tbuckley/cabot-search huggingface dataset:
Abstract 12054: Electro-anatomic Mapping Guided Endomyocardial Biopsy: A Systematic Review
Authors: Vaibhav Vaidya, Abhishek Deshmukh, Krithika Vasudevan, Ann Farrell, Leslie Cooper, Suraj Kapa, Peter Noseworthy, Douglas Packer, Samuel Asirvatham
Journal: Circulation (2016)

Introduction: Electro-anatomic mapping (EAM) has been studied as a modality to improve the sensitivity and reduce false negative rates with endomyocardial biopsy (EMB). We systematically reviewed the literature describing EAM guided EMB. Methods: An experienced librarian developed search strategies for Ovid MEDLINE, Ovid Embase, Ovid CDR, Cochrane Central, Scopus and Web of Science. There were no restrictions on language or publication date. Animal studies were excluded. Search strategy included MESH headings and keywords including endomyocardial biopsy and electroanatomic mapping. Results: Out of 139 studies initially identified, 16 (9 case series, 7 case reports) were included in this systematic review. EAM guided EMB was performed in 152 patients and results of 241 biopsies were available for analysis. The most common indications for EAM guided EMB were suspected arrhythmogenic right ventricular cardiomyopathy (ARVC), myocarditis and cardiac sarcoidosis (CS). While fluoroscopic visualization of the bioptome close to mapping catheter was the most commonly utilized biopsy technique (n=7 studies), direct visualization of bioptome on CARTO (n=4) and on NavX (n=2) were used as well. Low voltage areas had abnormal myocardial histology more commonly (range 60-100%) than normal voltage areas (range 11-52%). Sensitivity of low voltage areas for abnormal myocardium ranged from 60% to 82%. EAM guided EMB appears safe and adverse events were noted in only one study (remote hemopericardium). Conclusions: EAM guided EMB is a safe and efficacious method to improve the sensitivity and reduce the false negative rate of conventional fluoroscopy guided biopsy.
Abstract B21: Investigating targeted driver mutations and PD-L1 expression for improved therapy of non-small cell lung cancer
Authors: Akram Alwithenani, Marika Forsythe, Mathieu Castonguay, Wenda Greer, Gorden Flowerdew, Drew Bethune, Harry Henteleff, Madelaine Plourde, Aneil Mujoomdar, Daniel French, Micheal Johnston, Paola Marcato, Zhaolin Xu
Journal: Clinical Cancer Research (2018)

Abstract Most lung cancer patients are diagnosed at an advanced stage, limiting their treatment options to chemotherapies that have very low response rate. New therapies that target driver gene mutations (e.g., EGFR, ALK, ROS1, BRAF) are being used to treat patients who have tumors with these mutations. In addition, a type of immunotherapy called immune checkpoint inhibitor is being used to treat lung cancer patients. For instance, patients with tumors that express PD-L1 are responsive to anti-PD-1/PD-L1 therapy. Thus, being able to identify the presence of driver mutations and PD-L1 will help patients to benefit from different therapies. A total of 844 cases of non-small cell lung cancer samples have been profiled for the presence of EGFR, KRAS, BRAF, PIK3CA, and HER2 mutations by SNaPshot/sizing genotyping. Immunohistochemistry (IHC) was used to identify the protein expression of ALK and PD-L1. Histologic examination was performed to determine the pathologic type, grade, and lymphatic/vascular invasion. Statistical analysis revealed a number of correlations between the presence of the mutations, PD-L1 expression and the patient pathologic data. Specifically, it was determined that women had lung tumors with a significantly greater number of EGFR mutations than men (p value = 0.001). Examining the presence of ALK, EGFR, KRAS, BRAF, PIK3CA, and HER2 mutations against the presence of pleural invasions yielded a p-value of 0.071, which implies evidence that different mutations are not associated with pleural invasion. However, EGFR mutations were associated with the absence of vascular and lymphatic invasions in lung cancer patients (p value = 0.001, 0.002 respectively). In addition, while the expression of PD-L1 does not associate with the patients who express KRAS mutation, it is associated with lung cancer patients who express EGFR mutation (p value = 0.002). Knowing the mutational and PD-L1 status in lung cancer patients will help patients benefit from targeted therapies and/or checkpoint inhibitors. Citation Format: Akram Alwithenani, Marika Forsythe, Mathieu Castonguay, Wenda Greer, Gorden Flowerdew, Drew Bethune, Harry Henteleff, Madelaine Plourde, Aneil Mujoomdar, Daniel French, Micheal Johnston, Paola Marcato, Zhaolin Xu. Investigating targeted driver mutations and PD-L1 expression for improved therapy of non-small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B21.
Tumor-infiltrating lymphocytes in biallelic-CDK12 mutated prostate cancer.
Authors: Maialen Barrero, Mattia Rediti, Mateus Crespo, David Dolling, Pasquale Rescigno, Carlo Messina, Robert Chandler, Diletta Bianchini, Antonella Petremolo, Ruth Riisnaes, Ana Ferreira, Daniel Nava Rodrigues, Claudia Bertan, Adam Sharp, Semini Sumanasuriya, Alec Paschalis, Nina Tunariu, Joaquin Mateo, Suzanne Carreira, Johann S. De Bono
Journal: Journal of Clinical Oncology (2018)

