tbuckley/cabot-search huggingface dataset:
Phase 1/2 trial of FF-10502-01, a pyrimidine antimetabolite, in patients with advanced cholangiocarcinoma and solid tumors.
Authors: Filip Janku, Shiraj Sen, Shubham Pant, Lindsay Bramwell, Vivek Subbiah, Tracey Way, Milind M. Javle, Cassie Stone, Bhumika Prajapati, Shinji Hagiwara, Mary Johansen, Timothy Madden, Gary Maier, Ruth Ann Subach, Kazunori Saeki, Takeaki Suzuki, David S. Wages, Catherine A. Wheeler, Gerald Steven Falchook
Journal: Journal of Clinical Oncology (2019)

3008 Background: FF10502 is a synthetic pyrimidine nucleoside similar to gemcitabine (gem) with a sulfur in the pentose ring. FF10502 is a more potent inhibitor of DNA polymerase Beta than gem with activity in gem resistant patient (pt) derived xenograft models. FF10502 is avidly taken up into DNA and has greater activity against quiescent cells than gem. Methods: Pts &gt; 18 years old with advanced disease who had progressed on standard of care were enrolled into 9 dose levels to determine maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) and subsequently into two expansion cohorts: biliary or solid tumors (ST). FF10502 at doses of 8 to 135 mg/m 2 was administered iv on days 1, 8, 15 of a 28-day cycle until progressive disease or toxicity. PK/PD evaluations were performed on all pts. Response was assessed by RECIST 1.1. Results: 76 pts were treated; 35 pts in dose escalation, including 7 cholangiocarcinoma pts. MTD was 90 mg/m2. DLTs included 2 pts with hypotension at 135mg/m 2 (G3 and G4) and 1 pt each with G3 fatigue and G2 rash at 100mg/m 2 . In expansion, 19 cholangiocarcinoma, 3 gallbladder and 19 other pts (13 pancreatic, 2 urothelial, and 1 each ovarian, prostate, NSCLC, SCCHN each) were treated. 1 pt with prior rituximab for ITP developed PML. G3 treatment-related low platelets occurred in 3 pts at 90mg/m2 after cycle 1. There were 5 partial responses (PRs), including 4 pts who had progressed on prior gemcitabine: 3 of 26 pts with cholangiocarcinoma, 1 urothelial carcinoma and 1 chondroblastic osteosarcoma. 7 cholangiocarcinoma pts stayed on therapy for ≥6 months. FF10502 incorporation intoperipheral blood cellular DNA was seen, andbiomarkeranalysisdata to identify pts with higher potential for clinical response will be presented. Conclusions: FF10502 is well tolerated in pts with advanced cancers refractory to standard therapies. Early signals of efficacy warranting further exploration were seen in heavily pretreated cholangiocarcinoma pts (median: 4 prior therapies). Patient selection based on differential effects of FF10502 on DNA polymerases will be explored. Clinical trial information: NCT02661542.
Abstract 20560: Heart Rate Variability Evaluation in Patients With Long Standing Persistent Atrial Fibrillation Treated With Thoracoscopic Surgical Ablation With Ganglionic Plexi Ablation or Catheter Ablation - Recordings From Implantable Loop Recorder
Authors: Habib R Khan, Katerina Hnatkova, Ines Kralj-Hans, David G Jones, Wajid Hussain, Julian Jarman, Martin Cowie, Vias Markides, Marek Malik, Tom Wong
Journal: Circulation (2017)

Introduction: Ganglionic plexi (GP) are becoming ablation targets in treatments of atrial fibrillation (AF) and may have profound effect on cardiac autonomic status. However, this has not been full...
Case 20-1986
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Gregory L. Eastwood, Judith A. Ferry
Journal: New England Journal of Medicine (1986)

Presentation of CaseA 68-year-old man was admitted to the hospital because of diarrhea and chylous ascites.He was well until two years earlier, when diarrhea began and gradually worsened, with the passage of watery, brown, foul stools that floated in part and were interspersed with occasional formed stools. His weight fell from 81 to 76.4 kg. Eventually he passed as many as 10 to 11 stools daily, 3 or 4 of them during the night. A physician prescribed lactase, without benefit.Six months before entry he consulted a gastroenterologist. A blood count and the prothrombin time were normal. The . . .
