tbuckley/cabot-search huggingface dataset:
Clinical efficacy and safety in gastric cancer patients treated with apatinib: A retrospective real-world study.
Authors: Ning Li, Yali Du, Wenying Deng, Yijie Ma, Xinyi Yang, Liangyu Bie, Qiong Wu, Haiying Yang, Suxia Luo
Journal: Journal of Clinical Oncology (2019)

e15522 Background: This study aimed to explore the efficacy, safety of apatinib and analyze the effects of HER2 mutation status and treatment lines on gastric cancer (GC) patients (pts) treated with apatinib in real-world clinical practice. Methods: We retrospectively analyzed the study data from Linkdoc database with 270 pts who were pathologically or cytologically diagnosed GC and treated with apatinib during January 2015 to November 2018 in Henan Cancer Hospital. Survival was estimated by Kaplan-Meier method. Results: In this study, there were 180 (66.7%) male, with median age of 59 years. The vast majority of pts (259/95.9%) had adenocarcinoma and 86.3% of pts were in stage IV. HER2 was positive in 33.0% of 100 treated pts undergoing HER2 mutation testing. Apatinib was mainly used as second-line treatment (122/45.2%), followed by third-line (82/30.4%), first-line (56/20.7%), fourth- and further-line (22/8.1%), adjuvant (12/4.4%) and neoadjuvant treatment (1/0.4%). Pts received apatinib alone or combined with chemotherapy were 175 (64.8%) and 119 (44.1%), with 53.6% administered at an initial dose of 500 mg. Of all the 270 enrolled pts, the median progression free survival (mPFS) and median overall survival (mOS) were 4.3 months (95% CI: 3.5-5.0) and 6.1 months (95% CI: 5.1-8.4), respectively. For treatment lines subgroup, the mOS was 12.6 months (95% CI: 3.5-NE) in adjuvant treatment; 8.9 months (95% CI: 4.3-12.6) in first-line; 7.3 months (95% CI: 5.0-9.7) in second-line; 6.2 months (95% CI: 5.1-9.9) in third-line; 4.0 months (95% CI: 1.6-6.9) in fourth- and further-line treatment. For HER2-negative pts, the mOS was slightly longer than those of HER2-positive pts (5.7 months vs. 4.5 months), however, the difference was not statistically significant ( p = 0.5185). The most common adverse events were fatigue (25.9%), anemia (24.8%), hypertension (9.3%) and vomiting (9.3%). Conclusions: This real world study revealed that the clinical efficacy of apatinib in GC pts was satisfying and the toxicity was tolerable and controllable. Pts received apatinib in ≤ second-line treatment may gain better survival benefits, and little difference was found in survival outcomes between pts with or without HER2 mutations.
Early TIPS with covered stents versus standard treatment for acute variceal bleeding in patients with advanced cirrhosis: a randomised controlled trial
Authors: Yong Lv, Zhiping Yang, Lei Liu, Kai Li, Chuangye He, Zhengyu Wang, Wei Bai, Wengang Guo, Tianlei Yu, Xulong Yuan, Hongbo Zhang, Huahong Xie, Liping Yao, Jianhong Wang, Tao Li, Qiuhe Wang, Hui Chen, Enxin Wang, Dongdong Xia, Bohan Luo, Xiaomei Li, Jie Yuan, Na Han, Ying Zhu, Jing Niu, Hongwei Cai, Jielai Xia, Zhanxin Yin, Kaichun Wu, Daiming Fan, Guohong Han
Journal: The Lancet. Gastroenterology & hepatology (2019)
Genomic somatic alterations of human epidermal growth factor-2 (HER2) gene: A pan-cancer analysis.