5070 Background: Cyclin-dependent kinase 12 (CDK12) mutations have been described in lethal prostate cancer (PCa) and are reported to impact DNA repair including homologous recombination repair, and associate with an inflamed phenotype. Biomarker studies evaluating tumor infiltrating lymphocytes (TILs) enumeration have reported their prognostic and predictive utility. Here we evaluate the clinical outcomes and the immune-infiltrate characteristics of a cohort of PCa patients with biallelic CDK12 mutations. Methods: 418 PCa patients were sequenced in our Institution with targeted next-generation sequencing between February 2015 and December 2017. Biallelic-CDK12 cohort (n = 11) was compared to a control group (n = 47), including other mutations and monoallelic-CDK12 alterations. Immunofluorescence (IF) was performed on primary or metastatic tumor samples to identify TILs. Lymphocyte infiltration per cell type was examined using a negative binomial regression model with the sum of tumor area included as an exposure term. Kaplan-Meier method and Cox model were used for the survival analyses. Results: Among 418 patients sequenced, 20 were CDK12 mutant (4.8%), of which 11 (2.6%) had biallelic mutations. The median overall survival (OS) from diagnosis was 7.6 years for the control group and 10.0 years for the biallelic-CDK12 cohort (HR 0.63; 95%CI 0.27-1.51; P = 0.30). One biallelic-CDK12 mutated patient was excluded from IF analysis due to poor quality tumor tissue. TIL counts/mm2 were significantly higher in CDK12 mutated tumors, with higher CD4+ (95%CI 0.11-1.94; P = 0.03), CD8+ (95%CI 0.24-2.18; P = 0.02) and overall T cell counts (95%CI 0.09-1.73; P = 0.03). No significant difference was noted for CD4+/FOXP3+ (95%CI -1.49-0.69; P = 0.47). Conclusions: This is the first study reporting survival outcomes and TILs characteristics in biallelic-CDK12 mutated PCa. Despite being limited by the retrospective design and limited sample size, these pilot data provide a rationale to further explore the role of biallelic-CDK12 mutations in PCa as a predictive biomarker for immunotherapy.
Rigosertib (RIG) in combination with azacitidine (AZA) to modulate epigenetic effects and to overcome clinical resistance to hypomethylating agents (HMA) in myelodsyplastic syndromes (MDS).
Authors: Pratima Chaurasia, Fumiko Isoda, Tylar Novy, Jamari Ross, Rosalie Odchimar-Reissig, Erin P Demakos, Shyamala Chendal Navada, E. Premkumar Reddy, Lewis R. Silverman
Journal: Journal of Clinical Oncology (2016)

