tbuckley/cabot-search huggingface dataset:
Patient preferences for symptom-driven or regular preventer treatment in mild to moderate asthma: findings from the PRACTICAL study, a randomised clinical trial
Authors: Christina Baggott, Helen K. Reddel, Jo Hardy, Jenny Sparks, Mark Holliday, Andrew Corin, Barney Montgomery, Jim Reid, Davitt Sheahan, Robert J. Hancox, Mark Weatherall, Richard Beasley, James Fingleton
Journal: European Respiratory Journal (2020)

Symptom-driven low-dose inhaled corticosteroid–formoterol is safe and effective in mild asthma and has been recommended as one of the preferred treatment regimens at steps 1 and 2 in the 2019 update of the Global Initiative for Asthma. However, there are no data on patient preferences for this regimen. A subgroup of participants in the PRACTICAL study (ACTRN12616000377437), a randomised controlled trial comparing symptom-driven budesonide–formoterol with maintenance budesonide plus as-needed terbutaline completed a survey on treatment preferences, satisfaction, beliefs and experience at their final study visit. 306 (75%) out of 407 eligible participants completed the survey. Regimen preference was strongly associated with randomised treatment, as were preferences for and beliefs about preventer inhaler use. Combination preventer and reliever as-needed therapy was preferred by 135 (90%, 95% CI 85.2–94.8%) out of 150 who were randomised to as-needed budesonide–formoterol, and by 63 (40%, 95% CI 32.7–48.1%) out of 156 who were randomised to maintenance budesonide. By contrast, twice-daily preventer inhaler with a reliever inhaler as required was preferred by 15 (10%) out of 150 of those randomised to as-needed budesonide–formoterol and 93 (60%) out of 156 of those randomised to maintenance budesonide. Satisfaction with all study inhalers was high. Of patients randomised to as-needed budesonide–formoterol 92% (n=138) were confident using it as a reliever at the end of the study. Although most participants preferred the regimen to which they had been randomised, this association was much stronger for those randomised to budesonide–formoterol as needed, indicating that most patients preferred as-needed corticosteroid–formoterol therapy if they had experienced it.
Phase III, international, randomized trial of adjuvant <i>nab</i>-paclitaxel plus gemcitabine (<i>nab</i>-P + G) versus gemcitabine (G) for resected pancreatic cancer (APACT): Recurrence patterns.
Authors: Vaibhav Sahai, Josep Tabernero, Eric Van Cutsem, Michele Reni, Margaret A. Tempero, Eileen Mary O'Reilly, Jordan Berlin, Hanno Riess, David Goldstein, Mingyu Li, Brian Lu, Stefano Ferrara, Philip Agop Philip
Journal: Journal of Clinical Oncology (2020)

704 Background: APACT did not meet the primary endpoint of independently assessed disease-free survival (DFS) with nab-P + G vs G; overall survival showed a nominal improvement. Here, we report recurrence patterns by resection status. Methods: A total of 866 treatment-naive patients (pts) with histologically confirmed pancreatic cancer, R0/R1 resection, CA19-9 &lt; 100 U/mL, and ECOG PS ≤ 1 received 6 cycles of nab-P + G or G on days 1, 8, and 15 Q28 days. Stratification: resection (R0/R1); lymph node status (LN+/−); geographic region. Disease recurrence was per investigator review of CT/MRI scans. Results: Of 571 (66%) pts with investigator-assessed DFS events (median follow up, 35.4 mo), 543 had radiographic progression with 764 recurrent lesions (≥ 20 events: liver, 271; unspecified abdominal organ, 152; lung, 130; surgical bed, 70; mesenteric nodes, 54). Most pts (73%) had only abdominal, 61% had only distant, and 10% had only local recurrence (Table). Although more pts with R1 vs R0 status had recurrence (72% vs 60%), patterns were generally similar, and local recurrence was similarly low. Conclusions: Most recurrences in APACT were distant and in abdomen (liver). Recurrence patterns were generally similar in pts with R0 and R1 status, with low rates of local recurrence. These data may help make more informed pt management decisions. Additional data on patterns by baseline characteristics will be presented. Clinical trial information: NCT01964430 . [Table: see text]
Bundled Payment Reform and Dialysis Facility Closures in ESKD
Authors: Sayna Norouzi, Bo Zhao, Ahmed Awan, Wolfgang C. Winkelmayer, Vivian Ho, Kevin F. Erickson
Journal: Journal of the American Society of Nephrology (2020)

