tbuckley/cabot-search huggingface dataset:
Molecular differences between lymph nodes (LNs) and distant metastases (mets) in colorectal cancer (CRC).
Authors: Alberto Puccini, Joanne Xiu, Richard M. Goldberg, Axel Grothey, Anthony Frank Shields, Mohamed E. Salem, Andreas Seeber, Francesca Battaglin, Martin D. Berger, Wafik S. El-Deiry, Ryuma Tokunaga, Madiha Naseem, Wu Zhang, Sukeshi Patel Arora, Moh'd M. Khushman, Michael J. Hall, Philip Agop Philip, John Marshall, Wolfgang Michael Korn, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2019)

3130 Background: LNs mets are thought to occur before distant mets. However, lymphatic and distant mets arise from independent subclones of the primary tumor, suggesting that LNs are not essential intermediaries for distant mets. We aimed to comprehensively characterize the molecular profile of LN mets and to explore the differences between LN vs distant mets and primary tumors. Methods: Tumor samples from primary CRCs, LNs, and distant mets were analyzed using NGS (MiSeq on 47 genes, NextSeq on 592 genes), immunohistochemistry. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. Results: In total, 11871 tumors samples were examined, comprising primaries (N = 5862), distant (N = 5605) and LNs mets (N = 404). The most frequently mutated genes in LNs were TP53 (72%), APC (61%), KRAS (39%), ARID1A (20%), and PIK3CA (12%). LNs showed a higher mean TMB (13 mut/MB) vs distant mets (9, P &lt; .0001). TMB-high (17mut/MB) was more frequent in primaries and LNs vs distant mets (9.5% and 8.8% vs 4.2%, P &lt; .001 and P = .001, respectively), as well as MSI-H (8.8% and 6.9% vs 3.7%, P &lt; .001 and P = .017, respectively). TMB-high is significantly higher in LNs vs distant mets and primaries (P &lt; .0001), independent of MSI-H status. Analyzing distant mets by location, LNs showed higher TMB compared to lung, liver and peritoneum mets (P &lt; .0001). Overall, LNs showed significantly different rates of mutations in APC, KRAS, PI3KCA, KDM6A, and BRIP1 (P &lt; .01 for all comparisons) vs primaries; while presenting a distinct molecular profile compared to distant mets ( TP53 72 vs 67%; KRAS 39 vs 50%; RNF43 7 vs 4%; ATM 5 vs 3%; KDM6A 4 vs 1%; BRCA2 4 vs 2%; MSH6 3 vs 2%; PTCH1 4 vs 1%; BRCA1 2 vs 1%; GNAS 2 vs 5%; P &lt; .05 for all comparisons). Our cohort of 30 paired samples confirmed the molecular heterogeneity between primaries, LNs, and distant mets. Conclusions: This is the largest study to investigate the molecular differences between LNs mets, distant mets and primary tumors in CRC patients. Our data support the hypothesis that lymphatic and distants mets harbor different mutation profiles which suggests that they may arise from distinct subclones.
Development of an artificial intelligence model to predict survival at specific time intervals for lung cancer patients.
Authors: Smita Agrawal, Vivek Vaidya, Prajwal Chandrashekaraiah, Hemant Kulkarni, Li Chen, Karl Rudeen, Babu Narayanan, Orr Inbar, Brigham Hyde
Journal: Journal of Clinical Oncology (2019)

6556 Background: Survival prediction models for lung cancer patients could help guide their care and therapy decisions. The objectives of this study were to predict probability of survival beyond 90, 180 and 360 days from any point in a lung cancer patient’s journey. Methods: We developed a Gradient Boosting model (XGBoost) using data from 55k lung cancer patients in the ASCO CancerLinQ database that used 3958 unique variables including Dx and Rx codes, biomarkers, surgeries and lab tests from ≤1 year prior to the prediction point, which was chosen at random for each patient. We used 40% data for training, 25% for hyper-parameter tuning, 20% for testing and 15% for holdout validation. Death date available in the Electronic Health Record was cross checked by linkage to death registries. Results: The model was validated on the holdout set of 8,468 patients. The Area Under the Curve (AUC) for the model was 0.79. The precision and recall for predicting survival beyond the three time points were between 0.7-0.8 and 0.8-0.9 respectively (see table). This compares favourably to other lung cancer survival models created using different machine learning techniques (Jochems 2017, Dekker 2009). A Cox-PH model created using the top 20 variables also had a significantly lower performance (see table). Analysis of input variables yielded distinctive patterns for patient subgroups and time points. Tumor status, medications, lab values and functional status were found to be significant in patient sub cohorts. Conclusions: An AI model to predict survival of lung cancer patients built using a large real world dataset yielded high accuracy. This general model can further be used to predict survival of sub cohorts stratified by variables such as stage or various treatment effects. Such a model could be useful for assessing patient risk and treatment options, evaluating cost and quality of care or determining clinical trial eligibility. [Table: see text]
A phase Ib clinical trial on intratumoral administration of autologous CD1c (BDCA-1)<sup>+</sup> myeloid dendritic cells (myDC) in combination with ipilimumab (IPI) and avelumab (AVE) plus intravenous low-dose nivolumab (NIVO) in patients with advanced solid tumors.
Authors: Julia Katharina Schwarze, Gil Awada, Louise Cras, Ramses Forsyth, Ivan Van Riet, Bart Neyns
Journal: Journal of Clinical Oncology (2019)

