tbuckley/cabot-search huggingface dataset:
Evidence for selective silencing of MHC-binding neoepitopes to avoid immune surveillance.
Authors: Rahul Parulkar, Andrew Nguyen, J Zachary Sanborn, Charles Joseph Vaske, Stephen Charles Benz, Sandeep K. Reddy, Shumei Kato, Razelle Kurzrock, Christopher Szeto
Journal: Journal of Clinical Oncology (2019)

2591 Background: Overall response rates to immune checkpoint inhibition (ICI) are &lt; 50% even in TMB-high patients (e.g. Checkmate-227), suggesting other mechanisms of immune escape exist beyond expressing checkpoints. At least 18% of somatic-specific exonic DNA variants are not expressed into mRNA (Rabizadeh, 2018), yet the selection criteria for which variants to silence remains unclear. We sought to determine if immunogenicity of variants factors into their suppression. Methods: Somatic-specific single nucleotide variants (SNVs) were identified from paired tumor/normal whole-exome sequencing (WES), and annotated as expressed if observed in &gt; = 2 RNAseq reads. MHC1 binding affinity for 9-mer neoepitope peptides resulting from said SNVs were predicted using NetMHC within presented HLA-types. Cases with &gt; 200 non-synonymous exonic mutations were designated as TMB-high in accordance with Rizvi et al, 2015. Tumor immune activity was inferred by RNAseq expression of 6 checkpoint/TME markers, as well as by estimating immune infiltration using RNAseq deconvolution of immune genesets (Bindea et al 2013). Significant associations between TMB, neoantigen-load, expressed neoepitope binding affinities, and immune activity were analyzed. Results: Within a clinical database of 1,363 cases with T/N/R sequencing, a total of 147,015 potential neoepitopes were identified. A small but significant enrichment was observed for silencing neoepitopes that are predicted to bind MHC1 (OR = 1.22, p = 2.4e-78 one-sided Fishers test). The silencing rate was similar between the 17% of patients with high TMB vs others, but was increased in 35% of all patients with high inferred immune infiltration (N = 490, OR = 1.30, p = 1.8e-31). A further silencing enrichment was observed in 19% of all patients displaying high immune activity but low PDL1 expression (N = 263, OR = 1.44, p = 4.0e-45). Conclusions: We observe significant preferential silencing of MHC binding neoepitopes. Specifically, when tumor infiltrating immune cells are activated, silencing neoepitopes may be an alternative to checkpoint expression for avoiding an immune cascade. Patients with TILs and silenced neoepitopes may benefit from epigenetic priming therapy prior to ICI therapy.
A retrospective analysis of venous thromboembolism trends in chemotherapy-induced anemia: Red blood cell transfusion versus erythrocyte stimulating agent (ESA) administration.
Authors: Emily Jane Bryer, David H. Henry
Journal: Journal of Clinical Oncology (2019)

e14685 Background: Anemia is a common and unfortunate consequence of chemotherapy; patients receiving a variety of chemotherapy regimens often develop chemotherapy–induced anemia (CIA), which contributes to poor outcomes including increased mortality. Prompt and effective treatment of CIA is essential to prevent fewer chemotherapy dose delays and reductions. Optimal therapy of CIA is controversial and involves the solitary and combined use of intravenous iron, red blood cell (RBC) transfusions, and erythropoietin stimulating agents (ESAs). Despite the baseline coagulopathies present in patients with malignancy, administration of both RBC transfusions and ESAs is associated with venous thromboembolism (VTE). It remains unknown whether the risk of VTE in patients with CIA is greater among patients who receive RBC transfusions or ESAs. Methods: A retrospective single-institution study analyzed 7360 patients with varying malignancies who developed CIA and received ESAs and RBC transfusion from 1998-2017. These patients were evaluated for subsequent development of VTE and categorized by prior receipt of RBC transfusion or ESA. Results: Among the 7360 patients with CIA, 5503 received either RBC transfusion or ESA and 1857 received both. Among all patients, 3466/7360 (47.1%) developed a VTE. The absolute risk of developing a VTE with receipt of a RBC transfusion was 0.38 compared to 0.19 with ESA. Patients with CIA who received RBC had twice the risk of developing a VTE compared with those who received ESA (p &lt; 0.0001). Conclusions: While both RBC transfusion and ESA administration are independently associated with VTE, our data suggests a greater risk of VTE development with RBC transfusion as compared with ESA administration.[Table: see text]
Low likelihood that potential germline findings identified during somatic tumor testing are evaluated: Room for improvement.