In 2011, inclusion of injectable medications into an expanded ESKD payment bundle prompted concerns that dialysis facilities facing higher costs might close, disrupting care delivery and access to care. Whether this policy change influenced dialysis facility closures is unknown.To examine whether facility closures increased after 2011 and whether factors influencing closures changed, we analyzed US Renal Data System registry data to identify all patients receiving in-center hemodialysis from 2006 through 2015 and to track dialysis facility closures. We used interrupted time series logistic regression models and estimated marginal effects to examine immediate and longer-term changes in the likelihood of being affected by facility closures following payment reform. We also examined whether associations between selected predictors of closures indicating populations at "high risk" of closure (patient characteristics, facility characteristics, and geography-related characteristics) and closures changed after payment reform.Dialysis facility closures were uncommon over the study period. In adjusted models, the relative odds of experiencing a closure declined by 37% (odds ratio [OR], 0.63; 95% confidence interval [95% CI], 0.59 to 0.67) immediately after payment reform and declined by an additional 6% (OR, 0.94; 95% CI, 0.91 to 0.97) annually thereafter, corresponding to a 0.3% lower absolute probability of closure in 2015 in association with payment reform. Patients who were black and who dialyzed at small, hospital-based facilities experienced slight increases in closures following payment reform, whereas Hispanic and Medicare/Medicaid dual-eligible patients experienced slight decreases in closures.Expansion of the ESKD payment bundle was not associated with increased closure of dialysis facilities, although the likelihood of closures changed slightly for some higher-risk populations.
重症心機能障害を併発した強皮症患者の治療に難渋した一例 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: 有賀伸, 榊原守, 野澤篤史, 穴田真奈美, 納谷昌直, 絹川真太郎, 古本智夫, 筒井裕之
Journal: Circulation (2009)
Secukinumab in the treatment of moderate to severe hidradenitis suppurativa: Results of an open-label trial
Authors: Rachel G. Casseres, Lisa Prussick, Pedro Zancanaro, Brooke Rothstein, Deep Joshipura, Ami Saraiya, Yana Turkowski, Shiu Chung Au, Abdulaziz Alomran, Rana Abdat, Minawaer Abudu, Courtney Kachuk, Nicole Dumont, Alice B. Gottlieb, David Rosmarin
Journal: Journal of the American Academy of Dermatology (2020)
Tislelizumab plus chemotherapy as first-line treatment for unresectable, locally advanced recurrent/metastatic esophageal squamous cell carcinoma.
Authors: Harry H. Yoon, Ken Kato, Richard Hubner, Eric Raymond, Aiyang Tao, Sumei Liu, Ibrahim Qazi, Jian-Ming Xu
Journal: Journal of Clinical Oncology (2020)

TPS462 Background: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer, particularly in Asian countries. Inhibition of the PD-1/PD-L1 axis has demonstrated antitumor activity in patients with advanced unresectable or metastatic ESCC. Tislelizumab, an investigational humanized IgG4 monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Results from early phase clinical studies suggest tislelizumab, as a single agent or in combination with chemotherapy, was generally well tolerated and had antitumor activity in patients with solid tumors, including ESCC. Methods: This global, phase 3, randomized, placebo-controlled, double-blind study (NCT03783442) is designed to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line treatment of unresectable, locally advanced recurrent or metastatic ESCC. Adult patients with histologically confirmed unresectable ESCC, or locally advanced recurrent/metastatic disease with a ≥6 month treatment-free interval, are eligible; palliative radiation administered &gt; 4 weeks from study initiation is allowed. Patients who received prior anti-PD-(L)1, anti-PD-L2, or first-line therapy are ineligible. Patients (n≈480) will be randomized 1:1 to receive tislelizumab 200 mg IV every 3 weeks (Q3W) plus investigator-chosen chemotherapy (ICC) or placebo plus ICC. ICC options include: platinum (plat; cisplatin 60-80 mg/m 2 or oxaliplatin 130 mg/m 2 IV Q3W) + 5-FU 750-800 mg/m 2 by continuous IV infusion over 24 hours for 5d Q3W; or plat + capecitabine 1000 mg/m 2 orally BID for 14d Q3W; or plat + paclitaxel 175 mg/m 2 IV Q3W. Progression-free and overall survival are primary endpoints; secondary endpoints include objective response rate, duration of response, and health-related quality of life. Safety will be assessed by monitoring adverse events, physical examinations, vital signs, and electrocardiograms. This study is actively enrolling. Clinical trial information: NCT03783442.
Genomic characterization of HBV-infected hepatocellular carcinoma patients using circulating tumor DNA.
Authors: Daniel Lin, Zhong Ye, Chun Wang, Qiang Wei, Li Bingshan, James Posey, Hushan Yang
Journal: Journal of Clinical Oncology (2020)