AB1081 A COMPARATIVE STUDY ON THE FEATURES OF THE SPINAL INVOLVEMENT IN SAPHO SYNDROME
Authors: Xiaoli Deng, Shuang Gao, Lihua Zhang, Le Song
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> SAPHO syndrome is a rare disease with the typical involvement of the anterior chest wall. The spinal involvement is more often than we thought and less understood by us. <h3>Objectives</h3> To assess the clinical and imaging features of the spinal involvement in SAPHO syndrome. <h3>Methods</h3> Patients diagnosed with SAPHO syndrome in Peking University Third Hospital from 2006 to 2018 were recruited. Patients were divided into spinal involvement group and non-spinal involvement group. Patients with AS (ankylosing spondylitis) were recruited as control group. Their clinical data, laboratory data and imaging data (CT, MRI and radionuclide imaging) were collected and were conpared. All the patients with SAPHO syndrome were followed up regularly. <h3>Results</h3> Totally 46 SAPHO patients were included (17 male and 29 female) and 34 patients (73.9%) had spinal involvement. The mean age was 50.2±10.9 years and the mean disease duration was 5.4±6.4 years. 50 patients with AS were also included. Compared with non-spinal involvement group, the age at disease onset in spinal involvement group was older, the disease duration was longer,t;he CRP elevation was more often and the anterior chest wall involvement was less often (table 1). In spinal involvement group, the thoracic spine was most commonly involved and the vertebral inflammatory changes including bone marrow edema were often seen. These patients were more likely to suffer from cervical spine involvement, endplate inflammation and spondyldiscitis (table 2). All the SAPHO patients with spinal involvement were followed up. 30 patients received NSAIDs plus DMARDS/biologics and the symptoms improved. Reexamined imaging data of 10 patients were available and the spinal involvement became better. <h3>Conclusion</h3> 73.9% of SAPHO patients had spinal involvement and they were more likely to suffer from cervical spine involvement, endplate inflammation and spondyldiscitis. The combination of NSAIDS and biologics/DMARDs were helpful to improve the symptoms. <h3>References</h3> [1] Mcgauvran A M, Kotsenas A L, Diehn F E, et al. SAPHO Syndrome: Imaging Findings of Vertebral Involvement.[J]. Ajnr Am J Neuroradiol, 2016, 37(8). <h3>Acknowledgement</h3> This study was supported by a Project of the National Natural Science Foundation of China (81501390). <h3>Disclosure of Interests</h3> None declared
Brigatinib (BRG) versus crizotinib (CRZ) in Asian versus non-Asian patients (pts) in the phase III ALTA-1L trial.
Authors: Myung-Ju Ahn, HyeRyun Kim, James Chih-Hsin Yang, Ji-Youn Han, Jong Seok Lee, Maximilian J. Hochmair, Jacky Yu-Chung Li, Gee-Chen Chang, Ki Hyeong Lee, Cesare Gridelli, Rosario Garcia Campelo, Angelo Delmonte, Dong-Wan Kim, David Kerstein, Quanhong Ni, Pingkuan Zhang, Sanjay Popat, D. Ross Camidge
Journal: Journal of Clinical Oncology (2019)

9026 Background: We report an analysis of BRG vs CRZ in Asian vs non-Asian pts with ALK inhibitor–naive, ALK+ NSCLC from ALTA-1L (NCT02737501). Methods: Pts were randomized 1:1 to BRG 180 mg QD (7-day lead-in at 90 mg) or CRZ 250 mg BID. Primary endpoint: blinded independent review committee (BIRC)-assessed PFS (RECIST v1.1). Secondary efficacy endpoints: BIRC-assessed ORR, intracranial (i) ORR, and iPFS. Results: 275 pts were randomized; 108 Asian (BRG/CRZ, n = 59/49), 167 non-Asian (n = 78/89); median age: Asian, 55/56 y; non-Asian, 60/60 y. 32/24% of Asians vs 22/28% of non-Asians received prior chemotherapy for advanced disease; 36/33% vs 24/28% had baseline CNS metastases. As of 19 Feb 2018, median follow-up was 10.1/10.0 mo (BRG/CRZ) in Asians vs 11.0/9.0 mo in non-Asians, with 12 vs 20 PFS events in Asians and 24 vs 43 in non-Asians. In Asians, median BIRC-assessed PFS (mo) was not reached (NR; 95% CI 11.2–NR) with BRG vs 11.1 (9.2–NR) with CRZ (HR 0.41 [95% CI 0.20–0.86]; log-rank P= 0.0261); in non-Asians, BRG PFS was NR (NR) vs 9.4 (7.3–NR) with CRZ (HR 0.54 [0.33–0.90]; log-rank P= 0.0132) (Table). AE profile of each drug was similar in Asians vs non-Asians. Most common any-grade AEs (≥25%) in Asians in BRG arm: diarrhea; elevated blood CPK, ALT, and AST. Discontinuation due to AE (BRG/CRZ): 8.5/6.3% in Asian pts; 14.3/10.1% in non-Asian pts. Conclusions: BRG showed comparable improvement in PFS vs CRZ both in Asians and non-Asians in ALK inhibitor–naive ALK+ NSCLC. Clinical trial information: NCT02737501. [Table: see text]
Immune-related gene signature in predicting prognosis of early-stage colorectal cancer patients.