Authors: Heather Wright, Cuke Melissa, Edmund Folefac, Claire F. Verschraegen, Marie Wood
Journal: Journal of Clinical Oncology (2019)

e13037 Background: Genomic testing, useful for treatment planning, may indicate the presence of a germline mutation. We evaluate the incidence of potentially actionable germline mutations detected via genomic testing and determined rates of follow-up referrals for genetic counseling and germline testing among patients with potential germline mutations. Methods: This was a retrospective chart review of patients who underwent genomic testing at The University of Vermont Cancer Center (UVMCC). Test reports were reviewed for mutations in 24 genes associated with hereditary cancer and recognized as clinically actionable by the American College of Medical Genetics. Medical record review was performed to identify patients referred for genetic counseling and results of germline testing. Results: Between 8/2009 and 9/2016 157 patients underwent genomic testing at UVMCC. Eighty-one percent (127/157) had a mutation in ≥ 1 gene associated with hereditary cancer (range 0-4 mutations per patient), and 46% (73/157) had mutations in more than one gene. Potential germline mutations were most commonly identified in TP53, CDKN2A, RB1, PTEN, STK11 and APC (each with mutations in &gt; 10% of patients). To date only 12% (15/127) of patients with potential germline mutations have been referred for genetic counseling. Two were referred for evaluation of findings seen on genomic testing others being referred for personal or family history of cancer. The majority (11/15) of referred patients have undergone genetic testing with 27% (3/11) having germline mutations identified; 2/3 of which were also identified on genomic testing. Conclusions: Genomic testing can be an important tool for identifying hereditary cancer syndromes. While the majority (81%) of patient’s undergoing genomic testing had mutations genes associated with hereditary cancer, the low rate of referral (12%) for genetic counseling to determine if these are truly germline represents a significant missed opportunity. Identification of germline mutations has implications for both the patient (for treatment and risk of second cancers) and their family. Patients and their providers should be aware of the potential for germline findings when genomic testing is performed.
Efficacy of entrectinib in patients (pts) with solid tumors and central nervous system (CNS) metastases: Integrated analysis from three clinical trials.
Authors: Salvatore Siena, Robert Charles Doebele, Alice Tsang Shaw, Christos Stelios Karapetis, Daniel Shao-Weng Tan, Byoung Chul Cho, Dong-Wan Kim, Myung-Ju Ahn, Matthew Krebs, Koichi Goto, Pilar Garrido Lopez, Anna F. Farago, Herbert H. F. Loong, Diego Tosi, Minal A. Barve, Brian P. Simmons, Chenglin Ye, Susan Eng, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2019)

3017 Background: Entrectinib potently inhibits kinases encoded by the NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated data (31 May 2018 cut-off) from 3 Phase 1/2 entrectinib trials (ALKA-372-001, EudraCT 2012-000148-88; STARTRK-1, NCT02097810; STARTRK-2, NCT02568267) for a large cohort of adults with ROS1 fusion-positive NSCLC ( ROS1+) or NTRK fusion-positive solid tumors ( NTRK+), with/without baseline CNS metastases. Methods: Pts had locally advanced/metastatic NTRK+ or ROS1+ tumors by nucleic acid-based confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were at wk 4, then every 8 wk by blinded independent central review (RECIST v1.1). Primary endpoints: ORR, DOR. Secondary endpoints: CBR, PFS, OS, intracranial efficacy and safety. Results: Most pts had ≥1 prior therapy; 33% had baseline CNS metastases. Outcomes for the ROS1+ NSCLC (n = 53) and NTRK+ solid tumors (n = 54; 24% sarcoma, 18% NSCLC) efficacy evaluable data sets are shown (table). Entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2. Conclusions: Entrectinib induced clinically meaningful durable responses in pts with ROS1+ NSCLC or NTRK+ solid tumors with or without CNS disease. Clinical trial information: NCT02097810; NCT02568267. [Table: see text]
Molecular characterization of trophoblast cell surface antigen 2 (Trop-2) positive triple negative breast cancer (TNBC).
