tbuckley/cabot-search huggingface dataset:
A phase I/II trial adding poly(ADP-ribose) polymerase (PARP) inhibitor veliparib to induction carboplatin-paclitaxel (Carbo-Tax) in patients with head and neck squamous cell carcinoma (HNSCC) Alliance A091101.
Authors: Michael J. Jelinek, Nathan R. Foster, Alexander J. Zoroufy, Jonas A. De Souza, Gary K. Schwartz, Pamela N. Munster, Tanguy Y. Seiwert, Everett E. Vokes
Journal: Journal of Clinical Oncology (2018)

6031 Background: This phase I/II study evaluates safety and efficacy of veliparib, a PARP inhibitor, with induction carbo-tax in patients (pts) with locoregionally advanced HNSCC. Since PARP is involved in DNA repair, inhibition of PARP may augment damaging effects of chemotherapy on tumor DNA. We report on the completed phase I portion of the trial. Methods: Eligible pts had newly diagnosed stage IVa-b non-oropharyngeal cancer (OPC) or stage IVa-b, human papillomavirus-negative OPC. The primary endpoint is the maximum tolerated dose (MTD) or recommended phase II dose using a 3+3 pt cohort design. Pts received induction carboplatin (AUC 6 day 1), paclitaxel (100 mg/m2 day 1, 8, 15), and veliparib (days 1-7) every 21 days for 2 cycles. Veliparib doses were 200, 250, 300 and 350 mg BID. Standard chemoradiotherapy followed induction. Results: 20 pts enrolled. Two withdrew prior to treatment, leaving 18 pts for analysis. Median age was 62.5 years: 50% were female. Primary sites (# pts) included hypopharynx (5), larynx (5), oral cavity (4), oropharynx (3) and nasal cavity (1). The most common grade (gr) 3+ adverse events (AEs) were decreased neutrophil count (33%), decreased platelet count (33%) and anemia (11%). Gr 3+ hematologic AEs were more common at higher veliparib doses. Three pts had gr 4 AEs, all hematologic (1 pt: neutropenia, 1 pt: thrombocytopenia (dose-limiting), 1 pt: both). The recommended phase II dose and MTD for veliparib in combination with carbo-tax is 350 mg. Of 13 pts currently evaluated for response, 9 (69%) had partial or complete response. At an early median follow-up of 16.7 months (mo) across dose levels for all pts, the 12-mo overall survival was 76% (95% CI: 55-100%), and 12-mo progression-free survival was 75% (95% CI: 54-100%). Medians have not been reached. Data for 350 mg is not fully mature. Conclusions: Addition of veliparib 350 mg BID on days 1-7 to carbo-tax was well tolerated in pts with advanced HNSCC. This dose is higher than previously tested in other trials. Hematologic toxicities were the most common AEs. Support: U10CA180821, U10CA180882; Clinical trial information: NCT01711541.
Enhancing FcγR-mediated antibody effector function during persistent viral infection
Authors: Andreas Wieland, Alice O. Kamphorst, Rajesh M. Valanparambil, Jin-Hwan Han, Xiaojin Xu, Biswa P. Choudhury, Rafi Ahmed
Journal: Science Immunology (2018)

Persistent viral infections can interfere with FcγR-mediated antibody effector functions by excessive immune complex (IC) formation, resulting in resistance to therapeutic FcγR-dependent antibodies. We and others have previously demonstrated that mice persistently infected with lymphocytic choriomeningitis virus (LCMV) are resistant to a wide range of depleting antibodies due to excessive IC formation. Here, we dissect the mechanisms by which two depleting antibodies overcome the obstacle of endogenous ICs and achieve efficient target cell depletion in persistently infected mice. Efficient antibody-mediated depletion during persistent LCMV infection required increased levels of antibody bound to target cells or use of afucosylated antibodies with increased affinity for FcγRs. Antibodies targeting the highly expressed CD90 antigen or overexpressed human CD20 efficiently depleted their target cells in naïve and persistently infected mice, whereas antibodies directed against less abundant antigens failed to deplete their target cells during persistent LCMV infection. In addition, we demonstrate the superior activity of afucosylated antibodies in the presence of endogenous ICs. We generated afucosylated antibodies directed against CD4 and CD8α, which, in contrast to their parental fucosylated versions, efficiently depleted their respective target cells in persistently infected mice. Efficient antibody-mediated depletion can thus be achieved if therapeutic antibodies can outcompete endogenous ICs for access to FcγRs either by targeting highly expressed antigens or by increased affinity for FcγRs. Our findings have implications for the optimization of therapeutic antibodies and provide strategies to allow efficient FcγR engagement in the presence of competing endogenous ICs in persistent viral infections, autoimmune diseases, and cancer.
A genomic signature based in IGF1R-network in breast cancer.
Authors: Andrea C. Gomez, Jhajaira M. Araujo, Claudio J. Flores, Rodolfo Velazco, Henry Leonidas Gomez, Joseph A. Pinto
Journal: Journal of Clinical Oncology (2017)

