tbuckley/cabot-search huggingface dataset:
ADAPTeR: A phase II study of anti-PD1 (nivolumab) therapy as pre- and post-operative therapy in metastatic renal cell carcinoma.
Authors: Mark Stares, Samra Turajlic, Andrew J.S. Furness, Kroopa Joshi, David Nicol, Martin Eric Gore, Lisa M. Pickering, Nicos Fotiadis, Steve Hazell, Aspasia Soultati, Andrew Rowan, Karen O'Meara, Karl Peggs, Charles Swanton, Sergio Quezada, James M. G. Larkin
Journal: Journal of Clinical Oncology (2016)

TPS4583 Background: Cytoreductive nephrectomy may be beneficial in patients with metastatic clear cell renal cell carcinoma (mccRCC). However, there are currently no standard pre-operative systemic therapies. The anti-PD1 agent, Nivolumab, has demonstrated survival improvements in patients with mccRCC, but responses are limited to only 25% of those treated. This highlights the need to identify predictive biomarkers of response and resistance to guide treatment decisions. Methods: ADAPTeR is a single center exploratory phase II study to assess the safety of nivolumab in patients with mccRCC undergoing nephrectomy. Exploratory endpoints include correlating changes in biomarkers with clinical outcomes. Key inclusion criteria are: histologically confirmed mccRCC with no prior systemic therapy. 19 patients will receive Nivolumab, 3mg/kg every two weeks, for eight weeks prior to nephrectomy. Nivolumab will then be restarted and continued for as long there is clinical benefit. Peripheral blood and multi-region samples of tumour tissue will be taken at baseline, the time of nephrectomy and disease progression. Next generation sequencing of tumour tissue DNA and RNA will be used to map somatic mutations and predict candidate neo-antigens. Tumour samples will be evaluated by multi-parametric flow cytometry allowing phenotypic characterization of tumour infiltrating lymphocytes (TILs), focusing on the expression of key co-inhibitory and co-stimulatory molecules, functional markers and correlation with clinical outcomes. The relative abundance of immune cell subsets including CD4+FoxP3+/CD4+FoxP3-/CD8+ T lymphocyte and myeloid compartments will be quantified and correlated with clinical outcomes Multiplex immunohistochemistry and quantitative automated immunofluorescence will be used to map the tumour immune landscape, assessing both distribution and spatial relationships between TILs and myeloid compartments. Quantitative high-throughput sequencing will be used to characterise the intratumoral T cell repertoire and T cell clonality longitudinally, through therapy, with tracking of these clones in the peripheral blood. ADAPTeR is open to recruitment. Clinical trial information: NCT02446860.
Correlation of PBMC CD62L<sup>low</sup> CD4+ T cells with irILD after nivolumab therapy.
Authors: Ou Yamaguchi, Hiroshi Kagamu, Fumikazu Sakai, Atsuto Mouri, Ayako Shiono, Harue Utsugi, Fuyumi Nishihara, Takahiro Uchida, Yu Miura, Kosuke Hashimoto, Yoshitake Murayama, Kunihiko Kobayashi
Journal: Journal of Clinical Oncology (2018)

e21018 Background: Antibody blockade of programmed death (PD)-1 has led to significant prolongation of overall survival in metastatic cancers, including non-small cell lung cancer (NSCLC). However, some patients develop immune-related adverse events (irAEs), including interstitial lung disease (ILD). Interestingly, in our institution the discontinuation of anti-PD-1 therapy due to immune-related ILD (irILD) resulted in durable disease control, rather than immediate disease progression. In the checkmate003 trial, 4 patients who discontinued anti-PD-1 therapy because of irAEs survived for more than 5 years without any further therapy. Based on these results we hypothesized that irILD evoked by anti-PD-1 therapy was not merely an adverse event, but a part of an antitumor T-cell reaction. At the 2017 ASCO meeting, we reported that the CD4+ T cells that downregulated CD62L (CD62Llow) in the peripheral blood could be a biomarker to predict antitumor effects of anti-PD-1 therapy. Methods: We analyzed PBMCs in 93 patients with NSCLC who received the anti-PD-1 antibody nivolumab after obtaining written informed consent. The patients received nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks. We examined the clinical findings and imaging characteristics of ILD. Broncho-alveolar lavage (BAL) analysis was performed in 6 patients who developed irILD. Results: Nineteen patients with NSCLC developed an irILD shadow on computed tomography. The patients who developed irILD had significantly more CD62Llow CD4+ T cells in PBMCs (P < 0.01) and heavy smoking history (P = 0.017). The tumor volume reduction rate, time to progression, and overall survival were significantly better in patients with irILD (P < 0.001, P < 0.01, and P = 0.03, respectively). Cellular components of BAL showed increased lymphocyte populations. Most T cells infiltrating the irILD were CD62Llow. Conclusions: These results show that irILD was associated with favorable outcomes with anti-PD-1 therapy. The CD62Llow CD4+ T cells correlated with antitumor reactivity and likely mediated irILD development. Long-term follow-up of PBMCs after discontinuation of anti-PD-1 therapy are ongoing. Clinical trial information: 20719.