Authors: Katia Khoury, Rebecca Feldman, Paula Raffin Pohlmann, Arielle Lutterman Heeke, Zoran Gatalica, Yvonne Veloso, Gregory A. Vidal, Lee S. Schwartzberg, Sandra M. Swain, Claudine Isaacs, Filipa Lynce
Journal: Journal of Clinical Oncology (2019)

e14651 Background: Trop-2 is a glycoprotein found in various carcinomas, known to play a role in tumor development and progression. A humanized antibody drug conjugate (ADC) targeting Trop-2 for delivery of the topoisomerase-I (TOPO1) inhibitor SN-38 (payload) is currently in clinical development for TNBC. Clinical response in a previously reported phase I/II study was associated with Trop-2 immunohistochemistry (IHC) staining intensity (Bardia A et al. J Clin Oncol 2017). Herein we investigated the prevalence of Trop-2 expression in an unselected cohort of TNBC tumors, and the association with other markers of interest that could suggest novel drug combinations. Methods: A cohort of 68 TNBC specimens with available archival tumor submitted to Caris Life Sciences were tested via protein expression (IHC) for Trop-2 with dichotomous categorization for results. Positivity required at least 10% of tumor cells to be stained, with an intensity of 1+ (weak), 2+ (moderate) and 3+ (strong), with same cutoff used in ongoing clinical trials of Trop-2 ADC. Comprehensive molecular profiles were performed using 592-gene next generation sequencing (average read depth 500X). Chi-square tests were used for statistics. Results: The median age in this cohort was 54 (range: 28-90). 38 (56%) tumors were positive for Trop-2. There was no difference in age distribution between Trop-2 positive and negative tumors. Trop-2 expression was present in 48.6% (17/35) and 63.6% (21/33) of primary and metastatic sites, respectively. TOPO1 by IHC was negative in 11 (29%) of Trop-2 positive tumors. Trop-2 expression was inversely associated with PIK3CA and RB1 mutations (p = 0.012 and 0.011, respectively). There was no difference in PDL1 expression by IHC, tumor mutational burden (TMB), BRCA1/2 or other homologous recombination deficiency gene mutations between Trop-2 positive and negative tumors. Conclusions: In a cohort that used the same cutoffs in ongoing trials with Trop-2 ADC, we found a lower prevalence of Trop-2 positivity in TNBC than what has been previously reported. One third of Trop-2 positive tumors were TOPO1 negative which may have treatment implications given the pharmacology of ADC currently in development.
Different expression and prognostic implications of PD-L1 in tumor cells and immune cells with the SP263 monoclonal antibody in Chinese urothelial carcinoma patients.
