tbuckley/cabot-search huggingface dataset:
TCT-557 Impact of a Suspended Lead Suit on Physician Radiation Doses Across Patient BMI Categories During Coronary Angiography
Authors: Lahdan Refahiyat, David Benavides, Thomas Crane, Sheetal Maragiri, Erica Osip, Emily Pardington, Abbey Mulder, Jessica Parker, Stacie VanOosterhout, Ryan Madder
Journal: Journal of the American College of Cardiology (2018)
Tobacco Carcinogen–Induced Production of GM-CSF Activates CREB to Promote Pancreatic Cancer
Authors: Supriya Srinivasan, Tulasigeri Totiger, Chanjuan Shi, Jason Castellanos, Purushottam Lamichhane, Austin R. Dosch, Fanuel Messaggio, Nilesh Kashikar, Kumaraswamy Honnenahally, Yuguang Ban, Nipun B. Merchant, Michael VanSaun, Nagaraj S. Nagathihalli
Journal: Cancer Research (2018)

Although smoking is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC), the molecular mechanisms underlying PDAC development and progression in smokers are still unclear. Here, we show the role of cyclic AMP response element-binding protein (CREB) in the pathogenesis of smoking-induced PDAC. Smokers had significantly higher levels of activated CREB when compared with nonsmokers. Cell lines derived from normal pancreas and pancreatic intraepithelial neoplasm (PanIN) exhibited low baseline pCREB levels compared with PDAC cell lines. Furthermore, elevated CREB expression correlated with reduced survival in patients with PDAC. Depletion of CREB significantly reduced tumor burden after tobacco-specific nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) treatment, suggesting a CREB-dependent contribution to PDAC growth and progression in smokers. Conversely, NNK accelerated PanIN lesion and PDAC formation via GM-CSF-mediated activation of CREB in a PDAC mouse model. CREB inhibition (CREBi) in mice more effectively reduced primary tumor burden compared with control or GM-CSF blockade alone following NNK exposure. GM-CSF played a role in the recruitment of tumor-associated macrophages (TAM) and regulatory T cell (Treg) expansion and promotion, whereas CREBi significantly reduced TAM and Treg populations in NNK-exposed mice. Overall, these results suggest that NNK exposure leads to activation of CREB through GM-CSF, promoting inflammatory and Akt pathways. Direct inhibition of CREB, but not GM-CSF, effectively abrogates these effects and inhibits tumor progression, offering a viable therapeutic strategy for patients with PDAC.
P04.60 Genomic profile of tumorigenesis in a patient with Turcot syndrome
Authors: P Karschnia, E Z Erson-Omay, A J Huttner, R K Fulbright, M Günel, J M Baehring
Journal: Neuro-Oncology (2018)

Turcot syndrome (TS) represents a rare hereditary phenotype of mismatch repair (MMR) deficiency and is characterised by familial clustering of primary brain tumors in combination with abdominal tumors. MMR-deficient tumors in the setting of TS exhibit a characteristic molecular pattern: length variations in microsatellite DNA denoted as microsatellite instability (MSI). We performed a detailed molecular analysis of a patient with TS including whole exome sequencing (WES) of two metachronous tumors. A 60-year-old woman was found to have a left frontal tumor when she presented with dysphasia and a right hemiparesis. Her personal history revealed an endometrioid uterine adenocarcinoma at the age of 55. Family history was remarkable for numerous malignancies. Subtotal resection of the frontal mass revealed glioblastoma, WHO grade IV (IDH1 negative, MGMT unmethylated). The patient was treated with standard radiochemotherapy followed by adjuvant temozolomide. MRI of the brain revealed no evidence for tumor progression after one year. Molecular analysis included immunohistochemistry for mismatch repair proteins as well as WES for samples of the patient’s blood, endometrial carcinoma, and glioblastoma. A heterozygous germline missense mutation in exon 4 of the MMR-gene MSH6 was found (hg19:2: 48030652: T>C, p. L1089S), which was predicted to be deleterious by SIFT and PolyPhen. The endometrial carcinoma and the glioblastoma had both lost expression of MSH6 per immunohistochemistry and displayed MSI (endometrial carcinoma: MSI-high; glioblastoma: MSI-low). For the endometrial carcinoma, no somatic aberration of MSH6 was identified by means of WES. A somatic missense mutation within the proofreading domain of DNA polymerase delta (POLD1) was detected (hg19:19: 50909713: G>A, p.S478N). For the glioblastoma, WES revealed a somatic missense mutation on the second allele of MSH6 and a somatic PTEN frameshift variant. Both tumors showed a missense mutation of TP53 and were hypermutated. Only five cases of TS-associated brain tumors with a heterozygous germline mutation of MSH6 have been reported. According to Knudson’s hypothesis, a somatic ‘second hit’ of the same gene is necessary for the inactivation of MSH6 and tumorigenesis. We were able to identify this second hit for the patient’s glioblastoma, but not for the endometrial carcinoma. However, mutations of the Polε/Pol∂ enzyme complex encoded by POLD1 may somatically inactivate MMR-genes in endometrial carcinomas and may represent an alternative pathway for loss of MMR-genes and MSI. Vice versa, despite the lack of MSH6 within the glioblastoma tissue, MSI was low for the patient’s brain tumor. Therefore, this study emphasizes the hypothesis that MMR-genes contribute to tumorigenesis in the brain through unknown mechanisms other than MSI.
