tbuckley/cabot-search huggingface dataset:
P01.122 Safety, immunogenicity and optimization of the IMA950 multipeptide vaccine combined with Poly-ICLC in newly diagnosed HLA-A2 malignant glioma patients
Authors: D Migliorini, V Dutoit, M Allard, S Mohan, A Lobrinus, D Merkler, M Vargas, P R Walker, A Patrikidou, P Dietrich
Journal: Neuro-Oncology (2018)

The clinical development of immunotherapy is still limited for patients with malignant glioma. We report the results of a phase I/II study of the IMA950 multipeptide vaccine adjuvanted with the TLR3 agonist poly-ICLC in association with radiochemotherapy in newly diagnosed HLA-A2+ malignant glioma patients. Patients with newly diagnosed GBM (n=16) and grade III astrocytoma (n=3) were treated concomitantly with radiochemotherapy with the IMA950 multipeptide vaccine and poly-ICLC. The first 6 patients received IMA950 i.d. and poly-ICLC i.m. Afterwards, the protocol was amended and patients received IMA950 and poly-ICLC mixed and injected s.c. (n=7) or i.m. (n=6). Primary endpoints were safety and immunogenicity. Secondary endpoints were OS, PFS at 6 and 9 months, as well as immunological characterization of peripheral CD4 and CD8 T cell responses. The IMA950/poly-ICLC vaccine was safe and well tolerated. Four patients presented cerebral edema with rapid recovery with standard management. For the first 6 patients, vaccine-induced CD8 T cell responses were restricted to a single peptide and CD4 responses were not detectable. After optimization of the vaccine formulation, we observed multipeptide CD8 and sustained Th1 CD4 T cell responses. For the entire cohort (n=19), CD8 T cell responses to a single or multiple peptides were observed in 63.2% and 36.8% of patients, respectively. An encouraging median overall survival of 21 months was obtained in this non-selected patient population. Using previously identified immunogenic GBM antigens, we provide insights into optimization of vaccines generating effector T cells for glioma patients.Support: Gateway for cancer research, Rising Tide Foundation, Fondation Lionel Perrier, Association Frederic Fellay, Fondation Privée des Hôpitaux Universitaires de Genève, OncoSuisse (to PYD, KFS 3270-08-2013), Fond’action, Association Marietta
The number of tumorspheres derived from circulating epithelial tumor cells (CETCs) as an independent predictor for the presence of metastasis in colorectal cancer patients.
Authors: Dorothea Schott, Monika Pizon, Ulrich A. Pachmann, Katharina Pachmann
Journal: Journal of Clinical Oncology (2016)

e23006 Background: Colorectal cancer is one of the most commonly diagnosed and lethal cancers worldwide. Tumor recurrence and metastasis are two critical survival-influencing factors. Circulating cancer stem cells are a rare subpopulation of tumor cells circulating in the blood of cancer patients. They are suspected to be responsible for tumor growth, metastasis, resistance towards therapy and thus progression. Culture of tumorspheres has been used to detect cancer stem cells from primary tumor material or cell lines. We have established an effective method for identification of cancer stem cells from circulating tumor cells in the blood of patients with colorectal cancer with subsequent phenotypic and genotypic characterization. Methods: Metastatic and non-metastatic colorectal cancer patients with detectable CETCs were included in the present study. CETCs were enumerated and subsequently cultured under conditions favoring growth of tumorspheres. Immunofluorescence and qRT-PCR were applied to examine the metastatic ability of tumorspheres in vitro Results: Only a small fraction of CETCs had the ability to form tumorspheres. Patients with metastatic disease had more tumor spheres, than non-metastatic patients (median 48 vs 15 spheres per 100 µl blood) indicating that the number of tumor spheres is dependent on stage of disease. Analysis of surface markers showed high levels of EpCAM and CD 133 expression. Furthermore, spheres had high enzymatic activity for ALDH 1. Array qRT-PCR analysis revealed that tumorspheres express genes of pluripotency such as SOX2, OCT4 and NANOG. There was no sphere formation in 50 healthy subjects. Conclusions: This study demonstrates that tumor stem cells are present in peripheral blood from metastatic and non-metastatic colorectal cancer patients. A more complete understanding of the biology of cancer stem cells will translate into the development of better chemotherapeutic and biological agents for the treatment of colorectal cancer.