Authors: Xinhua Zhu, Yong Zhou, Yuzi Zhang, Shangli Cai
Journal: Journal of Clinical Oncology (2019)

3112 Background: Human epidermal growth receptor 2 (HER2) is a well-known oncogenic drive gene with multiple targeted therapeutic options. In this study, we aim to assess the landscape of HER2 alterations in solid tumors and evaluate the feasibility of circulating tumor DNA (ctDNA) tested by next-generation sequence (NGS) as a tool to detect HER2 alterations. Methods: Alterations of HER2 by NGS (Illumina NextSeq 500) were queried in 3D Medicines database. The mean depth of tissue and circulating tumor DNA (ctDNA) test was 500X and 5000X, respectively. 11,013 patients tested using tumor tissue and 6,970 patients tested using ctDNA were included in this analysis. Results: Of 11,013 patients tested using tumor tissue, any HER2 and known or likely deleterious HER2 mutations were identified in 739 (6.7%) and 531 (4.8%) patients, respectively. Of 531 patients who carried known or likely deleterious HER2 mutations, 263 (49.5%) had HER2 amplification and 259 (48.8%) had single nucleotide variations (SNVs). Across all tumor types, breast cancer was found to have the highest frequency of HER2 amplification (14.9%, 48/323), followed by gastric cancer (6.6%, 31/470) and biliary tract cancer (5.8%, 33/571). Moreover, 11% (8/73) of duodenal cancer, 4.5% (7/154) of urothelial cancer, 3.8% (18/470) of gastric cancer, 3.1% (142/4555) of lung cancer, 2.9% (17/571) of biliary tract cancer, 2.8% (44/1562) of colorectal cancer and 2.7% (9/323) of breast cancer carried known or likely deleterious HER2 SNVs. Of 6970 patients tested using ctDNA, any HER2 and known or likely deleterious HER2 mutations were identified in 592 (8.5%) and 277 (4.0%) patients, respectively. In the ctDNA cohort, 15.7% (36/230) of breast cancer and 3.1% (5/161) of biliary tract cancer carried HER2 amplification. However, 11.6% (20/173) of gastric cancer had HER2 amplification tested by ctDNA which was higher than that tested using tissue. Furthermore, 5.6% (13/230) of breast cancer, 4.5% (2/44) of urothelial cancer, 3.4% (6/173), 2.5% of biliary tract cancer and 2.0% (94/4586) lung cancer harbored known or likely deleterious HER2 SNVs in ctDNA cohort. Conclusions: HER2 alterations existed across tumor types and the landscape of genomic alterations in HER2 gene varied according to different type of tumor. In addition, ctDNA can be used as a potential tool to detect HER2 alterations.
Practice variation on hospital level in the systemic treatment of metastatic colorectal cancer in the Netherlands: A population-based study.
Authors: Lotte Keikes, Miriam Koopman, Martijn M. Stuiver, Valery Lemmens, Martijn G.H. van Oijen, Cornelis J. A. Punt
Journal: Journal of Clinical Oncology (2019)

6612 Background: Population-based data on the implementation of guidelines for cancer patients in daily practice are scarce. Therefore, we evaluated practice variation patterns and associated variables in the systemic treatment of metastatic colorectal cancer (mCRC) between 2008 and 2015 in the Netherlands. Methods: We selected a random sample of adult mCRC patients diagnosed from 2008 to 2015 from the National Cancer Registry in 20 Dutch hospitals. We examined the influence of patient, demographic and tumor characteristics on the odds of being treated with systemic therapy according to the current guideline and assessed its association with survival. Results: Our study population consisted of 2222 mCRC patients of whom 1307 patients received systemic therapy for mCRC. Practice variation was most obvious in the use of bevacizumab and anti-EGFR therapy in patients with (K)RAS wild-type tumors. Administration rates did not differ between hospital types but fluctuated between individual hospitals for bevacizumab (8-92%; p&lt;0·0001) and anti-EGFR therapy (10-75%; p=0·05). Bevacizumab administration was inversely correlated to higher age (OR:0·2; 95% CI: 0·1-0·3) comorbidity (OR:0·6; 95% CI: 0·5-0·8) and the presence of metachronous metastases (OR:0·5; 95% CI: 0·3-0·7), but patient characteristics did not differ between hospitals with low or high bevacizumab administration rates. Exposure to bevacizumab (HR:0·8; 95% CI: 0·7-0·9) and anti-EGFR therapy (HR:0·6; 95% CI: 0·5-0·8) was associated with prolonged survival. Conclusions: We identified significant inter-hospital variation in targeted therapy administration for mCRC patients, which may affect outcome. Age and comorbidity were inversely correlated with non-administration of bevacizumab, but did not explain inter-hospital practice variation. Our data strongly indicate that practice variation is based on individual strategy of hospitals rather than guideline recommendations or patient-driven decisions. Individual hospital strategies are an additional factor that may explain the observed differences between real-life data and results obtained from clinical trials.
