tbuckley/cabot-search huggingface dataset:
Apartinib in combination with S-1 for the second-line treatment of advanced pancreatic cancer (APC).
Authors: Junjie Hang, Lixia Wu, Ruohan Yin, Muhan Liu, Kequn Xu
Journal: Journal of Clinical Oncology (2020)

TPS781 Background: The prognosis for patients with advanced pancreatic cancer (APC) is extremely dismal. First-line treatment for APC is gemcitabine/5-FU-based chemotherapy with no standard second-line treatment. Anti-angiogenic therapy combined with chemotherapy have showed its effects in improving the outcomes in a variety of cancers. Apatinib is an oral tyrosine kinase inhibitor that selectively targets VEGFR2. Some preclinical studies and several case reports showed the anti-tumor effect of apatinib in pancreatic cancer, but there is no evidence from clinical trial to confirm it. This study aims to evaluate the efficacy and safety of apartinib in combination with S-1 as the second-line therapy for patients with APC. Methods: In this open-label, single-arm, randomized phase II study, we will recruit 30 patients with pathologically proven advanced pancreatic cancer after the failure of first-line chemotherapy. All patients are aged 18-70 years with ECOG PS 0-2 and will receive apatinib at an initial dose of 500mg/d on a continuous basis, and oral S-1 (60mg/d for BSA &lt; 1.25m 2 , 80mg/d for 1.25&lt;BSA &lt; 1.5m 2 , and 100mg for BSA &gt;1.5m 2 , orally) twice a day on days 1-14 of a 21-day cycle. Primary endpoint is PFS. Secondary endpoints include OS, duration of response, ORR and DCR. The safety of apartinib + S-1 will be evaluated by CTCAE v4.0. Translational research will be performed in blood (before and on-treatment): cytokine panel to explore predictive and prognostic biomarkers. Clinical trial information: NCT03662035.
Association of vitamin D intake with decreased risk of immune checkpoint inhibitor-induced colitis.
Authors: Kevin Tyan, Shilpa Grover, Michael Dougan, Ryan J. Sullivan, Anita Giobbie-Hurder, Steven Blum, Jeffrey Joseph Ishizuka, Taha Qazi, Rawad Elias, Kruti Vora, Alex Ruan, William Martin-Doyle, Lauren Eastman, Meredith Davis, Maria Gargano, Rizwan Haq, Elizabeth Iannotti Buchbinder, Patrick Alexander Ott, F. Stephen Hodi, Osama E. Rahma
Journal: Journal of Clinical Oncology (2020)

89 Background: There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. Methods: We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination blockade between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariate logistic regression analyses. External validation was performed on an independent cohort from Massachusetts General Hospital. Results: The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). The odds of colitis were higher in patients treated with ipilimumab either as monotherapy or in combination with nivolumab compared to those treated with pembrolizumab. Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1–0.9). These results were confirmed in the validation cohort of 169 patients of whom 49 developed ICI colitis (29%). Pretreatment neutrophil/lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1–0.9) only in the discovery cohort. Conclusions: This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and GVHD. This observation should be validated prospectively in future studies. [Table: see text]
Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH
Authors: Christopher W Wasson, Giuseppina Abignano, Heidi Hermes, Maya Malaab, Rebecca L Ross, Sergio A Jimenez, Howard Y Chang, Carol A Feghali-Bostwick, Francesco del Galdo
Journal: Annals of the Rheumatic Diseases (2020)