CONFIRM: A phase III randomized trial to evaluate the efficacy of nivolumab versus placebo in relapsed mesothelioma.
Authors: Dean Anthony Fennell, Emma Victoria Kirkpatrick, Kelly Cozens, Sarah Danson, Gerard G. Hanna, Jason Francis Lester, Joanne Lord, Mavis Nye, Christian H.H Ottensmeier, Peter Wojciech Szlosarek, Nicola L. Steele, Daniel T Barnes, Karan D Vadher, Tom Maishman, Stephanie J Hill, Gareth Griffiths
Journal: Journal of Clinical Oncology (2018)

TPS8586 Background: Mesothelioma, an incurable, apoptosis-resistant cancer, represents a growing health burden but remains under-researched, with limited treatment options. Despite a significant number of clinical studies in the second line setting, no randomized study has been positive. Early promising signals of activity relating to both PD-L1 and PD-1 targeted treatment in mesothelioma warrant a randomized phase III trial to evaluate the efficacy of nivolumab. Methods: CONFIRM is the first ever placebo controlled, randomized phase III trial of a PD-1/PD-L1 immune checkpoint inhibitor in mesothelioma. The primary objective is to determine if nivolumab increases overall survival (OS). Secondary endpoints include progression-free survival; response rate; safety/tolerability; quality of life and cost per QALY. A translational study will determine if sensitivity to nivolumab differs according to PD-L1 expression (subgroups < 1%, 1-49%, ≥50%); and the correlation between OS and mutational burden, estimated by genome-wide analysis of CNAs, and immunotranscriptomic profile. The trial is coordinated by the CRUK Southampton Clinical Trials Unit, within the Centre for Cancer Immunotherapy, UK. The trial aims to recruit 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy, from UK sites between March 2017-2021. Current enrolment at 01 Feb 2018 was 63. Patients will be randomized 2:1 (treatment: control), stratified according to epithelioid vs. non-epithelioid, to receive 240mg nivolumab (anti PD-1 antibody) monotherapy or saline placebo as a 30 minute intravenous infusion. Allocation will be double blind. Treatment will be every 14 days until disease progression for max. 12 months. Trial follow up will continue for 6 months after the last participant has progressed, or completed or discontinued treatment. The trial is powered (80% with 2-sided 4% significance level) to detect a hazard ratio of 0.7 using an adjusted Cox regression model (time to event) and will be analyzed using intention-to-treat. This trial is funded by Cancer Research UK (C16728/A21400) and Bristol Myers Squibb (CA 209-841). Trial registrations: NCT03063450, ISRCTN79814141. Clinical trial information: NCT03063450.