Authors: Jia Ke, Xuanhui Liu, Xiaofeng Jiang, Yufeng Chen, Zerong Cai, Ping Lan, Xiaojian Wu, Feng Gao
Journal: Journal of Clinical Oncology (2019)

3586 Background: Immune-related genes (IRGs) were found to be associated with the prognosis of colorectal cancer (CRC) patients. The aim of this study was to evaluate the impact of IRGs in predicting prognosis of early-stage CRC patients. Methods: According to the CIT microarray data set, 309 early-stage CRC patients were selected for generation of immune-related gene signature (IRGS). 5 independent data sets included 1587 CRC patients with complete prognostic information were divided into a training cohort (566 patients) and two validation cohorts (624 patients in validation-1 and 397 patients in meta-validation). Prognostic analysis were performed to test the predictive value of IRGS. Results: Of 309 early-stage CRC patients, a prognostic immune signature included 23 immune-related genes was constructed. In the training cohort, when considering patients with early tumor stage (I or II), IRGS significantly stratified patients into immune low- vs high-risk groups in terms of disease-free survival (HR = 5.03, 95%CI = 2.94-8.62, P &lt; 0.001). Similarly, higher IRGS was correlated with significantly worse prognosis of early-stage CRC patients in validation-1 (HR = 2.71, 95%CI = 1.44-5.08, P = 0.001) and meta-validation cohort (HR = 3.10, 95%CI = 1.60-6.00, P &lt; 0.001). When compared with Oncotype DX, we found IRGS achieved an improved survival correlation in the training cohort (mean C-index, 0.85 vs 0.65) and the validation-1 cohort (mean C-index, 0.72 vs 0.61). After integrated with clinical characteristics, IRGS remained as an independent prognostic factor after adjusting for T stage and TNM stage of tumor in multivariate analysis (HR = 2.02, 95%CI = 1.61-2.53, P &lt; 0.001). Furthermore, IRGS stratified immune low-risk group patients with adjuvant chemotherapy showed even worse disease-free survival when compared with those without adjuvant chemotherapy (HR = 5.66, 95%CI = 3.153-10.16, P &lt; 0.001 in the training cohort and HR = 3.21, 95%CI = 1.74-5.92, P &lt; 0.001 in the validation-1 cohort). IRGS identified immune high-risk group obtained a significantly higher immune and stromal infiltration (P &lt; 0.001). Particularly, the percentages of Macrophages M2 and CD8 + T cells infiltration were significantly different between these two groups. Conclusions: The proposed prognostic IRGS is a promising system for estimating DFS of colorectal cancer patients, especially those in early-stage. Further studies are needed to evaluate the clinical utility of this system in predicting prognosis of colorectal cancer patients.
Urinary excretion of components of the renin-angiotensin-aldosterone system in patients having localized renal cancer.
