tbuckley/cabot-search huggingface dataset:
Circulating LncRNAs as predictive biomarkers by molecular subtypes in advanced breast tumors.
Authors: Javier Salvador, Maria Luisa Pecero, Ana Gil, Maria Rodriguez de la Borbolla, Manuel Ruiz, Alvaro Montano, Rosario Gonzalez, Marta Benavent Viñuales, Sonia Molina
Journal: Journal of Clinical Oncology (2017)

e23041 Background: Breast cancer is the most common malignant tumor in women worldwide. The leading breast cancer deaths are due to advanced disease stage. For this reason, identification of novel breast cancer progression-associated biomarkers would enhance the clinical management of each patient. Long non-coding RNAs (LncRNAs) are defined as noncoding RNAs longer than 200 nucleotides and are involved in several regulatory processes, such as regulation of gene expression. Moreover, it has been described that LncRNA expression is deregulated in different human diseases such as breast cancer. However, it is unclear if circulating LncRNAs could be used as progression biomarkers of breast cancers. The purpose of this study was to evaluate the role of circulating LncRNAs in patients with advanced breast cancer. Methods: Expression of 84 LncRNAs was quantified by “RT2 IncRNA PCR Array Human Cancer PathwayFinder” (Qiagen) in plasma from 24 subjects (12 patients with advanced breast cancer and 12 healthy subjects). cDNAs were pooled into four groups, two groups containing a mixture of six patients with advanced breast cancer and another two groups containing a mixture of six cDNAs from healthy subjects. Three differentially expressed LncRNAs were selected for validation by specific real-time PCR assay. Results: Three deregulated LncRNAs were identified and validated in patients with advanced breast cancer versus healthy subjects. We found that LncRNAs GAS5 and ZFAS1 expression was decreased in the Luminal, Her2-positive and Triple Negative advance cancer groups compared to healthy subjects. In contrast, LncRNA RMRP expression was increased in Luminal and Her2-positive advance cancer groups. To our knowledge, there are no publications relating the LncRNA RMRP expression with advance breast cancer research. Conclusions: These results contribute to unreveal the role of circulating LncRNAs as biomarkers in the advanced breast cancer and provide novel non-invasive tools in this disease.
Treatment patterns among patients diagnosed with stage IV cancers who died within one month of diagnosis.
Authors: Helmneh M. Sineshaw, Rachel A. Freedman, Kimmie Ng, Raymond U. Osarogiagbon, Kathryn Jean Ruddy, Ahmedin Jemal
Journal: Journal of Clinical Oncology (2018)

6526 Background: Little is known about the factors associated with treatment in patients diagnosed with metastatic cancers and who die soon after diagnosis. We examined patterns of treatment in patients diagnosed with metastatic lung, colorectal, breast, and pancreatic cancer who died within one month of diagnosis. Methods: Using the National Cancer Data Base, we identified de novo stage IV lung, colorectal, breast, and pancreatic cancer patients ages ≥18 years and diagnosed between 2004-2014 who died within one month of diagnosis. We used descriptive analyses to calculate percentages and multivariable logistic regression analyses to generate adjusted odds ratios for receipt of specific types of treatment. Results: Among 97,884 patients, 66% had lung, 18% pancreatic, 12% colorectal, and 3.7% breast cancer. Surgery was least common in pancreatic (0.4%) and most common in colorectal (28.8%) cancer. Rates of chemotherapy ranged from 5.8% in colorectal to 11.3% in lung and breast cancer. Rates of radiation ranged from 1.2% in pancreatic to 18.7% in lung cancer. Endocrine therapy was initiated for 23.7% of patients with hormone receptor-positive breast cancer. Over the study period, surgery for colorectal and breast cancer, chemotherapy and radiation treatment for lung cancer, and chemotherapy for breast and pancreatic cancer progressively declined (P trend < 0.01). Age, insurance, and facility type were strongly associated with receipt of treatment across most cancer types. Uninsured patients had 43% lower odds of receiving surgery for colorectal cancer, 34% lower odds of initiating chemotherapy for lung cancer, and 47% lower odds of initiating chemotherapy for breast cancer compared with their privately insured counterparts. Compared with patients with lung cancer treated at NCI-designated cancer centers, those treated at community cancer centers had 48% lower odds of initiating radiation. Conclusions: Treatment of patients diagnosed with imminently fatal metastatic cancer (death within one month of diagnosis) varied markedly by cancer type and patient/facility characteristics. More research is needed to identify patients with imminently fatal metastatic cancer who would benefit from early treatment.
Abstract 18140: Effective Point Electric Stimulation for Cardiac Spiral Wave Termination
Authors: Naoki Tomii, Masatoshi Yamazaki, Tatsuhiko Arafune, Haruo Honjo, Nitaro Shibata, Ichiro Sakuma
Journal: Circulation (2016)