MET-UBE2H Fusion as a Novel Mechanism of Acquired EGFR Resistance in Lung Adenocarcinoma
Authors: You-cai Zhu, Wen-xian Wang, Zheng-bo Song, Qu-xia Zhang, Chun-wei Xu, Gang Chen, Wu Zhuang, Tangfeng Lv, Yong Song
Journal: Journal of Thoracic Oncology (2018)
TCT-149 The Effect of Chronic Obstructive Pulmonary Disease on Patients With Non-ST-Segment Elevation Myocardial Infarction: A 2014 Nationwide Analysis
Authors: Mariam Khandaker, Zuhair Khandker, Bing Yue, Xin Wei, Natasha Garg, Eyal Herzog, Basera Sabharwal
Journal: Journal of the American College of Cardiology (2018)
Abstract 11409: Kappa-opioid Stimulation Following Chronic Cardiac Pressure Overload Increases Endothelial Caveolae Formation and Benefits Cardiac Function
Authors: Alice E Zemljic-Harpf, Daniel N Deussen, Mugdha A Joshi, Basheer F Alas, Yash J Vainshnav, Sushil K Mahata, David M Roth, Hemal H Patel
Journal: Circulation (2016)

Activation of kappa (κ) -opioid receptors (OR) protects from cardiac ischemia reperfusion injury. A critical role for caveolae in opioid mediated cardio-protection has been shown but these findings have not extended beyond the myocyte. The rationale here was to test if chronic κ- OR activation ameliorates pressure overload induced heart failure after transverse aortic constriction (TAC) and determine potential molecular mechanisms. Ten week-old male C57BL/6J mice underwent TAC or Sham surgery. Cardiac function was assessed by echocardiography before TAC/Sham, and consecutively at weeks 2, 4, 6, 8 and 10 to determine cardiac function (%EF), and wall thicknesses (LVPWd). Two weeks after TAC/Sham, daily i.p. injections with a selective κ-OR, U50488H (U50, TOCRIS®, 1.25mg/kg, IP), or vehicle (V, ddH 2 O) were started. Eleven weeks post-TAC (pTAC), hearts were analyzed by transmission electron microscopy (TEM, n=2 each) and immuohistochemistry (n=4 each). Four weeks pTAC LVPWd in TAC+U50 mice were increased compared to TAC+V, and %EF unchanged (mm±SEM; Sham+V 0.67±0.01, TAC+V 0.81±0.02, Sham+U50 0.66±0.01,TAC+U50 0.93±0.03, n=6-7, p &lt;0.007). Ten weeks pTAC %EF was reduced in TAC+V compared to Sham+V, but preserved in TAC+U50 hearts compared to Sham+U50 (%EF±SEM; Sham+V 68.9%±1, TAC+V 49.5%±8; Sham+U50 73.6%±1.7,TAC+U50 65.3%±6, ns; p&lt;0.02; n=6-7each). Eleven weeks pTAC, TEM revealed preserved mitochondrial utrastructure, and electron dense intercalated discs in pTAC+U50 animals. TAC+V hearts showed “bleached” intercalated discs and swollen mitochondria. U50 increased endothelial caveolae formation in Sham+U50 and TAC+U50 hearts (Cav/μm, 13.3 fold upregulation in Sham+U50 vs Sham+V; and a 3.7 fold increase in TAC+U50 vs TAC+V, p&lt;0.004, 15 cells/heart). Immunohistochemical analysis revealed intracellular accumulation of connexin-43 in TAC+V treated mice, but connexin-43 localization was preserved to membranes in TAC+U50 hearts. We show for the first time that chronic κ-OR activation via U50,488H increased caveolae formation in cardiac endothelial cells, improved cardiac ultrastructure and prevented pressure overload induced heart failure. U50,488H administration may offer a novel treatment option in patients prone to heart failure.
A closer look at some National Clinical Trials Network sites and their recruitment ability.
Authors: Frank Makosiej, Montessa Lizaso
Journal: Journal of Clinical Oncology (2017)

e18055 Background: Targeted therapies have prompted clinical trials centers to screen large numbers of patients of a particular tumor type and to test further to identify those with molecular targets that meet the criteria of the study protocol. In March of 2014, the NCI converted Cooperative Groups into National Cancer Trials Network (NCTN) to better address the scientific needs and challenges these more innovative treatments introduce. The Alliance for Clinical Trials in Oncology is one of the five US Oncology Network groups, and Lead Academic Participating Sites (LAPS) are academic institutions recognized to be able to enroll high numbers of patients onto NCTN trials. Some LAPS sites were recognized to overlap into the Alliance Network as well. An analysis of their recruitment rates and comparison to non-LAPS or non-Alliance sites were reviewed. Methods: Between the years of 2011 to 2016, Covance Xcellerate captured over 2,688 unique Investigators participating in cancer trials in the United States. Seven hundred, seventy-four, cancer trials were involved. Nine hundred, forty-eight unique sites were identified. Results: On a site view, those institutions that were part of the Alliance Network enrolled patients at a median rate of 0.24 pts/site/mo, while LAPS sites recruited at a faster median enrollment rate of 0.33 pts/site/mo. Sites that overlapped within both networks enrolled at a rate of 0.30 pts/site/mo, and sites that were not members of either the Alliance or LAPS network enrolled at a rate of 0.23 pts/site/mo. When analysis of recruitment rate was narrowed further to look at individual investigators that were members of these networks or not, investigators representing from both Alliance and LAPS, their median enrollment rate was slightly higher at 0.33 pts/site/mo when compared to those investigators that were only members of LAPS network. Also, those sites that part of Alliance and LAPS recruited the most patients into studies. Conclusions: Sites that are members of networks such as the Alliance or LAPS, can recruit more patients into a clinical trial at a faster rate than sites that were not participants of the Alliance or LAPS.