Authors: Roman Osokin, Oleg Ivanovich Kit, Ekaterina Komarova, Igor Aboyan, Elizaveta Komarova
Journal: Journal of Clinical Oncology (2019)

e14725 Background: The aim of the study was exploring the content of components of the renin-angiotensin-aldosterone system (RAAS) in the urine of renal cancer (RC) patients depending on the clinical and morphological characteristics. Methods: In the urine of patients having localized renal cancer Т1N0M0 (the main group, n = 40) the level of angiotensinII (ATII), angiotensin-converting enzymes (ACE and ACE2) was studied by the ELISA with excretable creatinine taken into account in order to eliminate the differences of diuresis. The control group was made up of 35 healthy donors. Results: In patients of the main group, the content of ATP in the urine is 71,5% higher (р = 0,003) than in the healthy donors. In 50% of the patients, the range of fluctuations of ATI in the urine from the lower to the upper quartile amounts to 4,2-9,8 pg/µmol of creatinine against 2,1-5,2 pg/µmol of creatinine in the healthy ones.The level of ACE and ACE2 in the patients as compared to the healthy donors is also 35,4% and 24,5% higher, respectively (at p &lt; 0,05). The proportion of increment ΔATII/ΔACE in the patients amounted to 2,2±0,1as compared to the healthy donors, that of ΔATII/ΔACE2 – to3,2±0,2. Meanwhile, ΔACE/ΔACE2 was 1,6±0,1, which confirms the predominance of the activity of ACE. In patients of the main group, no statistically valid difference of the urinary excretion value of ATII, ACE and ACE2 has been identified between the subgroups depending on the RC stage T1a, Т1bas well as on dimensions of the tumor nodes. However, in case of the RC with G2 tumor differentiation grade as compared to the G1, the content of ATII, ACE and ACE2 in the urine is 3,5; 2,5 and 2,1 times higher, respectively (p &lt; 0,05). Conclusions: In patients having localized renal cancer, increased urinary excretion of components of the renin-angiotensin-aldosterone system has been found. The content of angiotensin II in the urine exceeds the activity of angiotensin-converting enzymes, which may be related to the alternative ways of its formation under tumor growth. The content of the RAAS components in the urine in patients having localized renal cancer does not depend on the stage and dimensions of the tumor but it correlates with the differentiation grade.
Genomic and transcriptomic landscape of oral pre-cancers (OPCs) and risk of oral cancer (OC).
Authors: William Nassib William, Won-Chul Lee, J. Jack Lee, Heather Y. Lin, Agda Karina Eterovic, Adel K. El-Naggar, Ann M. Gillenwater, Marlese Pisegna, Pan Tong, Lerong Li, Xianjun Tian, Hai T. Tran, Pierre Saintigny, Jing Wang, Vassiliki Papadimitrakopoulou, Scott Michael Lippman, Phillip Andrew Futreal, John Heymach, Jianjun Zhang
Journal: Journal of Clinical Oncology (2019)

6009 Background: The molecular landscape of OPCs and its association with neoplastic progression is largely unknown. We report the results of high throughput DNA/RNA profiling of OPCs from pts in the Erlotinib Prevention of Oral Cancer trial (EPOC), with long-term prospective follow-up. Methods: We performed next generation sequencing of 201 cancer genes (MD Anderson T200 platform) in 170 OPCs from EPOC, and RNA profiling using HTG EdgeSeq Oncology Biomarker Panel containing 2,560 transcripts in a subset of 141 OPCs. 73 pts developed invasive OC during a median follow up of 7.3 years, from whom 23 paired OCs were profiled to characterize the evolutionary trajectory from OPCs to OCs. OPC molecular features were correlated with OC-free survival. Results were compared with TCGA invasive OC DNA/RNA profiles and an independent set of 86 OPCs with RNA data. Results: Similar to TCGA, C &gt; T was the predominant substitution. The top mutated genes in OPCs were TP53 (29%), CDKN2A (15%), NOTCH1 (11%) and PIK3CA (7%), which were also frequently mutated (albeit at higher rates) in OCs from EPOC or TCGA. There was a progressive increase of tumor mutation burden (TMB, P &lt; 0.05) and frequency of high-risk TP53 mutations (P = 0.02) from hyperplasia, to dysplasia, to invasive OCs (P &lt; 0.05). Median TMB was higher in OPCs from pts who developed OC (2.45 mut/Mb) vs those who did not (1.22 mut/Mb) (P &lt; 0.01). Pts with TP53 mutated OPCs had shorter OC-free survival compared to TP53 wild-type (HR 1.81, 95% CI 1.13-2.90, P = 0.01). A prognostic score was derived from a Cox regression model which identified 12 mRNA transcripts associated with OC risk (HR 4.72, 95% CI 2.51-8.86, P &lt; 0.01), and which was validated in the independent set of 86 OPCs (HR 2.68, P &lt; 0.01). This score was also associated with shorter overall survival when applied to invasive OCs from TCGA pts (HR 2.72, P &lt; 0.01). Conclusions: This is the first large-scale cohort of OPC pts with long-term, prospective follow up and comprehensive RNA/DNA profiling. We demonstrated an association between TMB, TP53 mutations, a 12-gene RNA signature score in OPCs, and OC risk. This study may provide a framework for similar efforts of pre-cancer molecular profiling in the oral cavity and other sites, such as the PreCancer Atlas of the NCI.
