tbuckley/cabot-search huggingface dataset:
Is there a link between value as defined by ESMO-MCBS and uptake of new drugs?
Authors: Peter Lindgren, Bengt Jönsson, Thomas Hofmarcher, Nils Erik Wilking
Journal: Journal of Clinical Oncology (2016)

6620 Background: There has been an increased interest in ways of measuring the value of new therapeutic options in oncology. Recently the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) have been introduced as one such measure. The objective of the scale is to assist decisions about value and cost-effectiveness of new therapies by classifying therapeutic advances according to their relative clinical benefit based on pre-defined criteria. We hypothesize that the perceived value of a new drug would be a major driver of its widespread use, and therefore that one way of establishing the extent of which the scale captures value would be how well it correlates with actual use. Methods: This was a retrospective study analyzing data on sales from the member states of the European Union plus Norway and Switzerland. The study included drugs launched between 2004 and 2013 also having a published ESMO-MCBS score. In cases where more than one score had be assigned, we used the one related to the first published trial. We analyzed uptake of the drugs for a time period up to three years after launch. Uptake was defined as sales (€) per case. Death caused by the type of cancer the drug being indicated for at launch adjusted for the maximum proportion of these being candidates for treatment was used as the definition of a case. T-tests were used to test differences between groups. Results: 17 drugs were identified distributed across the ESMO-MCBS categories 2 - 5 (3 drugs had received a score of 2, 3 a score of 3, 10 a score of 4 and 1 a score of 5, the later having only one full year of follow-up). Drugs in group 4 had higher mean 3-year sales in absolute terms compared to group 2 and 3 (25,512 € per case compared to 8,179 and 11,204 € per case), with the same pattern being true for each individual year of sales post launch. Differences were not statistically significant, possibly due to the very large variation within group 4. Conclusions: Although there seemed to be a tendency for drugs with higher ESMO-MCBS rating to have higher sales, the large variations among drugs classified as belonging to group 4 highlight a potential problem with the scale to discriminate value for drugs within this group.
Significant systemic and CNS activity of RET inhibitor vandetanib combined with mTOR inhibitor everolimus in patients with advanced NSCLC with <i>RET</i> fusion.
Authors: Tina Cascone, Vivek Subbiah, Kenneth R. Hess, Sarah Nelson, Monique B. Nilsson, Ishwaria Mohan Subbiah, Siraj Mahamed Ali, David Paul Carbone, Ravi Salgia, Taofeek Kunle Owonikoko, Funda Meric-Bernstam, Robert Charles Doebele, John Heymach
Journal: Journal of Clinical Oncology (2016)

9069 Background: RET gene fusions (RET+) occur in 1% of NSCLC and are established oncogenic drivers. The RET inhibitors vandetanib & cabozantinib have antitumor activity in RET + NSCLC pts. However resistance rapidly emerges to monotherapy. To address the need for more active regimens we investigated the combination of vandetanib (V) with mTOR inhibitor everolimus (E)(NCT01582191). Methods: In vitro cell proliferation studies and western blot analysis of protein phosphorylation following treatment with V or E alone, & in combination, were performed on 2 cell lines expressing the CCDC6-RET fusion protein, LC-2/ad (NSCLC) & TPC1 (papillary thyroid cancer). V and E were administered PO QD x 28 days. Tumor responses were assessed by RECIST. RET fusions were detected by FISH and/or or next generation sequencing (NGS) using at least 50 ng of DNA. Results: In vitro, V inhibited phosphorylation of the CCDC6-RET protein & abrogated signaling through MAPK, while only modestly inhibiting phosphorylation of p70-S6 kinase and S6 ribosomal protein, whereas E robustly decreased the activation of these mTOR effectors & had no effect on MAPK. Monotherapy V or E inhibited cell proliferation in LC-2/ad and TPC1 cells, but combination was superior to either monotherapy. Among 13 stage IV NSCLC pts on the trial, the median age: 62 (21-75 years) & 5 pts (38%) were male. Common AE’s included:G1-G3 diarrhea (7, 54%); G1 mucositis (5, 39%). Six pts had tumors harboring RET fusions by NGS (KIF5B-RET, 4; CCDC6-RET, 2), while another 2 pts were FISH+, but NGS–). Across the NSCLC pts best responses were PR (5; 38%), and SD (n = 5; 38%). Among the 6 pts with RET fusions, 5 achieved PR (83%), including a cabozantinib progressor, and 1 SD (16%) with 24 % decrease. RET+ was associated with clinical response (P= 0.0047 for PR in RET + vs. RET– pts). The combination demonstrated significant CNS activity in 3/3 (100%) RET+ pts with brain metastases. Conclusions: V and E demonstrated significant activity in RET re-arranged NSCLC, with responses observed in 6 of 6 (100%) of patients with RET+ NSCLC identified by NGS. Antitumor activity was observed in CNS and cabozantinib-refractory disease. Further studies are warranted. Clinical trial information: NCT01582191.
TP53 mutations and programmed cell death ligand-1 expression in solid tumors: Associations with clinical factors and outcomes.
Authors: Ed Kheder, Kenneth R. Hess, Yan Xing, Maria Angelica Cortez, Vivek Subbiah, Filip Janku, Siqing Fu, Aung Naing, Daniel D. Karp, Sarina Anne Piha-Paul, Timothy Anthony Yap, Shubham Pant, Jordi Rodon Ahnert, Hussein Abdul-Hassan Tawbi, James William Welsh, Funda Meric-Bernstam, David S. Hong
Journal: Journal of Clinical Oncology (2018)