Abstract 16055: Ongoing Prothrombotic State in the Early Phase of Pneumonia
Authors: Roberto Cangemi, Camilla Calvieri, Roberto Carnevale, Marco Falcone, Cristina Nocella, Patrizia Ferroni, Pasquale Pignatelli, Gloria Taliani, Armando D'Angelo, Francesco Violi
Journal: Circulation (2015)

Introduction: Respiratory tract infections are associated with an increased risk of acute cardiovascular and cerebrovascular events. Of note, pneumonia may be associated with arterial and venous thrombosis but the underlying pathophysiological mechanisms are still unclear. Hypothesis: Our aim was to investigate if in patients with community-acquired pneumonia (CAP) a pro-thrombotic state does exist and its relationship with plasma levels of endotoxin. Methods: One hundred-four consecutive patients with CAP, admitted to the University-Hospital Policlinico Umberto I of Rome, Italy, were prospectively recruited and followed up until discharge. At admission and at discharge endotoxin and systemic markers of clotting activation including protein C activity (aPC) and F1+2 were analyzed. Hospitalized patients matched for sex, age, atherosclerotic risk factors but without any type of infections were used as controls. Results: At admission CAP patients showed higher plasma levels of F1+2 (237 [164, 388] vs. 163 [136-313] pmol/L; p=0.023) and lower levels of aPC (36.3 [19.7, 52.4] vs.49.8 [43.7-56.0] pmol/L, p&lt;0.001) compared to controls. Moreover, CAP patients disclosed lower aPc/F1+2 ratio (0.13 [0.07, 0.26] vs.0.28 [0.16-0.37; p&lt;0.001), a global marker of imbalance between thrombin generation and the anticoagulation system. At discharge aPC plasma levels and aPC/F1+2 significantly increased, while F1+2 significantly decreased (p&lt;0.001). Baseline LPS were significantly higher in patients than controls (230±34 vs 27±22 pg/ml; p&lt;0.001); in patients a significant decrease of serum LPS was detected at discharge. Serum LPS values were correlated directly to F1+2 (Rs= 0.402, p&lt;0.001) and inversely to aPC/F1+2 (Rs=-0.303; p&lt;0.002). In a multivariable regression analysis CURB65 (β=-0.410 p&lt;0.001) and LPS (β=-0.261 p&lt;0.001) were significantly associated to aPC/F1+2. Conclusion: CAP patients disclose a significant increase of thrombin generation rate along with a reduced Protein C activity. Changes of clotting activation are significantly associated with LPS suggesting endotoxemia as a key factor in determining enhanced thrombin generation in CAP patients.
Phase III, randomized, double blind, placebo-controlled trial of sorafenib in desmoid tumors (Alliance A091105).