Introduction: Low energy defibrillation by point electric shocks has been explored. Several experimental and computer simulation studies revealed that timing and location of stimulation are crucial factors for post-shock cardiac spiral wave (SW) dynamics. However, it is still challenging to terminate single SW by point electric shocks reliably. Hypothesis: Relative position of a point electric shock with a moving spiral wave tail and an anatomical block line determines defibrillation success and failure. Method: Spiral waves were induced on a perfused 2D whole rabbit heart model by S1-S2 shock protocol, followed by a point biphasic shock (+10V 4ms, -10V 2ms) from an electrode. The stimulation electrode was located on LV surface near AV groove, an anatomical block line. Electric shocks were applied at different timings, from 240ms to 310ms after S1-S2 shocks. Transmembrane potential was measured by optical mapping in 512x512 pixels, 1000 fps. Trajectories of the spiral core which moved rapidly just after t...
TCT-74 SCOUT Study: Trialign results at 30 days from combined US and EU cohort for the treatment of functional TR
Authors: Christopher Meduri, Rebecca Hahn, Charles Davidson, Scott Lim, Tamim Nazif, Mark Ricciardi, None vivek rajagopal, Gorav Ailawadi, Mani Vannan, James Thomas, Susheel Kodali
Journal: Journal of the American College of Cardiology (2018)
Phase 1 trial evaluating MRG-106, a synthetic inhibitor of microRNA-155, in patients with cutaneous t-cell lymphoma (CTCL).
Authors: Francine M. Foss, Christiane Querfeld, Pierluigi Porcu, Youn H. Kim, Theresa Pacheco, Ahmad Sami Halwani, Jennifer DeSimone, Basem M. William, Anita G Seto, Judy Ruckman, Michele L Landry, Aimee L Jackson, Linda A Pestano, Brent A Dickinson, Mark Sanseverino, David M Rodman, Paul Rubin, Gilad Shalag Gordon, William S. Marshall
Journal: Journal of Clinical Oncology (2017)

7564 Background: MRG-106 is an oligonucleotide inhibitor of miR-155, a microRNA with a strong mechanistic link to CTCL, selected based on its activity in mycosis fungoides (MF) cell lines. The objective of this first-in-human study is to evaluate the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary efficacy of MRG-106 in MF patients. Methods: This Phase 1 trial employs a dose-escalation design to evaluate either intratumoral (IT, 75 mg/dose) or subcutaneous (SC, ≤ 900 mg/dose) administration of MRG-106. Patients were required to have biopsy-proven stage I-III MF and plaque- or tumor-stage lesions. Results: Fifteen patients (12M/3F, median age 59 years) have been dosed over 1-4 weeks. All patients tolerated the IT or SC administrations well with only minor local injection reactions in 8 patients. Thirteen of 15 patients completed dosing as scheduled. There were no clinically significant MRG-106 related adverse events with the exception of one grade 3 pruritus. The MTD has not yet been reached. In the IT cohort, a reduction of ≥50% in the baseline Composite Assessment of Index Lesion Severity (CAILS) score was observed in the MRG-106 treated lesions in all 4 evaluable patients who completed dosing; such responses were maintained to the End of Study visit (Day 28 or 35). Histological examination of pre- and post-treatment biopsies of the MRG-106-injected lesion from most patients revealed a trend in reduction in neoplastic cell density and depth; 1 patient had a complete loss of the neoplastic infiltrate. Gene expression analysis of the pre- and post-treatment biopsies showed reduction of the PI3K/AKT, JAK/STAT, and NFkB survival pathways and increased cell death consistent with the expected MRG-106 mechanism of action. In the SC cohorts, 3/8 patients had a maximal decrease in their modified Severity-Weighted Assessment Tool (mSWAT) of &gt; 39% indicative of a significant response. One patient at the 900 mg SC dose level had a possible flare of their disease after 3 doses that resolved after 3 weeks. Conclusions: Based on favorable clinical safety, efficacy and PK data, additional patients are being accrued. Updated results will be presented as available. Clinical trial information: NCT02580552.
Evaluation of safety and efficacy of ipilimumab and nivolumab (ipi+nivo) combination in patients (pts) previously treated with anti-PD-1 antibodies (PD1): A single-center experience.
Authors: Soo Park, Gregory A. Daniels
Journal: Journal of Clinical Oncology (2017)