Overcoming genetically based resistance mechanisms to PD-1 blockade.
Authors: Davis Yuri Torrejon, Gabriel Abril-Rodriguez, Jennifer Tsoi, Ameya Champhekar, Anusha Kalbasi, Katie Marie Campbell, Giulia Parisi, Cristina Puig-Saus, Gardenia Cheung-Lau, Tom Wohlwender, Beata Berent-Maoz, Catherine Grasso, Begoña Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas
Journal: Journal of Clinical Oncology (2019)

2584 Background: Mechanism-based strategies to overcome resistance to anti-PD1 therapy are urgently needed. Using CRISPR/Cas9 genome editing tools, we developed acquired resistant models through JAK1/2 and B2M loss of function (LoF) mutations in human melanoma cell lines and in the murine MC38 colon carcinoma, known for high mutational load and good response to anti-PD-1. We hypothesized that the downstream activation of the IFN-receptor pathway or the activation of natural killer (NK) cells would overcome this resistance. Methods: We studied signaling changes in four human cell lines (parental and LoFs) exposed to IFN-gamma using RNAseq. In addition, we analyzed the in-vivo antitumor activity in MC38 variants with anti-PD1 and characterized the tumor microenvironment using mass cytometry (CyTOF). Finally, we tested strategies to overcome resistance mechanisms with SD-101 (TLR-9 agonist) and bempegaldesleukin (NKTR-214, CD-122 biased agonist) with the extent of CD8 and NK1.1 depletion. Results: RNAseq differential gene expression analysis showed that the IFN-gamma induced increased expression of antigen presenting machinery, IFN-gamma signaling and chemokines (CXCL9/10) was lost in JAK1/2-LoF human melanoma cell lines. The significant antitumor activity of anti-PD-1 against MC38 parental cell line was lost in JAK1/2 and B2M LoF sublines, and CyTOF analysis revealed that anti-PD-1 therapy was unable to increase tumor CD8+ T-effectors in these LoF tumors. The intratumoral administration of SD-101 (50 μg/injection q4dx3wks) was able to overcome local resistance even in non-injected sites in JAK1/2 and IFNAR-type-I LoF tumors, and systemic administration of bempegaldesleukin (0.8 mg/kg, q9dx2, i.v.) was able to overcome resistance in B2M LoF with significantly increased survival (Table). Depletion studies showed complete abrogation of anti-tumor response with anti-NK1.1 in JAK1 LoF and B2M LoF, and partial abrogation with anti-NK1.1 or anti-CD8 in JAK2 LoF tumors. Conclusions: Even in the extreme setting of genetic resistance to PD-1 blockade by JAK1/2 LoF, resistance can be overcome by SD-101, a TLR9 agonist, while resistance of B2M LoF can be overcome by bempegaldesleukin (NKTR-214), a CD-122 biased agonist. Our findings support the testing of these rational mechanistic strategies in patients with a-PD1 resistance. [Table: see text]
Comprehensive molecular characterization of clinical response in ramucirumab-treated gastric cancer patients: Phase II trial with integrated genomic profiling.