Retrospective analysis of management and outcome of advanced soft tissue sarcomas (STS) with rare histology.
Authors: Atul Sharma, Naresh G, Aditi Aggarwal, Adarsh Barwad, Ekta Dhamija, Rambha Panday, Venkat Sampat kumar, Anjali v Ramdulari, Sameer Rastogi
Journal: Journal of Clinical Oncology (2018)

e23564 Background: There is sparse data for the management and outcome of rare histology advanced STS Methods: Retrospective database from 2015-January 2018 was analyzed, rare advanced STS (15%) were compared to more common advanced STS (85%) in terms of outcomes. Pubmed search was done to review literature for the management of advanced STS with rare histology Results: 156 advanced STS were registered out of which 23 patients belonged to rare histology; majority being males 16( 69%) with median age 36 (18-61 yrs). Rare histology were pulmonary myxoid sarcoma, pulmonary intimal sarcoma (PIS), gastrointestinal neuroectodermal tumor (GNET), sclerosing epitheloid angiosarcoma, extraskeletal myxoid chondrosarcoma (EMC), inflammatory myofibroblastic tumor (IMFT), lymphangiosarcoma (L), glomangiosarcoma, epitheloid hemangioendothelioma (EHE) 1( < 1%) each, desmoplastic small round cell tumor (DSRCT) 2(1%), solitary fibrous tumor (SFT) 3(2%), fibrosarcomatous variant of dermatofibrosarcoma protuberans 5(3%), alveolar soft part sarcoma (ASPS) 4(3%).19 (82%) patients were metastatic while 4 (17%) had locally advanced disease. Extrapulmonary metastatic sites were liver 3 (15%), peritoneum 3 (15%), lymph nodes 2 (10%), bone 2 (10%). Therapies received were pazopanib 6(26%), imatinib 5(22%), doxorubicin based therapy 4(17%), sunitinib 2(9%), sorafenib 2(9%), temozolamide & bevacizumab 1(4%), cisplatin & methotrexate 1(4%), observation 2(9%). After median follow up of 13 months, median overall survival was not reached in this group and was 12 months in the whole cohort. Pubmed search for the last ten years revealed 103 articles guiding the management of STS of rare histology Conclusions: Rare tumors had better outcome which could be attributed to their favorable biology. Besides, they had predilection for metastasis to extrapulmonary sites. There was scarce literature to guide management of STS with rare histology. Publishing of data pertaining to management of these tumors should be encouraged to guide the management of STS with rare histology Diagnosis No. of Articles n (%) PIS 5 (5%) GNET 2 (2%) EMC 6 (6%) IMFT 1 (1%) L 9 (9%) EHE 10 (10%) DSRCT 33 (33%) SFT 14 (14%) ASPS 23 (23%)
A hybrid genipin-crosslinked dual-sensitive hydrogel/nanostructured lipid carrier ocular drug delivery platform
Authors: Yibin Yu, Ruoxi Feng, Jinyu Li, Yuanyuan Wang, Yiming Song, Guoxin Tan, Dandan Liu, Wei Liu, Xinggang Yang, Hao Pan, Sanming Li
Journal: Asian Journal of Pharmaceutical Sciences (2018)

The objective of this study was to develop a novel hybrid genipin-crosslinked dual-sensitive hydrogel/nanostructured lipid carrier (NLC) drug delivery platform. An ophthalmic anti-inflammatory drug, baicalin (BN) was chosen as the model drug. BN NLC was prepared using melt-emulsification combined with ultra-sonication technique. Additionally, a dual pH- and thermo-sensitive hydrogel composed of carboxymethyl chitosan (CMCS) and poloxamer 407 (F127) was fabricated by a cross-linking reaction with a nontoxic crosslinker genipin (GP). GP-CMCS/F127 hydrogel was characterized by FTIR, NMR, XRD and SEM. The swelling studies showed GP-CMCS/F127 