e14556 Background: All clinical trials studying ipi+nivo have involved treatment-naive pts. Knowledge about the safety and efficacy of ipi+nivo is limited for pts previously treated with PD1. Methods: Nine pts were retrospectively evaluated and treated with ipi (3 mg/kg) and nivo (1 mg/kg) q3wk for 4 doses followed by maintenance nivo q2wk after progression on PD1 from 10/2014 to 11/2016. Data regarding clinical history, treatment response, and toxicity were collected. Results: Six pts had advanced melanoma, 2 pts had metastatic HNSCC (mHNSCC), and 1 pt had recurrent parotid myoepithelial carcinoma. Age ranged from 44 to 86. Eight pts had ECOG PS 0-1; 1 pt had ECOG PS 2. Three melanoma pts were BRAF+; 1 was BRAF WT and 2 were NRAS+. Both mHNSCC pts were p16+. Pts received a median of 3 prior lines of treatment including chemotherapy and immune treatments encompassing ipi, PD1, 4-1BB agonist, autologous TILs, high-dose IL2, IFN, T-VEC, and TLR8 agonist. All 9 pts received pembro prior to ipi+nivo; 1 pt received both pembro and nivo separately. Median number of PD1 doses prior to ipi+nivo was 10 (range 3-13). All 9 pts received all 4 doses of ipi+nivo without delay. Seven pts received nivo maintenance for median number of 11 cycles (range 1-22). Two pts were unable to receive nivo maintenance due to progressive disease (PD) and instead were treated with ipi+T-VEC and BRAF/MEK inhibition. Objective responses were seen in 6/9 pts (67%) with 2 radiological CRs and 4 radiological PRs. PD was seen in 3/9 pts (33%) including in the 1 pt with ECOG PS 2; all 3 pts died from clinical deterioration unrelated to ipi+nivo treatment. CRs were observed in 1 BRAF+ and 1 NRAS+. 7/9 pts (78%) had ≥1 clinically significant irAE and 3 of these pts required systemic steroids. Five pts are still receiving maintenance nivo with clinical benefit. One pt with CR was taken off nivo maintenance, remains disease-free, and is now on surveillance. Conclusions: Ipi+nivo demonstrated significant anti-tumor activity in pts previously treated with PD1. The toxicity profile is consistent with known irAEs. While this is a small series, these data support the use of ipi+nivo after PD1 failure.
P01.075 Understanding cognitive functioning in diffuse glioma patients: the relevance of IDH mutation status and functional connectivity
Authors: J Derks, S Kulik, P Wesseling, T Numan, A Hillebrand, P C de Witt Hamer, J C Reijneveld, C J Stam, M Klein, L Douw
Journal: Neuro-Oncology (2018)

Isocitrate dehydrogenase (IDH) mutation (IDH-mut) is an important marker for survival in diffuse glioma patients. Patients with an IDH-mut glioma have a better prognosis but more often suffer from epilepsy. Patients with a wildtype glioma (IDH-wt) are generally older and more often have cognitive deficits. Regardless of IDH status, cognitive deficits in glioma patients are associated with altered functional connectivity throughout the brain as calculated through statistical correlations between regional neurophysiological activity patterns measured with magnetoencephalography (MEG). Cognitive variation in glioma patients is specifically related to altered theta (4–8 Hz) and alpha (8–13 Hz) band functional connectivity. We investigated whether global brain functional connectivity differs between patients with an IDH-mut and IDH-wt diffuse glioma, and whether this measure reflects variations in cognitive functioning in these subpopulations beyond the associated differences in age and epilepsy. IDH mutation status was determined in 54 diffuse glioma patients via immunohistochemistry (31 IDH-mut, 23 IDH-wt). We recorded MEG and patients underwent cognitive testing. Global functional connectivity between 78 atlas regions spanning the entire cortex was calculated in the theta and alpha frequency bands. Group differences in cognition and global functional connectivity were tested. Next, the association between functional connectivity and cognitive performance was tested. As expected, patients with IDH-mut glioma were younger (P = 0.001) and more often had epilepsy (P = 0.010). Patients with IDH-wt glioma showed poorer verbal memory (P = 0.027, corrected for age, education and presence of epilepsy). More importantly, patients with IDH-wt glioma had lower functional connectivity in the alpha band than patients with IDH-mut glioma (P = 0.015, corrected for age and presence of epilepsy). Alpha band functional connectivity was positively associated with executive functioning (P = 0.049) and information processing speed (P = 0.009), regardless of IDH status and corrected for age, education, and presence of epilepsy. These results suggest that global functional connectivity is lower in patients with IDH-wt diffuse glioma compared to patients with IDH-mut diffuse glioma. Moreover, functional connectivity relates to cognitive performance in both IDH-wt and IDH-mut diffuse glioma patients, regardless of age, education and presence of epilepsy. These findings contribute to our understanding of cognitive functioning in patients with diffuse glioma in general, and cognitive deficits in patients with IDH-wt glioma specifically.
Prognostic and predictive plasma cytokines and angiogenic factors (CAF) in patients (pts) with advanced non-clear cell renal cell carcinoma treated with first-line sunitinib or everolimus: Results from the ESPN trial.
Authors: Pavlos Msaouel, Amado J. Zurita, Shixia Huang, Eric Jonasch, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2016)