e14012 Background: Intratumoral (IT) myDC play a pivotal role in initiating antitumor immune responses and "re-licensing” of antitumor cytotoxic T-lymphocytes within the tumor microenvironment. IT injection of anti-PD-L1 IgG 1 mAb AVE and anti-CTLA-4 IgG 1 mAb IPI may reduce the number of regulatory T cells and lyse PD-L1 + tumor cells, thereby releasing tumor antigens that can be captured and processed by IT co-administered CD1c (BDCA-1) + myDC, reinvigorating the cancer immunity cycle. Methods: Patients (pts) with advanced solid tumors who failed standard therapy were eligible for IT injections of ≥1 non-visceral metastasis with IPI (max total dose of 10 mg) and AVE (max total dose of 40 mg) plus IV NIVO (10 mg) on day 1 followed by IT injection of autologous, non-substantially manipulated CD1c (BDCA-1) + myDC on day 2. Administration of AVE, IPI, and NIVO was repeated every 14 days thereafter. Primary endpoints were safety and feasibility. Repetitive FNA cytology/IHC of treated lesions was performed. Results: In this ongoing trial, 6 pts (3x melanoma, 1x epithelial ovarian carcinoma, 2x triple negative breast carcinoma) were treated with IT injection of a median of 27,2x10 6 (range 10-43x10 6 ) CD1c (BDCA-1) + myDC and a median of 5 (range 2-10) study drug administrations. At time of this analysis 3 pts are evaluable for response: an ongoing PR ( &gt; 8 months) was documented in a melanoma pt who previously progressed on PD-1 and CTLA-4 inhibitors. In 2 other melanoma pts regression of the injected metastases coincided with progression of non-injected metastases. Adverse events consisted of transient grade(G)2 local pain at injection site in 2 pts, G1 pruritus in 2 pts, G2 pneumonitis in 1 pt, G1 rash in 1 pt, and pruritus and redness of the skin overlaying the injected lesion in 1 pt. Analysis of cytology/IHC results is ongoing. Conclusions: IT injection of autologous CD1c (BDCA-1) + myDC with IT co-injection of AVE and IPI plus IV low-dose NIVO is feasible and tolerable and resulted in encouraging early signs of anti-tumor activity in injected as well as non-injected lesions. Clinical trial information: NCT03707808.
Lysolipid receptor cross-talk regulates lymphatic endothelial junctions in lymph nodes
Authors: Yu Hisano, Mari Kono, Andreane Cartier, Eric Engelbrecht, Kuniyuki Kano, Kouki Kawakami, Yanbao Xiong, Wenji Piao, Sylvain Galvani, Keisuke Yanagida, Andrew Kuo, Yuki Ono, Satoru Ishida, Junken Aoki, Richard L. Proia, Jonathan S. Bromberg, Asuka Inoue, Timothy Hla
Journal: The Journal of Experimental Medicine (2019)

Sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) activate G protein–coupled receptors (GPCRs) to regulate biological processes. Using a genome-wide CRISPR/dCas9–based GPCR signaling screen, LPAR1 was identified as an inducer of S1PR1/β-arrestin coupling while suppressing Gαi signaling. S1pr1 and Lpar1-positive lymphatic endothelial cells (LECs) of lymph nodes exhibit constitutive S1PR1/β-arrestin signaling, which was suppressed by LPAR1 antagonism. Pharmacological inhibition or genetic loss of function of Lpar1 reduced the frequency of punctate junctions at sinus-lining LECs. Ligand activation of transfected LPAR1 in endothelial cells remodeled junctions from continuous to punctate structures and increased transendothelial permeability. In addition, LPAR1 antagonism in mice increased lymph node retention of adoptively transferred lymphocytes. These data suggest that cross-talk between LPAR1 and S1PR1 promotes the porous junctional architecture of sinus-lining LECs, which enables efficient lymphocyte trafficking. Heterotypic inter-GPCR coupling may regulate complex cellular phenotypes in physiological milieu containing many GPCR ligands.
Tumor mutation burden in biliary tract cancers with ERBB family or DNA damage repair gene mutations.
Authors: Yongjie Zhang, Ningjia Shen, Wenlong Yu, Xiaohui Fu, Jia Song, Jing Zhao, Yuzi Zhang, Shangli Cai
Journal: Journal of Clinical Oncology (2019)

e15602 Background: Biliary tract cancers (BTCs) are aggressive malignancies associated with resistance to chemotherapy. Though immunotherapy presents a promising results based on several studies, the overall response rate is relative low. Tumor mutation burden (TMB) has been considered as a predictive biomarker of immunotherapy. However, the association between common mutations and TMB in BTCs are still unclear. Methods: We analyzed 76 BTC samples (32 cholangiocarcinoma and 44 gallbladder cancer patients) from the Cancer Genome Altas (TCGA) by whole-exome sequencing and 408 samples (276 cholangiocarcinoma and 132 gallbladder cancer patients) from Chinese clinical cohort by 381-gene targeted sequencing. The association between ERBB family members or DNA damage repair (DDR) genes and TMB was explored, respectively. TMB was defined as total number of somatic non-synonymous mutations in coding region. Results: The mutation frequency of ERBB genes was similar between the TCGA cohort and the clinical cohort (cholangiocarcinoma, 13.6% vs 10.9%; gallbladder cancer, 21.9% vs 17.4%). However, DDR mutation rate from the TCGA data was greater than that from the clinical data without consideration the pathological type (cholangiocarcinoma, 40.9% vs 21.0%; gallbladder cancer, 62.5% vs 29.5%). In cholangiocarcinoma, any ERBB gene mutation was associated with higher TMB level in TCGA cohort (P = 0.0013) and clinical cohort (P = 0.0008). Any DDR gene mutation also significantly contributed to higher TMB in two cohorts (TCGA cohort, P = 0.0001; clinical cohort, P = 0.0139). In gallbladder cancer, the same result was discovered on the significant association between ERBB genes statue and higher TMB in both two data (TCGA cohort, P = 0.0370; clinical cohort, P = 0.0008). On the contrary, higher TMB level was observed in patients carrying any DDR alterations (P = 0.0017) in TCGA cohort, but the association was not found in Chinese cohort (P = 0.2660). Besides, prognosis analysis was performed on patients in TCGA cohort. Cholangiocarcinoma patients harboring any ERBB gene mutation represent significantly poorer overall survival (median, 10.6 vs. 40.1 months; HR, 3.37; P = 0.0186). Conclusions: Chinese BTC patients may exhibit distinct gene mutations. These findings were the supplement of better comprehending BTC genomic characteristics. Further studies are needed to evaluate the efficacy of immunotherapy in BTC patients with ERBB or DDR mutation in Chinese clinical cohort.
Upfront azacitidine (AZA) in juvenile myelomonocytic leukemia (JMML): Interim analysis of the prospective AZA-JMML-001 study.
Authors: Charlotte M. Niemeyer, Christian Flotho, Daniel B. Lipka, Jan Starý, Claudia Rössig, Andre Baruchel, Thomas Klingebiel, Concetta Micalizzi, Gérard Michel, Karsten Nysom, Susana Rives, Markus Schmugge Liner, Marco Zecca, Irith Baumann, Bouchra Benettaib, Jennifer Poon, Mathew Simcock, Meera Patturajan, Marry M. Van Den Heuvel-Eibrink, Franco Locatelli
Journal: Journal of Clinical Oncology (2019)

