tbuckley/cabot-search huggingface dataset:
Lower prevalence of PD-L1 expression in advanced non-small lung cancer in Brazil.
Authors: Ana Caroline Gelatti, Fernando Moura, Ana Maria Franco Gaiger, Mariana Petaccia de Macedo, Lisandro Ferreira Lopes, Facundo Zaffaroni, Vladmir Claudio Cordeiro De Lima, Gustavo Werutsky, Luiz H. Araujo, Samira Mascarenhas, Clarissa Mathias, Christina Shiang, Patricia Pacheco Viola, Mauro Zukin
Journal: Journal of Clinical Oncology (2018)

e21140 Background: Immune checkpoint inhibitors improved outcomes of patients with advanced non-small cell lung cancer (NSCLC). KEYNOTE-024 trial demonstrated that immunotherapy was superior to platinum-based chemotherapy in the first-line setting. However, only 30% of screened patients had programmed death receptor ligand-1 (PD-L1) expression above 50%. The prevalence of biomarkers in NSCLC may vary through different regions worldwide. Our study aims to describe the prevalence of PD-L1 expression in Brazil. Methods: Immunohistochemistry for PD-L1, antibody 22C3 PharmDx Dako, was performed in 4 reference laboratories in Brazil, from Aug/2017 to Dec/2017, in consecutive cases of advanced NSCLC considered for treatment with immunotherapy. Adequate samples had > 100 tumor cells per slide evaluable. PD-L1 staining was scored as < 1%, 1-49% or ≥50% positive membrane staining within tumor cells. Data were described using summary statistics. Categorical variables were compared using Pearson's chi-square test and adjusted residuals. All p-values < 0.05 were deemed to be statistically significant. Results: PD-L1 expression was assessed in 1018 cases of aNSCLC. Median age was 67 yo, 53.84% of the patients were older than 65 yo and 55.01% were male. Regarding histology, 53.93% had adenocarcinoma, 13.36%, squamous, 26.72%, unspecified NSCLC, 3.83%, other histologies, and 2.16%, losses. Of the 1018 cases, 16.6% presented PD-L1 expression ≥50%, 22%, 1-49%, and 61.39%, < 1%. There was no association between PD-L1 expression and sex or age (p = 0.594 and p = 0.708, respectively). The histological subtype showed association with PD-L1 expression (p = 0.0455). Among adenocarcinomas, 66.48% had no PD-L1 expression, 18.03%, had 1-49%, and 15.48%, ≥50%. Among squamous cell carcinomas, 55.15% did not show PD-L1 expression, 25% had 1-49%, and 19.85%, ≥50%. Conclusions: Our results indicate a lower prevalence of PD-L1 expression in NSCLC in Brazil. Possible reasons for this discrepancy are inadequate sample handling, pre-analytical issues, or epidemiology of the biomarker, all of which may impact the results of PD-L1 expression outside clinical trials. Real world data is needed to better understand the prevalence of this test worldwide.
Germline variants from paired somatic-germline testing in pancreatic cancer.
Authors: Pauline Funchain, Brandie Heald, Kevin White, Mary Buschmann, Kevin K. Roggin, Alok A. Khorana, Davendra Sohal
Journal: Journal of Clinical Oncology (2018)

e16259 Background: Recent data suggest that unselected pancreatic cancer has a germline mutation-positive rate of 3.5% from normal tissue sequencing (Shindo et al, JCO 2017). The role of paired somatic-germline testing in unselected pancreatic cancer patients has not been evaluated. Methods: Patients were identified from the Tempus database, the Chicago Pancreatic Cancer Initiative, and TCGA. All 23 genes with known association to familial pancreatic cancer in extant literature were selected for annotation. Germline alterations were included if the variant was annotated as loss of function (nonsense, frameshift, splice site) or if identified as high impact by internal analyses. Further manual curation using ClinVar and published literature was conducted. For somatic classification, driver variants were identified as loss of function and missense alterations with > = 10 Cosmic hits. Variants with high population frequency, non-coding, and benign per ClinVar were removed. Samples with loss of heterozygosity (LOH) were estimated using copy number of 1 and a corresponding somatic mutation in the same gene. Results: Of 404 patients with pancreatic cancer with paired tumor-normal sequencing, initial bioinformatic analysis identified 112 (28%) unique germline variants. From this set, manual curation resulted in 15 variants (3.7%) classified as pathogenic/likely pathogenic, 27 (6.7%) variants of unknown significance (VUS), 32 (7.9%) with conflicting pathogenicity reports (ranging from benign to VUS), and 16 (3.9%) previously unreported. Additionally, analyses of coinciding germline and somatic variations found multiple combinations of germline variants with potentially interacting somatic alterations, including LOH and somatic single nucleotide variants. Conclusions: Paired somatic-germline testing of unselected pancreatic cancer patients yielded a germline pathogenic variant rate of 3.7%, comparable to solitary germline testing rates. Paired sequencing displayed several mechanisms of LOH of germline variants in genes associated with hereditary predisposition to pancreatic cancer.