Authors: Qiaofeng Zhong, Ai-Ping Zhou, Jianzhong Shou, Jianming Ying, Yuankai Shi, Yue Yu, Yun Ling, Zhirong Shen, Yun Zhang
Journal: Journal of Clinical Oncology (2019)

e16040 Background: PD-L1 is expressed on tumor cells (TC) and tumor immune cell (IC) infiltrates. The aim of this study was to explore the expression and the clinical implications of PD-L1 in TC and IC with the SP263 monoclonal antibody and the correlation with clinicopathological features and survival prognosis in urothelial carcinoma(UC) patients. Methods: Formalin-fixed paraffin embedded tumor specimens were collected from 172 patients with UC who received nephroureterectomy or cystoscope biopsy in our center from 2009 to 2016. Tumor samples were evaluated for PD-L1 membrane expression by immunohistochemistry (IHC) using VENTANA PD-L1 (SP263) Assay performed on the automated BenchMark ULTRA platform. PD-L1 expression status was determined by PD-L1 membranous staining at any intensity on TC or IC.PD-L1 is defined as positive if either ≥25% TC or ≥25% IC express membranous PD-L1.Data was analyzed by SPSS software. Results: Among 162 patients, TC and IC infiltrate PD-L1 positivity were detected in 16 (9.9%) and 45 cases (27.8%), respectively. The PD-L1 positivity of TC in female (19.4%) was higher than that in male (7.1%), P = 0.029, and so was in the patients with lymph node metastasis (20.7%) than those without metastatic lymph node (7.5%) , P = 0.031.While these correlation were not observed with PD-L1 positivity in IC. PD-L1 positivity both in TC and IC were not related to age, smoking history, specimen type , tumor size , histology grade, pT, pN stage (P &gt; 0.05) .With a median follow-up of 60.9 months, patients with positive PD-L1 expression in IC have more favorable DFS (NR vs 26.3 months, P = 0.032) and OS (NR vs 71.2 months, P = 0.001) than those with negative PD-L1 expression in IC. More significant differences in DFS (NR vs 18 months, P = 0.002) and OS (NR vs 29.8months,P &lt; 0.001) were observed in patients with T2-4 and PD-L1 positive expression. However, We did not find a statistically correlation between PD-L1 positivity in TC and prognostic outcomes. Univariate and multivariate analyses revealed that patients with PD-L1 positive expression in TC had poorer DFS (HR = 2.573; 95% CI, 1.246–5.313;P = 0.011). Whereas positive PD-L1 expression in IC independently correlated with better OS (HR = 0.303; 95% CI, 0.137–0.671;P = 0.003). Conclusions: PD-L1 positivity in IC is higher than TC in urothelial tumor. Positive PD-L1 expression in IC is associated with better OS and DFS while no correlation between PD-L1 positivity in TC and outcome was observed.
Development and validation of a prognostic score for overall survival integrating baseline metabolically active tumor volume measured by <sup>18</sup>F-FDG PET/CT and clinical factors for metastatic colorectal cancer patients.
Authors: Erwin Woff, Alain Hendlisz, Lisa Salvatore, Federica Marmorino, Alfredo Falcone, Dario Genovesi, Assuero Giorgetti, Gabriela Critchi, Lieveke Ameye, Marianne Paesmans, Thomas Guiot, Hugo Levillain, Patrick Flamen
Journal: Journal of Clinical Oncology (2019)

3543 Background: This study aimed to develop and validate a prognostic score integrating baseline metabolically active tumor volume (MATV) and clinical factors in metastatic colorectal cancer (mCRC) patients. Methods: The development cohort included chemorefractory mCRC patients enrolled in two prospective multicenter non-randomized trials evaluating sorafenib/regorafenib as last line therapy. The validation cohort included mCRC patients from another center, treated with chemotherapy and bevacizumab as first line. Baseline MATV was defined as the sum of metabolically active volumes of all target lesions identified on the baseline 18 F-FDG PET/CT. MATV optimal cutoff for OS prediction was determined from the development cohort with Contal and O’Quigley’s method. MATV, age, gender, BMI, ECOG PS, years since diagnosis, and KRAS status were included in a multivariate analysis. A prognostic score to predict OS was developed from the development cohort using Cox proportional hazards model. Results: MATV and clinical factors were evaluable respectively in 155 and 122 patients of the development and validation cohorts. In univariate analysis, MATV with cutoff set at 100 cm³ identified two risk groups with different median OS (mOS) in both the development (4.5 vs 10.9 months, HR: 2.64; p &lt; 0.001) and validation cohorts (20.9 vs 42.9 months, HR: 2.39; p &lt; 0.001). A multivariate analysis identified four independent negative predictors of OS (high MATV, short time since diagnosis, poor PS, BMI &lt; 25). Combining these factors in a prognostic score for OS (best cutoff:-2) allowed to identify two risk groups with different mOS in the development (4.4 vs 13.4 months, HR: 3.67; p &lt; 0.001) and validation cohorts (25 vs 63.8 months, HR: 2.5; p = 0.001). Conclusions: In mCRC patients, the high prognostic value of baseline MATV found in the development cohort was confirmed by external validation, independently of patients’ treatment. In both the development and validation cohorts the prognostic score for OS allowed to identify two risk groups of mCRC patients with significantly different mOS. MATV and our prognostic score for OS should provide a firm basis for risk stratification, in clinical practice and research trials.