e16112 Background: There is a need for markers to guide treatment selection in non-clear cell renal cell carcinoma (nccRCC). We found that soluble tumor necrosis factor-α receptor-I (sTNFR-I) and interleukin (IL)-8 were associated with progression-free (PFS) and overall survival (OS) in pts with nccRCC treated with sunitinib (Bilen et al. Oncologist 2015). To confirm these findings and identify candidate predictive CAFs, we assessed pretreatment plasma samples from the randomized phase 2 ESPN trial comparing frontline sunitinib (S) with everolimus (E) for advanced nccRCC (Tannir et al. Eur Urol 2015). Methods: We measured the baseline concentrations of 30 CAFs by suspension bead multiplex assays in 37 pts: 16 (43%) treated with E and 21 (57%) with S. Cox proportional hazards models were built using a fully stepwise selection algorithm that included the CAFs and other candidate variables such as age, race, gender, prior nephrectomy, MKSCC and IMDC risk groups, performance status, treatment group, and tumor histology. Results: High levels, relative to the median, of IL-8 (HR = 3.13; 95% CI: 1.41, 6.92), IL-13 (HR = 3.36; 95% CI: 1.49, 7.58), and sTNR-RII (HR = 2.21; 95% CI: 1.04, 4.72) were independently associated with worse PFS. High IL-8 levels were also independently associated with worse OS (HR = 2.94; 95% CI: 1.4, 6.2). Treatment-by-CAF interaction analyses identified soluble gp130 (an inhibitor of IL-6 signaling) as the only significant predictor of differential PFS response to S vs E (p = 0.031). Whereas the PFS of patients with low sgp130 was similar in both treatment arms (p = 0.637), pts with high levels had a much shorter PFS when treated with E as opposed to S (1.4 vs. 5.8 months; Table). Conclusions: Our findings support the hypothesis that circulating TNF-R and IL-8 have prognostic value in nccRCC. Furthermore, high soluble gp130 levels predict benefit with S vs E. Clinical trial information: NCT01185366.Predictive effect of soluble gp130 on PFS for each treatment arm. Baseline Concentration Median PFS (months) Hazard Ratio p value Sunitinib Everolimus Soluble gp130 Low 4.7 2.7 1.282 0.637 High 5.8 1.4 0.300 0.024
Targeting the aryl hydrocarbon receptor/polyamine biosynthesis axis of evil for cancer therapy
Authors: Robert A. Casero
Journal: Journal of Clinical Investigation (2018)

The polyamine metabolic pathway has been considered a rational target for antineoplastic therapy since it was discovered that polyamines are absolute requirements for tumor initiation, growth, and, in some instances, survival. Although several promising preclinical studies have demonstrated the critical nature of polyamines for tumor growth, the clinical success of agents targeting polyamine metabolism have been lacking. In the accompanying article, Bianchi-Smiraglia et al. identify both a new target and new drug that inhibits polyamine biosynthesis, reduces intracellular polyamines, and inhibits the growth of several models of human multiple myeloma. These results are both intriguing and provide promise for moving such a strategy to the clinic.
Sphingosine-1-phosphate to regulate cancer apoptosis by modulating cathelicidin production.
Authors: Shivtaj Mann, Kyungho Park
Journal: Journal of Clinical Oncology (2018)