<h3>Background</h3> Systemic sclerosis (SSc) is characterised by autoimmune activation, tissue and vascular fibrosis in the skin and internal organs. Tissue fibrosis is driven by myofibroblasts, that are known to maintain their phenotype in vitro, which is associated with epigenetically driven trimethylation of lysine 27 of histone 3 (H3K27me3). <h3>Methods</h3> Full-thickness skin biopsies were surgically obtained from the forearms of 12 adult patients with SSc of recent onset. Fibroblasts were isolated and cultured in monolayers and protein and RNA extracted. HOX transcript antisense RNA (HOTAIR) was expressed in healthy dermal fibroblasts by lentiviral induction employing a vector containing the specific sequence. Gamma secretase inhibitors were employed to block Notch signalling. Enhancer of zeste 2 (EZH2) was blocked with GSK126 inhibitor. <h3>Results</h3> SSc myofibroblasts in vitro and SSc skin biopsies in vivo display high levels of HOTAIR, a scaffold long non-coding RNA known to direct the histone methyltransferase EZH2 to induce H3K27me3 in specific target genes. Overexpression of HOTAIR in dermal fibroblasts induced EZH2-dependent increase in collagen and α-SMA expression in vitro, as well as repression of miRNA-34A expression and consequent NOTCH pathway activation. Consistent with these findings, we show that SSc dermal fibroblast display decreased levels of miRNA-34a in vitro. Further, EZH2 inhibition rescued miRNA-34a levels and mitigated the profibrotic phenotype of both SSc and HOTAIR overexpressing fibroblasts in vitro. <h3>Conclusions</h3> Our data indicate that the EZH2-dependent epigenetic phenotype of myofibroblasts is driven by HOTAIR and is linked to miRNA-34a repression-dependent activation of NOTCH signalling.
Impact of prior irinotecan exposure on outcomes of metastatic pancreatic cancer (mPC) patients.
Authors: Eileen Mary O'Reilly, Andy Surinach, Allison Dillon, Paul Cockrum, Kenneth H. Yu
Journal: Journal of Clinical Oncology (2020)

667 Background: Published data suggests prior exposure to irinotecan infers a lower likelihood of benefit to liposomal irinotecan. This analysis seeks to expand this hypothesis by evaluating U.S. patterns of care to understand how prior irinotecan therapy impacts outcomes in mPC. Methods: Using the Flatiron Health database, data were extracted and analyzed for treated mPC patients (pts) in the 2L+ setting between Jan 1, 2014 and Jun 30,2019. Therapies of interest included: gemcitabine/ nab-paclitaxel (GnP), FOLFOX, FOLFIRI, FOLFIRINOX (FFX), and liposomal irinotecan/5-FU/LV (nal-IRI). The reference date for each treatment group was the date of treatment initiation. Prior irinotecan was defined as any irinotecan given in a prior regimen in mPC diagnosis. Cox proportional hazard (PH) methods were used to calculate mortality hazard ratios (HRs). HRs were adjusted to account for demographics and relevant covariates. Pts with prior exposure to irinotecan were used as the reference population for the Cox PH model (an HR &lt; 1 represents worse survival for exposed pts relative to the unexposed). Results: N = 1,978 were included in this analysis. The median age at treatment initiation, and the proportion of pts previously treated with irinotecan are reported in table. Crude mortality was: GnP pts, HR 0.93 [95% CI: 0.77 – 1.11, adjusted HR, 0.94, 0.76 – 1.15]; nal-IRI pts, HR 0.81 [0.64 – 1.02, adjusted HR: 0.89, 0.67 – 1.19]; HR for FOLFOX was 0.55 [0.38 – 0.78, adjusted HR: 0.51, 0.33 – 0.79]. HRs are not reported for FFX and FOLFIRI due to the small numbers with prior irinotecan exposure. Conclusions: In mPC, prior irinotecan treatment may not preclude benefit from later treatment with nal-IRI or GnP as can be seen from the adjusted and unadjusted HRs. These findings are hypothesis-generating and need to be considered in the context of wide CI’s, retrospective nature and the limitations of such data. Further study is required to understand the less-favorable signal observed with FOLFOX and prior irinotecan.[Table: see text]
Immune checkpoint blockade (ICB) response evaluation with MRI/MR elastography (MRE) in surgical and nonsurgical patients with HCC.
Authors: Aliya Qayyum, Rony Avritscher, Rizwan Aslam, Jingfei Ma, Mark David Pagel, Jia Sun, Yehia I. Abugabal, Manal Hassan, Hesham M. Amin, Asif Rashid, Sunyoung S. Lee, Robert A. Wolff, James C. Yao, Richard Ehman, Dan G. Duda, Ahmed Omar Kaseb
Journal: Journal of Clinical Oncology (2020)