575 Background: Hepatocellular carcinoma (HCC) is a leading cause of mortality, with Hepatitis B virus (HBV) infection as a dominant etiology. Surgery or ablation may be curative for early-stage HCC. Thus, effective detection strategies are needed. We investigated genomic aberrations in circulating tumor DNA (ctDNA) as a potential diagnostic marker of HCC in HBV-infected patients. Methods: We identified early stage (BCLC 0-A) HCC cases (n = 21) and cancer-free controls (n = 15) from a cohort of Asian patients with HBV, undergoing surveillance at Thomas Jefferson University Hospital between 2013-2017. Blood samples were collected. Circulating cell-free DNA was isolated from plasma and assayed by capture-based next-generation sequencing of a targeted panel of 23 genes implicated in HCC pathogenesis. Sequencing data analysis and somatic mutation identification were conducted using a computational pipeline. Using area under the curve (AUC) in receiver operating characteristic analysis, we evaluated gene alterations and clinical factors (age, gender, cirrhosis) in an exploratory early detection HCC model. Results: Mutant ARID1A, ATM, CDKN2A, CTNNB1, ERBB2, TP53 genes were increased in HCC cases relative to non-cancer patients (85.7% vs 53.3%, P = 0.058; 42.9% vs 6.7%, P = 0.025; 38.1% vs 6.7%, P = 0.051; 42.9% vs 0%, P = 0.005; 52.4% vs 13.3%, P = 0.016; 100% vs 66.7%, P = 0.008, respectively). HCC patients had higher prevalence of cirrhosis than controls (90.5% vs. 60%, P = 0.046). Using the 6 mutant genes alone, the AUC for discriminating HCC from non-cancer patients was 0.827 (95% confidence interval [CI]: 0.701-0.953), which was greater than the AUC for discriminating cirrhosis from non-cirrhosis (0.531). When the 6 mutant genes were combined with clinical factors, the AUC of the exploratory HCC detection model increased to 0.914 ( P= 0.045). Conclusions: We identified 6 genomic aberrations in ctDNA that were more prevalent in HCC patients compared with non-cancer patients. Combining these alterations with clinical factors may identify HCC in HBV-infected patients at an early stage. These findings warrant further validation in future studies.
Abstract 1771: Serum And Glucocorticoid-induced Kinase-1 (SGK-1) Dynamically Regulates Cardiac Fibrosis In A CTGF- Independent Manner
Authors: Michael A Rosenberg, Saumya Das, Pablo Quintero Pinzon, Chunyang Xiao, Sucharita Banerjee, Anthony Rosenzweig
Journal: Circulation (2008)

Intro: We previously reported that the mineralcorticoid-responsive kinase, SGK-1, is activated in cardiac hypertrophy and regulates cardiomyocyte (CM) growth and survival. SGK-1 has also been implicated in renal fibrosis through transcriptional induction of connective tissue growth factor (CTGF). In this study, we examined the role of CM SGK-1 activation in the development of cardiac fibrosis. Methods: We studied histology and electrophysiology in transgenic mice with cardiac-specific overexpression of constitutively-activated (SGK-CA) and kinase-dead (SGK-KD) SGK-1 protein. Protein and RNA expression were measured by Western blot and QRT-PCR, respectively, and SGK-KD mice were studied following transverse aortic constriction (TAC). Results: EKG analysis revealed QRS prolongation in SGK-CA mice compared with wild type (WT) littermates (22.3±6.6 ms vs. 15.7±4.3 ms, p&lt;0.05), which correlated with increasing age (R 2 0.44, p&lt;0.05). Histologically, SGK-CA mice displayed increased fibrosis on Mason’s trichrome stain compared with WT mice. Protein expression of connexin43 (Cx43) was decreased 33% in SGK-CA ventricles (p&lt;0.05), without a change in Cx43 RNA, consistent with post-transcriptional downregulation secondary to fibrosis. TGF-β RNA expression was increased in SGK-CA mice 1.44 fold (p&lt;0.05), as was the fibrosis marker fibronectin (1.22 fold, p&lt;0.05), while CTGF RNA expression was not significantly different between SGK-CA mice and wild type littermates. Following TAC, the SGK-KD mice displayed decreased cardiac fibrosis compared with TAC WT mice. Paradoxically, SGK-KD had increased expression of CTGF RNA vs. WT both at baseline (1.26 fold, p&lt;0.05), as well as after TAC (1.52 fold, p&lt;0.05), with both groups having &gt; 3 fold increase in CTGF RNA after TAC. TGF- β RNA expression also increased about 1.5 fold in each group with TAC, although there was no significant difference between SGK-KD and WT mice either at baseline or after TAC. Conclusion: Cardiomyocyte SGK-1 activation appears to play a dynamic role in the development of cardiac fibrosis as well as subsequent conduction disease. Our finding of a disconnect between fibrosis and induction of CTGF or TGF- β in SGK mice suggests that it works at least in part through independent pathways.
Clinical Response to T-DM1 in HER2-Amplified, KRAS-Mutated Metastatic Colorectal Cancer.
Journal: Journal of the National Comprehensive Cancer Network (2020)

