3 stage and serum albumin lower than normal level in no-BWL and BWL3 group were 65 and 67y.o, 59 and 77%, 88 and 54%, 75 and 69%, 34 and 31%, respectively. There was no significant difference inhistological therapeutic effect (grade 2-3) with 50% in no-BWL and 62% in BWL3 group (P = 0. 549). The incidence of postoperative grade 2 or higher pneumoniawas same in both group (23% vs 17%, P = 0. 695). The median overall survival (OS) was not reached in non-BWL group and 39.5 m in BWL3 group (P = 0.048), respectively. The median progression free survival (PFS) was not reached in non-BWL group and 39.5 m in BWL3 group (P = 0.382), respectively. In multivariate analysis, BWL is independent prognostic factor for OS (hazard ratio [HR] = 11.5, 95%CI: 2.45-53.8, P = 0.002). Conclusions: Our exploratory study demonstrated that body weight loss during first course of neoadjuvant DCF therapy for ESCC patients may be a prognostic factor for survival.