tbuckley/cabot-search huggingface dataset:
The role of type I interferon in prophylaxis of graft-versus-host disease.
Authors: Erik Thiele Orberg, Hendrik Poeck
Journal: Journal of Clinical Oncology (2018)

e19015 Background: Despite significant advances in allogeneic stem-cell transplantation (SCT), in AML – the most common indication for SCT – the 3-year-probability for survival remains only 27-59%. Graft-versus-host disease (GvHD) continues to severely impair outcomes, is detrimental to graft-versus-leukemia effect and contributes to infections by weakening donor cell engraftment; together these complications account for 33% of deaths within 100 days post-transplant. We have recently shown that induction of the pattern recognition receptor RIG-I via administration of triphosphate-RNA protected from GvHD. RIG-I is a cytoplasmic receptor and serves to detect dsRNA, triggering antiviral type I interferon (IFN-I) responses. However, our group demonstrated for the first time that IFN-I could be exploited to promote tissue regeneration following acute injury. New research suggests naturally-occurring microbial metabolites play an important role in protection against viruses in an IFN-I dependent manner. Our goal is to inquire whether metabolites and members of the human microbiota can be harnessed for treatment of GvHD. Methods: In mice, we generated organoids from small intestine and colon to address tissue regeneration (proliferation assay, histology, FACS) and signalling (qPCR, immunoblot) in response to IFN-I-inducing metabolite treatment. We studied treatment responses in a model of doxorubicin-induced gut epithelial damage. Results: IFN-I-inducing metabolite induced organoid growth and proliferation, increased expression of the antimicrobial peptide RegIIIγ as well as other ISG and enhanced NF-kB signalling. We observed better outcome following chemotherapy with reduced weight loss and improved recovery of intestinal stem cells. Conclusions: Treatment of SCT patients with broad-spectrum antibiotics is associated with increased mortality. The loss of protective effects of the intestinal microbiota during GvHD may be mediated by metabolites able to amplify protective IFN-I responses. Prophylactic administration of metabolites coupled with maintenance of a permissive microbiome may improve survival following SCT. Further study is necessary to explore the benefits of RIG-I activation to prevent and treat GvHD.
Abstract 17582: Monitoring Novel Anticoagulants Dabigatron, Rivaroxaban and Apixaban Using Modified Thrombelastography
Authors: Ramin Artang, Gregg Galloway, Jorn Dalsgaard Nielsen
Journal: Circulation (2015)

Background: Novel anticoagulants NOACS dabigatran DABI rivaroxaban RIVA and apixaban APIX do not require routine monitoring. There are situations where monitoring would be useful including bleedings, trauma, and thromboembolic events while on anticoagulation. The aim of this in vivo study was to assess the anticoagulant effect of NOACS with novel modified TEG assay containing ecarin and factor Xa concentrate. Methods: 9 healthy male volunteers were given single dose of oral DABI 150mg or RIVA 20mg or APIX 5mg and were phlebotomized at 0, 1 and 3 hours after intake of NOAC. Reaction time R was measured using TEG®5000. Concentrations (conc.) of DABI, RIVA and APIX were measured using chromogenic assay Biophen® DTI and DiXaI. Based on available literature on pharmacokinetics of NOACS, clinical range for each agent was estimated. The R values was correlated to the drug conc. and sensitivity SN, specificity SP, positive and negative predictive values (PPV&amp;NPV) for the minimum therapeutic range of each agent was calculated. Results: Using Ecarin assay, R was highly correlated with DABI conc. r = 0.96, p &lt; 0.0001. R value of &gt;5.7 had 88% SN 100% SP, 100% PPV and 95% NPV for DABI conc. of &gt;50ng/ml. Using Factor Xa assay, R was highly correlated with RIVA conc. r = 0.89, p &lt; 0.0001. R value of &gt;4.8 had 94% SN, 100% SP, 100% PPV, and 92% NPV for RIVA conc. of &gt;100ng/ml. Using Factor Xa assay R was highly correlated with APIX conc. r = 0.86, p &lt; 0.0001. R value of &gt;4.3 had 93% SN, 100% SP, 100 PPV and 93% NPV for APIX conc. of &gt;50ng/ml. Conclusion: We have for the first time demonstrated that TEG® point-of-care device can monitor the NOACS effect on the hemostasis with highly significant correlation with the drug levels of each agent. This novel technology is easy to use on whole blood without need for specialized expertise. Larger clinical studies are warranted for correlation of TEG findings and clinical outcome.
