tbuckley/cabot-search huggingface dataset:
Metabolic characteristics of esophageal carcinoma in a veteran population.
Authors: Theresa Ratajczak, Geetika Kumar, Heidar Albandar, Parker Redlien, Sara Yacyshyn, Roland Markert
Journal: Journal of Clinical Oncology (2016)

4023 Background: Esophageal cancer is projected to increase by 35% through 2025 in the U.S. We investigated whether the presence of metabolic syndrome components differed between these two cancers in a veteran population. History of gastroesophageal reflux disease (GERD) was also evaluated. Methods: Records of patients diagnosed with esophageal carcinoma between 1996-2014 were reviewed. Patients with incomplete documentation were excluded. Information on demographics, BMI before diagnosis, hypertension, hyperlipidemia, hyperglycemia, GERD, and diabetes mellitus (DM) type 2 was collected. Statistical analysis was performed using IBM SPSS Statistics 22.0 software and proper data-dependent statistical testing. Results: Of the 118 eligible patients, 81 were classified as having adenocarcinoma (EAC) and 37 as having squamous cell carcinoma (SCC). Age at diagnosis for EAC and SCC was 67.1±9.7 vs. 67.0± 10.8 years, (p = 0.83). Compared to SCC, patients with EAC were more likely to be white than African American (98.8% vs. 59.5%, p < 0.001). Veterans with EAC had a higher mean pre-diagnosis BMI than those with SCC (29.7±6.5 vs. 25.0±8.0 kg/m2, p < 0.001). Patients with EAC were more likely to have hyperlipidemia (59% vs. 35%, p = 0.015), GERD (51% vs. 22%, p = 0.003), hyperglycemia (44.4% vs. 27.0%, p = 0.07) and type 2 DM (37% vs. 19%, p = 0.049) than those with SCC. The two groups did not differ on HTN (59.3% vs. 56.8%, p = 0.80). Pre-diagnosis BMI (OR = 1.11; 95% CI = 1.01 to 1.21) and GERD (OR = 3.60; 95% CI = 1.27 to 10.19) were independent predictors of type of cancer – i.e., significant after controlling for the other variables. Hyperlipidemia (OR = 1.94 [0.63 to 5.92]) and Type 2 DM (OR = 1.08 [0.32 to 3.67]) were not independent predictors of type of esophageal cancer. Conclusions: We found that type of cancer (EAC or SCC) was associated with presence of certain components of metabolic syndrome (i.e., pre-diagnosis BMI, GERD, hyperlipidemia, and diabetes mellitus type 2) with the former two being independent predictors of EAC when compared to SCC. With the increasing incidence of obesity, GERD, and metabolic syndrome in the Western world, it is important to evaluate the relationship of common morbidities to esophageal carcinoma, which for EAC has also risen.
Mechanism-guided repurposing: Effect of deferiprone on the eIF5A hydroxylation-dependent synthesis of proline cluster-containing proteins (PccPs) in uterine serous carcinoma (USC).