HER2 amplification has been identified in 2% to 3% of all colorectal cancers (CRCs). Although the prognostic role of HER2 amplification in metastatic CRC (mCRC) is unclear, studies have highlighted it as a therapeutic target. In addition, several studies have shown that HER2 amplification is implicated in the resistance to EGFR-targeted therapies. Other studies have provided scientific evidence to support the use of HER2-directed therapies in HER2-amplified CRC; however, thus far this benefit has been limited to the RAS wild-type population. There is an ongoing clinical need to identify novel means of targeting HER2 amplifications in the rare settings of HER2-amplified, RAS-mutated CRC. This case report presents a 58-year-old man with HER2-amplified mCRC and a KRAS G12D mutation whose disease progressed on all standard cytotoxic therapies as well as dual HER2 targeting using trastuzumab and pertuzumab. He subsequently derived a clinical benefit with metastatic lung disease regression on trastuzumab emtansine (T-DM1). He eventually experienced disease progression in the liver after 6 every-3-week cycles. The patient's response and disease progression were associated with ongoing decline in the HER2 copy number on the circulating tumor DNA assay, suggesting that the mechanism of resistance was related to the loss of HER2 amplification or the emergence of non-HER2-amplified CRC clones. This represents the first report of clinical benefit with T-DM1 in KRAS-mutated HER2-amplified CRC.
Immunomodulatory effects of tumor treating fields (TTFields) on colon cancer models.
Authors: Tali Voloshin, Noa Kaynan, Shiri Davidi, Yaara Porat, Anna Shteingauz, Mijal Munster, Rosa S Schneiderman, Catherine Tempel-Brami, Einav Zeevi, Karnit Gotlib, Shay Cahal, Moshe Giladi, Eilon D. Kirson, Uri Weinberg, Adrian Kinzel, Yoram Palti
Journal: Journal of Clinical Oncology (2020)

136 Background: Tumor Treating Fields (TTFields) are clinically approved in glioblastoma and malignant pleural mesothelioma as an anti-mitotic treatment modality delivered via noninvasive application of low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. We evaluated whether TTFields (150 kHz) induced colon cancer cell death can be perceived as immunogenic and suitable for combination with anti-programmed cell death protein 1 (anti-PD-1; immune checkpoint inhibitor) therapy. Methods: Murine colorectal carcinoma cells (CT-26) were treated with TTFields using the inovitro system. Immunogenic cell death was evaluated by assessing changes in the levels of calreticulin (CRT) on the surface of treated cells, phosphorylation of eukaryotic translation initiation factor alpha (eIF2α), and secretion of ATP and high-mobility group box 1 (HMGB1). For in-vivo studies, CT-26 cells were subcutaneously implanted in BALB/c mice. The mice were treated with TTFields (150 kHz), anti-PD-1 (200 μg/mouse), or a combination of the 2 modalities. Tumor volume was monitored and flow cytometry analyses performed for phenotypic characterization of infiltrating immune cells. Results: We demonstrate that cancer cell death under TTFields application exhibited release of HMGB1, ATP secretion from cells, and ER stress leading to CRT translocation to the cell surface, all of which are signs of immunogenic cell death. The combined treatment of colon tumor-bearing mice with TTFields plus anti-PD-1 led to a significant decrease in tumor volume compared to anti-PD-1 alone or to the control group. Significant increases in CD45+ tumor infiltrating cells were observed in the TTFields plus anti-PD-1 group. We demonstrate significant increases in both CD8 and CD4 T-cells in tumors treated with combination therapy, and in CD8 in tumors treated with anti-PD-1 alone. Conclusions: Our results establish the potential of TTFields therapy to induce immunogenic cell death. We also demonstrate efficacy of concurrent application of TTFields and anti PD-1 therapy in mouse cancer models. These data suggest that TTFields plus anti-PD-1 combination treatment may achieve tumor control by further enhancing anti-tumor immunity.
Probable usual interstitial pneumonia pattern on chest CT: is it sufficient for a diagnosis of idiopathic pulmonary fibrosis?
Authors: Jun Fukihara, Yasuhiro Kondoh, Kevin K. Brown, Tomoki Kimura, Kensuke Kataoka, Toshiaki Matsuda, Yasuhiko Yamano, Atsushi Suzuki, Taiki Furukawa, Hiromitsu Sumikawa, Osamu Takahashi, Takeshi Johkoh, Tomonori Tanaka, Junya Fukuoka, Naozumi Hashimoto, Yoshinori Hasegawa
Journal: European Respiratory Journal (2020)