Risk factors of fast growing melanomas in a French prospective cohort.
Authors: Caroline Gaudy Marqueste, Laura Troin, Nausicaa Malissen, Anderson Loundou, Sandrine Monestier, Stéphanie Mallet, Sylvie Hesse, Quentin Magis, Marie-Aleth Richard, Florent Grange, Jean-Jacques Grob
Journal: Journal of Clinical Oncology (2017)

e21042 Background: Rate of growth (ROG) of the primary tumor is a known prognostic factor in melanoma (MM). Fast growing melanomas (FGMM) could account for an important part of the thick tumors which still exist despite earlier and earlier detection. Methods: All patients referred for a primary mm to two French Dermatology Department from the period 2012-2016 were prospectively enrolled in an observational case control study. ROG was calculated as the ratio of Breslow thickness to time to mm development according to patient, following a well-established process. FGMM were defined as those with a ROG &gt; 0.5 mm/month and MMs with a ROG ≤05mm/month were used as controls. Differences in epidemiological, clinical and pathological features were evaluated with univariate and multivariate analysis. Results: 464 patients were enrolled. 149 mm (32.1%) were FGMM. Factors associated with FGMM in univariate analysis were age &gt; 70 years (p = 0.006), tumor location (p = 0.032), histological subtype (p = 0.021), median thickness (p &lt; 0.001), ulceration (p &lt; 0.001), high mitotic rate ( &gt; 1/mm 2 )(p = 0.002), sentinel node involvement (p = 0.008), hair color at the age of 20 (p = 0.011), lower NSAIDS consumption (p = 0.012) and lower number of sunburns (p = 0.002). Age &gt; 70 years (OR 1.88 95%CI 1.19-2.98, p = 0.007), ulceration (OR 3.70 95%CI 2.05-6.61) p &lt; 0.001), sentinel node involvement (OR 1.93 95%CI 1.01-3.69 p = 0.046), regression (OR 0.37 95%CI 0.15-0.94) p = 0.037) and NSAIDS exposure (OR 0.29 95%CI 0.11-0.78, p = 0.014) remained associated with FGMM in multivariate analysis. OS and PFS were significantly lower in the FGMM group (HR 1.98 (95%CI 1.11-3.54, p = 0.02) and HR 1.79 (95%CI 1.17-2.73, p = 0.007), respectively). Conclusions: Fast growth characterizes a subset of primary mm which are intrinsically more aggressive and have different risk factors than other MM, namely more frequent in the elderly and with no association with skin type, nevus count or sun exposure. Association with ulceration could reflect a specific immune context. Negative association with NSAIDS exposure warrants more investigation, since it may have therapeutic implications.
Prognosis and molecular subtypes of breast cancer in Qatar: The first national report.