Authors: Hartmut M. Hanauske-Abel, Mainul Hoque, Sukwinder Singh, Debra S. Heller, Patricia Soteropoulos, Deborah A. Lazzarino, Paul E. Palumbo, Patricia Fitzgerald-Bocarsly, Bernadette Cracchiolo
Journal: Journal of Clinical Oncology (2016)

e23159 Background: Hydroxylation of eIF5A by deoxyhypusyl hydroxylase (DOHH) forms its hypusine residue, which relieves stalling within the ribosomal exit tunnel of a subset of nascent, cellular or viral PccPs. We tested the hypothesis that NIH 353, an antibody selectively recognizing hydroxylated eIF5A (OH-eIF5A) in tumor biopsies, can identify PccP-dependent cancers and thus guide the development of oncologically relevant eIF5A hydroxylation inhibitors by low-risk drug-based lead discovery (DBLD) or high-risk de novo drug development. Methods: Receptor-guided drug discovery; immunohistochemistry; Western; cell culture; flow cytometry; drug spectrometry. Results: DOHH active site mapping, confirmed by crystallography (Structure 23: 882-892 [2015]), identified deferiprone as a docking-compliant drug. NIH-353, immunoreative only to OH-eIF5A (Gynecol Oncol 94: 217-222 [2004]), prominently stained biopsies of USC, but not of endometrioid carcinomas. In the USC cell line ARK-1, deferiprone at clinically relevant concentration for 48 hours inhibited eIF5A hydroxylation ( ≥ -80%) along with the synthesis of the PccP Hsp27/HSPB1 ( ≥ -60%; Cancer Res 74: 552-562 [2013]). Cyclin B2 and stathmin-1, both representative for the USC gene expression subtype of endometrial carcinomas (Nature 497: 67-73 [2013]), were also inhibited ( ≥ -60%), whereas actin was unaffected. Deferiprone caused cell cycle arrest and transient epithelial differentiation of ARK-1, followed by rapid lethality after 72 hours of exposure. The same concentration had no deleterious effect on non-malignant uterine epithelial cells (ECC-1) even after 144 hours, assessed by transepithelial resistance. Conclusions: The library of FDA-approved drugs contains medicines with DOHH inhibitor side activity that disrupt the aggressive gene expression subtype involving PccP synthesis, as in USC. The DBLD approach, guided by the atomic level 3D resolution of the DOHH active site, facilitates targeted proof-of-principle trials and targeted optimization of drug pioneers to derive next-generation compounds.
Efficacy of olanzapine for prevention of chemotherapy-induced nausea and vomiting: A systematic review and meta-analysis.
Authors: Rohit Kumar, Naina Singh, Romy Jose Thekkekara, Sunny R K Singh, Sarah Elizabeth Harrington, Mousami Shah
Journal: Journal of Clinical Oncology (2017)

e21692 Background: Olanzapine is an atypical antipsychotic medication which has shown efficacy in prevention of chemotherapy-induced nausea and vomiting (CINV) in multiple trials. This study aims to investigate the efficacy of Olanzapine to prevent CINV with an up-to-date systematic review and meta-analysis. Methods: A literature search of Ovid MEDLINE, Embase and Cochrane library was performed to identify randomized controlled trials of olanzapine compared to other antiemetic therapy (5HT3 and/or NK1 antagonist with or without steroids) for prevention of CINV in patients age &gt;=18 years up until December 2016. The primary endpoint was no emesis or nausea episodes in acute (0-24hrs), delayed (24-120hrs) and overall (0-120hrs) period in patients receiving highly or moderately emetogenic chemotherapy (HEC or MEC). Statistical analysis was performed using Review Manager (RevMan 5.3). The Mantel–Haenszel method was applied and random effect analysis model was used to calculate risk ratios. Results: From the literature, 12 RCTs met the inclusion criteria. The age range of patients was 18-89 years. Seven trials included only patients who received HEC while 5 trials included patients receiving either HEC or MEC in various proportions. Olanzapine was statistically superior for 5 primary endpoints except for no nausea in acute period (Table 1). In the non-steroids cohort, olanzapine was superior for no emesis in all 3 periods but statistically significant only for delayed period. Conclusions: Olanzapine is superior to other antiemetic therapy for prevention of CINV. It is less expensive and can improve patient’s quality of life and chemotherapy adherence. [Table: see text]
Protein‐Engineered Biomaterials for Cancer Theranostics
Authors: Xiaowen Liu, Chao Wang, Zhuang Liu
Journal: Advanced Healthcare Materials (2018)

Abstract Proteins are an important class of biomaterials promising a variety of applications such as drug delivery, and imaging or therapy, owing to their biodegradability, biocompatibility, as well as inherent biological activities acting as enzymes, recognizing molecules, or therapeutics by themselves. Over the few past decades, different types of proteins with desired properties have been widely explored for biomedical applications. Many therapeutic proteins have now entered clinical use. This review therefore summarizes various strategies in the engineering of biomaterials for delivery of therapeutic proteins, as well as the recent development of protein‐based biomaterials for cancer theranostics.