e23187 Background: The insulin-like growth factor 1 receptor (IGF1R) is a member of the receptor tyrosine kinase family and has been involved in tumor transformation and survival of malignant cells. The evaluations of interactions networks of this protein could be helpful to find new therapeutic targets and prognostic factors. Our aim was to develop a genomic signature for disease-free survival (DFS) based on IGF1R signaling. Methods: We identified in STRING v.10.0 a set of proteins participating in the network of IGF1R. Analysis was done with a high confidence (0.7). We identified GEO datasets of microarray experiments containing gene expression profiling of breast tumors. The end point was DFS. We use one discovery set (GSE25066, N = 508) and two validations sets (GSE42568, N = 121; GSE1456, N = 318). Univariate Coxph identified a first set of genes that were screened in a multivariate analysis and then evaluated in Km-plotter (http://kmplot.com). Genes significantly associated with the DFS were analyzed in a multivariate Coxph to estimate regression coefficients to develop a linear score. Results: Analysis in STRING identified 100 proteins whose coding genes were evaluated in a first univariate analysis identifying 30 genes. The multivariate analysis identified 5 genes associated with the DFS (VCL, IARS, IRS1, IGF1R and MAKP3). The bioinformatics platform Km-plotter selected IRS1, IARS, IGF1R and MAKP3 as predictors for DFS. The multivariate analysis with the stepwise method selected only three genes, IARS HR = 147.82 (P &lt; 0.001, 95% CI: 11.60-1883.35); IGF1R HR = 0.11 (P &lt; 0.001, 95% CI: 0.04-0.31) and MAKP3 HR = 0.36 (P = 0.012, 95% CI: 0.16-0.80) as significantly associated with the DFS. With the regression coefficients, we developed the follow signature: (-1.026 x MAPK3) + (-2.250 x IGF1R) + (4.996 x IARS). The median score in the discover set (0.544) was able to identified patients at different risk of recurrence (P &lt; 0.001 in the Logrank test), using the median using as cutoff the signature was able to discriminate two groups of different risk of recurrence in GSE42568 and GSE1456 validation sets (P &gt; 0.02 and P &gt; 0.03, respectively). Conclusions: We were able to develop a genomic predictor based in the network of IGF1R. In ours study IGF1R was associated to good prognosis.
Current risk stratification for colorectal cancer screening using a blood-based RNA test.
Authors: Choong-Chin Liew, Changming Cheng, Kris See, Shi Qian, Kee Liang Ong
Journal: Journal of Clinical Oncology (2016)

e15090 Background: Colorectal cancer (CRC) is a highly curable and preventable carcinoma if detected early, and the two most widely-accepted CRC screening tests are the fecal occult blood test (FOBT) and colonoscopy. FOBT is, however, affected by such factors as diet and drugs, resulting in low specificity. Colonoscopy thus remains the gold standard for CRC diagnosis; however, colonoscopy is invasive, requires bowel preparation and may cause pain, bleeding and even bowel perforation. Thus it is estimated that only about 50% of FOBT positive patients are willing to accept colonoscopy. Methods: We used a minimally invasive blood RNA test, ColonSentry, to quantitatively evaluate a patient’s current risk of having CRC. This test, which accesses the expression of a seven-gene signature for CRC, stratifies an individual’s risk for having CRC within a range from one-tenth the risk to 10 times the risk of the average risk population (i.e., the population asymptomatic for CRC, with no personal history of benign colorectal polyps, colorectal adenomas, CRC or inflammatory bowel disease, and no first degree relative with CRC). Between April 2012 and December 2015, 1080 asymptomatic people underwent ColonSentry blood testing at our facilities in China and Malaysia. Some participants scoring two times the average risk or higher (≥ 2x) accepted colonoscopy and histological results were obtained. Results: Of the 1080 ColonSentry participants, 559 scored above the CRC risk of the average risk population. Eighty-seven patients with relatively high risk (≥ 2x) accepted follow-up colonoscopy and of these, 11 submitted histological results. Of those 11 patients, one was histologically identified as having CRC, 2 had tubular adenoma (pre-malignant), 4 had benign hyperplastic polyps, and 1 patient had a severe bowel inflammation. Only 3 patients had a normal colonoscopy and 1 of them has a family history of CRC. Conclusions: This study suggests that ColonSentry, a minimally-invasive risk-stratification blood RNA test, could help the majority of low-risk patients avoid over-examination for CRC and could aid decision-making in CRC detection. The test would also serve to promote colonoscopy compliance and uptake in patients at high risk for CRC.
Metastases from differentiated thyroid cancer - the Cleveland Clinic experience.
Authors: Gauri Bhuchar, Rushad Patell, Dimpi Desai, Alexandra Mikhael, Tobenna Igweonu Nwizu, Sankaran Shrikanthan, James Bena, Christian Nasr
Journal: Journal of Clinical Oncology (2016)