7020 Background: MDS is a challenging disease to treat due to intricate complexities at the molecular and epigenetic levels. AZA is the standard of care for patients (pts) with higher-risk disease, however, all pts ultimately fail treatment due to primary or secondary resistance. Overcoming AZA resistance is a clinical imperative. Initial results of a Phase I/II study of AZA combined with RIG, an allosteric “ras mimetic” that binds to the Ras Binding Domain including ras, raf and PI3 Kinase pathways, in pts with MDS demonstrated an overall response rate of 77%; 64% in pts following HMA failure (Navada et al ASH 2015). Methods: We investigated the in vitro effects of RIG combined with AZA on two cell lines: AML (BW90), MDS (MDS-L) and pt bone marrow samples obtained prior and after one cycle of AZA and RIG. Results: Q-PCR studies demonstrated that individual treatment of BW90 and MDS-L with RIG or sequential treatment with AZA (AZA/RIG or RIG/AZA) altered the class I, II and IV histone deacetylases (HDACs), DNA methyl transferases (DNMT1, 3a and 3b) and chromatin remodelers (KDM2a, SET1, JMJD3 and LRWD1) transcript levels in cellular context suggesting that RIG potentially acts as a chromatin modifying agent (CMA), in both cell lines and pts. Treatment with RIG also altered global histone post-translational modifications (PTMs) including methylation (H3K4me3, H3K4me2, H3K27me3, and H3K27me2) and acetylation (H3K9ac, & H3K18ac) levels associated with transcriptional activation or repression in both the cell lines and pt samples. Treatments with RIG either alone or combined with AZA differentially governed cellular proliferation, cell cycle arrest, apoptosis, histone PTMs, altered expression of cell cycle related proteins, and inactivation of PI3/AKT signaling pathway in a cell specific manner. Conclusions: RIG combined with AZA can overcome clinical AZA resistance in MDS pts. RIG potentially functions as a CMA, in combination with AZA and significantly modifies global histone repression and activation suggesting that this combination may overcome AZA resistance through chromatin remodeling. Additional studies are underway.
Comparison of circulating tumor DNA (ctDNA) sequencing and tumor-based genotyping for the detection of <i>EGFR</i> mutations in non-small cell lung cancer (NSCLC).
Authors: Allen Li, Sanja Dacic, Timothy Francis Burns, Mark A. Socinski, Shira Abberbock, Liza Cosca Villaruz
Journal: Journal of Clinical Oncology (2017)

e20586 Background: Therapy for NSCLC is based on detection of actionable oncogenic drivers. Conventionally, targetable mutations are detected by tissue biopsy, which may be insufficient for molecular testing. Repeat biopsy is often required at the time of disease progression. Guardant360™ (G360) utilizes digital next-generation sequencing (NGS) to analyze ctDNA in plasma. Limited data exists on clinical outcomes of 3 rd generation EGFR tyrosine kinase inhibitors (TKIs) against T790M-mediated resistance detected by digital NGS in ctDNA. We hypothesize that G360 has high concordance in detecting actionable oncogenic drivers and similar clinical outcomes compared with tumor-based genotyping. Methods: G360 (Guardant Health, Inc.) was performed in 20 advanced NSCLC patients (pts) with matched tumor-based genotyping by either Sanger sequencing (N = 10) or Ion Torrent ApliSeq v.2 NGS (N = 10; Life Technologies, Fisher Scientific). Matched genotypes were done at diagnosis (N = 12) or at time of acquired resistance (N = 8). Sensitivity, specificity, and response to EGFR TKIs (RECIST V1.1) were determined. Overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier method. Objective response rates (ORR) were calculated by MedCalc(r) software. Results: Compared with tumor-based testing, G360 has high concordance for EGFR exon 19 deletion, T790M and L858R (90%, 85% and 100%, respectively) and high specificity (100%, 93.3%, and 100%, respectively). OS of pts with T790M or L858R were similar between those detected by G360 and by tumor-based testing (p &gt; 0.99). Pts who received 3 rd generation EGFR TKIs (4 osimertinib, 1 PF-06747775) after detected T790M in plasma (N = 4) had similar ORR (50% vs 25% with difference of 25%, 95% CI (-0.45 to 0.75)) and median PFS (7.5 vs 6.0 mos, p = 0.63) as those detected by tumor-based testing (N = 4). Conclusions: G360 showed high concordance for EGFR actionable mutations. Clinical outcomes of 3 rd generation EGFR TKI treatment in T790M+ disease were similar between those detected by G360 and those detected by tumor testing. G360 represents a viable option for pts who are not candidates for solid tumor biopsies.
MSI-high and MSI-stable colorectal carcinomas (CRC): A comprehensive genomic profiling (CGP) study.
Authors: Siraj Mahamed Ali, Laurie M. Gay, Julia Andrea Elvin, Jo-Anne Vergilio, Shakti H. Ramkissoon, James Suh, Eric Allan Severson, Sugganth Daniel, Jonathan Keith Killian, Alexa Betzig Schrock, Jon Chung, Garrett Michael Frampton, David Fabrizio, Lee A. Albacker, Vincent A. Miller, Robert John Corona, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2018)