TCT-147 High wattage electronic cigarette vaping after coronary stenting induces arterial hypoxemia: a randomized clinical trial
Authors: Martin Chaumont, Wael Zaher, Quentin de Hemptinne, Rachid Briki, Ahmad Awada, Dariouch Dolatabadi, Jean-Paul Bar, Philippe Van De Borne, Nadia Debbas
Journal: Journal of the American College of Cardiology (2018)
Outcomes of melanoma brain metastases treated with stereotactic radiosurgery with and without concurrent immune checkpoint therapy.
Authors: Jessica Yang, Laurent Dercle, Andrew M. Yaeh, Randy Yeh, Daniel K. Manson, Shumaila Saad, Bruce N. Jeffrey, Michael B. Sisti, Guy M. McKhann, Tony J. C. Wang, Lawrence H. Schwartz, Richard D. Carvajal
Journal: Journal of Clinical Oncology (2017)

e21026 Background: Evidence supports a synergistic effect between immunotherapy and radiotherapy. In this single-institution study, we compared outcomes of patients (pts) with melanoma brain metastases (BMs) who received Gamma Knife Radiosurgery (GKRS) with and without concurrent immune checkpoint blockade (ICB). Methods: Using an IRB-approved protocol, we identified pts with melanoma BMs who received GKRS from 5/2000 to 8/2016. Treatment was deemed concurrent if patients had GKRS within 4 weeks of ICB. Irradiated lesion control, tumor growth rate (TGR; percent change in product diameters per month), distant brain control, overall response rate (ORR) by modified WHO criteria, best response, and overall survival (OS) were compared. Results: 28 pts were identified: 17 (34 BMs total) received GKRS alone; 11 (23 BMs total) received concurrent GKRS/ICB. ICB included: ipilimumab (n = 3), anti-programmed death-1 (anti-PD-1) therapy (n = 4), and combined ipilimumab + nivolumab (n = 4). In comparing baseline characteristics between the GKRS alone and GKRS/ICB groups: median age was 65 v. 59 years, proportion of males was 53% v. 73%, 41% v. 45% had prior neurosurgery, and median number of prior systemic therapies was 1 v. 0. There was no difference in irradiated lesion control (6-month control rate 86% v. 96%; n = 57; p = 0.65), median TGR (-14% [range -100% to +61%] v. -20% [range -71% to 0%]; n = 42 lesions, p = 0.38), or distant brain control (6-month control rate 68% v. 60%; p = 0.51; median follow-up 8.6 months v. 8.0 months) with GKRS/ICB v. GKRS alone. The ORR with GKRS alone v. GKRS/ICB was 61% v. 47% (p = 0.33), and the median maximum reduction in BM bidimensional measurement was -69% v. -45% (p = 0.43). Median OS from the date of GKRS was not reached for the GKRS/ICB group and was 16.6 months for the GKRS alone group (p = 0.03). Conclusions: There was no difference in local lesion control, TGR, or distant brain control with concurrent GKRS/ICB compared to GKRS alone, but the study was limited by small patient numbers and biased by closer follow-up in the GKRS/ICB group. OS was longer with concurrent ICB, likely reflecting the survival improvement with immune checkpoint inhibitors.
Pembrolizumab (pembro) versus investigator’s choice of paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer (UC): 5-year follow-up from the phase 3 KEYNOTE-045 trial.
