tbuckley/cabot-search huggingface dataset:
Genomic features of lung cancer patients harboring germline mutations associated with hereditary cancer syndromes.
Authors: Jian Sun, Weiran Wang, Danhua Wang, Hongling Yuan, Tonghui Ma
Journal: Journal of Clinical Oncology (2021)

e20511 Background: Smoking and air pollution are the major causes of lung cancer; however, numerous studies have demonstrated that genetic factors also contribute to the development of lung cancer. Here, we reported an analysis of genomic features in 65 lung cancer patients with autosomal-dominant or autosomal-recessive inheritance of germline mutations. Methods: We retrospectively reviewed next-generation sequencing data of 26,904 lung cancer patients in a Chinese cohort. The germline mutation patterns, as well as the co-occurrence with somatic driver mutations were analyzed. Results: A total of 65 (0.24%) patients with heterozygous germline mutations associated with hereditary cancer syndromes were detected, including 27 (0.10%) patients with autosomal-dominant inheritance (BRCA1, BRCA2, RET and TP53) and 38 (0.14%) patients with autosomal-recessive inheritance (ATM, BLM, FANCA, FANCG, MUTYH, NBN, RECQL4 and WRN). Comparing to patients with autosomal-dominant inheritance (Age 56±17.8), patients with autosomal-recessive inheritance (Age 65±11.7, P = 0.009) were older, and there is no gender difference. Additionally, 66.7% (18/27) of patients with autosomal-dominant inheritance were identified co-mutated actionable variations, such as 12 patients harboring mutations in exon 18–21 of EGFR, 2 patients harboring ERBB2 exon 20 insertions, 3 patients harboring mutations in exon 2 of KRAS and 1 patient harboring EML4-ALK fusion. The coexistence of germline autosomal-dominant mutations and somatic driver mutations indicated that germline mutations have weak impact on lung cancer. Simultaneously, 52.6% (20/38) of patients with autosomal-recessive inheritance were identified co-mutated actionable variations, such as 15 EGFR+ patients, 2 ERBB2+ patients and 3 KRAS+ patients. And there was no significant difference in population frequency of co-mutated actionable variations between the two groups. Conclusions: In summary, studies on germline mutations of lung cancer patients may help to elucidate the etiology and mechanism of lung cancer, and may help for early detection and diagnosis, targeted therapy and improved prevention strategies.
Postoperative adjuvant dose-dense chemotherapy with bevacizumab and maintenance bevacizumab after neoadjuvant chemotherapy for advanced ovarian cancer: A phase II AGOG/TGOG trial.
Authors: Wei-Chun Chen, Hung-Hseuh Chou, Lan-Yan Yang, Huei-Jean Huang, Wei-Yang Chang, Hao Lin, Ren-Chin Wu, Min-Yu Chen, J. Timothy Qiu, Kuan-Gen Huang, Angel Chao, Ting-Chang Chang, Chyong-Huey Lai
Journal: Journal of Clinical Oncology (2021)