480 Background: Currently, there is a lack of imaging biomarkers of immunotherapy outcome in hepatocellular carcinoma (HCC). The study aim was to determine if HCC enhancement on MRI and stiffness change measured by magnetic resonance elastography (MRE) can predict immunotherapy response. Methods: This was a prospective, Institutional Review Board approved study of 38 patients with HCC treated with immune checkpoint blockade (ICB) therapy. All patients had liver MRI/MRE and HCC biopsy at baseline, and MRI/MRE with biopsy or resection after 6 weeks therapy. HCC stiffness (kPa) was measured on MRE elastograms (liver stiffness maps). HCC enhancement and change in stiffness were compared with treatment response to ICB in 1) non-surgical patients (pembrolizumab), and 2) surgical patients (nivolumab +/- ipilimumab). For non-surgical patients, treatment response was defined as overall survival &gt;1 year. For surgical patients, treatment response was defined as &lt;50% viable tumor at time of resection. Analysis was performed using descriptive statistics and Spearman correlation; p-value &lt;0.05 was considered statistically significant. Results: Twenty-five patients were evaluable. Median age was 67 years (32, 78). Etiology of liver disease was NASH (n=8), HCV (n=8), HBV (n=2) and unknown (n=7). Treatment response occurred in 11/25 (44%) patients. Median HCC size and change in size were 4.7 cm (1.2, 14.0) and –0.32 cm, respectively. Median baseline HCC stiffness and change in stiffness were 5 kPa (2.2, 12.4) and –0.1 kPa (–2.2, 1.5), respectively. Median change in HCC size for responders and non-responders was –1.2 cm (–4.8, 0.4) and 0 cm (–1.5, 1.1), respectively (p = 0.02). Treatment response was associated with absence of portal venous phase capsular enhancement and increase in HCC stiffness, (p&lt;0.001). Conclusions: Capsular enhancement and MRE stiffness change may be useful biomarkers of immune cell activated response to ICB therapy.
Biomarker exploration for SHR-1210 plus GEMOX as first-line treatment in advanced biliary tract cancer.
Authors: Xiaofeng Chen, Hao Wu, Xiaofeng Wu, Qianwen Shao, Feipeng Zhu, Xiaofeng Qian, Fengjiao Zhao, Weidong Mao, Jing Sun, Jian Wang, Gaohua Han, Huajun Li, Dongqin Zhu, Liuqing Zhu, Changxian Li, Poshita kumari Seesaha, Yang Shao, Yanhong Gu, Xiangcheng Li, Yongqian Shu
Journal: Journal of Clinical Oncology (2020)