Authors: Joaquim Bellmunt, Andrea Necchi, Ronald De Wit, Jae-Lyun Lee, Lawrence Fong, Nicholas J. Vogelzang, Miguel A. Climent Durán, Daniel P. Petrylak, Toni K. Choueiri, Winald R. Gerritsen, Howard Gurney, David I. Quinn, Stephane Culine, Cora N. Sternberg, Jin Zhi Xu, Blanca Homet Moreno, James Luke Godwin, Dean F. Bajorin, David J. Vaughn, Yves Fradet
Journal: Journal of Clinical Oncology (2021)

4532 Background: Pembro was approved for the treatment of locally advanced or metastatic UC that progressed during or after a platinum-containing regimen, based on the phase 3 KEYNOTE-045 (NCT02256436) trial that showed significantly improved OS with use of pembro. Updated results are presented from KEYNOTE-045 after &gt;5 y of follow-up since the last patient (pt) was randomized. Methods: KEYNOTE-045 is a randomized, multisite, open-label, phase 3 trial. Pts with histologically or cytologically confirmed UC, progression after platinum-containing chemo, ECOG PS 0-2, measurable disease per RECIST v1.1, and ≤2 prior lines of systemic therapy were eligible. Pts were randomly assigned 1:1 to receive pembro 200 mg Q3W or investigator’s choice of paclitaxel 175 mg/m 2 Q3W, docetaxel 75 mg/m 2 Q3W, or vinflunine 320 mg/m 2 Q3W. Primary end points are PFS (RECIST v1.1, blinded central review) and OS. ORR and duration of response (DOR) were key secondary end points. Results: As of Oct 1, 2020, among 542 enrolled pts, median time from randomization to data cutoff was 62.9 mo (range 58.6-70.9). 9.4% and 0% of pts in the pembro and chemo arms, respectively, completed 2 years of therapy. Median OS was longer for pembro vs chemo (10.1 vs 7.2 mo; HR, 0.71 [95% CI, 0.59-0.86]) overall and in pts with CPS ≥10 (8.0 vs 4.9 mo; HR, 0.59 [95% CI, 0.40-0.86]). For pts with CR or PR, median OS was not reached and 16.4 (95% CI, 11.3-25.1) mo in the pembro and chemo arms, respectively (Table). OS rates at 48 mo were 16.7% for pembro and 10.1% for chemo; 60-mo OS rates were 14.9% and 8.7%, respectively. OS benefit with pembro vs chemo continued regardless of age, ECOG PS, prior therapy, liver metastases, baseline hemoglobin, time from last chemo, histology, risk factors, and chemo choice. Median DOR for responders was longer for pembro vs chemo (29.7 mo [1.6+ to 60.5+] vs 4.4 mo [1.4+ to 63.1+]), and a greater proportion of responses lasted ≥48 mo (40.9% vs 28.3%, Kaplan-Meier) and ≥60 mo (32.8% vs 28.3%). ORR was higher for pembro vs chemo (21.9% vs 11.0%; difference 10.8% [95% CI, 4.6-17.0]). Fewer pts given pembro vs chemo experienced a treatment-related AE of any grade (62.0% vs 90.6%) or grade ≥3 (16.9% vs 50.2%). Conclusions: After 5 y, pembro maintained clinically meaningful OS benefit vs chemo in pts with locally advanced or metastatic UC that progressed during or after platinum-based chemo. Pts who responded to pembro experienced a durable response (median &gt;2 y). Clinical trial information: NCT02256436 .[Table: see text]
Impact of dose reductions on 5-year efficacy in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) from DASISION.
