tbuckley/cabot-search huggingface dataset:
Genomic profiling and targeted therapy in cholangiocarcinoma to yield positive clinical outcomes.
Authors: Lincoln Nadauld, Eric Goold, Brian P. Tudor, Heather Gilbert, Karen Yin Lin, James M. Ford, Derrick S. Haslem
Journal: Journal of Clinical Oncology (2016)

e23162 Background: Cholangiocarcinoma is an uncommon gastrointestinal malignancy that remains relatively understudied even as its worldwide incidence continues to climb. The treatment options for patients with advanced disease are few. Molecular profiling of cholangiocarcinomas can identify actionable genomic alterations that represent novel treatment options for patients with refractory disease. The clinical outcomes associated with targeted treatments in cholangiocarcinoma remain largely unreported. Methods: We reviewed a cohort of 315 patients with advanced solid malignancies who had genomic tumor testing in our precision cancer genomics program. We identified 16 cholangiocarcinoma patients and analyzed their genomic results to report the most common genomic alterations associated with advanced cholangiocarcinoma; and, we reviewed the responses (according to RECIST 1.1 criteria) of four patients who subsequently received molecularly targeted therapy directed at actionable genomic alterations. Results: In the cohort of 16 cholangiocarcinoma patient samples, 14 harbored actionable molecular alterations, 8 of whom harbored alterations in the FGF Receptor family. The most frequent molecular alterations were found in TP53, ERBB2, ATM, FGFR1, FGFR2, and CDKN2A. 4 of 14 patients with an actionable alteration received molecularly targeted therapy. Three patients received pazopanib to target FGFR pathway alterations resulting in two partial responses, and one case of disease progression. A fourth patient received Trametinib to target an HRAS alteration which resulted in stable disease for 10 months. Conclusions: Genomic profiling of cholangiocarcinomas reveals the presence of multiple actionable alterations that represent novel treatment opportunities. Targeting FGFR family pathway alterations with Pazopanib resulted in a positive clinical outcome in three patients suggesting this may represent a viable treatment alternative in advanced cholangiocarcinoma. The presence of a durable positive response to RAS pathway inhibition indicates the need for further investigation of this approach in cholangiocarcinoma. These results support the advancing precision cancer medicine paradigm.
The application of electronic medical records (EMRs) as a virtual comparator arm in a lung cancer clinical trial: A case study.
Authors: Ketan Patel, Mario Ouwens, Norah Shire, Sajan Khosla
Journal: Journal of Clinical Oncology (2017)

e18098 Background: Single-arm and open-label clinical studies are common in oncology drug development, leading to a frequent need for contextualization of results and provision of other means of comparison for cost-effectiveness models. The utility of current approaches such as naïve comparisons, historical control benchmarking, and match-adjusted interventional controls is limited. An alternative approach is the use of routinely collected data from Electronic Medical Records (EMRs). This study sought to determine if overall survival (OS) in advanced non-small cell lung cancer patients from a clinical trial comparator arm could be replicated using EMR data. Methods: De-identified EMR-derived patient data from Flatiron Health were matched via propensity scores to Project Data Sphere clinical trial data for study NCT00457392 of sunitinib plus erlotinib versus erlotinib alone to compare overall survival outcomes. A Cox regression model stratified for dataset was used to estimate the hazard ratio and 95% confidence interval for OS. Results: The Kaplan Meier curves were comparable for the first period after start of treatment, but differed after median survival was reached, with the Flatiron dataset achieving longer median OS. This deviation was strongly associated with differences in post-erlotinib treatment options introduced between the clinical trial period and the EMR period. Splitting the Flatiron data in two, related to the period from which the data were obtained (pre- or post-2013), resulted in a better match for the period closer to the trial [HR: 1.12 (0.93,1.35), P = 0.219] than for the later period [HR: 1.23 (1.01,1.5), P = 0.039]. Conclusions: Our results demonstrate that the time period in which EMR data are collected is important when matching to trial data. EMR data can contextualize the OS benefit for single-arm or uncontrolled trials run in the same time period. Further exploration of time-varying effects on OS is warranted.
P04.64 Molecular characterization of glioma patient derived orthotopic xenografts to improve outcome of preclinical studies
Authors: A Golebiewska, A Hau, A Oudin, L Houben, D Stieber, F Azuaje, T Kaony, A Muller, F Hertel, M Mittelbronn, R Bjerkvig, S P Niclou
Journal: Neuro-Oncology (2018)