Association of atrial fibrillation with colorectal and breast cancer: A systematic review and meta-analysis.
Authors: Muhammad Zain Farooq, V V Pavan Kedar Mukthinuthalapati, Noman Lateef, Tariq Jamal Siddiqi, Nisar Asmi, Saad Malik, Sri Harsha Patlolla, Irbaz Bin Riaz, M. Hassan Murad, Hani M. Babiker
Journal: Journal of Clinical Oncology (2019)

e13096 Background: Several studies have reported the association between atrial fibrillation (AF) and malignant cancer. Recently, results from a large cohort within the Women’s Health Study showed increased incident risk of breast, colon and lung cancer in patients with AF. Therefore, we performed a systematic review to assess the available evidence and a meta-analysis to define the strength of this association. Methods: MEDLINE, Cochrane and Scopus databases were searched for all prospective studies that reported the association between AF and presence of cancer. The HR for incident risk of common cancers was recorded (Breast, Lung, Colorectal) in patients with and without AF. Lung cancer was excluded because the data required for the analysis was not consistently reported. The DerSimonian-Laird random effects meta-analysis was performed to derive pooled Hazard Ratio (HR) estimates for incident risk of colorectal and breast cancer in patients with AF. Q-test was used to assess between-study heterogeneity; I 2 statistic was computed to expresses the percentage of the total observed variability due to study heterogeneity. Results: A total of 390,479 participants in 3 prospective studies were included in the analysis. Mean age of participants was 66.3 ± 6.5 with mean follow up for 12.6 years. Patients with atrial fibrillation had 27% more risk of developing colorectal cancer [HR 1.27 (1.07-1.51) p &lt; 0.005, I 2 = 73%] and 14% more risk of developing breast cancer [HR 1.14 (1.03-1.26) p = 0.01, I 2 = 37%] as compared to those without atrial fibrillation. Applying these hazard ratios to age adjusted yearly incidence ratios from 2000-2015, one in 5824 new onset AF cases will develop CRC and one in 7474 new onset AF cases will develop breast cancer. Conclusions: There is small but statistically significant increase in risk of subsequent diagnosis of colorectal or breast cancer diagnosis in patients with AF. Shared risk factors such as old age or systemic disease processes may explain this association. While the results of this analysis raise interesting questions for future search, these results should not be used as basis to initiate cancer screening for an occult cancer in a patient with AF.
Predatory journals in psychiatry
Authors: Jaafar Omer, Shvan H Mohammed, Rawezh Q Salih, Fahmi H Kakamad, Tomas M Mikael, Karukh K Mohammed, Masrur S Aziz, Dahat A Hussein, Goran A Qadr, Abdulwahid M Salih
Journal: The Lancet Psychiatry (2019)
Polyphenol-Based Particles for Theranostics
Authors: Qiong Dai, Huimin Geng, Qun Yu, Jingcheng Hao, Jiwei Cui
Journal: Theranostics (2019)

Polyphenols, due to their high biocompatibility and wide occurrence in nature, have attracted increasing attention in the engineering of functional materials ranging from films, particles, to bulk hydrogels.Colloidal particles, such as nanogels, hollow capsules, mesoporous particles and core-shell structures, have been fabricated from polyphenols or their derivatives with a series of polymeric or biomolecular compounds through various covalent and non-covalent interactions.These particles can be designed with specific properties or functionalities, including multi-responsiveness, radical scavenging capabilities, and targeting abilities.Moreover, a range of cargos (e.g., imaging agents, anticancer drugs, therapeutic peptides or proteins, and nucleic acid fragments) can be incorporated into these particles.These cargo-loaded carriers have shown their advantages in the diagnosis and treatment of diseases, especially of cancer.In this review, we summarize the assembly of polyphenol-based particles, including polydopamine (PDA) particles, metal-phenolic network (MPN)-based particles, and polymer-phenol particles, and their potential biomedical applications in various diagnostic and therapeutic applications.
EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome
Authors: Shengjiang Tan, Laëtitia Kermasson, Angela Hoslin, Pekka Jaako, Alexandre Faille, Abraham Acevedo-Arozena, Etienne Lengline, Dana Ranta, Maryline Poirée, Odile Fenneteau, Hubert Ducou le Pointe, Stefano Fumagalli, Blandine Beaupain, Patrick Nitschké, Christine Bôle-Feysot, Jean-Pierre de Villartay, Christine Bellanné-Chantelot, Jean Donadieu, Caroline Kannengiesser, Alan J. Warren, Patrick Revy
Journal: Blood (2019)
Elevated serum activin A and PD-L1 and survival in the CCTG MA.31 phase III trial (trastuzumab vs. lapatinib) in first-line HER2+ metastatic breast cancer.
Authors: Prashanth Reddy Moku, Lois E. Shepherd, Suhail Ali, Kim Leitzel, Wendy R. Parulekar, Liting Zhu, Shakeel Virk, Dora Nomikos, Samuel Aparicio, Karen A. Gelmon, Joseph Drabick, Leah Cream, Scott Halstead, Hyma Vani Polimera, Ashok Maddukuri, Aamnah Ali, Joyson Poulose, Howard Spiegel, Bingshu E. Chen, Allan Lipton
Journal: Journal of Clinical Oncology (2019)

1031 Background: In MA.31 the trastuzumab-taxane combination led to longer PFS than lapatinib-taxane in HER2+ metastatic breast cancer (MBC). In MA.31 we previously reported the prognostic/predictive utility of pretreatment serum PD-L1 (SABCS 2018, PD3-10) and serum activin A (SABCS 2016, P6-07-06) separately; here we evaluate them combined. Methods: MA.31 accrued 652 centrally and/or locally-identified HER2-positive patients, and pretreatment serum was available for 382 patients (184 in trastuzumab arm, 198 in lapatinib arm). The ELLA immunoassay platform (ProteinSimple, San Jose, CA) was used to quantitate serum PD-L1, and ELISA for activin A (R&amp;D Systems, Minneapolis, MN). Results: In correlation analysis, pretreatment serum PD-L1 was moderately correlated with serum activin A (r = 0.21, p = 0.004). In univariate analysis for OS, the combination of higher serum PD-L1 and higher serum activin A (median cutpoints) (vs. both low) was significant for shorter OS in the trastuzumab arm (HR 6.62, p=0.0005) and in the lapatinib arm (HR 3.25, p=0.0003)(table). In multivariate analysis for OS (17 covariates included), elevated serum activin A/PD-L1 combination remained the most significant independent covariate in the trastuzumab arm (HR 12.40, p=0.001), and in the lapatinib arm (HR 5.2, p=0.0001). Conclusions: In the CCTG MA.31 trial, elevated pretreatment serum activin A (TGF-B superfamily) and PD-L1 was associated with a shorter OS to HER2-targeted treatment. Multiple mechanisms, including immune evasion, may decrease the effectiveness of HER2-targeted therapy. Elevated serum activin A and PD-L1 may identify HER2-positive MBC patients who would benefit from inhibitors of the HER2, PD-1, and activin A pathways. [Table: see text]