Biologicals targeting T helper cell subset differentiating cytokines are effective in the treatment of murine anti-myeloperoxidase glomerulonephritis
Authors: Poh-Yi Gan, Amy Chan, Joshua D. Ooi, Jonathan Dick, Kei Nagai, Kim M. O’Sullivan, Virginie Oudin, Raymond Shim, A Richard Kitching, Stephen R. Holdsworth
Journal: Kidney International (2019)
REG4 as a novel biomarker of lung adenocarcinoma with mutated KRAS and TTF-1 low expression.
Authors: Hui Yu, Si Sun
Journal: Journal of Clinical Oncology (2019)

e14541 Background: Recent research has classified lung adenocarcinoma patients with KRAS mutation into three subtypes by co-occurring genetic events in TP53 (KP subgroup), STK11/LKB1 (KL subgroup) and CDKN2A/B inactivation coupled with low expression of the TTF-1 (KC subgroup). The aim of this study was to identify novel biomarkers through searching the candidate molecules that contributing to lung adenocarcinoma pathogenesis, especially KC subtype. Methods: We analyzed the publicly available database and identified the candidate REG4 using the E-GEOD-31210 dataset, and then confirmed by TCGA dataset. In addition, an independent cohort of 55 clinical samples was analyzed by quantitative real-time PCR analysis. Functional studies and RNA sequencing were performed after the silencing REG4 expression. Results: REG4, an important regulator of gastro-intestinal carcinogenesis, was highly expressed in KRAS mutated lung adenocarcinoma with low expression of TTF-1 (KC subtype). The results were validated both by gene expression analysis and immunohistochemistry study in an independent 55 clinical samples from Fudan University Shanghai Cancer Center. Further in vitro and in vivo functional assays revealed silencing REG4 expression significantly reduce cancer cell proliferation and tumorigenesis. Moreover, RNA sequencing and GSEA analysis displayed that REG4 knockdown might induce the cell cycle arrest by regulating G2/M checkpoint and E2F targets. Conclusions: Our results indicate that REG4 plays an important role in KRAS-driven lung cancer pathogenesis and is a novel biomarker of lung adenocarcinoma subtype. Future studies are required to clarify the underlying mechanism of REG4 in the division and proliferation of KC tumors and its potential therapeutic value.
Apatinib for locoregionally recurrent or metastatic nasopharyngeal carcinoma after failure of first-line chemotherapy: A multicenter, phase II trial.