e17546 Background: 20-year survival in patients with thyroid cancer is more than 90%, however, this number decreases by half in those with distant metastasis. Our study elucidates the predilection of different histologies of thyroid cancer to metastasize to particular sites and factors that affect survival in these groups. Methods: We conducted a retrospective study of patients with metastatic thyroid cancer at the time of initial diagnosis who were seen at the Cleveland Clinic between 1990 and 2010. Patients with anaplastic and medullary cancer were excluded. Patients were grouped based on histology and organ involvement. Association between cancer type and metastasis location was evaluated using Fisher exact tests. Kaplan-Meier estimates of survival were calculated for histology, age groups, and number of sites of metastasis. Results: Study population comprised 133 patients with metastatic thyroid cancer. Median age at diagnosis was 61 years; 62% were males; 87% were Caucasian. 102 patients had papillary thyroid cancer (PTC), 26 had follicular thyroid cancer (FTC), and 5 had Hurthle cell cancer (HCC). FTC and HCC were grouped together for the analysis. 93% patients with PTC had lung involvement vs 84% patients with FTC (p = 0.13, OR = 0.4, CI = 0.12-1.4). 53% of the patients with metastatic PTC had bone involvement vs 78% patients with FTC (p = 0.038, OR = 3.1, CI = 1.03-9.6). 10 year survival rate was found to be significantly different between the following groups: FTC vs PTC (50% vs 65%, p = 0.042), age > = 45 years vs < 45 years (55% vs 80%, p = 0.012), and multiple sites of metastases vs single site of metastasis (54% vs 71%, p = 0.012). 68% of the patients with FTC had multiple sites of metastases compared to 45% of patients with PTC (p = 0.027, OR = 2.6, CI = 1.09-6.0). Conclusions: Lung is the most common site of metastasis in both FTC and PTC. However, patients with FTC are more likely than those with PTC to have bone involvement. Patients with FTC are also more likely to have multiple sites of metastases. Older patients, those with FTC and patients with multiple sites of disease involvement have a poorer prognosis than those that are younger, have PTC and only one site of metastasis.
Abstract 17240: Ventricular Unloading and Improved Oxygen Delivery With LVAD Support Correlates With an Increase in Angiogenesis and TIE-1 Expression
Authors: Eman A Hamad, Nirag Jhala, Theodore Vasiliadis, Kamil Amer, Rene Alvarez, Yoshiya Toyoda, He Wang
Journal: Circulation (2016)

Background: Ventricular unloading with the use of a left ventricular device (LVAD) is used for patients with advanced heart failure. The use of LVAD has been reported to lead to myocardial recovery...
A novel homebrew real-time PCR assay to detect ALK rearrangements in lung cancers and lymphomas.
Authors: Hui Yu, Xun Ye, Xia Meng, Liu Fang, Xingjiang Hu, Jialei Wang, Jianhua Chang, Qifeng WANG, Qunling Zhang, Ye Guo, Haiquan Chen, Kai Xue
Journal: Journal of Clinical Oncology (2016)