3574 Background: High levels of microsatellite instability (MSI-H) is an approved biomarker for the selection of immunotherapy across solid tumor types. Given the high prevalence of MSI high in CRC, we used CGP to uncover additional therapy targets associated with MSI status. Methods: Hybrid capture-based CGP was performed on 8,004 clinically advanced CRC. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability status (MSI-H or MS-Stable, MSS) was determined by principal components analysis of optimal homopolymer loci. Results: Of the 8,004 mCRC, 402 (5%) MSI-H and 7,602 (95%) MSS. Patient age and gender distribution did not differ between the 2 groups. Significant GA differences were found: MSS mCRC featured more KRAS, TP53 and APC GA, whereas MSI-H mCRC had more BRAF, PIK3CA, BRCA2 and ALK GA (Table). As expected, GA in the 4 genes associated with heritable CRC (HNPCC) were significantly enriched in MSI-H tumors. In addition, RNF43 correlated with MSI-H status. Median TMB was markedly higher in the MSI-H samples, 96% of which featured ≥20 mutations/Mb, compared to only 1% of MSS mCRC. Mutation frequencies and false discovery rate corrected p values from chi-squared analysis are presented below. Conclusions: MSI-H mCRC feature GA in RNF43, BRAF, PIK3CA, ALK and BRCA2 and near universal high TMB, impacting potential responses to both targeted and immunotherapies. MSS mCRC is characterized by more KRAS and TP53 GA frequencies and low TMB. GA in receptor kinases such as in ERBB2 and ALK are more often found in MSI-H mCRC, but are present in both types and represent additional potential targets for treatment strategies. MSI-High CRC (402) MSI-Stable CRC (7,602) Significance Median Age and (range) in years 62 (8-201) 58 (13-88) Gender 50% female 46% female Mean GA/tumor 18.5 5.8 P < < 0.0001 KRAS 30% 52% P < 0.0001 TP53 34% 78% P < < 0.0001 BRAF 36% 8% P < < 0.0001 PIK3CA 33% 18% P < 0.0001 ERBB2 7% 5% NS MSH6 29% 1% P < < 0.0001 MLH1 17% < 1% P < < 0.0001 MSH2 15% < 1% P < < 0.0001 PMS2 6% < 1% P < < 0.0001 RNF43 55% 3% P < < 0.0001 BRCA2 21% 2% P < 0.02 APC 44% 80% P < < 0.0001 ALK 3% 1% P < 0.0001 Median TMB (mut/Mb) 47 4 P < 0.0001 TMB ≥10 mut/Mb 99% 5% P < 0.0001 TMB ≥20 mut/Mb 96% 1% P < 0.0001
Typical bronchial NETs as a misleading biology.
Authors: Dalvinder Mandair, Leonidas-Nikolaos Diamantopoulos, George Demetriou, Faidon Laskaratos, Christos Toumpanakis, Martyn E. Caplin
Journal: Journal of Clinical Oncology (2017)

8528 Background: Bronchial Neuroendocrine tumours (NETs) are rare with an incidence of between 0.2 – 2 per 100,000 population. There has been an increase in prevalence due to increased awareness, enhanced immunohistochemistry and greater use of Computed tomography (CT). Bronchial NETs are classified according to the WHO guidelines developed in 2004 where they are graded by histological classification into ‘typical’, ‘atypical’ NETs or small and large neuroendocrine carcinoma’s (NECs). Typical NETs are regarded as being low-grade malignant however metastatic disease can still develop. Aims: We sought to determine the incidence of metastatic typical bronchial NETs, their survival and investigate the imaging and treatment used in their management. Methods: We performed a retrospective analysis of all bronchial NETs managed at our centre from 2001 to 2016. From those identified as typical NETs, we analysed clinical records in those with advanced disease (Stage IV). Results: From a total of 251 bronchial NETs, there were 147 ‘Typical’ NETs, 30(20%) of whom had advanced disease compared to 82 'Atypical' bronchial NETs of whom 55 had advanced disease (67%). The median age at diagnosis was 58 (range 24-77). In the 'Typical' NETs, 24/30 had liver metastases, 19/30 skeletal metastases, and 16 had carcinoid syndrome (CS). Functional imaging with FDG PET scan was positive in 7/10 patients and somatostatin receptor scintigraphy (SRS) positive in 16/20 and in 4/11 there was avidity with both. 20 patients were treated with somatostatin analogues predominantly for CS symptoms. 11 patients treated with peptide radiolabelled receptor targeted therapy (PRRT) with a median Time-To-Progression (TTP) of 27 months. 11 patients received chemotherapy with median TTP of 16 months with 4 patients demonstrating partial response. Conclusions: Typical bronchial NETs can lead to advanced disease in up to 20% of patients. Their behavior can be aggressive and is not predictable by histology alone. Functional imaging with both FDG and SRS may help determine the most appropriate treatment. Both PRRT and chemotherapy can be considered in progressive disease.
Combating of non-small-cell lung cancer (NSCLC) through EGFR/PD-L1 bispecific antibody generated by Lock-and-Key method.
Authors: Lei Zhao, Fan Zhang, Lingling Li, Shixue Chen, Yi Hu
Journal: Journal of Clinical Oncology (2018)