Authors: Wei Jiang, Jinghui Liang, Yufei Pan, Xiaolan Ruan, Rui Cai, Zhuokai He, Qiuqiu Chen, Rongjun Zhang, Xi Yang, Meilian Liu, Bo Zhao, Zhengchun Liu, Zhijie Niu
Journal: Journal of Clinical Oncology (2019)

6030 Background: Concordant programs for patients with nasopharyngeal carcinoma (NPC) who failed to first-line chemotherapy after locoregional recurrence or metastasis are not yet available. Here, we investigated the efficacy and safety of apatinib as an second-line treatment in these patients. Methods: In this multicenter, phase II trial, patients of NPC with disease progression after failure of first-line chemotherapy were treated with apatinib (500mg/d).The primary endpoint of this study was objective response rate (ORR), secondary endpoints included progression free survival (PFS), overall survival (OS) and toxicity. Results: Between January and December 2017, 33 patients were finally enrolled onto the analysis from three centers in China. The baseline characteristics were summarized in Table. Of the 12 patients achieved a partial response and no complete responses were observed, yielding an ORR of 36.3%. Additionally, 6 patients (18.2%) experienced stable disease of at least 5 months in duration, and the disease control rate was 54.5%. At a median follow-up time of 14 months (range 1-22), median PFS was 5.0 months (95% CI, 2.3 to 7.7). The median OS had not reached, and the 1-year OS rate was 83.1%. The most common adverse events (grade 1 to 2) related to apatinib were hypetension (42.4%), hand-foot syndrome (54.5%), proteinuria (12.1%) and oral ulcer (24.2%). Conclusions: Apatinib showed a well therapeutic effect and a manageable safety profile for patients of advanced NPC after previous chemotherapy. Further study in combination with chemotherapy and other targeted agents in patients with NPC is warranted. Baseline demographic and disease characteristics. Clinical trial information: NCT03130270. [Table: see text]
Generation of an immortalized erythroid progenitor cell line from peripheral blood: A model system for the functional analysis of <i>Plasmodium</i> spp. invasion
Authors: Erik J. Scully, Estela Shabani, Gabriel W. Rangel, Christof Grüring, Usheer Kanjee, Martha A. Clark, Mudit Chaand, Ryo Kurita, Yukio Nakamura, Marcelo U. Ferreira, Manoj T. Duraisingh
Journal: American Journal of Hematology (2019)

Abstract Malaria pathogenesis is caused by the replication of Plasmodium parasites within the red blood cells (RBCs) of the vertebrate host. This selective pressure has favored the evolution of protective polymorphisms in erythrocyte proteins, a subset of which serve as cognate receptors for parasite invasion ligands. Recently, the generation of RBCs from immortalized hematopoietic stem cells (HSCs) has offered a more tractable system for genetic manipulation and long‐term in vitro culture, enabling elucidation of the functional determinants of host susceptibility in vitro. Here we report the generation of an immortalized erythroid progenitor cell line (EJ cells) from as few as 100 000 peripheral blood mononuclear cells. It offers a robust method for the creation of customized model systems from small volumes of peripheral blood. The EJ cell differentiation mirrored erythropoiesis of primary HSCs, yielding orthochromatic erythroblasts and enucleated RBCs after eight days (ejRBCs). The ejRBCs supported invasion by both P. vivax and P. falciparum . To demonstrate the genetic tractability of this system, we used CRISPR/Cas9 to disrupt the Duffy Antigen/Receptor for Chemokines (DARC) gene, which encodes the canonical receptor of P. vivax in humans. Invasion of P. vivax into this DARC‐knockout cell line was strongly inhibited providing direct genetic evidence that P. vivax requires DARC for RBC invasion. Further, genetic complementation of DARC restored P. vivax invasion. Taken together, the peripheral blood immortalization method presented here offers the capacity to generate biologically representative model systems for studies of blood‐stage malaria invasion from the peripheral blood of donors harboring unique genetic backgrounds, or rare polymorphisms.
Effect of targeting CD40 for DC vaccination in pancreatic adenocarcinoma.