e23270 Background: More and more attention has been paid to molecular subtype of cancers, for example the detection of ALK rearrangements in the diagnosis and treatment of lung cancers and lymphomas. FISH and IHC are two routine methods to detect ALK rearrangements or hybrids. However, some difficulties such as biopsy samples, costs, and waiting time for results may negatively affect the application of these methods. Therefore, there is a need to explore a novel, cheap and rapid method to be a good complement in the field of ALK rearrangements detection. Methods: Microarray data analysis and real-time PCR studies had been used for this study. Results: We identified an EST (Expressed Sequence Tags) from Affymetrix microarray studies, and the correlation coefficiency between signal intensity of probesets corresponding to EST and ALK in 1037 cancer cells (Cancer Cell Line Encyclopedia) reached 0.92. By compare the EST transcript expression levels, it was capable to accurately discriminate 8 ALK rearrangements positive lymphomas or lung tumor samples from other 112 ALK rearrangements negative lymphomas or lung tumors. Moreover, the expression of EST added synergetic effect to a known method when measure ALK rearrangement status by compare ALK transcript 5’ and 3’ portion expression. Samples’ ALK rearrangement status had been confirmed by FISH and/or IHC methods. Selected ALK hybrid subtypes had been screened by multiplex PCR, and confirmed by sequencing and Amoyx PCR methods. Conclusions: A homebrew PCR assay has been proposed, by evaluate ALK rearrangement status from three aspects: ① Characterize the EST gene expression; ② Compare the 5’ portion and 3’ portion of ALK transcript; ③ Check detailed known ALK hybrid subtype variants. A significant advantage of such homebrew PCR assay is that it could be readily applied to specimens such as Fine Needle Aspiration, Plural Fluid, Cerebro-Spinal Fluid that may not be suitable for preparation of FFPE samples, serve as a good complementary to FISH and IHC methodologies. Moreover, such prototype assay is transferable to the FilmArray platform, which is a FDA-cleared multiplex PCR system that integrates sample preparation, amplification, detection and analysis.
Prognostic impact of cytomegalovirus (CMV) detection in colorectal cancer (CRC).
Authors: Michael Sangmin Lee, Sara R. Selitsky, Joel S. Parker
Journal: Journal of Clinical Oncology (2017)

e15120 Background: CMV is a widespread herpesvirus that lies latent in the majority of immunocompetent hosts but may reactivate and infect colon epithelium. Prior studies have identified CMV proteins in CRC tumors, where CMV superinfection may play an oncomodulatory role. CMV constitutively activates virally encoded chemokine receptors that may act as oncogenes via promotion of angiogenesis, proliferation, and migration. However, the clinical significance of CMV superinfection in CRC has not been clearly demonstrated. Methods: We obtained clinical and tumor characteristics from 355 CRC patients in The Cancer Genome Atlas (TCGA). TCGA RNA-seq was aligned to curated viral genomes from GenBank after first filtering out the reads that mapped to the human genome. Reads that mapped to CMV were quantified. Consensus Molecular Subtypes (CMS) by gene expression were obtained from www.synapse.org. Results: Among 355 CRC patients, 60 (16.9%) had CMV detected by RNA-seq. CMV+ was significantly associated with older median age (69.5 vs. 64 years, p = 0.016) and rectal rather than colon primary (odds ratio 3.76, 95% CI 1.87-7.57). CMV status was not significantly associated with stage, sex, race, microsatellite stability, BRAF/ KRAS/ NRAS mutation, or CMS subtype. On Cox univariate analysis, CMV+ was associated with inferior survival (HR 1.91, 95% CI 1.10-3.34), as were age (HR 1.03, 95% CI 1.01-1.05), stage (HR 2.00, 95% CI 1.54-2.59), and CMS4 subtype (HR 2.12, 95% CI 1.29-3.48). CMV+ remained significantly associated with inferior survival on multivariate Cox analysis when adjusting for age, stage, and CMS4 subtype. Conclusions: CMV+ as detected on RNA-seq is significantly associated with older age at diagnosis and rectal primary tumor and independently confers inferior prognosis. These findings warrant further investigation of the potential oncomodulatory role and prognostic value of CMV reactivation in CRC.
A randomized study of finite abiraterone acetate (AA) plus leuprolide (LHRHa) versus LHRHa in biochemically recurrent non metastatic hormone naïve prostate cancer (M0HNPC).
Authors: Eleni Efstathiou, Xuemei Wang, Amado J. Zurita, Shi-Ming Tu, Ana Aparicio, Jennifer Wang, Paul Gettys Corn, Sumit Kumar Subudhi, John C. Araujo, Lawanda K Reece, Lisa Pruitt, Michael L Vanalstine, Christopher Logothetis
Journal: Journal of Clinical Oncology (2018)