e15106 Background: Although monoclonal antibodies (mAbs) are widely used for the treatment of cancer, the acquired resistance is one of the prime obstacles for cancer treatment and development of novel antibodies with potent anti-tumor activities and specificities is urgently needed. Due to complex diseases are often multifactorial in nature, and involve redundant or synergistic action of disease mediators or upregulation of different receptors, bispecific antibodies with the capacity to blockade of multiple targets or binding sites are showing improved therapeutic efficacy against cancer. Although “knobs-into-holes” technique is an efficient way to generate bispecific antibody with whole IgG-architecture, the efficacy of different heavy chain hetero-generation and the thermostability remain questionable. How to efficiently generate bispecific antibodies with more efficiency and stability is critical for the development of novel antibodies against cancer. Methods: By using the structure-based computational design and long-time molecule dynamic simulation (5 µs), we have successfully developed a more efficient technique “Lock-and-key” to produce bispecific antibodies with more efficiency. Based on the parent EGFR antibody cetuximab and PD-L1 antibody atezolizumab, EGFR/PD-L1 bispecific antibody with whole IgG structure was designed. Results: With the benefits of bispecific antibody and whole IgG architecture, the bispecific antibody EGFR/PD-L1 exhibits potent anti-tumor efficacy than the parent antibody Cetuximab, Atezolizumab and the combination of Cetuximab and Atezolizumab. Conclusions: “Lock-and-Key” technique could be a more promising method to produce the herero-generation of antibody heavy chains. More importantly, bispecific antibody with whole intact IgG structure shows the advantages in cancer treatment. Antagonism of EGFR and PD-L1 through bispecific antibody could be a promising anti-tumor strategy against NSCLC.
The use of apatinib combined with chemotherapy in treating soft tissue sarcoma.
Authors: Chengjuan Fan, Chunhong Chen, Weixi Shen, Yang Du, Tao Xin
Journal: Journal of Clinical Oncology (2018)

e23524 Background: Soft tissue sarcomas (STS) are rare and aggressive malignancies that develop from the mesenchymal tissue. Despite advances in treatment methods, the prognosis of STS is very poor. Targets therapy combined with chemotherapy is very popular in recent years. Apatinib, a small molecule vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, plays antiangiogenic and antitumor roles. Methods: Three patients of STS were treated with apatinib combined with chemotherapy from Feb. 2016 to Sep. 2016, as detailed in the Table. The dose of apatinib was 250mg/d. Chemotherapy regimen was ifosfamide combined with pirarubicin or gemcitabine combined with carboplatin/DDP. Next generation sequence (NGS) was used to test the gene change of tumor. Results: The characteristics of patients are shown in the Table, all patients show partial response to apatinib combined with chemotherapy. Moreover, the three patients have achieved progression-free survival of 14, 9 and 11 months, respectively, which were much better than previous reported (about 6 months). The main toxicities were tolerable. The gene test showed many genes change, which were members of tumor angiogenesis pathway, including AKT1, MAP2K2, KRAS and PIK3CA. Conclusions: The results of NGS showed that there were many tumor angiogenesis related genes change in STSs. Apatinib as VEGFR-2 TKI, combined with chemotherapy could prolong the PFS, improve the quality of life. Apatinib may provide an additional option for the treatment of STS. Characteristics Patient 1 Patient 2 Patient 3 Age, years 32 27 18 Sex Female Female Female Primary tumor position Left nose Right thigh Left cheek Pathologic type Fibromyxoid sarcoma Angiosarcoma Rhabdomyosarcoma Stage of treatment with apatinib Locally advanced Lung and brain metastasis Locally advanced Treatment line 1 Surgery Surgery Ifosfamide and pirarubicin + Apatinib Treatment line 2 Second surgery + chemotherapy Pazopanib Treatment line 3 Ifosfamide and pirarubicin + Apatinib Gemcitabine and carboplatin/DDP+Apatinib PFS of Apatinib 14 months 9 months 11 months