10031 Background: Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for JMML patients (pts). Novel therapies controlling the disorder prior to HSCT are urgently needed. A phase 2, multicenter, open-label study was conducted to evaluate safety and anti-leukemia activity of AZA monotherapy prior to HSCT in pts with newly diagnosed (ND) JMML. Methods: AZA (75 mg/m 2 IV) was administered once daily on days 1–7 of each 28-day cycle (C). Primary endpoint was number of pts with clinical complete remission or clinical partial remission (cPR) at C3 day (D) 28 (C3D28). Results: 18 JMML pts (13 PTPN11-, 3 NRAS-, 1 KRAS-, 1 NF1-mutated) were enrolled from 09/2015 to 11/2017. Median (range) white blood cell and platelet (Plt) counts were 19.7 (4.3–59.0) × 10 9 /L and 28 (7–85) × 10 9 /L, respectively. DNA methylation class (MC) was high, intermediate (int), or low in 11, 5, and 2 pts, respectively. 16 pts completed C3 and 5 pts C6. 2 pts discontinued treatment (Tx) pre-C3D28 due to disease progression (PD). 6 pts (33%) had ≥ 1 grade (Gr) 3–4 manageable adverse event (AE) related to AZA. Most common Gr 3–4 AEs related to AZA were neutropenia (2) and anemia (2). 11 pts (61%) were in cPR at C3D28; 7 had PD at C3D28 or prior. All 7 pts of the int/low MC and 4/11 in high MC achieved cPR. 17 pts received HSCT at median of 58 days (37–518) from last AZA dose; 14 were leukemia-free at a median follow-up of 15.7 months (0.1–31.7) after HSCT. 2 pts (high MC) given HSCT relapsed after allograft. 16/18 pts were alive at a median follow-up of 19.8 months (2.6–37.3) from diagnosis. 1 pt discontinuing Tx prior to C3 died from PD; 1 non-responder died from transplant-related causes. Plt response in pts with cPR prompted retrospective comparison of Plt counts at time of HSCT with a historical registry control cohort. Pts with NF1-mutated JMML with higher Plt counts versus other genetic subtypes were excluded. While 7/16 (44%) study pts had Plt counts ≥ 100 × 10 9 /L at HSCT, only 10/58 (17%) historical cohort pts reached this cutoff ( P &lt; 0.01). Conclusions: This study shows that AZA monotherapy was well tolerated in pts with ND JMML. Although the long-term advantage of AZA Tx remains to be fully assessed, responses show it was effective in JMML and provided clinical benefit to pts in this study. Clinical trial information: NCT02447666.
TMB standardization by alignment to reference standards: Phase II of the Friends of Cancer Research TMB Harmonization Project.
Authors: Diana M. Merino, Lisa McShane, Matt Butler, Vincent Anthony Funari, Matthew David Hellmann, Ruchi Chaudhary, Shu-Jen Chen, Wangjuh Sting Chen, Jeffrey M. Conroy, David Fabrizio, Laura E MacConaill, Aparna Pallavajjala, Arnaud Papin, Mark Sausen, Victor J Weigman, Mingchao Xie, Ahmet Zehir, Chen Zhao, Paul M. Williams
Journal: Journal of Clinical Oncology (2019)

2624 Background: Tumor mutational burden (TMB) is a predictive biomarker of response to immune checkpoint inhibitors across multiple cancers. In Phase 1 of the Friends of Cancer Research Harmonization Project, we demonstrated a robust correlation between TMB estimated using targeted next-generation sequencing (NGS) gene panels and whole exome sequencing (WES) applied to MC3-TCGA data. These findings demonstrated variability in TMB estimates across different panels. Phase 2 evaluates sustainable TMB reference standard materials for TMB alignment to assess this variability. The goal of this effort is to establish best practices for estimating TMB in order to improve consistency across panels, for the sake of optimizing clinical application and facilitating integration of datasets generated from multiple assays. Methods: Fifteen laboratories with targeted panels at different stages of development participated. We identified a set of reference standards consisting of 10 well-characterized human-derived lung and breast tumor-normal matched cell lines. WES was performed using a uniform bioinformatics pipeline agreed upon by all team members (WES-TMB). Each laboratory used their own sequencing and bioinformatics pipelines (tumor-only and tumor-normal) to estimate TMB according to genes represented in their respective panels (panel-TMB). The association between WES-TMB and each panel-TMB was investigated using regression analyses. Bias (relative to WES-TMB) and variability in TMB estimates across panels were rigorously assessed. All analyses were blinded. Results: The set of reference standards spanned a clinically meaningful TMB range (4.3 to 31.4 mut/Mb). Preliminary data from 12 laboratories shows a good correlation between panel-TMB and WES-TMB in this empirical analysis. Across panels, regression R 2 values range 0.77-0.96 with slopes ranging 0.60-1.26. Calibration analyses that seek to minimize variability of TMB estimates across panels using the established set of reference standards are ongoing, as well as investigating cancer type dependence on the relationship between panel-TMB vs. WES-TMB, which will be available at the time of presentation. Conclusions: Preliminary findings demonstrate feasibility of using sustainable reference control cell lines to standardize and align estimation of TMB across different targeted NGS assays. Future studies aim to validate reference standard material as a reliable alignment tool by using formalin-fixed paraffin-embedded human tumor samples.
Derazantinib (DZB) provides antitumor efficacy regardless of line of therapy in patients (pts) with FGFR2-fusion positive advanced intrahepatic cholangiocarcinoma (iCCA).
Authors: Michele Droz Dit Busset, Bassel F. El-Rayes, William Proctor Harris, Nevena Damjanov, Gianluca Masi, Lorenza Rimassa, Sherrie Bhoori, Monica Niger, Nicola Personeni, Fadi S. Braiteh, Sara Lonardi, Stephan Braun, Marc Engelhardt, Mikael Saulay, Brian E. Schwartz, Julia Kazakin, Walid Labib Shaib, Vincenzo Mazzaferro, Kyriakos P. Papadopoulos
Journal: Journal of Clinical Oncology (2019)