Authors: Naser Elkum, Mohammed ElAnbari, Reem Al-Kuwari, Cristina Maccalli, Salah Gehani
Journal: Journal of Clinical Oncology (2018)

e13595 Background: Breast cancer (BC) is the leading cause of cancer morbidity and mortality among women in Qatar. Observations among oncologists in the MENA region highlighted that unlike the western populations, affected patients are younger, with more aggressive tumors often associated with worse prognosis. To identify the molecular characteristics of tumors and the prognosis for Qatari BC patients, we examined the distribution of BC molecular subtypes and their associations with clinical and pathological characteristics. Methods: Clinical and tumor characteristics data of 1309 BC patients were extracted from the Qatar national cancer registry and medical records from Hamad Hospital, Qatar. BC were diagnosed between 2005 and 2015. BC subtypes definitions were: Luminal-A (ER+ and/or PR+, Her2-), Luminal-B (ER+ and/or PR+, Her2+), TNBC (ER-, PR-, Her2-) and Her2+ (ER-, PR-, Her2+). Results: Median age at diagnosis was 48.5 years with 25% of patients below 42 years and 51% under 50 years. The proportions of Luminal-A, Luminal-B, TNBC and Her2+ BC subtypes were 44.5%, 25.7%, 15.2% and 14.7%, respectively. Remarkably, the distribution of luminal-A, luminal-B, Her2+ and TNBC subtypes were dissimilar compared to BC patients in Europe, South Africa, America and China. The four subtypes were significantly associated with age (p = 0.0013), where TNBC comprised the younger age of mean 46 years. Tumors of grade 2 and 3 were more dominant in patients for the four BC subtypes (P < 0.0001). Significant differences in the distribution of ki-67 among the four cancer subtypes (P < 0.0001) was detected: high tumor grade, stage, ER and PR (P < 0.0001). In comparison of ki-67 tertiles, patients with 3rd tertile ( > 50%) had a significant worse survival than patients of 1st (≤20%) or 2nd ( > 20% & < 50%) tertiles; log-rank P < 0.0001. Conclusions: This first Qatari study showed that Luminal-A subtype was the most frequent BC subtype, followed by Luminal-B. The proportion of TNBC, Luminal-B and Her2+ subtypes were higher compared to South Africa, China, Europe and white women in the US. Ki-67 was significantly higher compared with previous reports and was an independent prognostic factor for survival with the highest expression in TNBC and Her2+ molecular subtypes.
Evaluation of a spray-dried dispersion (SDD) formulation of MGCD265, a receptor tyrosine kinase (RTK) inhibitor, in a phase 1 study of patients (pts) with advanced solid tumors.
Authors: Sunil Sharma, Geoffrey Shapiro, Christian K. Kollmannsberger, James Christensen, Vanessa Roberts Tassell, Demiana Faltaos, Richard C. Chao, Herbert Hurwitz
Journal: Journal of Clinical Oncology (2016)

e14087 Background: MGCD265 is an ATP-competitive inhibitor of MET and Axl RTKs and has demonstrated anti-tumor activity in xenograft cancer models of MET or Axl dysregulation and in Phase 1 clinical trial pts selected for these alterations. Methods: Study objectives were to evaluate the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), safety, PK, PD, and clinical activity of MGCD265. Eligible pts received MGCD265 on Cycle 1 Day 1 and initiated continuous dosing on Cycle 1 Day 3 in 21-day cycles. PK/PD were evaluated after single and repeated dose administration. Results: 18 pts received MGCD265 – 12 in softgel capsules and 6 in SDD tablets. With softgel capsules the MTD was established at 1050 mg BID; treatment-related AEs ( > 20% all grades) included diarrhea, nausea, vomiting, fatigue, AST increase, ALT increase and lipase increase. With 500 mg SDD, exposures partially overlapped those observed with 1050 mg softgel capsules. 1 of 6 SDD pts experienced a dose-limiting toxicity (DLT) of Gr 3 transaminase increase without clinical symptoms. Treatment-related AEs reported in > 20% of pts included Gr 1-2 diarrhea and Gr 2 fatigue, with fewer patients treated for diarrhea. Dose escalation of SDD is ongoing at 1000 mg BID. The rates of absorption and elimination of the two formulations were comparable with a median tmax of 8 hrs and an average t1/2 of 40 ± 17 hrs for SDD versus 35 ± 12 hrs for softgel capsules. The extent of absorption was 1.8 times greater with SDD tablets. The observed Cave,ss and AUC0-12,ss were 480 ng/mL and 5757 ng•h/mL with 500 mg BID of SDD tablets and 561 ng/mL and 6731 ng•h/mL with 1050 mg BID of softgel capsules, respectively. Conclusions: The SDD tablet formulation of MGCD265 shows similar PK characteristics as the softgel capsule formulation but with greater bioavailability, thus reducing the pill burden, and a more favorable safety profile to date. Expansion cohorts of softgel capsules demonstrating antitumor activity in pts with NSCLC with genetic alterations for MET and AXL are ongoing and may include evaluation of the SDD formulation as emerging data confirm similar or greater exposure and a better safety profile. Clinical trial information: NCT00697632.