Authors: Mrinal M. Gounder, Michelle R. Mahoney, Brian Andrew Van Tine, Vinod Ravi, Steven Attia, Hari Anant Deshpande, Abha A. Gupta, Mohammed M. Milhem, Robert Martin Conry, Sujana Movva, Michael J. Pishvaian, Jeffrey Crawford, Tarek Sabagh, Robert G. Maki, William D. Tap, Robert A Lefkowitz, Narasimhan P Agaram, John Joseph Wright, Amylou C. Dueck, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2018)

11500 Background: DT is a rare cancer of connective tissue affecting young patients (pts), arising in any location, with a wide natural histories. DT is locally infiltrative and may cause pain, loss of mobility, bowel obstruction and visceral organ compromise. Death is rare. There is no standard of care (SoC), but surgery, observation and systemic therapies are used. S is an oral drug inhibiting VEGFR2/PDGFRB/RAF, showing activity in DT in case series. Methods: We conducted an international prospective study to evaluate efficacy of S (400 mg qd) in unresectable progressive (PD) or symptomatic DT. Pts were randomized 2:1 (S:P) and crossover to S upon RECIST 1.1 PD. Stratification: pain-level and disease site. Primary endpoint was progression-free survival (PFS). 75 pts yielded 90% power (1-sided α = 0.025, 1 interim analysis) to detect a hazard ratio (HR) of 0.4 (favoring S), assuming 6 month (mo) median (md) PFS for P and 15 mo for S, requiring 52 PFS events. Other endpoints: response rates (RR); toxicity (tox); overall survival; patient-reported outcome (PRO); tumor and imaging biomarkers. Results: 87 pts (37 P, 50 S) enrolled over 17 mo at 25 sites [69% female, md age 37 years (yr) (range 18-72), 62% chemo-naive, 9% prior RT]. Tumor location and pain level were balanced. 30% (11/37) P and 38% (19/50) S pts continue; 18% (9/50) ended S due to tox (0% P). 33% (16/49) S, 14% (5/36) P pts had grade 3-4 tox, primarily rash, hypertension, fatigue, pain. For the 1st 75 evaluable pts (med f/u 26 mo): PD 69% (22/32) P, 16% (7/43) S, 1 death (S); Durable partial RR 33% (14/43, 2–28 mo) on S and 21% (7/32, 4–17 mo) on P (p = 0.3); 1-yr PFS: 43%-P, 87%-S; Med PFS: 9.4 mo (95% CI 5.7-NE) for P, not reached for S [HR = 0.14 (95% CI 0.06-0.33), p<0.0001)]. Analyses of PRO, MRI T2 signal and tumor biopsy are ongoing. Conclusions: Phase III studies in rare cancers are feasible and rapidly conducted in an NCTN group setting. Here, S was well tolerated with significantly improved PFS. Spontaneous RR on P is consistent with observational trials in DT. The study exceeded its primary endpoint for PFS. DSMB recommended unblinding (P offered S). S may represent a new 1st-line or subsequent-line SoC in select pts with DT. Support: U10CA180821, U10CA180882, U24CA196171, R01FD005105. Clinical trial information: NCT02066181.
Dynamics of mutant BRAF V600E in free circulating DNA (fcDNA) of non-melanoma cancer patients (pts) in response to treatment with BRAF and MEK/EGFR inhibitors.
Authors: Morten Mau-Soerensen, Lise Barlebo Ahlborn, Lars Joenson, Olga Oestrup, Jane Preuss Hasselby, Eric Santoni-Rugiu, Finn Cilius Nielsen, Ulrik Niels Lassen, Christina Westmose Yde
Journal: Journal of Clinical Oncology (2016)

11531 Background: Therapies targeting mutant BRAF V600E have changed practice in the treatment of metastatic melanoma and are currently tested in other malignancies. Treatment response can be monitored by tracking tumor DNA released into the circulation as free circulating DNA (fcDNA). We studied the dynamics of BRAF V600E mutations in fcDNA isolated from patients (pts) with non-melanoma cancers during targeted therapy. Methods: Pts with exhausted treatment options included in the Copenhagen Prospective Personalized Oncology (CoPPO) research program were selected for targeted therapy against actionable driver mutations identified in freshly obtained tumor biopsies by whole exome sequencing (Illumina HiSeq2500). In pts with non-melanoma cancers harboring mutant BRAF V600E, plasma samples were collected at baseline and during targeted treatment. fcDNA was isolated and allele frequency of BRAF V600E mutations were quantified using droplet digital PCR. Results: Among 300+ patients included in the CoPPO research program, BRAF V600E mutations were identified in six patients with non-melanoma cancers who received targeted therapy (NSCLC, n = 1; bile duct cancer, n = 3; colon cancer, n = 2). Treatments included BRAF inhibitors (dabrafenib or vemurafenib) alone or in combination with MEK (trametinib) or EGFR inhibitors (panitumumab or cetuximab, colon cancer pts only). All pts but one had reductions in the size of target tumors. Two pts had partial responses as assessed by RECIST 1.1. The allele frequency of BRAF V600E increased within the first 24 hours after treatment initiation and subsequently decreased substantially. Dynamics of allele frequency correlated closely to treatment response. In all cases, timing of changes in allele frequency preceded documented radiological treatment response and/or progression. Analyses of tumor biopsies obtained post-treatment are ongoing. Conclusions: Targeting BRAF mutations in non-melanoma cancers seems feasible with the achievement of clinically relevant tumor activity. Quantitative measurements of BRAF V600E mutations in fcDNA represent a useful method to monitor treatment outcome. Clinical trial information: NCT02290522.