e15607 Background: FGFR2 fusions are prevalent in 13-22% of iCCA and known oncogenic drivers. DZB is a kinase inhibitor with potent pan-FGFR activity. In a non-comparative Phase 2a study, DZB was administered to 29 pts with FGFR2-fusion positive advanced, inoperable iCCA, either as first-line (1L) (n = 2), 2L (n = 13), 3L (n = 10), 4L (n = 2) or 5L therapy (n = 2). The objective response rate (ORR) with DZB was 21%, disease-control rate (DCR) 83% and median PFS 5.7 months (Mazzaferro et al. 2018 BJC). Data from biliary tract cancer studies suggest decreasing treatment effects of chemotherapy with increasing lines of treatment. Here, we present a post-hoc analysis of outcomes of pts treated with DZB in 1L/2L (n = 15) compared to pts treated post-2L (n = 14). Methods: Pts received 300 mg DZB QD PO. Eligibility criteria included locally confirmed, positive testing of FGFR2 fusion expression (FISH or NGS), ECOG PS 0-1. Objective responses were determined using RECIST 1.1. Disease control rate was defined as CR, PR or SD. Results: The mean age of pts treated in 1L/2L was 66y and 55y in post-2L; 73% were females in 1L/2L and 50% in post-2L treatment; other demographic variables were balanced between groups (87% vs 86% of liver target lesions, median baseline lesion size of 97.5 mm vs 109.5 mm, ECOG PS0 was 60% vs 71%). Of 15 1L/2L group pts, 12 (80%) had prior platinum-based chemotherapy as compared to all 14 pts in the post-2L group. In the 1L/2L and post-2L groups, ORR was 20% and 21%, DCR was 80% and 86%, and a reduction in sum of the largest diameter of target lesions was observed in 60% and 64% of pts, respectively. Median PFS was 5.5 mo (95% CI, 1.9-11.9) and 6.2 mo (3.6-9.2) for the 1L/2L and post-2L groups, respectively. Types of drug-related adverse events were similar in 1L/2L and post-2L. Conclusions: Anti-tumor efficacy of DZB in iCCA patients measured either by ORR, DCR, tumor shrinkage or PFS was numerically similar irrespective of treatment line. These data suggest that DZB is an effective treatment option that can be applied early in the treatment continuum of iCCA patients or at later stages to offer anti-tumor efficacy and disease control. Clinical trial information: 01752920.
Organization of Home Mechanical Ventilation in Portugal: Characterization of current centers and a pathway to uniformization
Authors: M.A. Mineiro, M.J. Guimarães, J.C. Winck
Journal: Pulmonology (2019)

Home Mechanical Ventilation (HMV) is increasing worldwide. Characterization of the Portuguese HMV Units. The HMV Team Group of the Portuguese Pulmonology Society prepared a questionnaire that was sent by e-mail addressed to Pneumology Department Directors throughout the country, and the responses were then analyzed. The results enabled a provisional classification of the Units, which followed specific criteria. Thirty centers were surveyed, of which 60% (18) sent the answers to the questionnaire. As for the results obtained, only one center was considered as a basic unit. Most centers (14/18) were considered specialized units. 3/18 centers were classified as highly complex multidisciplinary units. Of the 12 centers that did not answer the questionnaire, one refused to do it and another center was in transition period. Analysis of the results reveals the high number of patients treated with HMV in Portugal, supports the importance of creating protocols to standardize HMV countrywide, and audit its practice through the creation of a national register.