536 Background: We conducted a trial to evaluate the efficacy and safety of SHR-1210 (a humanized anti-programmed cell death receptor 1 antibody) plus gemcitabine and oxaliplatin (GEMOX) as in untreated patients (pts) with biliary tract cancer (BTC) (NCT03486678). This study is to explore the predictive biomarkers for efficacy. Methods: Baseline lymphocyte count and lactate dehydrogenase (LDH) level were obtained from routine tests. Gene mutation and tumor mutation burden (TMB) from baseline tissue and blood samples were tested by the next generation sequencing (NGS) with a 425-gene panel. The expressions of PD-L1 and markers for lymphocyte, natural killer cells, and macrophages in baseline tumor tissue samples were analyzed by immunohistochemistry (IHC). Results: The median progression free survival (PFS) and overall survival (OS) in this trial was 6.2m and 12.1m, respectively. Firstly, pts with normal LDH level (≤271 U/L) had a tendency for longer PFS (6.2m vs 5.0m, p = 0.053) and significantly longer OS (p = 12.6m vs 6.8m, p &lt; 0.001) than those with elevated LDH ( &gt; 271 U/L). Low baseline lymphocyte count (≤ 1.1×10 9 /L) was related to worse OS (12.6m vs 6.9m, p &lt; 0.001) and PFS (6.2m vs 3.9m, p = 0.021). Secondly, baseline tissue and ctDNA gene mutations were detected in 33 and 30 pts, respectively. Tissue analysis showed that pts with STK11 (p = 0.0254), CTNNB1 (p &lt; 0.001) and SMARCA4 (p = 0.0181) wild type showed significantly longer PFS than those with mutations. Pts with ARID1A gene wild type showed a tendency for longer PFS (p = 0.0634) and significantly longer OS (p = 0.0149). Gene mutations from baseline ctDNA revealed that pts with wild type SMARCA4, CTNNB1, STK11, and NF1 had longer PFS than those with mutations. Lastly, IHC meant that PD-L1 positivity may be related to longer PFS (TPS &gt; 1%, p = 0.08; IPS &gt; 1%, p = 0.05). Besides, pts with CD68+ HLA-DR+ macrophages &gt; 0.01%, CD68+ HLA-DR- macrophages&gt;2.5%, and CD56bright&gt;1.7% and CD56dim &gt; 0.05 also got PFS benefits (all p &lt; 0.05). TMB (cutoff = 7 muts/mbp) was not associated with PFS. Conclusions: Despite limited sample size, biomarkers from routine blood test, gene mutation and immune microenvironment can be helpful to stratify pts who are sensitive to immunotherapy in advanced BTC. Clinical trial information: NCT03486678.
The 3′ Untranslated Region Protects the Heart from Angiotensin II-Induced Cardiac Dysfunction via AGGF1 Expression
Authors: Lexi Ding, Shan Lu, Yu Zhou, Dayin Lyu, Changhan Ouyang, Zejun Ma, Qiulun Lu
Journal: Molecular Therapy (2020)

The messenger RNA (mRNA) 3′ untranslated regions (3′ UTRs), as cis-regulated elements bound by microRNAs (miRNAs), affect their gene translation. However, the role of the trans-regulation of 3′ UTRs during heart dysfunction remains elusive. Compared with administration of angiogenic factor with G-patch and forkhead-associate domains 1 (Aggf1), ectopic expression of Aggf1 with its 3′ UTR significantly suppressed cardiac dysfunction in angiotensin II-infused mice, with upregulated expression of both Aggf1 and myeloid cell leukemia 1 (Mcl1). Along their 3′ UTRs, Mcl1 and Aggf1 mRNAs share binding sites for the same miRNAs, including miR-105, miR-101, and miR-93. We demonstrated that the protein-coding Mcl1 and Aggf1 mRNAs communicate and co-regulate each other's expression through competition for these three miRNAs that target both transcripts via their 3′ UTRs. Our results indicate that Aggf1 3′ UTR, as a trans-regulatory element, accelerates the cardioprotective role of Aggf1 in response to hypertensive conditions by elevating Mcl1 expression. Our work broadens the scope of gene therapy targets and provides a new insight into gene therapy strategies involving 3′ UTRs. The messenger RNA (mRNA) 3′ untranslated regions (3′ UTRs), as cis-regulated elements bound by microRNAs (miRNAs), affect their gene translation. However, the role of the trans-regulation of 3′ UTRs during heart dysfunction remains elusive. Compared with administration of angiogenic factor with G-patch and forkhead-associate domains 1 (Aggf1), ectopic expression of Aggf1 with its 3′ UTR significantly suppressed cardiac dysfunction in angiotensin II-infused mice, with upregulated expression of both Aggf1 and myeloid cell leukemia 1 (Mcl1). Along their 3′ UTRs, Mcl1 and Aggf1 mRNAs share binding sites for the same miRNAs, including miR-105, miR-101, and miR-93. We demonstrated that the protein-coding Mcl1 and Aggf1 mRNAs communicate and co-regulate each other's expression through competition for these three miRNAs that target both transcripts via their 3′ UTRs. Our results indicate that Aggf1 3′ UTR, as a trans-regulatory element, accelerates the cardioprotective role of Aggf1 in response to hypertensive conditions by elevating Mcl1 expression. Our work broadens the scope of gene therapy targets and provides a new insight into gene therapy strategies involving 3′ UTRs.
Effect of postoperative apatinib treatment after resection of hepatocellular carcinoma with portal vein invasion: A phase II study.
Authors: Hui-Chuan Sun, Xiao-Dong Zhu, Jian Zhou, Qiang Gao, Ying-Hong Shi, Zhen-Bing Ding, Cheng Huang, Shuang-Jian Qiu, Ning Ren, Guo-Ming Shi, Jian Sun, Qing-Hai Ye, Xiao-Wu Huang, Xin-Rong Yang, Jia Fan
Journal: Journal of Clinical Oncology (2020)