SAT0284 An add-on training program involving breathing exercises, cold exposure, and meditation attenuates inflammation and disease activity in axial spondyloarthritis
Authors: G.A. Buijze, H.M.Y. De Jong, M. Kox, D. van Schaardenburg, R.M. van Vugt, C. Popa, P. Picckers, D.L. Baeten
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> A training program involving breathing exercises, cold exposure, and meditation (further referred to as: 'add-on training program') was shown to exert immunomodulating properties in healthy individuals undergoing experimental endotoxemia. <h3>Objectives</h3> Assessment of safety and anti-inflammatory effects of the add-on training program in patients with axial spondyloarthritis (axSpA). Primary objectives: safety (24 weeks) and change in serum CRP levels (week 8). Secondary objectives: changes in erythrocyte sedimentation rate (ESR), serum calprotectin levels, disease activity as measured by the ASDAS-CRP and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), quality of life measures (SF-36, EQ-5D), and hospital anxiety and depression scale (HADS). <h3>Methods</h3> 24 patients with moderatly active axSpA (ASDAS &gt;2.1 and CRP &gt;5 mg/L) were included in this trial. The intervention consisted of an 8 weeks add-on training program comprising three elements: breathing exercises (cyclic hyperventilation followed by breath retention), gradual cold exposure (immersions in ice cold water), and meditation (third eye meditation). An open-label randomised one-way crossover design was used to rule out regression to the mean by comparing an intervention group with a control group. <h3>Results</h3> There was no significant difference in adverse events between groups, with one serious adverse event (hypertensive crisis) occurring 8 weeks after end of the intervention and judged 'unrelated'. The study met its primary efficacy endpoint, with a significant decline in serum CRP at week 8 in the intervention group (median [interquartile range] from 10.2 [6.5–17.1] to 6.0 [3.9–15.6] mg/L; p=0.02), but not in the control group (from 8.7 [5.2–17.2] to 13.2 [7.9–20.1] mg/L; p=0.70). A similar trend was seen for serum calprotectin (p=0.065 in intervention versus p=0.31 in control), but not for ESR. In addition, ASDAS-CRP (p=0.02), BASDAI (p=0.04), SF-36 physical component score (p=0.01), EQ-5D (p=0.049), and EQ-5D VAS (p=0.02) decreased significantly in the intervention group, but not the control group. <h3>Conclusions</h3> This proof-of-concept study in axSpA revealed a significant decrease in serum CRP levels upon add-on training program, in the absence of safety signals. Together with the significant improvement in disease activity and quality of life, these findings warrant full-scale randomised controlled trials of this novel therapeutic approach in patients with axSpA and other inflammatory conditions. <h3>Disclosure of Interest</h3> None declared
Bladder cancer gene expression subtypes (60 gene signature) to define prognosis, differential immune response, and biomarker associations.