Authors: Sai Ping Lau, Nadine van Montfoort, Priscilla Kinderman, Melanie Lukkes, Jasper Dumas, Menno van Nimwegen, Dana Mustafa, Heleen Vroman, Thorbald van Hall, Sjoerd H. van der Burg, Joachim G.J.V. Aerts, Floris Dammeijer, Casper H.J. van Eijck
Journal: Journal of Clinical Oncology (2019)

e15783 Background: Although immunotherapy yields striking results in various malignancies, results in pancreatic cancer have been disappointing. Both a highly immunosuppressive tumor microenvironment and a dense desmoplastic stroma have been found to prohibit proper T-cell infiltration in these tumors, thereby preventing immunotherapy efficacy. We hypothesize that a rational and translational multistep approach is needed to sensitize pancreatic cancer to immunotherapy. In an aggressive murine pancreatic ductal adenocarcinoma model, we assessed the effectiveness of dendritic cell (DC) vaccination in combination with αCD40 treatment, as these treatments are known to induce effector T cells and degrade stroma, respectively. Methods: Immune competent C57BL/6 mice were inoculated subcutaneously with pancreatic tumor cells (KPC3). Mice with established tumors were vaccinated with tumor-loaded monocyte derived DCs and consequently treated with αCD40 agonistic antibodies. Tumor sizes were monitored over time. Immune responses were determined by flow cytometry of cells in peripheral blood, spleen and tumor. NanoString Technologies were applied on tumor samples. Results: A significant delay in tumor growth was found in the combination therapy arm compared to untreated mice and mice treated with DCs or αCD40 alone. Monotherapy had no effect on tumor growth. Survival of mice treated with the combination therapy was also improved compared to untreated mice or mice treated with monotherapy (P &lt; 0.001). Interim blood analysis showed significant increases in frequencies of activated and proliferating T cells in treated animals and those cells also displayed an effector memory phenotype. This was more pronounced for CD4 T cells in mice treated with DCs while αCD40 therapy induced a confined response in CD8 T cells. Increased frequencies of tumor infiltrating lymphocytes were found in all treated mice compared to untreated mice. mRNA expression analysis indicated less exhausted phenotype of intratumoral lymphoid cells in mice treated with DCs and αCD40 compared to monotherapy DCs or αCD40. Conclusions: These results demonstrate the potency of this novel form of combination immunotherapy and reveals a mechanistic insight into the requirements of effective immunotherapy in pancreatic cancer.
Role of anthracyclines in neoadjuvant anti-HER2 regimens for HER2+ breast cancer (BC): A network meta-analysis (NMA).
Authors: Giacomo Pelizzari, Lorenzo Gerratana, Debora Basile, Michele Bartoletti, Camilla Lisanti, Silvio Ken Garattini, Lucia Bortot, Carla Corvaja, Silvia Buriolla, Gianluca Curtolo, Mattia Garutti, Paola Di Nardo, Elena Torrisi, Lucia Da Ros, Andrea Freschi, Silvana Saracchini, Silvia Bolzonello, Gianmaria Miolo, Simon Spazzapan, Fabio Puglisi
Journal: Journal of Clinical Oncology (2019)

577 Background: It is matter of current debate which would be the best chemotherapy backbone of neoadjuvant HER2-targeted therapy for HER2+ BC. The TRAIN 2 trial showed no significant difference in terms of pathological complete response (pCR) when anthracyclines–based (CTA) or anthracyclines–free regimens (CT) were combined with dual HER2 blockade. However, it remains unclear how anthracyclines may influence the relative benefit across different anti-HER2 treatments. Methods: A systematic review was conducted which included all phase II/III randomized clinical trials (RCTs) comparing different neoadjuvant regimens for HER2+ BC. pCR (yT0/isN0) was the outcome of interest. Indirect comparisons of all combination of anti-HER2 agents with CTA or CT were estimated with a random-effects frequentist NMA. Estimated pCR rates were inferred adopting a Bayesian NMA. Results: 17 RCTs (3933 patients) were included. Overall, 8 arms were identified, comprising all possible combinations of CTA and CT with trastuzumab (H), lapatinib (L) and dual HER2 blockade (D) but also CTA and D only. Odds ratios (OR) for pCR and 95% confidence interval (CI) of selected NMA comparisons are shown in the table. Estimated rates of pCR for each treatment and 95% credible interval (CrI) are reported in the table. Conclusions: Through indirect comparisons, no significant pCR gain was found for CTA vs CT when combined to D, H and L. In particular, considering double vs single-agent anti-HER2 regimens, D-CT remains superior to H-CTA, supporting a possible omission of anthracyclines when dual anti-HER2 block is used. On the contrary, our pooled estimate suggests a more relevant role for anthracyclines when comparing H-CT/A vs CTA. Moreover, we estimated a 4% pCR gain for D-CTA vs D-CT, and an 8% higher pCR rate for H-CTA vs H-CT. [Table: see text]
Multicenter observational prospective study of nivolumab (Nivo) as 2+ line treatment in advanced refractory NSCLC pts: Clinical and quality of life outcomes.