514 Background: Adjuvant therapy for hepatocellular carcinoma (HCC) is an unmet need. Apatinib, a VEGFR2 inhibitor, showed antitumor activity and tolerable toxicity for advanced HCC in a phase 2 study. We were aiming to explore the safety and efficacy of apatinib in adjuvant settings after resection of HCC with portal vein tumor thrombosis (PVTT). Methods: This is a single-center single-arm phase 2 study. The key inclusion criteria were: (1) pathologically confirmed HCC; (2) underwent liver resection with curative intention within 4-6 wk before recruitment; (3) PVTT assessed by preoperative imaging or intraoperative findings. Eligible pts received apatinib at 500 mg/day for a maximum of 12 mo until unacceptable toxicity or tumor recurrence. The primary outcome was recurrence-free survival (RFS) defined as the interval between surgery and the diagnosis of tumor recurrence or death from any causes whichever comes first. The secondary outcome is overall survival (OS) and treatment safety. Results: From Aug 17, 2017 to Dec 18, 2018, 49 pts were screened, and 30 pts were recruited. PVTT were classified as Vp1 (n = 7), Vp2 (n = 11), and Vp3 (n = 12) according to the LCSGJ classification. As the data cutoff on Aug 22, 2019, 4 pts are still on treatment. The median follow-up was 14.3 mo (IQR 12.3-19.3). Median duration of treatment was 4.8 mo (IQR 2.0–8.8). 20 recurrence and 2 death occurred including one death without recurrence. The mRFS was 7.6 mo (95% CI, 3.7-11.5), and the 1-year RFS rate was 36.1%. The mOS was not reached, and 1-year OS rate was 93.3% (standard error, 4.6%). Treatment-related adverse events occurred in 29 pts (96.7%). Grade 3 or 4 adverse events were reported in 14 pts (46.7%) (Table). Dose modification due to adverse events was recorded in 23 pts (76.7%). Conclusions: Apatinib is tolerant in most pts after resection for HCC with PVTT. A controlled study is warranted to prove its efficacy on tumor recurrence. Clinical trial information: NCT03261791. [Table: see text]
Variation in genetic polymorphisms and gene expression of HLA-E to predict outcomes in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI/cetuximab: Data from the phase III FIRE-3 trial.
Authors: Madiha Naseem, Shu Cao, Sebastian Stintzing, Francesca Battaglin, Ryuma Tokunaga, Alberto Puccini, Martin D. Berger, Shivani Soni, Wu Zhang, Afsaneh Barzi, Volker Heinemann, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2020)