5540 Background: The objective of this study is to evaluate the safety and efficacy of adding bevacizumab to dose-dense adjuvant chemotherapy with bevacizumab maintenance after neoadjuvant chemotherapy (NAC) and interval debulking surgery (IDS) for stage III/IV ovarian, tubal, and primary peritoneal cancer. Methods: This phase II clinical trial using Simon's minimax two-stage design was conducted. At the first stage, 13 subjects were enrolled, and the trial would proceed to second stage if ≤3 subjects discontinued treatment for study-defined significant adverse events (AEs). Patients with stage III/IV ovarian, tubal, and primary peritoneal cancer deemed not feasible for primary cytoreductive surgery were enrolled after 3 to 4 cycles of NAC and IDS without disease progression. NAC could be either weekly paclitaxel (80mg/m 2 ) (dose-dense) plus 3-weekly carboplatin (AUC5-6) or 3-weekly conventional schedule. After IDS, postoperative dose-dense adjuvant chemotherapy for 3 cycles at least (best to 6 cycles), and 3-weekly bevacizumab 15mg/kg was given since postoperative cycle 2. Further 3-weekly maintenance bevacizumab 15mg/kg was given intravenously for 17 cycles. Results: Of the 22 enrolled subjects, 13 (59.1%) had no gross lesion after IDS. Of the 13 subjects enrolled on the 1st stage, one study-defined significant AE occurred, therefore the trial proceeded to the 2nd stage (n = 9). The median progression-free survival (PFS) was 22.1 months (95% confidence interval [CI], 13.7 – 30.5), and the median overall survival (OS) was 49.2 months (95% CI, 33.8 – 64.6). Peritoneal Cancer Index score at entering abdomen during IDS was significant for PFS (&gt;12 vs ≤ 12: p = 0.003). One of the 22 subjects did not receive any study treatment. In the safety analysis (n = 21), grade 3/4 AEs included thrombocytopenia of 38.1%, neutropenia 71.4%, and anemia 28.6%. Study-defined significant AEs of bowel perforation, poor-healing wound, and hypertension were found in 1 case each, respectively. Conclusions: This phase II trial demonstrated adding bevacizumab to dose-dense adjuvant chemotherapy with bevacizumab maintenance after NAC was feasible with tolerable toxicity and comparable PFS/OS as compared to other studies using bevacizumab in the NAC phase or dose-dense scheduling throughout. Clinical trial information: NCT02022917.
Characterising the background incidence rates of adverse events of special interest for COVID-19 vaccines across eight countries: a multinational network cohort study
Authors: X Li, A Ostropolets, R Makadia, A Shoaibi, G Rao, AG Sena, E Martinez-Hernandez, A Delmestri, K Verhamme, PR Rijnbeek, T Duarte-Salles, MA Suchard, PB Ryan, G Hripcsak, D Prieto-Alhambra
Journal: BMJ (2021)
Significance of molecular detection in diagnosis of benign and malignant thyroid nodules in China.
Authors: Yuntao Song, Jie Liu, Weiran Wang, Tonghui Ma
Journal: Journal of Clinical Oncology (2021)

e15028 Background: Ultrasound and ultrasound-guided fine needle aspiration (US-FNA) are a preferred method for judging benign and malignant thyroid nodules. For thyroid nodules that can’t be determined by FNA, molecular markers of thyroid cancer can be detected as assistant method. This study aim to verify the significance of molecular detection in diagnosis of benign and malignant thyroid nodules in China. Methods: We carried out a prospective study of 383 FNA samples of thyroid nodules, and performed targeted multi-gene NGS on most samples with FSZ-Thyroid NGS Panel V1, the result of which would be incorporated into the reference index for clinicians to decide whether a patient should undergo surgery. And postoperative pathology were followed up. The NGS targets were divided into three categories: high risk (BRAF V600E, TP53, PIK3CA, AKT1, CTNNB1, RET, KRAS with VAF≥30%, HRAS with VAF≥30%, NRAS with VAF≥30%, RET fusion, NTRK1 fusion, NTRK3 fusion, ALK fusion, BRAF fusion), low risk (BRAF non-V600E, EIF1AX, GNAS, TSHR, TERT, KRAS with VAF &lt; 30%, HRAS with VAF &lt; 30%, HRAS with VAF &lt; 30%, PPARG fusion, THADA fusion), benign like (EZH1, SPOP, ZNF148 or no mutations). Results: Among the 383 FNA samples, 333 of them were sequenced with FSZ-Thyroid NGS Panel V1, and 211 thyroid nodules were resected. Finally, postoperative pathology showed that 180 nodules was malignant and 31 was benign. Among the 180 malignant tumors, BRAF V600E (71.1%), RET fusion (7.8%), and TERT mutation (2.8%) were the top three most mutated genes; and there were also significant differences in frequency of some mutations between malignant tumors in different BSRTC class, including more BRAF V600E (83.6%) in class VI malignant tumors, more gene fusions (26.1%) in class V malignant tumors which was significantly higher than that in class VI (7%). And, the frequency of RAS mutations (8.3%) in class III and IV malignant tumors was higher than that of class V and VI. Here a test was considered as positive if a genetic alteration was annotated with High-Risk, and negative if Low-Risk or Benign-Like, the sensitivity and specificity for detecting malignant tumors in BSRTC class III-IV were 66.7% and 100%, respectively, and the total sensitivity and specificity for BSRTC class I-VI malignant tumors were 85.6% and 100%. In addition, 21 of 383 patients underwent Re-FNA. Among these 21 patients, 11 patients detected high risk mutations and 90.9% (10/11) underwent upgrade of BSRTC class on Re-FNA. As a comparation, among the remaining 10 patients who detected low risk or benign like sites, only 30% (3/10) underwent upgrade of BSRTC class on Re-FNA which suggested that the detection of high risk sites might predict the upgrade of BSRTC class on Re-FNA. Conclusions: Molecular testing can distinguish between benign and malignant thyroid nodules and predict the upgrade of BSRTC class on Re-FNA which could provide the reference for treatment decision-making of thyroid nodules in China.
Analysis of the relative copy numbers of TP63, YAP1 and KMT2D genetic loci and EGFR expression in orthotopic patient-derived xenografts of cardioesophageal cancer in immunodeficient mice.
Authors: Anna S. Goncharova, Evgeniy N. Kolesnikov, Ekaterina V. Zaikina, A. V. Volkova, M. V. Mindar, D. V. Khodakova, Ekaterina A. Lukbanova, L. Z. Kurbanova, Mikhail A. Kozhushko, Aleksandr E. Anisimov, Roman E. Myagkov, Sergey V. Sanamyants, Tanzila B. Katsieva
Journal: Journal of Clinical Oncology (2021)