Onset of neutropenia as an indicator of treatment response in the randomized phase II of TAS-102 vs placebo in Japanese patients with metastatic colorectal cancer (Study J003-10040030).
Authors: Tomohiro Nishina, Takayuki Yoshino, Eiji Shinozaki, Kentaro Yamazaki, Yoshito Komatsu, Hideo Baba, Akihito Tsuji, Kensei Yamaguchi, Kei Muro, Naotoshi Sugimoto, Yasushi Tsuji, Toshikazu Moriwaki, Taito Esaki, Chikuma Hamada, Takanori Tanase, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2016)

3557 Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Primary results of the J003-10040030 randomized phase 2 trial demonstrated a significant improvement in overall survival (OS) and progression-free survival (PFS) favoring TAS-102 vs placebo (pbo) in patients (pts) with metastatic colorectal cancer refractory/intolerant to standard therapies (Yoshino T, et al. Lancet Oncology 2012). Neutropenia is the most common TAS-102-associated adverse event and it has been hypothesized to reflect a relatively high FTD concentration in pts. Methods: Study J003 data were analyzed post hoc for correlations between initial onset of Grade 3/4 neutropenia and OS benefit. Results: Of 112 pts given TAS-102, 31 (28%) developed Grade 3/4 neutropenia in treatment cycle 1, 19 (17%) in cycle 2, and 8 (7%) in ≥ cycle 3. Onset of Grade 3/4 neutropenia at cycle 1 and 2 was associated with longer median OS compared to pts without neutropenia as summarized by the hazard ratio (against cycle-matched placebo control groups) and the corresponding median OS differences (see Table). Conclusions: Pts experienced Grade 3/4 neutropenia in cycle 1 and 2 showed a greater OS benefit over pbo. In contrast, pts who did not experience Grade 3/4 neutropenia appear to show no OS benefit. The occurrence of Grade 3/4 neutropenia might become an on-treatment predictive biomarker of TAS-102 and TAS-102 treatment should not be discontinued permanently due to the onset of Grade 3/4 neutropenia. The correlation between efficacy of TAS-102 and onset of neutropenia warrants further analyses. Clinical trial information: 090880. TAS-102/PBO1 n (%) TAS-102/PBO1 median OS (months) Hazard ratio (95% CI) All J003 (Full Analysis Set) 112(100)/57 (100) 9.0/6.6 0.56 (0.39-0.81) Earliest cycle of Grade 3/4 neutropenia onset in TAS-102 arm 1 31 (28)/57 (100) 13.0 /6.6 0.31 (0.17, 0.56) 2 19 (17)/18 (32) Not reached /9.8 0.28 (0.11, 0.75) ≥3 8 (7)/9 (16) 10.3 /10.8 1.07 (0.34, 3.36) None 54 (48)/57 (100) 6.3 /6.6 1.05 (0.70, 1.58) 1Number of PBO pts who entered cycle– no pbo patient exhibited neutropenia.