Authors: Rashida Orlova, Konstantin Laktionov, Larisa Bolotina, Valeriy Vladimirovich Breder, Anastasia Danilova, Elena Filippova, Anna Kornietskaya, Mikhail Kramchaninov, Eugenia Kushniruk, Dilorom Latipova, Evgeny Ledin, Anastasia Mochalova, Fedor Vladimirovich Moiseenko, Tatiana Nikitina, Sergey Orlov, Svetlana Protsenko, Ksenia Sarantseva, Daniil Stroyakovskiy, Anna Zinkovskaya, Tatyana Ionova
Journal: Journal of Clinical Oncology (2019)

e20567 Background: We aimed to evaluate clinical and quality of life (QoL) outcomes of Nivo as 2+ line treatment in NSCLC pts within expanded access program and real world practice. Methods: Adult pts with advanced refractory NSCLC were enrolled in 11 centers in RF. All the pts received Nivo 3 mg/kg q2w. Tumor response was assessed using RECIST v. 1.1, adverse events (AEs) – NCI CTCAE v3.0. Patients filled out RAND SF-36 and ESAS-R at baseline, 1, 3, 6 and 12 mos after treatment start. Overall survival (OS) and progression-free survival (PFS) curves were evaluated by the Kaplan-Meyer method and compared by the log-rank test. GEE method was used for QoL analysis; χ 2 test – for disease control rate (DCR) comparison. Results: The preliminary analysis was performed in the group of 200 pts with median follow-up 7.4 mos (65% – males; median age – 62 y.o.; ECOG 0-1 – 81%; former/current smokers – 70.5%; non squamous NSCLC – 64%; ≥2 lines of previous treatment – 53%, bone mts – 22%). DCR was revealed in 60.3% pts (108/179 pts, median first evaluation – 2.1 mos); 13 pts died before first response evaluation; 8 pts were not evaluated for response at cut-off. DCR was higher in squamous NSCLC (66%, squamous vs 51%, non squamous; χ 2 = 4.0, p = .045). Median OS – 11.5 mos (95%CI 8.3–14.7), median PFS – 4.2 mos (95%CI 3.5–4.9). Patients with poor ECOG (ECOG 2-3 vs 0-1: median OS – 5.6 mos vs 12.4 mos, median PFS – 2.7 vs 4.2 mos) and those with bone mts (with mts vs without mts: median OS – 5.0 vs 12.5 mos, median PFS – 2.8 vs 4.1 mos) had worse survival; log-rank p &lt; 0.05. QoL improved during 6 mos of treatment in more than 50% pts; average increase by 60% of mean Integral QoL Index (IQoLI) at different time-points was observed. Upon GEE, IQoLI improvement during 12 mos was revealed (p &lt; .0001). The severity of fatigue and dyspnea, which had the highest burden at base-line, decreased during 6 mos of treatment in more than 50% and 30% pts, consequently. AEs were registered in 32.7% pts (median of Nivo treatment – 2 mos); among them 17 pts had grades 3-4 AEs; 5 pts – SAEs. Conclusions: Preliminary results of this study support the acceptable efficacy and safety of Nivo in NSCLC pts. Nivo treatment leads to meaningful QoL improvement and decrease of symptom burden in this patient population.