hydrogel was both pH- and thermo-sensitive. The results of in vitro release suggested BN NLC gel can prolong the release of baicalin comparing with BN eye drops and BN NLC. Ex vivo cornea permeation study was evaluated using Franz diffusion cells. The apparent permeability coefficient ( P app ) of BN NLC gel was much higher (4.46-fold) than that of BN eye drops. Through the determination of corneal hydration levels, BN NLC gel was confirmed that had no significant irritation to cornea. Ex vivo precorneal retention experiments were carried out by a flow-through approach. The results indicated that the NLC-based hydrogel can prolong precorneal residence time. In conclusion, the hybrid NLC-based hydrogel has a promising potential for application in ocular drug delivery. An innovative hybrid drug delivery platform: genipin-crosslinked dual pH- and thermo-sensitive hydrogel/nanostructured lipid carrier has been exploited for ocular delivery of baicalin.
TCT-309 Angiography-derived fractional flow reserve in the SYNTAX II trial: diagnostic accuracy of QFR and clinical prognostic value of functional SYNTAX score derived from QFR
Authors: Taku Asano, Yuki Katagiri, Chun Chin Chang, Norihiro Kogame, Ply Chichareon, Kuniaki Takahashi, Rodrigo Modolo, Erhan Tenekecioglu, Carlos Collet, Vasim Farooq, Javier Escaned, Adrian Banning, Patrick Serruys, Yoshinobu Onuma
Journal: Journal of the American College of Cardiology (2018)
Dynamics of IGF-I, IGF-II and TGF-β1 in lung and liver in the early stages of metastasis in experiment.
Authors: Irina V. Kaplieva, Oleg Ivanovich Kit, Elena Mikhaylovna Frantsiyants, Evgeniy N. Kolesnikov, Lidia K. Trepitaki, Michail Averkin, Yulia A. Pogorelova, Leonid V. Kharin, M. N. Chernyak
Journal: Journal of Clinical Oncology (2016)

e23011 Background: Liver and lung metastases are frequent in cancer patients and are practically untreatable at the time of diagnosis. Oncological studies are now focused on the detection of markers for early metastasis prediction. A lot of data now support an important role of growth factors in tumor development and progression; however, these data are contradictory quite often. We performed a comparative study of dynamics of growth factors (IGF-I, IGF-II and TGF-β1 ) in the liver and lungs 1 and 2 weeks after metastasis to the organs. Methods: The study included 60 male Wistаr rats. Growth factors were determined by ELISA using standard test systems. Results: Levels of IGF-I and ТGF-β1 in the liver of intact rats were higher than in their lungs by 1.4 and 1.8 times, respectively, while IGF-II level in the liver was 2.3 times higher than in lungs. Common early signs of metastases to the both organs included: a) after 1 week of metastasis - unchanged IGF-I and similar IGF-II changes; b) after 2 weeks of metastasis – high ТGF-β1 level, 3.5 times higher than in intact liver and 1.5 times higher than in intact lungs. Distinguishing features were: a) increase in ТGF-β1 level after 1 week of metastasis in the liver and after 2 weeks in the lungs; b) opposite changes in IGF-I 2 weeks after metastasis (1.6 times increase in the liver and 1.7 times decrease in the lungs), as well as in IGF-II (1.5 times increase in the liver and 2.8 times decrease in the lungs). Conclusions: Dynamics of growth factors in the early stages of liver and lung metastasis development has both common and different features depending on the localization of the pathological process.