e15033 Background: Cardioesophageal cancer is a common tumor affecting the cardiac stomach and lower esophagus. Tumor heterogeneity is important, since it can cause the ineffectiveness of chemotherapy and radiotherapy due to individual characteristics of the neoplasm in different patients, as well as the intensification of invasion and metastasis. Our purpose was to analyze the relative copy numbers of TP63, YAP1 and KMT2D genetic loci and EGFR expression in orthotopic patient-derived xenografts of cardioesophageal cancer. Methods: The model of cardioesophageal cancer was created in Balb/c Nude mice with surgical bioptates of adenocarcinoma obtained from donors. The relative copy numbers of TP63, YAP1 and KMT2D genetic loci and EGFR expression were determined by Real-Time qPCR. Results: A PDX model of cardioesophageal cancer was successfully created by transplanting a moderately differentiated adenocarcinoma from a patient diagnosed with infiltrative ulcerative cancer of the lower third of the esophagus with a transition to the cardiac stomach into the distal esophagus of Balb/c Nude mice. The EGFR expression was elevated in patient tumor samples, compared to healthy tissues (p = 0.021) and gastric cancer xenografts (p = 0.07). Molecular genetic analysis demonstrated an association between an increased EGFR expression and changes in the relative copy numbers of TP63, YAP1, and KMT2D in donor samples compared to gastric cancer xenografts (p = 0.02, p = 0.026 and p = 0.042). Conclusions: The relative copy numbers of TP63, YAP1, and KMT2D were associated with intensified EGFR expression and changed with each new generation of orthotopic xenografts.
Circular RNA circRHOBTB3 represses metastasis by regulating the HuR-mediated mRNA stability of PTBP1 in colorectal cancer
Authors: Jiaxin Chen, Yizheng Wu, Xin Luo, Dongai Jin, Wei Zhou, Zhenyu Ju, Di Wang, Qing Meng, Huijuan Wang, Xiaotian Fu, Jianbin Xu, Zhangfa Song
Journal: Theranostics (2021)