12052 Background: The regulation of Programmed cell death ligand-1 (PD-L1) expression remains poorly understood. Preclinical data suggest that TP53, via microRNA-34, regulates PD-L1 expression in lung adenocarcinoma cell-line. We aimed to estimate the correlation between TP53 mutations and PD-L1 expression in solid tumors. Methods: We reviewed pathology, immunohistochemical (IHC) and mutational analysis reports of patients who were diagnosed with advanced solid tumors and treated at MD Anderson Cancer Center. We used Kaplan-Meier, logistic regression, and Cox PH regression, for statistical analysis. Survival was computed from date of biopsy used for mutational analysis. Results: We analyzed data from 302 patients [136(45%) female, 163 (55%) male; median age: 57 years, range (16-83); median OS: 43 month]. One hundred and three (34%) patients had TP53 mutations, 105 (35%) patients had PD-L1 ≥ 1%, and 50 (18%) had both. Tumor types (%): GI 41 (14%); GU 36 (12%); non-small cell lung cancer (NSCLC) 54 (18%); melanoma 40 (13%); sarcoma 27 (9%); head and neck (HNC) 21 (7%); others 83 (27%). The association between TP53 mutations and tumoral PD-L1 expression was significant across all patients [OR: 2.47, 95%CI (1.5-4.07). p = 0.0003], but changed significantly with tumor type (p = 0.021): OR: 5.3 sarcoma; 5.2 “other”; 3.6 NSCLC; 1.4 melanoma; 1.1 GU; 0.7 GI. The odds of PD-L1 expression increased with age [30 year increase OR: 1.84, 95%CI (1.01, 3.38). p = 0.044], but not sex [OR: 1.0, 95%CI (0.6, 1.7). p = 0.87]. TP53 mutation was associated with worse OS [HR = 1.6, 95% CI (1.1, 2.2). p = 0.010] and PD-L1+ with better OS [HR = 0.6, 95% CI (0.4, 0.8). p = 0.0042]. The effect of PD-L1 on OS did not depend on TP53 mutation status (p = 0.37). Among PD-L1+ and PD-L1- patients, OS was related to tumor type (p < 0.004). One-year survival rate of patients treated with PD-1 or PD-L1 inhibitors in phase I trials was independent of PD-L1/TP53 status (p = 0.53). Conclusions: PD-L1 expression is multifactorial. TP53 mutations are highly associated with PD-L1 expression across solid tumors but association significantly varies among tumor types.
Abstract 13801: Cardiopulmonary Bypass is Protective Against Shunt Thrombosis in Patients Undergoing Placement of Modified Blalock-Taussig Shunt
Authors: Jason T Patregnani, Anthony A Sochet, Darren Klugman, Yaser Diab, John Berger, Pranav Sinha
Journal: Circulation (2016)