Systemic immune-inflammation index and neutrophil to lymphocyte ratio for predicting tumor grade in neuroendocrine tumors.
Authors: Idris Yucel, Yasemin Kemal, Seda Gun, Guzin Demirag, Murat Derebey
Journal: Journal of Clinical Oncology (2018)

e16179 Background: A novel systemic immune-inflammation index named SII (SII = N×P/L), which is based on neutrophil (N), platelet (P) and lymphocyte (L) counts, has emerged and reflects comprehensively the balance of host inflammatory and immune status. In recent years, other markers of systemic inflammation, such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), have been identified as prognostic and predictive factors in various malignancies. We aimed to evaluate the potential value of SII, NLR and PLR for predicting tumor grade in neuroendocrine tumors (NET). Methods: This retrospective study was made of a total of 101 patients with neuroendocrine tumors who were diagnosed and treated between 2008 and 2016. Preoperative counts and levels of hematological parameters were obtained from the recorded computerized database. Results: 51 males and 50 females were included in the study. The median age at the time of diagnose was 53 years, range from 19 to 77. Most of the tumors were originated from the gastrointestinal and pancreatic area (75/101) where the others were arised from lung (17/101) and the other organs. 58 of the 101 patients were grade I, 8 patients were grade II and 35 patients were grade III. Statistically significant associations were found between NLR, SII and tumor grade. This statistical significance is due to difference of grade 1 and grade 3 tumors. (Table-1). No association was found between PLR and tumor grade. Conclusions: Our study results showed that NLR and SII are simple, cheap and easily available laboratory parameters that could be useful to predict tumor grade in NETs. Parameters Grade I Grade II Grade III P value Number of patients 58 8 35 NLR 3.68 ± 0.58 6.45 ± 2.74 5.40 ± 0.75 0.006 PLR 171.73 ± 11.48 227.85 ± 42.75 216.84 ± 27.74 ≥0.05 SII 909700.2 ± 143636 1475800.0 ± 543191 1520600.0 ±241000 0.003
A phase 1b trial of RORγ agonist LYC-55716 in combination with pembrolizumab to evaluate safety, efficacy, and immune biomarker profiles in patients with metastatic non-small cell lung cancer.
Authors: D. Ross Camidge, Shirish M. Gadgeel, Garry Alan Weems, H. Jeffrey Wilkins, Melissa Lynne Johnson
Journal: Journal of Clinical Oncology (2018)

TPS9111 Background: LYC-55716 is a first-in-class oral, small-molecule agonist of the retinoic acid receptor–related orphan receptor γ (RORγ) being developed as an immuno-oncology agent for solid tumors. In preclinical studies, LYC-55716 reduces tumor growth and enhances survival by reprogramming immune cell gene expression for improved anti-tumor effector functions and decreased immunosuppressive mechanisms. RORγ agonist treatment decreases expression of PD-1 and other co-inhibitory receptors, which may diminish checkpoint inhibition within the tumor microenvironment (TME). Additionally, in syngeneic tumor models, the addition of RORγ agonists enhances the activity of PD-1/PD-L1 inhibitors, which is associated with increased number and activation of tumor-infiltrating lymphocytes and decreased immune suppression. An open-label, multicenter Phase 1b trial is ongoing to assess the safety and tolerability of combining LYC-55716 and pembrolizumab (L+P) to treat patients with non–small cell lung cancer (NSCLC). Methods: The Phase 1b trial (NCT03396497) will evaluate the occurrence of dose-limiting toxicities (DLTs) and determine the recommended Phase 2 dose of L+P in adults with metastatic NSCLC receiving pembrolizumab treatment. Following a screening period, a run-in cohort (n = 3) will receive L+P to monitor for adverse reactions. If no DLTs occur, the main study cohort (n = 15) will receive L+P until disease progression or unacceptable toxicity. Planned pre-/post-treatment tumor biopsies and blood samples will be collected in the main study cohort. Primary endpoints are safety (monitoring of adverse events, physical examination, and lab results) and incidence of DLTs during the run-in period and further treatment. Secondary endpoints for the main cohort include profiling of immune biomarker changes, objective response rate and duration of response, and pharmacokinetics. Patients will be followed for progression-free and overall survival. Clinical trial information: NCT0336497.
Chemotherapy-related qualitative, quantitative, anatomic and volumetric changes of the major salivary glands during concurrent head and neck therapy.