Authors: Gregory M. Mayhew, Yoichiro Shibata, Jianping Sun, Charles M. Perou, David N. Hayes, Myla Lai-Goldman, Hawazin Faruki
Journal: Journal of Clinical Oncology (2018)

4538 Background: Gene expression subtypes provide valuable insight into tumor biology and potential therapeutic response. Differential expression of immune infiltrating cells and biomarkers, tumor mutation burden, therapeutic targets, and overall survival were examined in Muscle Invasive Bladder Cancer (MIBC) subtypes, luminal, luminal infiltrated, basal, and neuronal. Methods: Multiple MIBC datasets were assembled including TCGA (n = 408) and 2 other gene expression datasets (n = 305, n = 93). A reduced 60-gene subtyping signature was developed and subtype calls were compared to TCGA clustering. Signatures of multiple immune cells, single immune-biomarkers, drug target genes, proliferation, and mutation burden were examined for differential expression using the Kruskal-Wallis test. Differences in gene mutation distributions were evaluated using Fisher’s exact test. Survival differences were assessed using stratified cox models and Kaplan Meier plots. Results: Immune cell expression was significantly different across the subtypes in multiple datasets (T cells p < 0.001 and CD274(PD-L1) p < 0.002). The luminal subtype as compared to other subtypes showed lower immune expression for most markers. In the TCGA dataset, drug target genes were differentially expressed (FGFR2, FGFR3, and ERBB2 p < 1e-05), as was proliferation (p < 1e-20), and patterns were reproducible across datasets, with luminal and luminal-infiltrated subtypes showing higher expression of FGFR2, FGFR3, and ERBB2 and lower proliferation. Mutation frequencies of FGFR3 and RB1 varied across subtypes (p = 1e-05 and p = 0.0005), whereas mutation burden did not (p = 0.16), despite marked differences in immune infiltration. In the TCGA dataset, significant differences in survival were observed (p = 0.0385 adjusting for stage), with luminal and luminal-infiltrated, as defined by the 60 gene signature, showing better survival and basal worse survival. Conclusions: Biologic gene expression subtypes of MIBC using a reduced 60-gene signature reveal key differences in prognosis, immune cell expression, and drug targets. Subtypes provide potential biomarkers for targeted and immunotherapy response.
P04.49 The evaluation of anti cancer activity of isothiourea derivatives and CK2 inhibitors on cell lines of human glial tumor in vitro
Authors: E Pucko, R Ostrowski, K Zembrzuska, M Zielinska, E Matyja
Journal: Neuro-Oncology (2018)

Gliomas account for approximately 40% of all central nervous system tumours. Tumour progression is considered to be related to uncontrolled intracellular signal transduction pathways, including proteins kinases. Kinase activation plays an important role in cell viability and proliferation. Thus, the development of novel protein kinase inhibitors might lead to beneficial therapies in cancers. Two class of compounds: Caseine Kinase II inhibitors and isothiourea derivatives (ZKKs) are promising drugs with anticancer activity. CK2 is serine-threonine kinase that plays an important role in key cellular processes, including the cell cycle and resistance to apoptosis. ZKKs, such as N,N, -dimethyl -S-2,3,4,5,6-pentabromobenzylisothiouronium bromides, also inhibit the activity of various proteins. In the previous studies we have documented the cytotoxic effect of selected CK2 inhibitors and ZKKs. The present study was undertaken to continue the research on anti-cancer effect of isothiourea derivatives and CK2 inhibitors on the cell lines of glia-derived human tumours of different histological malignancy. We examined the cytostatic effect of modified isothiourea derivatives and CK2 inhibitors against adult human glioblastoma cell line (T98G) and the cell line derived from low-grade subependymal giant cell astrocytoma - SEGA. We analyzed cell viability (MTT metabolism assay) and cell proliferation (Multisizer3 Beckman Coulter cell counter). Western blot was used to evaluate the expression of anti apoptotic proteins. In all experimental groups there was a marked decrease in a total cell number, especially after 48 hours of treatment. Isothiourea derivatives and CK2 inhibitors reduced cell viability both in high-grade malignant glioblastoma and low-grade SEGA cells. The viability of SEGA cells showed a statistically significant decrease after treatment with N,Ni -Diisopropyl-S-(2,3,4,5,6- pentabromobenzylisothiouronium bromide), even at a very low concentration of 1 μM. T98G cells treated with new CK2 inhibitor (4,5,6,7-tetrabromo N2-metylo- N2-hydroksyetylo-2-aminobenzimidazol) also showed a statistically significant decrease of viability rate in comparison to the control cultures. Western blot analyses revealed that modified isothiourea derivatives at a concentration of 10 μM caused a reduction in the level of anti apoptotic proteins in the cell lines of human glial tumours. Caseine Kinase II inhibitors and isothiourea derivatives seem to be promising agents in anticancer therapy, including treatment of glioma-derived primary brain tumours. The inhibition suppression of antiapoptotic proteins seems to be involved in the therapeutic effect. The research was supported by the Foundation for the Development of Diagnostic and Therapy, Warsaw
Comparative analysis of the effect of bevacizumab maintenance regimens after first-line chemotherapy in patients with metastatic colorectal cancer (MCRC): A single institution experience.