Background: Tumor metastasis of colorectal cancer (CRC) is the main cause of death in most patients and the major difficulty in comprehensive CRC treatment. Circular RNAs (circRNAs) affect many biological functions in solid tumors. However, their mechanisms in CRC metastasis remain unclear. Methods: RNA sequencing (RNA-seq) and quantitative real-time PCR were performed to screen differentially expressed circRNAs between CRC tissues and adjacent normal tissues. CCK-8, cell migration and wound healing assays were performed to determine the functions of circRHOBTB3 in cell proliferation and metastasis. RNA pulldown and RNA immunoprecipitation assays were performed to verify the interaction between circRHOBTB3 and the HuR (ELAVL1) protein. Further RNA-seq and rescue experiments were applied to search for the downstream target. We also conducted a mouse xenograft model to elucidate the effect of circRHOBTB3 on cancer metastasis in vivo. Results: We identified circRHOBTB3 which is markedly downregulated in CRC tissues and cell lines. Furthermore, lower circRHOBTB3 levels were significantly associated with advanced clinical stages and greater risk of metastases. Overexpression of circRHOBTB3 suppresses tumor metastasis in CRC cells. Mechanistically, circRHOBTB3 binds to HuR, which is a ubiquitously expressed and functional RNA-binding protein (RBP) in CRC development, and promotes β-Trcp1-mediated ubiquitination of HuR. Normally, HuR binds to the 3'UTR of target mRNAs to facilitate their stabilization, whereas the interaction between circRHOBTB3 and HuR degrades HuR to reduce the expression level of the downstream target PTBP1. Furthermore, overexpressed circRHOBTB3 suppresses lung metastases in vivo, and this effect can be partly reversed by PTBP1 overexpression. In addition, the transcription of circRHOBTB3 can be improved by both FUS and ADARB2 in CRC cells. Conclusions: Our findings indicate that circRHOBTB3 exerts suppressive effects on CRC aggressiveness through the HuR/PTBP1 axis.
A single-shot Lassa vaccine induces long-term immunity and protects cynomolgus monkeys against heterologous strains
Authors: Mathieu Mateo, Stéphanie Reynard, Alexandra Journeaux, Clara Germain, Jimmy Hortion, Xavier Carnec, Caroline Picard, Nicolas Baillet, Virginie Borges-Cardoso, Othmann Merabet, Audrey Vallve, Stéphane Barron, Ophélie Jourjon, Orianne Lacroix, Aurélie Duthey, Manon Dirheimer, Gregory Jouvion, Pierre-Henri Moreau, Lyne Fellmann, Caroline Carbonnelle, Hervé Raoul, Frédéric Tangy, Sylvain Baize
Journal: Science Translational Medicine (2021)

A safe and protective Lassa virus vaccine is crucially needed in Western Africa to stem the recurrent outbreaks of Lassa virus infections in Nigeria and the emergence of Lassa virus in previously unaffected countries, such as Benin and Togo. Major challenges in developing a Lassa virus vaccine include the high diversity of circulating strains and their reemergence from 1 year to another. To address each of these challenges, we immunized cynomolgus monkeys with a measles virus vector expressing the Lassa virus glycoprotein and nucleoprotein of the prototypic Lassa virus strain Josiah (MeV-NP). To evaluate vaccine efficacy against heterologous strains of Lassa virus, we challenged the monkeys a month later with heterologous strains from lineage II or lineage VII, finding that the vaccine was protective against these strains. A second cohort of monkeys was challenged 1 year later with the homologous Josiah strain, finding that a single dose of MeV-NP was sufficient to protect all vaccinated monkeys. These studies demonstrate that MeV-NP can generate both long-lasting immune responses and responses that are able to protect against diverse strains of Lassa virus.
Pooled analysis of <i>POLE</i>-mutant colorectal cancer characteristics.
Authors: Sharon Li, Anshuman Panda, Aaron Ciner, Shridar Ganesan, Howard S. Hochster
Journal: Journal of Clinical Oncology (2021)