It is well recognized that long term cell cultures are poor models to study human cancer, largely because of loss of clonal heterogeneity, accumulation or loss of genomic alterations and adaptation to a highly artificial environment. Patient-derived orthotopic xenografts (PDOX) based on organotypic three-dimensional tumor spheroids from human glioma samples are proposed to represent a reliable and clinically-relevant animal model. A living biobank of PDOX models from 34 glioma patients (grade III and IV), including longitudinal patient samples with matched recurrent tumors, were generated by intracranial grafting of organotypic tumor spheroids in immunedeficient mice. Genetic/epigenetic analyses on patient biopsies and corresponding PDOX included array comparative genomic hybridization, transcriptional profiling, targeted sequencing and methylation arrays. Using an efficient orthotopic xenografting procedure we obtain an overall tumor take-rate of close to 80%. We show that glioma PDOX retain the genetic and epigenetic profiles of primary patient biopsies throughout several generations of xenotransplantation. In particular they not only faithfully recapitulate gene amplification and expression of EGFR and EGFRvIII variant in a reproducible manner, also amplification and expression of rarer patient-specific EGFR variants is maintained. Overall genome-wide transcriptomic profiles of PDOXs remain very similar to patient biopsies and correlate better with the GBM cohort of TCGA (538 GBM samples) than conventional cell lines. Observed differences at the transcriptomic level are largely based on the replacement of human to mouse stromal cells, which impacts on the molecular sub-classification of GBM. We conclude that glioma PDOX models reflect patient heterogeneity and treatment response, and represent appropriate avatars for reproducible pre-clinical trials. Furthermore, by combining profiling of the somatic mutational landscape with large-scale drug screening, PDOX-derived tumor organoids can be applied to elucidate druggable targets and tumor response profiles in a personalized patient-specific manner.
Generalizability of common cancer clinical trial eligibility criteria in the real world.
Authors: Safiya Karim, Yuan Xu, May Lynn Quan, Joseph C. Dort, Antoine Bouchard-Fortier, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2018)

e18616 Background: Clinical trials are the gold standard for evaluating novel interventions, but only a small proportion of patients participate. Strict eligibility criteria can contribute to low accrual and result in study findings that have poor generalizability. Using exclusion criteria common to most clinical trials, our aims were to 1) determine how many patients would be eligible vs. ineligible to enroll and 2) describe how actual treatments and outcomes differed between trial eligible and ineligible patients in the real world. Methods: We assembled a cohort of patients diagnosed with 11 common malignancies between 2004 and 2015 in a large Canadian province. We considered age > 75 years, anemia, co-morbid conditions (heart disease, uncontrolled diabetes, kidney disease, liver disease) and history of a prior malignancy and immunosuppression to be exclusion criteria. Logistic regression was used to characterize the likelihood of receiving cancer treatment. Cox regression models were constructed to determine cancer specific (CSS) and overall survival (OS). Results: We identified 125,316 patients with a cancer diagnosis, of which 53% were men and the median age was 66 (IQR 48-84) years. Approximately 38% of all patients were considered trial ineligible. The most common reasons for ineligibility were advanced age (24%) and heart disease (16%). In this ineligible group, 12%, 47%, and 19% still received chemotherapy (CT), surgery, and radiation (RT), respectively, outside of trials. Compared to eligible patients, ineligible patients were less likely undergo CT (OR = 0.51, 95%CI 0.49-0.53, p < 0.0001), surgery (OR: 0.72, 95%CI 0.68-0.76, P < 0.0001), or RT (OR: 0.70, 95%CI 0.67-0.73, P < 0.0001). Compared to ineligible patients who did not receive treatment, those considered ineligible but still underwent treatment experienced improved CSS (HR 0.75, 95%CI 0.74-0.77, P < 0.0001) and OS (HR 0.89, 95%CI 0.87-0.90, P < 0.0001). Conclusions: A significant proportion of real world patients are unable to participate in clinical trials due to stringent exclusion criteria, but many still received treatment outside of clinical trials and benefited from therapy. Eligibility criteria of oncology clinical trials should be broadened.
Cost and morbidity of surgical management of resectable gallbladder cancer (GBC): Results from the National Inpatient Sample database.
Authors: Christos Fountzilas, Devalingam Mahalingam, Joel Michalek, Sukeshi Patel Arora
Journal: Journal of Clinical Oncology (2017)