Gene expression analysis for improved subtyping of high-risk neuroblastoma.
Authors: Jacob Pfeil, Alexis Thornton, Ann Durbin, Ellen Kephart, Holly Beale, Lauren Sanders, Isabel Bjork, Olena Morozova, Sofie R. Salama, David Haussler
Journal: Journal of Clinical Oncology (2018)

10559 Background: One of the hallmarks of neuroblastoma is molecular heterogeneity, which leads to spontaneous remission in some patients and aggressive, resistant disease in others. Patients with low or intermediate risk have a high 5-year survival rate (90-95%), but high-risk neuroblastoma patients have a survival rate of 40% despite receiving high intensity therapies. Methods: Genome-wide transcriptome profiling can be used to stratify high-risk neuroblastoma patients and identify opportunities for molecularly targeted therapies. We developed a gene expression analysis for identifying molecular subtypes in large cancer gene expression cohorts (n > 100). Our method does not rely on a reference normal sample and thus can be applied to pediatric cancers where adequate normal samples are lacking. We applied the method to the TARGET NBL gene expression dataset (N = 162). Results: Our analysis identified 6,736 differentially expressed genes. We recapitulated amplification status of the transcription factor MYCN as originally determined in DNA-based assays by TARGET investigators (F1 score = 91%). We also identified two NTRK1 expression subtypes. The first was characterized by over-expression of MYCN, which downregulates expression of NTRK1. Tumors of the second subtype have lower activity for transcription factors that activate NTRK1 expression. Samples with the second subtype also have worse event-free survival than samples with higher NTRK1 expression (Log-rank test: p = 0.013). Thus, the low NTRK1/non-MYCN amplified subtype may benefit from an alternative treatment strategy. Finally, we used our gene expression approach to characterize the immune infiltrate of neuroblastoma patients and identified a subset of samples (~20%) with elevated expression of cytotoxic and regulatory T cell markers, including expression of inhibitory receptors and ligands. Conclusions: Our gene expression subtyping approach can tbe used to stratify high-risk neuroblastoma patients and identify opportunities for immunotherapy. Validation of this approach in preclinical models may lead to novel therapeutic strategies for high-risk neuroblastoma.
De novo EGFR T790M, KRAS and PIK3CA somatic mutations in cell free DNA in non-small cell lung cancer patients and clinical characteristics.