Recent studies have suggested that in patients with an idiopathic interstitial pneumonia (IIP), a probable usual interstitial pneumonia (UIP) pattern on chest computed tomography (CT) is sufficient to diagnose idiopathic pulmonary fibrosis (IPF) without histopathology.We retrospectively compared the prognosis and time to first acute exacerbation (AE) in IIP patients with a UIP and a probable UIP pattern on initial chest CT.One hundred and sixty IIP patients with a UIP pattern and 242 with a probable UIP pattern were identified. Probable UIP pattern was independently associated with longer survival time (adjusted hazard ratio 0.713, 95% CI 0.536-0.950; p=0.021) and time to first AE (adjusted hazard ratio 0.580, 95% CI 0.389-0.866; p=0.008). In subjects with a probable UIP pattern who underwent surgical lung biopsy, the probability of a histopathological UIP pattern was 83%. After multidisciplinary discussion and the inclusion of longitudinal behaviour, a diagnosis of IPF was made in 66% of cases. In IPF patients, survival time and time to first AE were not associated with CT pattern. Among subjects with a probable UIP pattern, compared to non-IPF patients, survival time and time to first AE were shorter in IPF patients.In conclusion, IIP patients with a probable UIP pattern on initial chest CT had a better prognosis and longer time to first AE than those with a UIP pattern. However, when baseline data and longitudinal behaviour provided a final diagnosis of IPF, CT pattern was not associated with these outcomes. This suggests diagnostic heterogeneity among patients with a probable UIP pattern.
ATP-Citrate Lyase Epigenetically Potentiates Oxidative Phosphorylation to Promote Melanoma Growth and Adaptive Resistance to MAPK Inhibition
Authors: Weinan Guo, Jinyuan Ma, Yuqi Yang, Sen Guo, Weigang Zhang, Tao Zhao, Xiuli Yi, Huina Wang, Shiyu Wang, Yu Liu, Wei Dai, Xuguang Chen, Qiong Shi, Gang Wang, Tianwen Gao, Chunying Li
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Enhanced lipogenesis and mitochondrial function are two critical metabolic characteristics in melanoma, but their crosstalk involved in tumor biology and targeted therapy remains unknown. ATP-citrate lyase (ACLY) is a crucial lipogenic enzyme that is greatly implicated in tumor development, but its role in mitochondrial function and melanoma pathogenesis has not been elucidated. Experimental Design: In vitro and in vivo functional experiments were performed to determine the effect of ACLY on melanoma growth. mRNA expression profile analysis and a panel of biochemical assays were used to investigate the role of ACLY in mitochondrial oxidative phosphorylation and the underlying mechanism. The effect of combined ACLY inhibition on the efficacy of MAPK inhibition therapy was also examined. Results: We first found that ACLY expression was increased in melanoma and facilitated cell proliferation and tumor growth both in vitro and in vivo. Subsequent mRNA expression profile analysis and functional studies unveiled that ACLY specifically activated MITF–PGC1α axis to promote mitochondrial biogenesis and melanoma growth. Mechanistically, ACLY enhanced the activity of acetyltransferase P300, increasing the histone acetylation at MITF locus to promote MITF–PGC1α axis transcription. More importantly, the combined inhibition of ACLY sensitized BRAF-mutant melanoma to MAPK inhibition by suppressing MITF–PGC1α axis. Conclusions: We demonstrate that ACLY epigenetically potentiates oxidative phosphorylation to promote melanoma growth and MAPK inhibition adaptive resistance. Our study discovers the novel crosstalk between lipogenesis and mitochondrial function in tumor biology and highlights targeting ACLY as a potent therapeutic approach via simultaneously impairing tumor growth and MAPK inhibition resistance in melanoma.
사례보고 : 백선 복용 후 발생한 독성 간손상 4예
Authors: 장종순 ( Jong Soon Jang ), 서의근 ( Eui Geun Seo ), 한철 ( Cheol Han ), 채희복 ( Hee Bok Chae ), 김순제 ( Soon Je Kim ), 이재동 ( Jae Dong Lee ), 왕준호 ( Joon Ho Wang )
Journal: Clinical and Molecular Hepatology (2008)