e24202 Background: Cathelicidin antimicrobial peptide (CAMP) is a molecule of the innate immune system. Recent publications have shown that CAMP induces cancer apoptosis via a caspase-independent pathway and is a key player in NK-cell mediated tumor suppression; suggesting that CAMP has a far more complex role than simply providing microbial defense. However, mechanisms surrounding denovo production of CAMP have remained unclear. Classically, CAMP production was deemed to be a byproduct of the Vit D pathway. However, in this study we show CAMP production via a novel, Vit D receptor independent pathway which is dependent on sphingosine-1-phosphate (S1P); suggesting that S1P functions as a signaling lipid which can modulate CAMP production. Methods: Human keratinocytes (KC) were incubated in ceramide and thapsigargin (positive control). Cell lysates were examined by qt-PCR, Western blot, and ELISA to quantify CAMP expression. siRNAs targeted against sphingosine kinase 1 and 2 (SPKH) and S1P lyase were utilized to evaluate role of S1P in CAMP production. Lastly, dual-luciferase reporter assay and BAY11-7082, NF-κB inhibitor, were used to assess role of NF-κB in S1P mediated CAMP production. Results: We show that CAMP production is mediated by S1P as revealed by the following 1) increased CAMP levels in ceramide group compared to control, p < .01, 2) decreased CAMP levels with introduction of siRNA against SPKH1, and 3) increased CAMP levels with introduction of siRNA against S1P lyase. Lastly, we show that S1P regulates CAMP production via NF-κB pathway as revealed by 1) attenuation of phospho-NF-κB (marker of NF-κB activation) by introduction of siRNA against SPHK1, and 2) attenuation of CAMP production with introduction of BAY11-7082, a NF-κB inhibitor. Conclusions: Our results display strong evidence that S1P modulates CAMP production and that this upregulation likely follows the activation cascade ceramide→sphingosine→S1P metabolism via NF-κB nuclear transcription factor. Most importantly, this data provides insight into a novel pathway for de-novo production of CAMP expression which may serve as a potential target for future cancer therapeutics as CAMP has been recently described to play a role in cancer apoptosis.
Association of response to whole-brain irradiation of brain metastases with molecular profile in non-small cell lung cancer.
Authors: Oscar Arrieta, Enrique Caballe-Perez, Alejandra Ramirez-Tirado, Alberto Mejia-Perez, Monika Blake, Diana Flores-Estrada, Eleazar Omar Macedo-Perez, Andres Felipe Cardona Zorrilla, Jaime G. De La Garza
Journal: Journal of Clinical Oncology (2016)

9096 Background: Brain metastases (BM) are one of the common sites of disease progression in non-small-cell-lung-cancer (NSCLC) and lead to treatment failure and impaired quality of life. We determined the impact of genetic alterations in EGFR, ALK and KRAS on the objective response rate (ORR), intracranial progression-free survival (IPFS) and overall survival (OS) of patients with BM after whole-brain irradiation (WBI). Methods: From January 2009 through June 2015, 231 NSCLC patients with BM at diagnosis were reviewed for eligibility. Among them, 121 patients were treated with WBI and without concurrent chemotherapy or tyrosine kinase inhibitors (TKIs) and have available genotyping status. Results: EGFR, KRAS, ALK and WT patients were found in 38.0%, 6.6%, 5.8% and 49.6%, respectively. Overall, ORR and disease control rate (DCR) were 61.2% and 76.0%, respectively. ORR for EGFR, KRAS, ALK and WT patients were 82.6%, 28.6%, 71.4% and 50.0%, respectively (P =0.002). EGFR was the only independent factor associated to treatment response to WBI (OR 8.9 [95% CI 2.2-35.2], P <0.001). High grade and KRAS mutations were independently associated with resistance to WBI. Median IPFS was 6.17 months [95% CI 4.6 -7.6]. IPFS for EGFR, KRAS, ALK and WT patients were 7.1, 4.5, 12.1 and 5.1 months, respectively (P =0.004). EGFR mutation status (HR 0.58 [95%CI 0.3-0.8], P =0.015) and KPS at BM ≥ 70 (HR 0.26 [95%CI 0.1-0.8], P =0.020) were associated with higher IPFS in the multivariate Cox-regression analysis. Median OS was 9.1 months [95% CI 7.4-10.9]. OS for EGFR, KRAS, ALK and WT patients were 9.3, 4.9, 12.1 and 9.2 months, respectively (P <0.001). Only intracranial objective response was associated with a higher OS (HR 0.25 [95%CI 0.1-0.4], P <0.001), while KRAS mutation positive status (HR 4.65 [95%CI 1.6-13.5], P =0.005) and carcinoembrionic-antigen ≥ 20 pg/ml at diagnosis (HR 1.48 [95%CI 1.1-2.1], P =0.039) were independently associated with worse OS. Conclusions: EGFR mutation is an independent predictive factor for objective response to WBI without concurrent TKI for BM in patients with NSCLC. KRAS mutation is an independent predictive factor for both BM treatment resistance and worse OS after BM.