Characterization of shared repertoires in tumor infiltrating lymphocytes.
Authors: Mark Woodcock, Benjamin Garrett Vincent
Journal: Journal of Clinical Oncology (2018)

e24149 Background: There is a high degree of interest in understanding the biology of tumor infiltrating lymphocytes (TILs). The extent of T cell receptor (TCR) sequence sharing between TILs and circulating T-cells, as well as the sequence-level determinants of TCRs shared between individuals, are currently unknown. Methods: TCR sequences were extracted from RNA sequencing from 9,296 patients' tumors in The Cancer Genome Atlas (TCGA), and their complementary determining region 3 (CDR3) -- the major antigen binding regions -- were characterized using publicly available software (MiXCR) and custom tools. CDR3 regions were compared against a data set of peripheral blood TCR repertoires from 100 healthy volunteers. Multi-variable regression analysis was used to identify parameters associated with shared clonotypes between individuals. Results: We observed a large amount of TCR sharing between TILs and the circulating lymphocytes of healthy volunteers (p < 0.000472). TIL CDR3 sequences which were more strongly shared within the TCGA data set were also significantly more likely to be shared with the healthy controls (p < 2.2e-16). Several CDR3 features were identified that correlate with shared clonotypes, or lack thereof, between individuals. These include the nucleotide sequences of the receptor segments involved, as well as the number of nucleotides inserted during T cell receptor recombination (Table 1). Conclusions: Our finding that a significant fraction of TILs are drawn from a circulating repertoire shared among distinct healthy individuals suggests that these TCRs are not tumor specific, or that shared elements of the healthy circulating TCR repertoire contain a portion of heretofore unknown tumor specific lymphocytes. Further experiments will be needed to distinguish between these possibilities, with implications for understanding the utility of TILs as biomarkers and therapeutic targets in cancer. Table 1. Coefficient Interval (95%) V-Region -0.18791 (-0.23613, -0.13968) D-Region -0.03835 (-0.053992, -0.02272) J-Region -0.03632 (-0.13893, 0.06629) V-D nucleotide additions 0.00604 (0.00552, 0.00656) D-J nucleotide additions 0.00660 ( 0.00606, 0.00712) Available Recombination Paths 4.1e-9 (3.9e-9, 4.3e-9)
Abstract 11175: The Effects of LCZ696 on Left Ventricular Remodeling in Hypertensive Patients - Results of a Double Blind, Randomized, Multicenter Trial
Authors: Roland E Schmieder, Frank Wagner, Michael Mayr, Christian Delles, Christian Ott, Christian Keicher, Solveig Aichner, Yasser Khder, Denise Yates, Diego Albrecht, Thomas Langenickel, Patrick Freyhardt, Rolf Janka, Jens Bremerich
Journal: Circulation (2016)

Background: Arterial hypertension and the resulting reduction in aortic distensibility impose increased hemodynamic load to the left ventricle and, if untreated may lead to left ventricular hypertrophy (LVH) and heart failure. Purpose: We analyzed the effects of LCZ696 on LV-structure and function as well as on regional and global aortic distensibility. Methods: We conducted a prospective, randomized, double-blind, parallel-group, multicenter study in 114 patients with mild to moderate hypertension. Patients were randomized to LCZ696 200/400mg o.d. or olmesartan (OLM) 20/40mg o.d. At baseline, 12 and 52 weeks left ventricular mass (LVM) index as well as local and global aortic distensibility were evaluated by 3 T magnetic resonance imaging (MRI) and pulse wave analysis, respectively. Results: Baseline characteristics, office BP (155.1±9.0/92.2±8.7 mmHg) and LVM index (72±15 g/m 2 ) were similar between treatment groups at baseline. After 