5002 Background: Intermittent Androgen Deprivation (ADT) is an acceptable treatment option in M0HNPC with no significant survival difference and improved quality of life versus (vs) continuous. AA improves survival in metastatic HNPC. We hypothesize that AA added to intermittent ADT will improve outcome without delaying testosterone (T) recovery. Methods: Patients (Pts) with PSA recurrent, after definitive local treatment, M0HNPC were randomized 1:1 to 8 month AA(1g/qd)+ prednisone (5mg /qd)+LHRHa vs LHRHa. Pts were eligible to cross over upon progression We primarily studied difference in PSA free survival. Secondary endpoints included time to T recovery, safety and associations with clinical/tumor characteristics. Sample size had 93% power to detect 1 year post treatment PSA free survival difference of 20 %. Stratification factors were radical prostatectomy (RPS) vs radiation (EBRT), PSA ≥ vs < 10, time to recurrence ≥ vs < 3yrs. Rising PSA of 0.2 confirmed by subsequent > 0.2 required after RPS and nadir PSA +2 for prior EBRT. Results: 197 of 200 randomized pts were treated (99 AA+LHRHa /98 LHRHa). Median age was 65 (range 42- 85), Performance Status 0, PSA 1 (0.3-33.3 ng/ml), T 346 (160-946 ng/dL). 186 (94%) had undergone RPS. 128 (65 %) had PSA relapse by Jan/18. Pts on 8 month AA+LHRHa had median PSA free survival 28.3 months (range 24.2—35.4) vs 21.1 (19.1-27.2) for LHRHa pts. (HR 0.62; 95 % Confidence Interval 0.44-0.88; p 0.007). Median time to T recovery for AA+LHRHa was 13.1 ms vs 12.9 for LHRHa. AA+LHRHa treatment outcome was favorable regardless of pretreatment PSA, Gleason Score, pathology, time to relapse from treatment, definitive treatment type, including if RPS +EBRT (57%). No Grade 4 adverse events (AE) or new safety concerns reported. Grade 3 AEs: arterial hypertension 6 (5 AA+LHRHa arm), liver function test elevation 4 (AA+LHRHa arm). Most common AEs were Grade 1 hot flashes (71%) and fatigue (51%) with no difference between arms. Conclusions: Findings support that 8 month treatment with Abiraterone Acetate plus LHRHa in M0HNPC improves PSA free survival compared to LHRHa without delay in testosterone recovery or significant safety concerns. Clinical trial information: NCT01786265.
Risk factors, patterns, and outcomes of late recurrence after liver resection for hepatocellular carcinoma: A multicenter cohort study in 734 patients over 15 years.
Authors: Xin-Fei Xu, Jiong-Jie Yu, Ju-Dong Li, Li-Yang Sun, Han Zhang, Ming-Da Wang, Zhen-Li Li, Ya-Hao Zhou, Wei-Min Gu, Hong Wang, Ting-Hao Chen, Feng Shen, Tian Yang
Journal: Journal of Clinical Oncology (2018)

e16108 Background: Late recurrence ( > 2 years) after liver resection of hepatocellular carcinoma (HCC) is usually considered as multi-centric tumors or de novo cancer formation. We aimed to investigate risk factors, patterns and outcomes of late recurrence after HCC resection. Methods: From a multicenter database from 2001 to 2015, 734 patients who were alive and recurrence-free at 2 years after curative resection of initial HCC were enrolled into this retrospective study. Univariate and multivariate Cox-regression analysis were used to identify independent risk factors of late recurrence. Patterns, treatments and outcomes of late recurrence were investigated and analyzed. Results: During a median follow-up of 78.0 months after surgery, 303 patients (41.3%) developed late recurrence. Multivariate analysis revealed that cirrhosis, macroscopic vascular invasion, satellites, and tumor size > 5cm were independent risk factors of late recurrence. Among them, 273 (90.1%) were sole intrahepatic recurrence, 30 (9.9%) were concurrent intrahepatic and extrahepatic recurrence, and none of them was sole extrahepatic recurrence; 165 (54.4%) patients received curative treatments for recurrent HCC, including re-resection, transplantation and local ablation. Multivariate analysis showed regular postoperative surveillance and receiving curative treatments were two independent protective factors of prolonging survival for those patients with late recurrence. Conclusions: Late recurrence is correlated with cirrhosis and certain tumor-related characteristics of initial HCC. The patterns of late recurrence suggest that postoperative surveillance after 2 years of surgery could be adjusted and more targeted. Regular postoperative surveillance improves the probability to receive curative treatments again, yielding to better outcomes for patients with late recurrence.