e15515 Background: Colorectal cancers (CRC) with pathogenic mutations in POLE (mPOLE) represent a unique subgroup with distinct clinical and molecular features and may exhibit a robust response to immune checkpoint blockade. Due to low prevalence, clinical features of this subgroup remain incompletely characterized. Methods: We utilized data from the Oncology Research Information Exchange Network (ORIEN) , using the Total Cancer Care (TCC) protocol in 18 centers across the US, to identify mPOLE CRC cases through October 2020. Prevalence, genomic and clinical features of mPOLE CRC within ORIEN were compared with other public databases, including AACR GENIE (version 8.0) , TCGA pan-cancer atlas, and a cohort from DFCI via cbioportal . Given the small sample size of mPOLE patients in each cohort, we pooled available data to compare characteristics of mPOLE CRC with CRC cases without pathogenic mutations in POLE (wtPOLE). Results: Detailed results are illustrated in the table. Out of 1564 CRC patients in ORIEN, 140 patients (9%) had POLE mutations, but only 11 patients (&lt;1%) had pathogenic POLE mutations, compared to &lt;2% in TCGA, &lt;1% in DFCI, and &lt;0.5% in the AACR GENIE cohorts. mPOLE CRC was associated with significantly higher tumor mutational burden and lower copy number alterations in all cohorts with data. In ORIEN, median age at diagnosis was significantly lower in mPOLE patients and at least 5 years younger than mPOLE patients from other cohorts. No other variable was statistically significant within ORIEN. When available clinical data from all cohorts were pooled, mPOLE was significantly associated with male sex, younger age at diagnosis, and early stage (I/II) disease. Conclusions: The ORIEN data set showed &lt;1% patients with pathogenic POLE mutations. When pooled with the available public data sets, we see emergence of a unique clinical phenotype. Additional outcome data from ORIEN TCC database will be reported. We acknowledge the participation and assistance of the ORIEN investigators, with thanks. wtPOLE vs mPOLE in pooled and individual large cohort studies.[Table: see text]
Myasthenia gravis-associated thymoma and myasthenia gravis-free thymoma have distinct somatic mutation and gene expression profiles.
Authors: Yi Zhang, Xiaomo Li, Gaojun Lu, Tonghui Ma, Kejian Shi
Journal: Journal of Clinical Oncology (2021)

8573 Background: A significant proportion of thymoma patients have concurring autoimmune diseases such as myasthenia gravis (MG). However, the molecular signature of myasthenia gravis-associated thymoma (MGT) is largely unknown. Genomic and transcriptomic profiling of MGT may provide valuable insight to the etiology of MGT and facilitate the development of effective therapeutic approaches. Methods: To study the molecular signature of MGT, 26 thymoma patients were divided into two subgroups according to their clinical presentations. One group included 16 thymoma patients associated with MG (MGT) and the other group had 10 patients without MG (MGF). We profiled the genomic and transcriptomic changes of tumor samples from both subgroups with whole exome sequencing (WES) and RNA sequencing (RNA-seq). Results: The WES results indicated that more genes were mutated in the MGF subgroup than the MGT group, although the difference between two subgroups was not statistically significant. There were only five mutated genes ( NBPF1, HRAS, ATAD3B, IFITM3 and MUC4) appeared total mutation frequency exceeded 10%. NBPF1 is the most frequently mutated gene, seen in 25% of the MGTs (4/16) and 10% (1/10) of the MGFs. Neuroblastoma breakpoint family member 1 encoded by NBPF1 was involved in several cancer types including gastric cancer and neuroblastoma, but there is no report on the link of NBPF1 with thymoma or MG. Recent studies showed that NBPF1 is a negative regulator of Akt-p53-Cyclin D and PI3K/mTOR signal pathways. Recurrent mutations in HRAS was only observed in MGFs but not MGTs. Genes mutated in more than one patient were NBPF1, ATAD3B, RPDM9, LOC642131, ADAM21, CGNL1, MUC4 and MUC2 in the MGT subgroup, while only three genes HRAS, CSPG4 and IFITM3 were mutated in more than one patient in the MGF subgroup. Moreover, RNA-seq data identified 106 significantly differentially expressed genes, including 54 upregulated and 52 downregulated genes in the MGT subgroup, further pathway enrichment analysis revealed that the Hippo, Wnt, TGF‐β and focal adhesion signaling pathways were significantly downregulated in the MGT subgroup compared with the MGF subgroup. Conclusions: Our findings provide new insights for the etiology of thymoma with and without MG. mTOR signaling pathway is a key regulator of immune response. Importantly, the protein level of some components in the mTOR pathway was reduced in MG caused-atrophic muscle. Further investigation is warranted to examine the functional roles of NBPF1 in mTOR signaling regulation and the etiology of MG-associated thymoma.
Killers in the Brain: Essays in Science and Technology from the Royal Institution.
Authors: Saty Satya-Murti
Journal: BMJ (2000)