52 weeks of treatment, decrease in office systolic BP was greater in the LCZ696 group than in the OLM group (-4.99 [95% CI -9.46 to -0.53] mmHg, p=0.029). Compared to OLM, treatment with LCZ696 resulted in a greater decrease in LVM index at 12 weeks (-4.05 [95% CI -7.9 to -0.2] g/m 2 , p=0.039) and at 52 weeks (-3.27 [95% CI -6.2 to -0.34] g/m 2 , p=0.029). After adjustment for office SBP at follow-up, the change in LVM index at 12 weeks (p=0.0356) and at 52 weeks (p=0.0189) remained significantly greater in the LCZ696 group. Local aortic distensibility measured by MRI in the ascending, proximal and distal descending aorta did not show any significant difference between groups. LCZ696 was associated with a larger decrease of central pulse pressure compared to OLM (-3.50 [95% CI: -6.15 to -0.85] mmHg, p=0.01) at 52 weeks. Both treatments were safe and well tolerated. Conclusion: In patients with hypertension, LCZ696 reduced LVM to significantly greater extent than OLM. Since reduction of LVM is associated with improved cardiovascular prognosis, the observed effect of LCZ696 on LVM is of clinical relevance.
Optimal thoracic radiation dose in limited stage small cell lung cancer.
Authors: Madhusmita Behera, Xinyan Zhang, Renjian Jiang, Rathi Narayana Pillai, Pretesh R Patel, Suchita Pakkala, Conor Ernst Steuer, Nabil F. Saba, Taofeek Kunle Owonikoko, Chandra Belani, Fadlo Raja Khuri, Walter J Curran, Suresh S. Ramalingam, Kristin Ann Higgins
Journal: Journal of Clinical Oncology (2017)

8562 Background: Several studies have demonstrated improved overall survival in limited stage small cell lung cancer (LS-SCLC) patients (pts) with the addition of thoracic radiation therapy (RT) to chemotherapy. However, the optimal dose of thoracic RT when given daily, which is the most common practice pattern in the US, is yet to be firmly established. We analyzed outcomes associated with once-daily low dose (LD) RT relative to once-daily high dose (HD) RT for LS-SCLC in the National Cancer Data Base (NCDB). Methods: The NCDB was queried to capture pts with LS-SCLC treated with thoracic RT from 2004-2013. The cohort of pts that received 60 Gy (LD) was compared with the cohort that received RT ≥70 Gy (HD). The univariate (UV) association of overall survival (OS) was assessed using Cox proportional hazards models and log-rank tests. A multivariable (MV) Cox proportional hazard model and Kaplan-Meier (KM) analyses were performed to compare the LD vs. HD cohorts. Propensity score matching method was also implemented to reduce treatment selection bias. All analyses were performed using SAS Version 9.4. Results: A total of 5,159 pts (LD-3441; HD- 1718) were included in the analysis. Pt characteristics (LD/HD): median age 65/64 yrs; males 44/46%; whites 89/88%, academic centers 28/31%, Charlson-Deyo comorbidity score 0- 61%/64%; government insured 61/57%. 96% of pts in LD and 95% in HD cohorts had received chemotherapy. On MV analysis, no differences were found in OS between HD and LD RT(HR 0.98, p = 0.5), which was confirmed by KM analysis with 5-yr survival of 21% in LD vs 21.5% in HD (p = 0.8). On MV analysis of OS stratified by comorbidity score, LD was associated with significantly better survival compared to HD in pts with a comorbidity score of 1 and above (HR 0.87, p = 0.02). The LD group also had a better 5-yr survival than HD group in pts with higher comorbidity score (19% vs 14%, p = 0.01). No difference in survival was noted between the two cohorts for pts with no recorded comorbidities (HR 1.03, p = 0.6). Conclusions: In LS SCLC pts, survival was similar in pts who received daily RT of 60 Gy compared to those that received 70 Gy and above. In pts with worse performance status, those who received LD RT of 60 Gy had better survival.