Authors: Yeohan Song, AMR Mohamed, Hibah Ismail, Nadine Abdallah, Malini Surapaneni, Gregory Dyson, Mandana Kamgar, Alaa Akhras, Jayadev Mettu, Abdelrahman Ahmed, Anteneh A. Tesfaye, Philip Agop Philip, Anthony Frank Shields
Journal: Journal of Clinical Oncology (2017)

e15032 Background: The majority of patients with metastatic colorectal cancer (MCRC) will ultimately experience disease progression following initial therapy. Although phase III clinical trials show that continued maintenance therapy improves progression free and overall survival in MCRC, the optimal maintenance regimen with an acceptable safety profile is still undetermined. This study aimed to assess outcomes of bevacizumab-containing maintenance therapy after first line chemotherapy for MCRC. Methods: One hundred thirteen patients (46 males, 67 females) with MCRC diagnosed between 2005 and 2014 who received chemotherapy at Karmanos Cancer Institute were included in this retrospective analysis. Induction treatment for most patients consisted of either 5-FU or capecitabine-based chemotherapy with either oxaliplatin or irinotecan and with or without bevacizumab. Eighty percent of patients who received bevacizumab with induction also received it as part of maintenance therapy. Results: After stratifying for age (dichotomized at 65 years) and induction therapy bevacizumab, there was no difference in PFS for induction regimens with or without bevacizumab (p = 0.67). For patients who received capecitabine as maintenance chemotherapy, the addition of bevacizumab resulted in non-significant larger hazard of a PFS event (HR = 1.46, p = 0.36). Among those who received 5-FU maintenance, the addition of bevacizumab resulted in non-significant smaller hazard of a PFS event (HR = 0.48, p = 0.11). There was no difference in observed toxicities between patients who received bevacizumab and those who did not (p = 0.38), with further sub-set analysis showing no increased toxicities among those who received 5-FU (p = 0.76) and those who received capecitabine (p = 0.16). Conclusions: In patients with metastatic colorectal cancer, there was no difference in efficacy or safety when adding bevacizumab to either 5-FU or capecitabine for maintenance after first line chemotherapy. Based on our results, tolerability and compliance with oral capecitabine ought to be a key factor in determining the choice of maintenance in patients with MCRC.
Promoting breast health education, Access and screening mammography for women with Cultural and financial barriers: A community engagement and outreach project in the city of milwaukee,Wisconsin (USA).
Authors: Sailaja Kamaraju, Melissa DeNonomie, Natasha Sahr, Anjishnu Banerjee, Kate Krause, Elaine Drew
Journal: Journal of Clinical Oncology (2016)

e18060 Background: Access and adherence to breast cancer screening guidelines is challenging for women with language, cultural, and financial barriers. We partnered with several community sites in the City of Milwaukee, the mobile mammography coach, and the Wisconsin Well Woman Program (WWWP). We organized monthly, small group workshops with the help of a multi-lingual navigator, community health workers, and translators. The 12-month program provided delivery of mammograms through the mobile coach, free to eligible women > 45 years. Methods: We administered survey evaluations, demographic surveys, and pre- and post-tests of breast cancer knowledge. Descriptive statistics, test for proportions and McNemar's test were used to summarize and analyze the results. Qualitative answers reflecting barriers are also summarized. Results: 195 women of several ethnicities (mean age 44) attended the workshops: 49% were ≥ 45 years old and 45% insured. Among the insured, a higher proportion of women reported prior screening mammography, while fewer women had no screening due to multiple barriers. Several women (both insured and uninsured) suffered from language barriers, fear of disease, transportation, and religious beliefs; these were addressed in small group-focused sessions. Under WWWP guidelines, 28 women were eligible for the free mammogram. Surveys of breast health knowledge showed significant improvement from pre- to post-workshop. Conclusions: Our community-academic partnership model provided culturally-tailored breast health education with the help of multilingual staff members. Adherence to screening mammography is heavily influenced by, but does not entirely depend upon, insurance status and indicates a greater need for culturally competent breast health education for women with multiple barriers.