Authors: Jorge E. Cortes, Andreas Hochhaus, Hagop M. Kantarjian, François Guilhot, Vamsi K. Kota, Timothy P. Hughes, Suresh Shelat, Li Li, Elias Jabbour
Journal: Journal of Clinical Oncology (2017)

7051 Background: Dasatinib (DAS) dose modifications generally mitigate adverse events (AEs) without affecting efficacy for responding patients (pts). A 2-year retrospective analysis of DASISION showed that rates of cytogenetic and molecular responses remained higher for pts given DAS vs imatinib (IM), even when daily doses were modified (Jabbour ASH 2011). Efficacy was not compromised due to dose reductions to manage DAS-related AEs. Here, we report results from a 5-year analysis evaluating the impact of dose reductions on efficacy in pts from DASISION. Methods: In DASISION (NCT00481247), pts with treatment-naïve CML-CP were randomized to receive either DAS (100 mg once/day; N = 259) or IM (400 mg once/day; N = 260). Up to 2 dose reductions were permitted for AEs (DAS: 80 mg, then 50 mg; IM: 300 mg, then 200 mg). Efficacy in all pts was evaluated retrospectively by 5 years. Results: Molecular response rates remained higher for DAS than IM, independent of dose reductions, and were comparable in pts with and without dose modifications in each arm (table). Overall, 95 (37%) DAS- and 44 (17%) IM-treated pts had dose reductions at any time due to AEs. Median average daily dose was 83 mg DAS and 328 mg IM for pts with reductions for any cause and 82 mg DAS for pts with reductions due to pleural effusion. The most common AEs resulting in dose reduction were hematological toxicity for IM (9%) and pleural effusion for DAS (12%). Conclusions: A 5-year retrospective analysis of DASISION showed molecular responses remained higher for DAS vs IM when daily doses were modified due to AEs. Dose reductions for any cause, including pleural effusion, did not affect efficacy (MMR rates were not reduced). In this analysis, for pts who experienced AEs, DAS dose reductions to 80 mg or 50 mg were safe and effective treatment options. Clinical trial information: NCT00481247. [Table: see text]
Abstract 11639: Multivessel Versus Culprit-only Revascularization for Patients With St-segment Elevation Myocardial Infarction and Multivessel Disease Undergoing Primary Percutaneous Coronary Intervention
Authors: Wen Zheng, Xue-Dong Zhao, Yu-Jiao Zhang, Shao-Ping Nie
Journal: Circulation (2016)

Introduction: Primary percutaneous coronary intervention (PCI) to recanalize the infarct related artery (IRA) has become the first-choice therapy for ST-segment elevation myocardial infarction (STEMI) during past decades, while the value and optimal timing for PCI in non-IRA with stenosis is unknown. Objective: To examine the long-term outcomes and timing strategy for complete revascularization. Methods: 1,039 STEMI patients with multivessel disease were divided into who received only-IRA PCI (555 patients) or complete revascularization including immediate PCI during the index-procedure (57 patients) or staged PCI within 90 days from the index-procedure (427 patients). The primary outcome was a composite of cardiac death, myocardial reinfarction, ischemic stroke or repeat revascularization. Results: During a mean follow-up of 47 months, the primary outcome occurred in 146 patients with only-IRA PCI and 102 patients with complete revascularization respectively (HR for complete revascularization,0.633;95%CI,0.445-0.900; P =0.011). This benefit mainly showed on the decreased risk for cardiac death, MI and repeat revascularization. The differences of the primary outcome between immediate PCI and staged PCI was non-significant (HR, 3.910;95%CI,0.852-17.949; P =0.079), but staged time interval was associated with risk-adjusted outcomes (HR 0.886;95%CI,0.797-0.984; P =0.024). A further analysis suggested 10 days or later could be a safe cutoff point for PCI in non-IRA (HR, 0.213;95%CI,0.063-0.717; P =0.013). Conclusion: In patients presenting for primary PCI with multivessel disease, complete revascularization significantly lowered the rate of the long-term endpoint compared with treating only the IRA. The optimal time for treating non-IRA assigned over 10 days after the index-procedure could improve survival.
Phase 3, randomized, double-blind trial of pembrolizumab plus epacadostat or placebo for cisplatin-ineligible urothelial carcinoma (UC): KEYNOTE-672/ECHO-307.