Introduction: Enhancements in surgical technique and cardiopulmonary bypass (CPB) technology have contributed to dramatically improved outcomes of staged palliation for single ventricle patients. However, in-hospital mortality after first stage palliation procedures remains high at 16%. Systemic to pulmonary artery shunt (SPS) thrombosis is a major contributor to morbidity in these patients with an incidence reported between 5 to 37%. Cardiopulmonary bypass is known to have hypocoagulable sequelae. Hypothesis: Hypocoagulable sequelae of CPB are protective against early thrombosis of systemic to pulmonary artery shunts. Methods: We performed a retrospective cohort study from January 2008 through December 2014 of all children undergoing single ventricle palliation with a SPS. Early shunt thrombosis was defined as clinical hypoxemia necessitating cardiac catheterization, with angiographic evidence of a thrombosis within the shunt during the same admission. Cohorts with and without early shunt thrombosis and those with and without CPB were compared using Wilcoxon sign rank sum test, Student’s t-test and Fisher’s exact test as appropriate. Unadjusted logistic regression was used to assess independent predictors for development of shunt thrombosis. Results: Within the study period a total of 75 neonates underwent placement of SPS (with CPB n = 25, without CPB n = 50) with an operative mortality of 11%( 8/75). In this cohort, 12% (9/75) patients developed an early shunt thrombosis during the index admission. All instances of shunt thrombosis were observed in cases performed without CPB (without CPB n = 9; with CPB n =0) (p = 0.03). Unadjusted logistic regression of CPB on early shunt thrombosis yielded an odds ratio of 0.14 (95% CI: 0.01-0.93, p = 0.04). Conclusions: Patient’s undergoing SPS placement without CPB have an increased incidence of shunt thrombosis as compared to those with CPB. Additional studies to understand the hypocoagulable sequelae of CPB are required and may help in preventing shunt thrombosis in patients undergoing SPS.
Trend in treatment aggressiveness at the end of life in an Italian homogeneous area: Preliminary data.
Authors: Davide Tassinari, Ilaria Panzini, Elisabetta Fabbri, Chiara Cherubini, Davide Gallegati, Lucia Rossi, Oriana Nanni, Ilaria Massa, Marco Maltoni
Journal: Journal of Clinical Oncology (2016)

e18227 Background: To assess the attitude of physicians in treating with antineoplastic treatments patients with advanced cancer at the end of life. Methods: The records of all cancer patients deceased in Romagna in 2013 were reviewed. For all the patients were reported name, sex, age in 2013, kind of disease, kind of treatment, date of the last administration of chemotherapy, date of death, cumulative costs of the antineoplastic treatments. Primary aim of the trial was to assess the length from the last administration of chemotherapy and death; secondary end points were to assess the differences in the different districts of the Area, the kind and the costs of the treatments. The results are the preliminary phase of an integrated process of audit in the area on the effectiveness of the integration of oncology and palliative care on the comprehensive quality of care in favor of patients with advanced cancer. Results: Romagna is an homogeneous area of the north-east of Italy accounting 1123093 inhabitants and 3460 deaths for cancer in 2013 (3.08x10-3 inhabitants). Three districts with 2 oncologic departments and 1 cancer center exist in the area, with respectively 335199, 391997 and 395897 inhabitants and 967, 1293 and 1200 deaths for cancer in 2013 (2.88, 3.29 and 3.13x10-3inhabitants). The number of the patients treated in the last 30 and 14 days of life and the cumulative costs of the treatment are reported in the table. Conclusions: Our preliminary data confirms the attitude of clinicians in treating patients until the last part of life. This attitude probably reduces the comprehensive quality of the care, but does not seem to represent a significant factor increasing the costs of the treatments. The differences between the districts, although partly due to the different vocations of the centers probably need a clinical audit to assess the reasons of the phenomenon. Center Treated in the last 30 days of life Cumulative costs (x 1000€) Treated in the last 14 days of life Cumulative costs (x 1000€) District 1 34 (10.97%) 18.293 14 (4.52%) 9.337 District 2 60 (13.27%) 118.513 22 (4.87%) 39.480 Cancer Center 128 (25.81%) 81.904 62 (12.5%) 28.847 Romagna 222 (17.64%) 218.71 98 (7.79%) 77.665
Possibility of detection of circulating tumor cells (CTCs) in blood of patients with lung cancer.
Authors: Inna Arnoldovna Novikova, Oleg Ivanovich Kit, Andrey Vladimirovich Bakhtin, Olesya N. Selyutina, Rukiyat Isaeva, Sergey P. Pyltsin, Elena Petrovna Ulianova, Elena Bondarenko
Journal: Journal of Clinical Oncology (2016)