MiR-340 inhibits breast cancer cell progression by revering EZH2 mediated miRNAs dysregulated expression.
Authors: Zhendong Shi, Jingjing Liu, Yunhui Hu, Sheng Zhang, Jin Zhang
Journal: Journal of Clinical Oncology (2016)

e23191 Background: The anti-tumor activity of miR-340 has been recently characterized in breast tumor cells. However, the mechanisms underlying miR-340 induced cell growth and invasion in triple-negative breast cancer (TNBC) have not been well elucidated. Methods: In this study, we found that miR-340 expression was negative correlated with EZH2 expression in TNBC sample tissues and cell lines. Results: Subsequent luciferase reporter assay confirmed that EZH2 (Enhancer of zeste homolog 2) was a novel molecule target of miR-340. Upregulated MiR-340 expression levels by mimics transfection significantly inhibited the MDA-MB-231 and MDA-MB-468 breast cancer cells proliferation, invasion and migration actitvity, and also induced more cell apoptosis. Meanwhile, miR-340 upregulation inhibited the tumor growth in an orthotopic MDA-MB-231 breast cancer mouse models. Furthermore, we found the reduced EZH2 expression by miR-340 mimics transfection also decreased the DNMT1, H3K27me3, β-catenin and P-STAT3 expressions, which ultimately resulted in the blockage of miR-21 activity and the induction of miR-200a/b expressions. Conclusions: Taken together, our results identified miR-340 as a tumor suppressor in TNBC, moreover, an EZH2 medicated regulatory loop was also established. Post-transcriptional suppression of EZH2 expression not only blocked STAT3 mediated miR-21 trans-activation, but also reversed the miR200a/b silencing by reducing DNMT1 and H3K27me3 expression. MiR-21 inhibition and miR-200a/b expression trigged by miR-340 cooperated in the TNBC progression.
Efficacy and safety of sunitinib and everolimus as front-line treatment for nonclear cell RCC: A pooled-analysis from randomized trials.
Authors: Carlo Messina, Marco Messina
Journal: Journal of Clinical Oncology (2017)

e16069 Background: Non-clear Renal cell carcinoma (non-ccRCC) accounts for about 25% of all RCC and generally is responsible for a poorer outcome in metastatic setting. Optimal treatment for patients with metastatic non-ccRCC has not been established yet; therefore Sunitinib and Everolimus still represent two feasible options as frontline therapy, given the results reported from single-arm trials and expanded access studies. Hence, we provided a pooled analysis from prospective randomized trials to evaluate the benefit and risks of these therapies for patients with metastatic-non-ccRCC. Methods: A systematic search of literature was carried out using Medline, Embase, ESMO and ASCO library with no data restriction up to December 2016, to identify relevant studies on this topic. Eligible studies had to fulfill the following criteria: randomized prospective trial comparing the efficacy of Sunitninb and Everolimus as first line therapy in patients with m-non-ccRCC. Studies excluded: non-randomized prospective trials, subgroup analysis data deriving from randomized prospective trials carried out on metastatic ccRCC population. No language restriction was applied. Data were pooled using RevMan 5.3 software. Results: The literature search identified 29 potential titles and abstracts of whom only 2, recruiting a total of 176 metastatic-non ccRCC patients (Sunitinib: 84, Everolimus: 92), fulfilled our eligible criteria and were included in the pooled analysis. A trend towards better outcome in terms of PFS and OS was reported among patients with non-cc RCC enrolled in Sunitinib arm. Sunitinib vs Everolimus: PFS [HR]:0,83 [0,38-1,78]; OS [HR]: 0,67 [0,37-1,21]. Moreover Sunitinib was associated with more Grade 3-4 adverse events HR: 3.06 [1,60-5,84]. Conclusions: This pooled analysis reported a trend towards favoring Sunitinib versus Everolimus for the first line treatment of patients with metastatic non-ccRCC, although statistical significance was not reached. Sutent was associated with more Grade 3-4 toxicieties. Further prospective randomized phase III trials are required to clarify the better therapeutic option for this subset of patients.