245 Background: HLA-E is an MHC Class I antigen which inhibits NK cell activity by binding to CD94 receptor. Overexpression of HLA-E on crc cells is associated with poor prognostic outcomes and has recently been associated with microsatellite instability. As cet enhances NK cell activity which is dependent on HLAE, this study aims to assess whether differences in HLAE gene expression and polymorphisms lead to different outcomes. Methods: Genomic DNA from blood samples of pts treated with first-line FOLFIRI-cetuximab (cet, n = 129) and FOLFIRI-bevacizumab (bev, n = 107) was genotyped through the OncoArray, a custom array manufactured by Illumina. Gene expression levels were measured from 102 tumor samples of pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. PFS and OS outcomes were investigated for an HLAE genetic polymorphism, rs1264457, where G &gt; A leads to glycine &gt; arginine, where glycine has stronger affinity for NK cell receptor. Results: FOLFIRI/cet and FOLFIRI/bev cohort characteristics: median FU (29.1/26.7mo); PFS (12.8/11.5mo); OS (49.8/31.4mo); RAS WT (64%/62%) and RAS mut (15%/16%). Overexpression of HLAE was associated with poor OS (log2 &gt; 13, 30 vs 34 mo) in cet arm (P &lt; .05). No significant association was observed with PFS. Multivariable analysis showed that HLAErs1264457 carriers with any A allele (n = 65) had better PFS than pts with G/G genotype (n = 18) in RAS WT pts treated with FOLFIRI/cet (12.9 vs 12.3 mo; HR = 2.36; 95%CI = 1.14-4.88; p = 0.021). A non-significant trend of improved OS was seen among carriers of A allele than G/G genotype (56.2 vs 40 mo). These effects were not observed in Ras mut pts. No significance was observed in FOLFIRI/bev overall or FOLFIRI/bev RAS WT pts. Conclusions: Overexpression of HLAE leads to poor OS among pts treated with FOLFIRI/cet. Poor PFS was seen among pts treated with cet who are RAS wt carrying polymorphisms allowing for increased binding to NK cell receptor, which in turn enhances HLAE inhibitory function of NK cell lysis. Addition of mAb against HLAE, which have been shown to restore NK cell mediated cell lysis, needs investigation in this pt population.
Immunotherapy for nonsmall cell lung cancer: a new therapeutic algorithm
Authors: Thierry Berghmans, Anne-Marie Dingemans, Lizza E.L. Hendriks, Jacques Cadranel
Journal: European Respiratory Journal (2020)

After a nihilistic period lasting for decades, major progress in nonsmall cell lung cancer (NSCLC) therapy were linked to the introduction of platinum-based regimens, third generation chemotherapeutic drugs and, more recently, with the discovery of oncogenic driver mutations and the development of very effective targeted therapies [1]. However, for a long time, despite known significant immune dysregulations in the lung cancer environment, clinical trials with immune therapy failed to be superior to standard therapy. Adjuvant vaccination was one of the most recent prominent failures [2]. Immunotherapy is a new approach for the treatment of lung cancer with impressive long-term results <http://bit.ly/35GVzAn>
Response to: ‘Dupilumab as a <i>potential</i> steroid-sparing treatment for IgG4-related disease’ by Della-Torre <i>et al</i>
Authors: Rachel S Simpson, Jason K Lee
Journal: Annals of the Rheumatic Diseases (2020)

Correspondence responsetreatment out of fear of side effects and failed to disclose this to their healthcare provider.However, we recognise the fact that we have observed the remission of IgG4-RD in only a single patient and that larger randomised control trials would ideally provide the most robust evidence to conclude the safety and efficacy of dupilumab for IgG4-RD.Due to the fact that IgG4-RD is a rare condition in which the prevalence is actually unknown because it is commonly misdiagnosed or unrecognised, 6 this can be a profound limiting factor to recruitment in such trials.We advocate for these randomised control trials to be done and believe that our case provides strong rationale to further explore the uses of dupilumab for IgG4-RD.