e15663 Background: GBC is the most common biliary tract cancer. Based on a retrospective, single-institution data, extended cholecystectomy (EXT) has been recommended over simple cholecystectomy (CHOL) in tumors T2 and above. Retrospective data indicate increased morbidity/mortality with removal of more than 3 segments of the liver compared to CHOL and the effect on long-term survival is unclear. Therefore, we sought to identify short-term outcomes of hospitalization, such as cost and morbidity, for surgical treatment of GBC. Methods: The National Inpatient Sample/Healthcare Cost and Utilization Project (NIS/HCUP) for years 2010, 2011, 2012 and 2013 was surveyed for GBC hospitalizations. Hospitalizations for non-surgical management of GBC were excluded. Results: We identified 5,612 cases; mean age in EXT was 66.8 years vs. 72.4 in CHOL (p&lt;0.001). Patients insured through Medicare were less likely to have EXT (OR: 1.5, 95% CI 1.125-2.064; p=0.007). No difference based on race (OR: 1.14, 95% CI 0.854-1.519; p=0.38). Surgical/Medical morbidity is presented in Table 1. In-hospital mortality was 3.3 vs. 4.1% for EXT and CHOL, respectively (p=0.55). Mean length of stay was higher in the EXT group (9.8 vs. 8.3 days, p=0.03), cost ($32,782 vs. 22,667.3, p=0.003) and total charges ($111,714.7 vs. 81,432.9, p&lt;0.001). Conclusions: EXT for resectable GBC is associated with higher cost of care, probably related to higher risk for surgical site infection and stump leak. Until more evidence for overall survival benefit from EXT in this rare tumor emerges, referral of patients to high-volume centers with the hepatobiliary surgery expertise is recommended. [Table: see text]
High Risk of Fatal and Nonfatal Venous Thromboembolism in Myotonic Dystrophy
Authors: Maximilien Sochala, Raphaël Porcher, Tanya Stojkovic, Henri Marc Bécane, Anthony Béhin, Pascal Laforêt, Guillaume Bassez, Sarah Leonard-Louis, Bruno Eymard, Denis Furling, Denis Duboc, Karim Wahbi
Journal: Circulation (2018)

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TCT-360 Assessment of Heart Team’s Treatment Decision Variability: Insights from the SYNTAX III Revolution trial.
Authors: Yoshinobu Onuma, Francesco Alamanni, Gianluca Pontone, Stefano De Martini, Xavier Orry, Damien Mandry, Daniele Andreini, Taku Asano, Yuki Katagiri, Marie-Angele Morel, Jeroen Sonck, Patrick Serruys, Carlos Collet
Journal: Journal of the American College of Cardiology (2018)
Some parameters of the local immunity of patients with cancer of the oral mucosa and tongue.
Authors: Irina V. Aedinova, Oleg Ivanovich Kit, Inna Arnoldovna Novikova, Galina I. Zakora, Elena Yurievna Zlatnik, Olesya N. Selyutina, Elena Petrovna Ulianova, Pavel V. Svetitskiy, Viktoriya L. Volkova
Journal: Journal of Clinical Oncology (2016)