e23095 Background: The purpose of the study was to assess the possibility of detection and to compare CTCs in patients with non-small cell (NSCLC) and small cell (SCLC) lung cancer using the CellSearch system. Methods: Analysis of the number of CTCs, taking into account morphological characteristics and expression of markers of adhesion of epithelial cells EpCAM, CD45, cytokeratins 8, 18 and 19 in peripheral blood of 11 stage IV NSCLC patients and 9 stage IV SCLC patients aged 50-69 years (mean age 52.3±4.8) was performed using CellSearch Veridex System, Janssen. Results: CTCs were detected in 16 (80%) of 20 patients with lung cancer in an amount of 1 to 980 cells in 7.5 ml of the blood; in patients with NSCLC – 10 of 11 patients (91%), SCLC – 6 of 9 patients (66.7%). CTCs amount in SCLC was 1 to 980 cells, in NSCLC – from 1 to 13 cells. 1-10 CTCs were found in 50% (8 of 16 patients), 11-100 CTCs – 25% (4 of 16 patients), over 100 CTCs – 25 % (4 of 16 patients). Patients with > 100 CTCs prevailed in the SCLC group (66.6%, 4 of 6 patients), while the lowest and average amounts were observed in 16.7% (1 patient) each. NSCLC patients showed the opposite results: 80% (8 of 10 patients) with the lowest CTCs level and 20% (2 of 10 patients) with average level; high CTCs level was not observed in this group. Conclusions: The study demonstrated the prospects of the CellSearch system in detection of CTCs with CD45-/CK8/18+/CK19+ immunophenotype in patients with SCLC and NSCLC. We observed higher tumor cell detection rate in patients with generalized lung cancer and decreased CTCs detection rate in NSCLC compared to SCLC. CTCs in the blood of NSCLC patients were found 1.4 times more often than in SCLC patients; however, NSCLC showed the low CTCs level prevailing, while in SCLC the high level prevailed.
Incorporating 4D into Bioprinting: Real‐Time Magnetically Directed Collagen Fiber Alignment for Generating Complex Multilayered Tissues
Authors: Marcel Betsch, Catalin Cristian, Ying‐Ying Lin, Andreas Blaeser, Jan Schöneberg, Michael Vogt, Eva Miriam Buhl, Horst Fischer, Daniela Filipa Duarte Campos
Journal: Advanced Healthcare Materials (2018)

In vitro multilayered tissues with mimetic architectures resembling native tissues are valuable tools for application in medical research. In this study, an advanced bioprinting strategy is presented for aligning collagen fibers contained in functional bioinks. Streptavidin-coated iron nanoparticles are embedded in printable bioinks with varying concentrations of low gelling temperature agarose and type I collagen. By applying a straightforward magnetic-based mechanism in hydrogels during bioprinting, it is possible to align collagen fibers in less concentrated hydrogel blends with a maximum agarose concentration of 0.5 w/v%. Conversely, more elevated concentrations of agarose in printable blends show random collagen fiber distribution. Interestingly, hydrogel blends with unidirectionally aligned collagen fibers show significantly higher compression moduli compared to hydrogel blends including random fibers. Considering its application in the field of cartilage tissue engineering, bioprinted constructs with alternating layers of aligned and random fibers are fabricated. After 21 days of culture, cell-loaded constructs with alternating layers of aligned and random fibers express markedly more collagen II in comparison to solely randomly oriented fiber constructs. These encouraging results translate the importance of the structure and architecture of bioinks used in bioprinting in light of their use for tissue engineering and personalized medical applications.
Identification of a prognostic molecular signature composed of 3 genes involved in immunity in muscle-invasive bladder cancer.
Authors: Constance LE Goux, Diane Damotte, Sophie Vacher, Nicolas Barry Delongchamps, Mathilde Sibony, Benoit Terris, Marc Zerbib, Ivan Bieche, Geraldine Pignot
Journal: Journal of Clinical Oncology (2017)

e16029 Background: Immunotherapy in bladder cancer appears to be promising. The aim of this study was to evaluate the involvement of 33 genes of anti-tumor immunity in a wide range of muscle-invasive bladder cancers (MIBC) and to identify new prognostic markers. Methods: The levels of expression of 33 genes involved in anti-tumor immunity were analyzed by real-time quantitative RT-PCR on a consecutive series of 83 TVIM and 15 normal bladder samples. Tissue samples were taken on a cystectomy patch in patients operated between 2002 and 2006. All patients have signed informed consent. The results of the transcriptomic analysis were confirmed by immunohistochemistry and coupled with survival analysis. Results: Of the 33 genes studied, 24 (72.7%) were significantly overexpressed compared to normal bladder tissue. In univariate analysis, overexpression of OX40L was significantly associated with a pejorative prognosis in terms of recurrence-free survival and overall survival (p = 0.0027 and p = 0.014 respectively) while overexpression of CD8 was associated with a better prognosis (p = 0.024 and p = 0.029 respectively). A clustering analysis allowed us to identify a molecular signature composed of 3 genes ( OX40L, CD8 and TIGIT) allowing to separate the tumors into 3 distinct prognostic subgroups. In a multivariate analysis including all clinico-pathological and molecular factors significant in univariate, molecular signature was an independent prognostic factor in terms of recurrence-free survival and overall survival (p = 0.0007 and p = 0.007 respectively). Conclusions: We identified several genes involved in the immune response during bladder urothelial carcinogenesis, as well as a molecular signature composed of 3 genes ( OX40L, CD8 and TIGIT) associated with MIBC prognosis, suggesting a potential interest in Individual step.
Clinicopathological characteristics and prognosis of gastrointestinal cancer with neuroendocrine differentiation.
Authors: Meili Chen, Jieyu Chen, Lixia Yu, Xiaoping Qian, Baorui Liu, Jia Wei, Mi Yang
Journal: Journal of Clinical Oncology (2018)