Ed Peter Day 

Oxford University Press, £18.99, pp 184

ISBN 0 19 850540 x

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Killers in the Brain is a guiltless reminder of our venerable scientific lineage and of our reneged responsibilities. The book comprises a compilation of selected Friday evening discourses at the Royal Institution. In eight scholarly monographs we learn about Faraday's brilliance, allergies associated with civilisation, inflammation in the brain, the scientific basis of “Murphy's law,” and the physiology of …

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Hepatic arterial infusion chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: A biomolecular exploratory, randomized, phase 3 trial (The FOHAIC-1 study).
Authors: Ning Lyu, Ming Zhao
Journal: Journal of Clinical Oncology (2021)

4007 Background: Advanced hepatocellular carcinoma (HCC) with mega liver masses and macrovascular invasion were commonly observed at the first diagnosis, while with less extrahepatic metastases (77.5% vs. 37.9%). However, in clinical trials IMbrave150, SHARP, and Asia-Pacific SHARP, the percentage of extrahepatic metastases reached 63%, 53%, and 68.7%, respectively, while macrovascular invasion only accounted for 38%, 36%, and 36%. Unlike the previous and ongoing phase 3 clinical trials exploring the optimal systemic medication in the first-line treatment of advanced HCC, this study mainly focused on a population with a heavy intrahepatic tumor burden. Methods: In this open-label, phase 3 trial, patients were randomly assigned in a 1:1 ratio to undergo hepatic arterial infusion chemotherapy (HAIC) of FOLFOX regimens (HAIC-FO) or sorafenib treatment. Patients in the HAIC-FO group were recommended to receive tumor and normal tissue biopsy to search for the potential genomic biomarkers in predicting the response to treatment. Results: Between May 2017 and May 2020, 551 patients were recruited. Two hundred sixty eligible patients were randomly assigned to receive HAIC-FO (n = 130) or sorafenib (n = 132) and were included in the intention-to-treatment population. Macrovascular invasion with or without extrahepatic metastasis was present in 82.8% of patients (84.6% and 81.1%; P = 0.446). The median tumor diameter was 11.7 cm (IQR 8.3-14.0) of the HAIC-FO group and 10.8 cm (8.7-13.6) of the sorafenib group (P = 0.439). The percentage of patients with &gt; 50% tumor volume involvement of the liver was 41.5% and 39.4%, respectively (P = 0.724). At the time of data cutoff (Oct 31, 2020, at 190 deaths [79 of HAIC-FO and 111 of sorafenib]), patients receiving HAIC-FO had a median overall survival of 13.9 months (95%CI 10.6-17.2), compared with 8.2 months (7.5-9.0) for those receiving sorafenib (HR 0.408 [95%CI 0.301-0.552], P &lt; 0.001). Tumor downstaging occurred in 16 (12.3% of 130) patients of the HAIC-FO group, including 15 (93.8%) receiving curative surgery or ablation and finally achieving a median overall survival (progression-free survival) of 20.8 (16.4) months (95%CI 9.1-32.5 [7.5-25.3]) with a 1-year rate of 93.8% (68.8%). Analyses of predictive biomarkers based on the whole genome sequencing were ongoing in the HAIC-FO group. Conclusions: This randomized phase 3 study proved that HAIC-FO had superior efficacy and survival outcome than sorafenib in the first-line treatment of primary diagnostic, advanced HCC, indicating that patients with heavy intrahepatic tumor burden, HAIC-FO monotherapy might be a better strategy than sorafenib. Clinical trial information: NCT03164382.
Abstract 14581: Vascular Access and Closure Management in Patients With Severe and Morbid Obesity Undergoing Transcatheter Aortic Valve Replacement
Authors: Jose Tafur Soto, Natalia Giraldo, Michael Bates, Patrick E Parrino, Stephen R Ramee
Journal: Circulation (2019)

Background: Severe and morbid obesity (S/MO) (Body mass index>=35 Kg/m2) is a current epidemic that poses major challenges in vascular access and closure during transcatheter aortic valve replaceme...