TCT-85 Endovascular Repair of Penetrating Atherosclerotic Ulcers With the Cardiatis Multilayer Flow Modulator Implant as an Alternative to Covered Endografts to Preserve Branch Vessel Patency
Authors: Daniela Tirziu, Rodney White, William Gray, Cody Pietras, Mohammed Imran Ghare, Alexandra Lansky
Journal: Journal of the American College of Cardiology (2018)
P05.25 Helical tomotherapy for whole- brain irradiation with integrated boost to multiple brain metastases: dosimetric analysisandclinical outcomes
Authors: Y Ma, J Xiao, N Bi, Y Xu, Y Tian, H Zhang, Y Zhang, Q Liu, R Zhao, S Yang, J Yi, Y Li
Journal: Neuro-Oncology (2018)

A retrospective study was conducted to analyze the dose distribution characteristics, and to evaluate the feasibility and toxicities of whole brain radiation (WBRT) with simultaneously integrated boost (SIB) by helical tomotherapy (HT) in the treatment of multiple brain metastases (BMs). From 2014 to 2017, 43 patients with three or more BMs were analyzed. WBRT was delivered with 40 Gy in 20 fractions and SIB was 60 Gy in 20 fractions by HT. For some BMs larger than 6 cm3, gross tumor volume (GTV) was contracted by 2 mm to create Boost, which was given 66 to 70 Gy simultaneously. BMs located in brainstem were given 50 Gy in 20 fractions. Patients were reevaluated by magnetic resonance imaging (MRI) after 13 to 15 fractions. The radiation field would be shrunk if the gross target volume (GTV) was reduced. Target Coverage (TC), conformation index (CI), prescription isodose/ target volume ratio (PITV) and homogeneity index (HI) was accessed. Clinical endpoints included local recurrence- free survival (LRFS), intracranial progresstion- free survival (IPFS), progression- free survival (PFS), overall survival (OS) and toxicities. The median age was 61 (36- 81) years old. The median lesion number was 6 (3- 36) and median total volume of GTV was 8.74 cc (0.37- 120.3 cc). Median Dmean of GTV was 63.1 Gy (50.2- 72.6 Gy). There were 9 lesions located in brainstem, which received median dose of 52.5 Gy (51.3- 53.3 Gy). Seventeen large BMs received simultaneously boost, with median volume of 12.15 (6.79- 34.18) cm3. Mean ± standard deviation for GTV amounted to TC was 0.96 ± 0.028, CI 0.51 ± 0.164, PITV 2.09 ± 1.245, and HI 0.12 ± 0.066, respectively. TC and HI for whole brain were 0.95 ± 0.033 and 0.43 ± 0.161, respectively. 25.6% of patients got re-planned and the dose of normal tissue reduced. The median follow-up time was 14.4 months (2.0- 40.9 months). One-year LRFS, IPFS, PFS and OS were 95.7%,79.9%,39.4% and 85.6%, respectively. There were no grade 3- 5 toxicities. Helical tomotherapy for WBRT and SIB shows excellent conformity and homogeneity, and it’s efficient and safe for patients with multiple BMs. Lesions that get shrunk during treatment should be re-planned to reduce the dose of normal tissue.
Disparities in resection of hepatic metastases in colon cancer.