Authors: Arjun Vasant Balar, Elizabeth R. Plimack, Petros Grivas, Andrea Necchi, Maria De Santis, Lei Pang, Stephen Michael Keefe, Kevin O'Hayer, Yufan Zhao, Ronald De Wit
Journal: Journal of Clinical Oncology (2018)

TPS4587 Background: For patients ineligible to receive cisplatin, there is less benefit but still toxicity with alternative first-line cytotoxic chemotherapy. Upregulation of programmed death 1 (PD-1) and indoleamine 2,3- dioxygenase 1 (IDO1) enzyme may be therapeutically relevant in metastatic UC. Pembro is a PD-1 inhibitor effective in treatment of locally advanced/metastatic UC in cisplatin-ineligible and platinum-refractory patients. Epacadostat is a potent and highly selective oral inhibitor of IDO1. A recent phase 1/2 trial of pembro plus epacadostat (ECHO-202/KEYNOTE-037, NCT02178722) yielded encouraging efficacy and safety data in patients with advanced UC. Methods: KEYNOTE-672/ECHO-307 (NCT03361865) is a randomized, active-controlled, double-blind, global phase 3 trial conducted to evaluate efficacy and safety of first-line pembro in combination with epacadostat or placebo in cisplatin-ineligible patients with advanced/metastatic UC. Eligibility criteria include age ≥18 years; confirmed unresectable/metastatic UC of the urinary tract; ineligible for cisplatin-based therapy; no prior systemic chemotherapy for unresectable/metastatic UC (neoadjuvant/adjuvant treatment with platinum-containing chemotherapy with recurrence > 12 months permitted); ECOG performance status 0-2; and available tumor sample for PD-L1 analysis. Patients will be randomly assigned 1:1 to receive pembro 200 mg IV Q3W plus epacadostat 100 mg orally twice daily (continuously) or pembro plus placebo. Randomization will be stratified by Bajorin risk score (0, 1, 2) and PD-L1 expression (combined positive score ≥10 or < 10). Treatment will continue until disease progression, unacceptable toxicity, or completion of 35 pembro infusions. Imaging will be performed every 9 weeks for first 12 months and every 12 weeks thereafter. Adverse events will be assessed per NCI CTCAE, version 4.0. Dual primary end points are progression-free survival per blinded independent central review and overall survival. Secondary end points include objective response rate, patient-reported outcomes, and safety. Target enrollment is 650 patients. Clinical trial information: NCT03361865.
Role of infiltrating CD8 lymphocytes, microsatellite instability and h. pylori level in gastric cancer.
Authors: Angela Leonardo, Luis A. Bernabe, Miluska Castillo Garcia, Joselyn Sanchez, Carolina Belmar-Lopez, Valeria Villegas, Eduardo Payet, Eloy Ruiz, Iván Chávez, Carlos Chavez, Carlos Castaneda Altamirano
Journal: Journal of Clinical Oncology (2018)

e16096 Background: Modulation of immune system has demonstrated tumor response in Gastric Cancer. Tumor infiltrating lymphocytes and microsatellite instability are predictive biomarkers for response to anti-PD-L1 drugs in different malignancies, however, studies confirming it in gastric cancer are lacking. We evaluate the role of infiltrating CD8 lymphocytes over clinicopathological features including clinical stage, H. pylori presence, microsatellite instability and survival in Gastric Cancer. Methods: Frozen and paraffin samples of Gastric Cancer were prospectively collected from 100 patients who were referred to surgery. H. pylori genes (UreA and HspA) were evaluated through qPCR in frozen samples and CD8, PMS2, MLH1, MSH6 and MSH2 stains were evaluated through IHC in tissue microarrays from paraffin samples. CD8 stained slides was scanned and automatized counts was performed by BX63 Olympus in 5HPF (stained cells/ total cells x100). Data were collected from medical and pathology reports and statistical analysis was performed by R. Results: Median age was 66 years and 55% were male, most tumors were HG-3 (43%), diffuse subtype Lauren classification (37%) and pathology stage III (46%), the most frequent location was the antrum (63%). UreA or HspA genes of H. pylori were present in 79%. Microsatellite instability was found in 30%. Median CD8 TIL count were 0.045% and higher values was associated to grade (p = 0.007), stage (p = 0.022) and syncronous Atrophic Gastritis (p = 0.025). CD8 TIL count had a trend to be associated with microsatellite instability (p = 0.13). CD8 TIL count was not associated to UreA (p = 0.54) nor HspA (p = 0.52) levels. Survival analysis found that gender (p = 0.047), grade (p = 0.047) and stage (p = 0.022) were associated with longer OS. CD8 TIL had a trend (p = 0.065), and microsatellite instability (p = 0.34) had no association with OS. Conclusions: Tumor-infiltrating CD8 lymphocytes could influence clinicopathological features including survival in gastric cancer. This study was supported by the CIENCIACTIVA-CONCYTEC, under the contract #197-2015-and 204-2015, FONDECYT.