Authors: Bryan M Rabatic, David Zaenger, Nicholas A Madden, Joseph A Marascio, Jeffrey Campbell, Katharine N Ciarrocca, Scott S DeRossi, Darko Pucar, Edward M Marchan, John G Stewart, Ahmad Amoush, Sherif Shaaban, Molly K Nettles, Mahboubeh Pishgou, J Kenneth Byrd, Arturo Solares, Frank Mott, Feng-Ming (Spring) Kong, Catherine L Ferguson, Waleed F Mourad
Journal: Journal of Clinical Oncology (2016)

e17522 Background: Without organ preservation techniques, the toxicity associated with external beam radiation therapy (e.g. xerostomia), adversely affects a patient’s quality of life (QOL). Complicating these changes are multi-modality treatments, particularly, the use of concurrent chemoradiotherapy (CCRT). Here, we compare the chemotherapy effect on the saliva chemistry, anatomic position and volume of the major salivary (parotid and submandibular) glands during CCRT. Methods: This is a pilot study of 10 patients diagnosed with H&N carcinoma treated at our institution from 2014-2015. Daily image-guided intensity modulated radiotherapy and platinum-based concurrent chemoradiotherapy was used. Assessed, were the volume and anatomic positions of the salivary glands at CT simulation and the 12th, 25th, and final fractions. We measured gland translation to a bony reference then, compared the gland volume at the above time points. The Mann-Whitney U test was used for the significance of chemotherapy and gland changes. Saliva was tested at the completion of treatment. Results: Average cohort age was 60, comprised of 7 males and 3 females. There were 6 stage IVA, 2 stage III, 1 stage II, and 1 recurrent, primarily oropharyngeal, squamous cell carcinoma diagnoses. For all glands, mean volume loss was 30% with a mean medial displacement of 6-7mm. Six of 10 patients received weekly or q3w chemotherapy. CCRT resulted in a non-significant mean gland volume loss of 33% (2.5 – 49%), compared to a mean of 25% (8 – 45%) with RT alone. Volume loss was greatest by the first 12 fractions of treatment. For submandibular glands, there was a trend of 36% greater volume loss with CCRT (p= 0.07). No differences in unstimulated/stimulated saliva output or pH was seen between the two groups. Conclusions: Our data suggests a connection with use of concurrent chemotherapy and salivary gland changes. Due to a small sample size, these differences were not statistically significant, however, we are increasing our study size in light of this important result. We wish to identify when gland changes occur, the effect on saliva chemistry, and assess QOL to design an adaptive CCRT paradigm to maximize QOL.
P04.26 The novel therapeutic curcumin enhances targeted bacteriophage mediated in-vitro cell death in primary human DIPG
Authors: G Samarth, K Suwan, M Al-Bahrani, P Asavarut, A Hajitou
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is one of the most aggressive paediatric brainstem tumours, with a dismal prognosis and a 90% mortality rate within 2 years. Over the last 50 years, DIPG patients have seen no increase in survival, owing to progress being hindered by a lack of tissue available for in-vitro study, the critical anatomical location of the pons and the impermeability of the blood-brain barrier (BBB). In this in-vitro study, we describe the use of cancer gene therapy using the targeted-bacteriophage vector to deliver the therapeutic TNFα transgene to DIPG cells, in combination with the novel therapeutic, curcumin, which constitutes the spice turmeric (Curcuma longa). We evaluated the in-vitro cytotoxicity of curcumin in 2D tissue cultures of primary DIPG cells, with cell-viability measured after treatment with varying concentrations of curcumin for 72 hours. Next, we assessed the gene transduction and cell-killing efficacy of the targeted-hybrid bacteriophage, using the Luciferase and TNFα transgenes, at day 3 post-transduction. Lastly, we assessed the effect of combination therapy by adding concentrations of curcumin to DIPG cells at day 3 post-transduction by the bacteriophage, once again evaluating Luciferase expression and cell-killing. Here, we report for the first time, the in-vitro cytotoxicity of curcumin in this DIPG cell line, with significant cell death seen at as low as 37.5μM. Secondly, we show that primary DIPG cells can be successfully transduced with the targeted-modified bacteriophage vector, containing the TNFα gene, leading to TNFα-mediated cell death. Lastly, we show that the combination of curcumin with the targeted-bacteriophage vector led to enhanced DIPG cell death, due to increased bacteriophage-mediated transgene expression. We have shown that combination chemovirotherapy of curcumin and the targeted bacteriophage is efficacious in-vitro, warranting further in-vivo work to assess the safety and efficacy after systemic delivery.