Authors: Madalyn G. Neuwirth, Andrew J Epstein, Giorgos Karakousis, Ronac Mamtani, Emily C. Paulson
Journal: Journal of Clinical Oncology (2017)

e18062 Background: Evidence suggests that resection of synchronous hepatic metastases (SHM) in Stage IV colon cancer is safe and can improve survival in select patients. Little is known, however, about the use of hepatic resection in this setting on a population level. Methods: A retrospective cohort study was performed of Stage IV colon cancer patients during 2000-2011 in SEER-Medicare data who had diagnosis codes confirming SHM. Univariate and multivariate logistic regression were used to identify patient factors related to receipt of hepatic resection. Results: There were 11,351 patients with colon cancer and SHM. 465 (4.1%) underwent surgical hepatic resection. The proportion increased steadily over time from 2000-2003 (3.5%) to 2009-2011 (5.1%) (p = 0.03). Patients who were older with higher comorbidity burden were less likely to undergo hepatic resection (Table 1). Additionally, the odds of hepatic resection were 30% lower for African-American patients than for white patients (OR 0.70, p = 0.05). Odds of hepatic resection were 44% lower for patients from ZIP Codes with &gt; 20% poverty than for patients from areas with &lt; 5% poverty (OR 0.56, p &lt; 0.001). Interestingly, among patients who underwent no surgical treatment at all, only 12% saw a surgeon after diagnosis. This number increased over time from 7.7% in 2000 to 15.9% in 2011 (p &lt; 0.001). Similar disparities noted above were seen with regard to being evaluated by a surgeon. Conclusions: Despite evidence supporting the safety and efficacy of hepatic resection in the setting of SHM, few patients are seen by surgeons and go on to receive hepatic surgery. Additionally, access to hepatic resection is notably lower for African Americans and patients from areas with higher poverty rates. [Table: see text]
Characterization of <i>KEAP1-NRF2</i> genomic alterations across diverse tumor types: Co-occurring alterations, survival outcomes, and implications for targeting cancer metabolism.
Authors: Shiraj Sen, Kenneth R. Hess, Jason Roszik, Kenna Rael Shaw, John Heymach, Le Huang, Gary K. Schwartz, Funda Meric-Bernstam, Vivek Subbiah
Journal: Journal of Clinical Oncology (2018)

2558 Background: CRISPR–Cas9-based genetic screening and metabolomic analyses have revealed that KEAP1-NRF2-mutated cancers depend on increased glutaminolysis and are vulnerable to glutaminase inhibition. However, alterations in KEAP1-NRF2 have yet to be clinically characterized. Methods: We analyzed clinical and next gen sequencing data from pts treated at MD Anderson Cancer Center and performed bioinformatic analyses of alteration frequency using TCGA data on cBio Portal to characterize KEAP1-NRF2 alterations and used Kaplan-Meier analysis to identify associations with overall survival (OS). Results: Among 189 pts with KEAP1 or NRF2 alterations (alts) at MDACC (97 with each, 5 with both), median age was 65 yrs (range: 18-89), 52% were females, 80% Caucasian, 11% Hispanic, and 5% African-American. KEAP1-NRF2 alts were most common in NSCLC (19%), cholangiocarcinoma (8%), breast (7%), and renal cell CA (7%). Mean number of co-occurring alts was 8 (range:0-73). We identified 69 unique alts in KEAP1, most commonly Q619del (11%) and V369A (9%), and 68 unique alts in NRF2, most commonly E79Q (6%) and G31A (6%). Median OS in the entire cohort was 966 days. Of the 1505 co-alts identified with KEAP1, most common were TP53 (57%), ARID1A/B/2 (55%), PI3K-encoding genes (37%), and NOTCH1 (29%). Of the 817 unique co-alts identified with NRF2 alts, most common were TP53 (52%), PI3K-encoding genes (36%), ARID 1A/B/2 (25%), and BRCA1/2 (19%). Co-alts in TP53, SWI/SNF complex, mTOR pathway, and NOTCH pathway genes did not impact survival. In TCGA, KEAP1-NRF2 alts were most common in NSCLC (26%), uterine (15%), breast (10%), and cholangiocarcinoma (9%). KEAP1-NRF2 alts were associated with decreased survival in lung adenocarcinoma (LUAD), 49 vs 33 months, log rank p = 0.02. Conclusions: KEAP1-NRF2 alts are prevalent across diverse tumor types and associated with decreased survival in LUAD. They most frequently co-occur with alts in TP53, SWI/SNF complex, and mTOR pathway genes but these co-occurring alts did not impact survival in our cohort. A Basket trial of Glutaminase Inhibitor (BeGIN) CB839 in patients with KEAP1/ NRF2 aberrant tumors is planned.