e17529 Background: Evaluation of the local immunity factors in oncological patients is an important problem with theoretical and practical aspects. The purpose of this study was comparative analysis of the local immunity factors in patients with tongue and oral cavity cancer without metastases, with regional metastases and with recurrences. Methods: Levels of some cytokines were determined by ELISA and levels of the main subpopulations of T-lymphocytes and macrophages were determined by immunohistochemistry (IHC) using Dako antibodies in tissue homogenates of tumor and peritumoral zone samples of patients with cancer of the oral mucosa and tongue (n = 60). Results: A higher content of anti-inflammatory cytokines IL-1ß, IL-6, IL-8 (by 3-10 times; P < 0.05) was found in tumor tissue of patients with and without metastases in comparison with their peritumoral zone. Tissues of recurrent tumor and peritumoral zone did not show such differences which supposed similarity in immunological characteristics of visually non-malignant tissue and the tumor one, as well as the loss of its features limiting proliferative potential of the tumor. Levels of interferons, IL-2 and IL-10 in tissue samples were not high and did not differ between tumor and peritumoral zone or between groups of patients. IHC in all groups revealed the prevalence of CD8+ T-lymphocytes in lymphocytic-macrophage infiltrate and a marked infiltration with CD68+ macrophages; CD4+ lymphocytes were solitary and located separately in stroma and areas of tumor growth. In primary tumors, CD68+ macrophages amounted up to 20% of infiltrate in tumor parenchyma and 20-40% at the border between tumor and peritumoral zone. In metastases and recurrences, CD8+ lymphocyte content in stroma and parenchyma of tumor was lower. Level of CD68+ macrophages did not exceed 10% in the group with metastases, while an abundant diffuse infiltration with macrophages was noted in stroma and parenchyma (up to 40% of infiltrate) in recurrences. Conclusions: The studied local immunity factors can contribute to the progression and dissemination of tumor.
Exposure-response and PD-L1 expression analysis of second-line avelumab in patients with advanced NSCLC: Data from the JAVELIN Solid Tumor trial.
Authors: James L. Gulley, David R. Spigel, Karen Kelly, Joseph Aisner, Vikram K. Chand, Andre Koenig, Hugues Dolgos, Shaonan Wang, Claire F. Verschraegen
Journal: Journal of Clinical Oncology (2017)

9086 Background: Avelumab is a fully human anti‒PD-L1 IgG1 antibody showing promising efficacy and safety in patients (pts) with non-small cell lung cancer (NSCLC) and other tumors. Here, we present exposure–response (E–R) and PD-L1 expression analyses of second-line (2L) avelumab treatment in pts with NSCLC from a phase 1 trial (NCT01772004). Methods: Pts with NSCLC received 2L avelumab 10 mg/kg IV every 2 weeks (Q2W) until progression or unacceptable toxicity. Serum samples were taken at various time points for pharmacokinetic (PK) analysis. Trough concentrations after first dose (Ctrough first-dose ) were predicted using an identified linear 2-compartment population PK (popPK) model without covariates other than pt body weight. Objective response rate (ORR) was evaluated (RECIST v1.1), and correlated with tumor cell (TC) PD-L1 expression (clone 73-10). Pooled safety data from various tumors in the large phase 1 trial were assessed. Results: In 184 avelumab-treated pts, unselected for PD-L1 expression, ORRs were 8.7%, 10.9%, 19.6%, and 17.4% for increasing quartiles of Ctrough first-dose (Q1–4). Using ≥1%, ≥5%, ≥50%, and ≥80% PD-L1 staining cutoffs, pts in the upper half of exposure (Ctrough first-dose Q3–4 [n = 92]), had ORRs of 25% (n = 59), 26% (n = 39), 33% (n = 21), and 43% (n = 14), respectively. Higher avelumab exposure was associated with a modest increase in immune-related adverse events (irAEs). PopPK modeling suggested Ctrough first-dose could be optimally increased with alternate avelumab dosing (10 mg/kg weekly vs Q2W, or 20 mg/kg Q2W [simulated median Ctrough first-dose 48 μg/mL vs 18 μg/mL, or 36 μg/mL]). Conclusions: Avelumab has shown clinical activity and acceptable safety in multiple tumors similar to other agents in class. Preliminary analysis of a cohort of pts with 2L advanced NSCLC shows a trend for higher ORR with increasing avelumab Ctrough first-dose quartiles and with higher levels of TC PD-L1 expression. Although this apparent E–R observation may be confounded by single-dose testing or other factors, this analysis provides rationale for studies of more intensive avelumab dosing regimens to assess further clinical benefit in pts with advanced NSCLC. Clinical trial information: NCT01772004.
Abstract 11756: St-segment Elevation Myocardial Infarction in Young Patients - Analysis of Age Specific Risk Factors and Outcome-parameters
Authors: A. Fach, J. Schmucker, L. A Mata Marin, H. Wienbergen, S. Bünger, P. Conradi, E. Fiehn, R. Hambrecht
Journal: Circulation (2015)