Authors: Seung Kim, Sung Yong Oh, Se Hoon Park, Kyung Kim, Joon Oh Park, Young Suk Park, Won Ki Kang, Jeeyun Lee
Journal: Journal of Clinical Oncology (2019)

4064 Background: The absence of tumor cells enables an enriched stromal environment to generate RNA signatures and through assembling genes involved in tumor stroma, four distinct stromal signatures that reflected biological processes such as signature vascular mature (VM), vascular mature/inflammatory (VMI), vascular immature/noninflammatory (VINI) and inflammatory alone (I) depending on mature of vasculature. We hypothesized that these stromal specific signatures may provide additional information to the pre-existing TCGA/ACRG subtypes when predicting response to anti-angiogenesis agent such as ramucirumab. Methods: We conducted a single-center phase II trial in which we treated 61 unselected patients with metastatic GC with ramucirumab plus paclitaxel as second line therapy and performed pre-planned integrated genomic profiling. Results: Sixty-two patients were enrolled in this study between May 2014 and June 2017. The cut-off date for treatment outcome analysis was January 2, 2019, at which time response evaluations were available for 57 patients with a median follow-up of 30.2months. In an intent-to-treat analysis cohort, there was no CR and 22 patients achieved confirmed PRs resulting in an ORR of 35.5% (95% CI: 23.6 – 47.4). The response rate to ramucirumab was considerably enriched in VM/VMI group (29.2%) (P = 0.0003) when compared to I ( &lt; 10%) or VINI group ( &lt; 10%). The strongest response defined by maximal response to ramucirumab was shown in GC patients with VM/VMI signatures. Of note, VM/VMI patients had prolonged duration of response to ramucirumab/paclitaxel demonstrating that these patients not only respond to ramucirumab but also had durable response. Conclusions: This is the first study to demonstrate a clinically robust correlation between stromal-based signature and response to anti-angiogenesis inhibitor in GC. Clinical trial information: 02628951.
Preventing excess narcotic prescriptions in MIS urologic oncology discharges (PENN): A prospective cohort quality improvement initiative.
Authors: Ruchika Talwar, Leilei Xia, Juan Serna, Daniel Lee, Justin Ziemba, Thomas J. Guzzo
Journal: Journal of Clinical Oncology (2019)

6502 Background: In the setting of the national opioid crisis, there is increasing interest in non-narcotic pain strategies, particularly for oncology patients. Robotic urologic surgeries for cancer have been shown to result in less pain than open approaches. We hypothesized that the majority of these patients could be safely discharged with adequate analgesia without opioids. Methods: This prospective cohort study aimed to reduce narcotics prescribed at discharge after robotic radical prostatectomy (RARP), robotic radical nephrectomy (RARN) and robotic partial nephrectomy (RAPN). Prior to 9/2018, 100% of patients were discharged on varying amounts of oxycodone (range: 75-337.5 oral morphine milligram equivalents [MME]). We implemented a standard non-opioid analgesia pathway with escalation options across the continuum of care. Patients received gabapentin 300 mg and acetaminophen 975 mg once PO pre-operatively, as well as gabapentin 300 mg every 8 hours, acetaminophen 975 mg every 8 hours PO, and ketorolac 15 mg every 6 hours IV post-operatively. If complaining of persistent pain despite the standing regimen, patients were given 50 mg or 100 mg of tramadol every 6 hours as needed for pain level 5-7 or 8-10 on the visual analog scale, respectively. If requiring further escalation, patients were given 5 or 10 mg of oxycodone every 6 hours as needed on the aforementioned scale. Regardless of escalation status, all patients were discharged on the standing non-narcotic protocol. If escalated, ten pills of tramadol 50 mg or oxycodone 5 mg were prescribed accordingly. Results: Our cohort (n = 170) consisted of patients undergoing RARP (n = 87), RARN (n = 25), RAPN (n = 58) between 9/1/2018-1/9/2019. Overall, 67.7% were discharged without opioids, 24.4% with ten pills of tramadol 50 mg (50 MME) and 8.2% with ten pills of oxycodone 5 mg (75 MME). On multivariate analysis, older age (OR: 0.961, 95% CI: 0.923-0.995, p = 0.026) was associated with lower odds of needing opioids at discharge. There was no difference in postoperative telephone encounters between those discharged with or without opioids. Conclusions: The majority of robotic surgery patients do not require opioids upon discharge. An escalation protocol allows for a patient centered approach to reduce narcotic prescribing while still addressing cancer and surgical pain.