e16161 Background: The phenomenon of neuroendocrine differentiation (NED) has been observed in gastrointestinal cancer for some time. However, the clinicopathological characteristics and prognosis of gastrointestinal cancer with neuroendocrine differentiation (GI-NED) remains controversial. Methods: This study collected 112 GI-NED patients with clear clinicopathological characteristics from Nanjing Drum Tower Hospital from January 2010 to November 2017. Survival rate was calculated by Kaplan-Meier curve and multivariate prognostic risk factors were analyzed by COX regression model. Results: 112 patients with GI-NED have the following characteristics: more male patients (79.5%), more located in stomach (87.5%), more in low degree of differentiation (89.3%), more in T3/T4 (73.2%), and main histological type was common adenocarcinoma (94.6%). The positive expression rates of CgA and Syn were 70.5% and 74.1%, both expression rate was 44.6%. Survival analysis showed no significant difference in survival curves between patients with high expression and low expression of neuroendocrine markers (P = 0.806, P = 0.766). Multivariate analysis showed that the patient age, tumor location and TNM stage were the risk factors affecting the prognosis (P < 0.05). Conclusions: Immunohistochemistry is the main method to diagnose GI-NED. Our study shows that the age, tumor location and TNM stage are related to the prognosis of patients. The expression of neuroendocrine markers Syn and CgA have no correlation with the prognosis of GI-NED.
Analysis of the University of North Carolina (UNC) and the Cancer Genome Atlas Project (TCGA) next generation sequencing (NGS) datasets to identify somatic mutations (SM) with prognostic significance in cutaneous melanoma (CM).
Authors: Stergios J. Moschos, Xiaobei Zhao, David N. Hayes
Journal: Journal of Clinical Oncology (2016)

9557 Background: Genotyping for therapy selection is now standard of care in advanced melanoma. The prognostic significance of genome-wide SM has not been adequately explored. Methods: Patient (pt) data (clinical followup, DNA and RNA sequencing) were obtained from large NGS projects, including pts enrolled in the UNC trial LCCC1108, pt with brain metastases, and the TCGA. SM were then characterized by the ANNOVAR software and filtered for functional significance. Only genes with SM variants in > 2% of samples were considered. We investigated the association between functional SM and overall survival (OS), using time-dependent linear regression models within an otherwise clinically similar risk pt group (AJCC stage III/IV). Detection of all relevant variant alleles was validated by RNA expression using the UNCeqR method. Results: To date, 267 pts met all above criteria (108 and 159 of pts were censored or dead, respectively). Median follow-up was 53.6 months. 19,753 of 274,466 SM showed potential functional importance and > 80% SM were validated by UNCeqR. 18 of 618 genes, which met the inclusion criteria were significantly associated with OS. Genes demonstrated both favorable [e.g. WHSC1, TPTE, STAG2, PPP6C with hazard ratios (HR) 0.29, 0.30, and 0.30, 0.45, respectively] and unfavorable (e.g. KIT, FGFR1, DNAH10, PLCB4, CNTN1, POU5F1, DBC1, CDX2 with HR 1.96, 2.04, 2.35, 2.62, 3.43, 3.71, 3.97, 5.93, respectively) associations with OS. Most SM were suggestive of a loss-of-function pattern consistent with tumor suppressor genes. Genes coding for proteins involved in non-MAPK mediated signal transduction pathways (KIT, FGFR1, PLCB4, CNTN1), motility (DNAH10), cell cycle progression (DBC1), and transcription embryologic control (POU5F1, CDX2) tended to associate with worse OS. Genes coding for proteins involved in m phase (STAG2, PPP6C) demonstrated a protective effect. Conclusions: Clinicians currently offering SM panels to pts for clinical decision making may consider including these genes for prognostic implications. Updated analysis will be reported at the time of presentation.