Authors: Won Jin Chang, Yeul Hong Kim
Journal: Journal of Clinical Oncology (2017)

e20561 Background: Several mechanisms for acquired drug resistance EGFR-TKIs in NSCLC have been suggested. These include EGFR T790M mutation and mutations in KRAS, and PIK3CA. Rarely, a de novoT790M mutation has been reported. However, the clinical significance of these mutations remains controversial. Here, we used highly sensitive methods to detect T790M, KRAS and PIK3CA mutations in cell free DNA (cfDNA) and evaluate the clinical significance of those mutations. Methods: The blood samples were collected from 125 patients with NSCLC. Ion AmpliSeq Cancer Hotspot Panel (ICP) using a targeted ultra-deep sequencing (mean depth 22,868x) was performed in cfDNA, which were validated with droplet digital PCR (ddPCR). Results: ICP detected EGFR T790M mutation in 30 of 125 cfDNA (24%), KRAS mutations in 18 (14.4%) and PIK3CA in 33 (26.4%). ddPCR confirmed concordant T790M results in 22 (73.3%) and KRAS in 13 (72.2%). The 8 of 22 (36.4%) in T790M and 2 of 13 (15.4%) in KRAS had simultaneous activating EGFR mutations in cfDNA or tumor tissue. The most single KRAS mutations appeared in codon 12 (n = 7, 63.6%) (3 in G12C, 2 in G12S, 1 in G12V and 1 in G12D) with three mutations in codon 13 (27.3%) and one mutation in codon 61 (9.1%). About 20% to 50% had bone or brain metastases at diagnosis in patients with these mutations. The 5 (62.5%) (4 PR and 1 SD) of 8 patients in T790M and 8 (61.5%) (All PR) of 13 in PIK3CA showed response or stabilization. The median time to disease progression after EGFR-TKIs treatment was 13.5 months in PIK3CA and not reached in T790M. Conclusions: The de novo T790M, KRAS and PIK3CA mutation was detected in 24%, 14.4% and 26.4% using ICP in cfDNA. In our study, the KRAS and EGFR mutation may not be mutually exclusive and PIK3CA mutations may be a factor associated with metastatic sites rather than predictive factor for EGFR-TKIs. In addition, we suggested that although the clinical presentation is more aggressive in patients with de novo T790M and PIK3CA mutation, the EGFR-TKIs could be used in patients who present with both activating EGFR mutations and those mutations.
Development of a method to quantify total and free irinotecan and 7-ethyl-10-hydroxycamptothecin (SN-38) for pharmacokinetic and bio-distribution studies after administration of irinotecan liposomal formulation
Authors: Wenqian Yang, Zimeng Yang, Jieru Liu, Dan Liu, Yongjun Wang
Journal: Asian Journal of Pharmaceutical Sciences (2018)

In 2015, liposomal formulation of irinotecan (ONIVYDE) has been approved by FDA and widely applied in the treatment of pancreatic cancer. ONIVYDE is a novel liposome formulation, entrapping CPT-11 in the aqueous core of vesicles using a modified gradient loading method. Due to toxicity concerns, it is essential to explore a rapid and reliable method to effectively isolate and quantify the non-liposomal, namely, free CPT-11and total CPT-11 in plasma. This study focuses on separation of non-liposomal CPT-11, evaluation of the pharmacokinetics of free CPT-11 and total CPT-11 and bio-distribution after intravenous administration of CPT-11 liposome. Free CPT-11 in plasma was separated by solid-phase extraction (SPE). The amount of total CPT-11 and main metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) in plasma was quantified by ultra-performance liquid chromatography-MS/MS. The calibration curves fitted well and lower limit of quantitation for SN-38, free CPT-11, total CPT-11 and CPT-11 in tissue and were 5 ng/ml, 10 ng/ml, 4.44 ng/ml and 25 ng/ml respectively. The recoveries, precision and accuracy of the method appear satisfactory. Using this method, the pharmacokinetics and bio-distribution of CPT-11 liposome formulation after an intravenous dose of 2.5 mg/kg were then investigated.