P04.57 Creating patient-specific computational head models for the study of tissue-electric field interactions using deformable templates
Authors: N Urman, S Levy, A Frenkel, A Naveh, H S Hershkovich, E Kirson, C Wenger, G Lavy-Shahaf, D Manzur, O Yesharim, Z Bomzon
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) are delivered to the brain through two pairs of transducer arrays placed on the patient’s scalp. TTFields distribution in the brain depends the array’s position, patient anatomy and the electric properties of the tissues and tumor. Preclinical studies show that the effect of TTFields is dose-dependent, and depends on the intensity of the TTFields. Therefore, it is important to understand how TTFields distribute in the brain, and how this distribution might influence disease progression. Studying TTFields distribution in the brain most often relies on numerically simulating delivery of TTFields to realistic computational models. Preparation of such models usually involves semi-automatic segmentation of MRI images, which can be a time consuming task. In addition, in clinical scenarios, MRI acquisition time is often reduced by increased slice spacing, limited field of view, or increased scan speed, leading inaccuracies in automated segmentation processes, and increasing the time required for model creation. Here we present a novel method designed to enable rapid model creation under those restrictions. A highly detailed healthy head model serves as a deformable template from which patient models are created. The first step is pre-processing, involving denoising and background noise reduction, as well as super-resolution algorithms when needed. To create the patient model, the tumor is first segmented manually and masked, leaving only healthy tissues in the MRI, which is then registered to the template space to yield the transformation from patient space to template space. The template is then deformed into the patient space using the inverse transformation, and the tumor is placed back creating a full patient model. Next, automatic identification of landmarks on the patient’s head is used to position the transducer arrays on the head, which are then introduced into the model. Finally, boundary conditions are set, and field distribution is simulated using Finite Differences Time Domain (FDTD) method (Sim4Life V3.0, ZMT-Zurich) We have simulated TTFields distribution of 317 patients treated with TTFields as part of the EF-14 trial. Our method is optimized for accurate contouring of tissues highly influencing the distribution of electric field (Scalp, skull, CSF, ventricles), and it is robust, having the ability to give sufficient results even when MRI data quality is low. Thus enabling a study correlating the spatial distribution of TTFields and patient outcome. Our process for rapidly creating patient presents a breakthrough that enables the first study in which the spatial distribution of therapeutic electric fields correlates with patient outcome. In the future this method can be used for clinical studies investigating other clinical indications of large datasets.
Evaluating the pattern of bone involvement in patient with lung cancer.
Authors: Thuriya AlSumyya, Yosra Ali, Nagham Ramzi Sheblaq, Mohammad Alkaiyat, Abdul Rahman Jazieh
Journal: Journal of Clinical Oncology (2016)

e20629 Background: Our study aims at evaluating the prevalence of bone metastases from non-small cell lung cancer (NSCLC) and describing the types of bone involvement, management approaches and outcome. Methods: A retrospective review of medical records of patients with NSCLC who were treated at the Department of Oncology at King Abdul-Aziz Medical City-Riyadh, KSA between January 2002 and December 2012. Results: Out of 259 patients, 116 patients (44.8%) were found to have skeletal metastases during their clinical course. Ribs were the most common site of metastatic disease. The most common skeletal related events (SREs) were bone pain (44%), spinal cord compression (18%), and pathological fracture (16.4%). Male patients (p = 0.016) with histological subtype adenocarcinoma (p = 0.001) tended to have more incidence of bone metastases. Bone involvement did not impact patient survival. Patients had worse survival if they had concomitant bone and liver metastases (p = 0.041), hypercalcemia (p = 0.001), and did not receive bisphosphonates (p = 0.05). Conclusions: Metastatic bone disease is very common problem in patients with lung cancer that leads to many serious events and impact the quality of life and require proper and timely management.