Introduction: ST-segment elevation myocardial infarction (STEMI) is relative rare in a population younger than 45years(y45). Despite the socio-economic impact, the specific risk factor (RF) profile in Y45 has been less studied as compared to older patients(pts). Hypothesis: This study compared STEMI pts in terms of age specific RF, severity of myocardial infarction (MI) and outcomes between 2006 and 2014. Methods: The Bremen heart center is exclusively responsible for emergency PCI in a metropolitan region of about 1 million inhabitants. Since 2006 all consecutive pts with STEMI were included in the Bremen Heart Registry. Results: Of the 6329 included pts 450 (7%) were y45. Young pts were significantly often active smokers (85 vs 40%, p&lt;0.01), characterized by a positive family history (FH) for cardiovascular disease (CVD) (44 vs 21%, p&lt;0.01) and obesity (body mass index &gt;30kg/m 2 : 29 vs 24%, p=0.04). These results were confirmed in a multivariate logistic regression model (table). While the number of young active smokers per year was constant (2006-09: 85% vs 81% in 2010-14, p=0.1), the proportion of obese pts increased significantly over time (2006-09:23% vs 36% in 2010-14, p&lt;0.01). Y45 more often suffer larger MI (creatin kinase &gt;3.000U/l: OR 1.7, 95% CI 1.3-2.1) and require prehospital resuscitation (OR 1.6, 95% CI 1.2-2.2). Despite these facts 30 day mortality (30dm) (2.4 vs 11.1%, p&lt;0.01) and 1year mortality (1ym) (3.6 vs 14.5%, p&lt;0.01) was significantly lower in y45. Conclusions: The results of this large registry-study demonstrate that STEMI in y45 is characterized by more extensive MI and higher rates of pre-hospital resuscitation events. Nether the less the 30dm and 1ym is significantly lower than in older pts. The dominating RF in young STEMI pts was active smoking (85%), followed by a positive FH and obesity. To optimize prevention strategies further investigations have to be enforced elucidating specific genetic determinants of CVD in young pts.
Two-stage oxygen delivery for enhanced radiotherapy by perfluorocarbon nanoparticles
Authors: Zaigang Zhou, Baoli Zhang, Haoran Wang, Ahu Yuan, Yiqiao Hu, Jinhui Wu
Journal: Theranostics (2018)

Tumors are usually hypoxic, which limits the efficacy of current tumor therapies, especially radiotherapy in which oxygen is essential to promote radiation-induced cell damage. Herein, by taking advantage of the ability of perfluorocarbon (PFC) to promote red blood cell penetration, we developed a simple but effective two-stage oxygen delivery strategy to modulate the hypoxic tumor microenvironment using PFC nanoparticles. Methods: We first examined the two-stage oxygen delivery ability of PFC nanoparticles on relieving tumor hypoxia through platelet inhibition. To evaluate the effect of PFC nanoparticles on radiation sensitization, CT26 tumor and SUM49PT tumor model were used. Results: In this study, PFC was encapsulated into albumin and intravenously injected into tumor-bearing mice without hyperoxic breathing. After accumulation in the tumor, PFC nanoparticles rapidly released the oxygen that was physically dissolved in PFC as the first-stage of oxygen delivery. Then, PFC subsequently promoted red blood cell infiltration, which further released O2 as the second-stage of oxygen delivery. Conclusion: The hypoxic tumor microenvironment was rapidly relieved via two-stage oxygen delivery, effectively increasing radiotherapy efficacy. The safety of all substances used in this study has been clinically demonstrated, ensuring that this simple strategy could be rapidly and easily translated into clinical applications to solve the clinical problems associated with tumor hypoxia.
Child Sexual Orientation and Gender Identity in the Adolescent Brain Cognitive Development Cohort Study
Authors: Jerel P. Calzo, Aaron J. Blashill
Journal: JAMA Pediatrics (2018)

The FDA does not have authority to ban tobacco sales in pharmacies.Therefore, this research could inform public opinion about such regulation at the state and local levels.Although strong public support for tobacco-free pharmacies exists, only 4 states have adopted such local ordinances, and efforts to pass state legislation have stalled.In the absence of voluntary or legislated actions to establish tobacco-free pharmacies, corporate-owned pharmacies should better prevent tobacco sales to minors, especially given the rapid adoption of state and local policies to increase the minimum legal purchase age from 18 to 21 years.Federal and state enforcement should consider targeting pharmacy chains with higher levels of noncompliance with the minimum legal sale age.