Abstract 18190: Associations Between Endothelial Injury, Severity of Post-cardiac Arrest Syndrome and Mortality After Out-of-hospital Cardiac Arrest
Authors: John Bro-Jeppesen, Jesper Kjaergaard, Michael Wanscher, Pär Johansson, Sisse Ostrowski, Christian Hassager
Journal: Circulation (2015)

Background: Post-cardiac arrest syndrome (PCAS) is characterized by systemic inflammation and endothelial dysfunction, which may exacerbate organ failure and may be related to adverse outcome. We sought to investigate the associations between trombomodulin (TM), a marker of endothelial cell injury, and severity of PCAS and the possible prognostic importance in comatose survivors of out-of-hospital cardiac arrest treated with targeted temperature management (TTM). Methods: We included 163 patients, randomly assigned to TTM at 33°C or 36°C for 24 h in the TTM-trial at a single center. Serum TM was analyzed at 0, 24, 48 and 72 hours after cardiac arrest and stratified in median value of TM for outcome analysis at each time point to a high or low TM group. Severity of PCAS was assessed daily by the Sequential Organ Failure Assessment score. Survival status was recorded at 180 days. Results: Corresponding values of TM and severity of PCAS correlated at each time point, baseline (r=0.31, p=0.0001), 24 h (r=0.52, p&lt;0.0001), 48 h (r=0.50, p&lt;0.0001) and 72 h (r=0.36, p&lt;0.0001). Levels of TM changed significantly within the first 3 days (p&lt;0.0001) with no significant difference between temperature groups, p interaction =0.32. At 24 h, the 180-day mortality rate in patients with high TM levels (&gt; 6.9 ng·ml -1 = median) was 42% compared to 18% in patients with low TM levels, p=0.002 (Figure), corresponding to an unadjusted hazard ratio of 2.6 (95%CI: 1.4-4.9), p=0.003. When adjusting for pre-hospital prognostic factors the hazard ratio for high TM levels at 24 h was 1.5 (95%CI: 0.7-3.1), p=0.31, with no significant interaction between level of TM and TTM-group, p=0.74. Analysis of TM at 48 and 72 hours showed similar results. Conclusions: Levels of TM are significantly elevated and associated with severity of PCAS with no effect of target temperature at 33°C or 36°C. High TM levels were associated with increased mortality, but the association was explained by confounding factors.
DNA damage ATR/Chk1 checkpoint signalling increases PD-L1 immune checkpoint activation and its implication for personalised combination therapy
Authors: N. Kumar, P. Yadav, A. Kumar, S. Beniwal, A. Kapoor, A. Kalwar
Journal: Annals of Oncology (2018)

Background: DNA double-strand break (DSB) is the most critical type of genotoxic stress. Clinical studies have revealed a link between genomic instability and response to anti-PD-1/PD-L1 therapy in cancer management. We investigated role of DBS repair and ATR/Chk1 DNA damage checkpoint in regulating PD-L1 expression and their use in therapy selection and study design. Methods: Protein expression data proteins and phosphoproteins with major clinical outcome endpoints were obtained from The Cancer Genome Atlas project. A statistical correlation analysis was performed between the expression and distribution DBS repair and ATR/Chk1 DNA damage checkpoint pathway and PD-L1. Signaling network was also analysed for of therapeutic target identification. Results: The expression and distribution patterns of PD-L1 was measured in 7694 samples from 32 cancer type. Increased expression of PD-L1 was associated with higher tumor stage and grade. Analyses of the DNA damage ATR/Chk1 checkpoint signalling revealed strong correlation of PDL1 expression. PD-L1 expression in was upregulated in response to DSBs with strong correlation with MRE11 (correlation coefficient (r) =0.39, p < 0.01), RAD51 (r = 0.33, p < 0.01). This upregulation requires ATM/ATR/Chk1 kinases (Chk2_pt68; r = 0.36, p < 0.01 and Chk1_ps296; r = 0.33, p < 0.01). Interestingly Jab-1 expression was corelated with both Chk-1(r = 0.27, p < 0.01) and PD-L1 (r = 0.22, p < 0.01). We further investigate for the possible signaling mechanism for the correlation and found activation of oncogenic signaling in a cancer type specific manner. PI3K/AKT/mTOR/S6K, INFgamma/ JAK/STAT/IRF1 and Ras/BRAF/MEK/ERK were involved in mechanism of increased PD-L1 expression. Conclusions: DSB-mediated immune activation is balanced by concomitant inhibitory signaling, via the checkpoint kinases ATM, ATR, and Chk1 drived PD-L1 expression in tumors. These observations have important clinical implications for therapy selection, particularly following progression on DNA damaging agents suggesting that PD-1/PD-L1 inhibitors may be a useful therapeutic strategy (with or without concurrent DNA damaging agents) for tumors. Legal entity responsible for the study: Narender Kumar. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.