tbuckley/cabot-search huggingface dataset:
Phase I study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors.
Authors: Sun Young Rha, Seung-Hoon Beom, Young Geun Shin, Dong-Seok Yim, Yong Wha Moon, Tae Won Kim, Sun Young Kim, Gun Min Kim, Hyo Song Kim, Jae-Ho Cheong, Young Woo Lee, Barbara Jean Geiger, Sanghee Yoo, Marc S. Rudoltz, Filip Janku
Journal: Journal of Clinical Oncology (2020)

3590 Background: IM156, a novel oral potent biguanide OXPHOS inhibitor of Protein Complex 1 (PC1) of the mitochondrial electron transport chain, causes AMPK phosphorylation, the downstream effects of which are detrimental to OXPHOS-dependent cancer cells prone to energy stress. Preclinical experiments with IM156 demonstrated activity in solid tumor and hematologic malignancy models as a single-agent and in combinations. Methods: This was an open label, first-in-human, multi-center, dose-escalation study ( NCT03272256 ) using a 3+3 design. The primary endpoint was to determine the maximum tolerated dose and/or recommended Phase 2 dose (RP2D) based on dose limiting toxicities (DLT), safety and tolerability. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics (PD) and preliminary signals of efficacy. Eligible patients were adults with advanced solid tumors refractory to standard therapies with ECOG Performance Status &lt;2, adequate organ function, and measurable disease (RECIST 1.1 or RANO [gliomas]). IM156 was administered orally every other day (QOD) or daily (QD) in 28-day cycles. Results: 22 patients (gastric cancer: N = 8; ovarian cancer: N = 3; colorectal cancer: N = 3; endometrial cancer: N = 2; sarcoma: N = 2; other: N = 4) were enrolled in 7 dose cohorts (100, 200, 400, 800, and 1,200 mg QOD; 800 and 1,200 mg QD). The most frequent treatment-related adverse events (TRAEs) were gastrointestinal (nausea [N = 16, 73%], diarrhea [N = 12, 55%], and vomiting N = 11, 50%]). Nausea, reported in 3 (14%) patients, was the only Grade 3 TRAE. No DLTs were reported; the RP2D declared was 800 mg as 1,200 mg QD was associated with Grade 2/3 nausea requiring dose modifications. PK demonstrated dose-proportional increases in C max and AUC 0-last reaching the expected efficacious range. PD demonstrated a decrease in tumor growth rate in 3 patients (1,200 mg QOD: N = 2; 800 mg QD: N = 1), and a decrease in VEGF and tumor markers in a patient with gastric cancer with neuroendocrine differentiation treated at 800 mg QD who remains on study in Cycle 11. Best response was stable disease in 7 (32%) patients. Conclusions: IM156 is the first PC1 OXPHOS inhibitor to have been successfully tested in patients with cancer with the identification of a RP2D. It was well tolerated at dose levels active in preclinical models, and demonstrated modest clinical activity in an unselected population of patients. Subsequent development will focus on OXPHOS-dependent tumors and in combinations with agents in which OXPHOS metabolism is a mechanism of resistance. Clinical trial information: NCT03272256 .
Artificial intelligence based on deep learning for differential diagnosis between benign and malignant pulmonary nodules: A real-world, multicenter, diagnostic study.
Authors: Tao Xu, Chuoji Huang, Yaoqi Liu, Jing Gao, Huan Chang, Ronghua Yang, Tianjiao Jiang, Zhaozhong Cheng, Wencheng Yu, Juncheng Zhang, Chunxue Bai
Journal: Journal of Clinical Oncology (2020)

9037 Background: Lung cancer is the most common cancer worldwide. Artificial intelligence (AI) platform using deep learning algorithms have made a remarkable progress in improving diagnostic accuracy of lung cancer. But AI diagnostic performance in identifying benign and malignant pulmonary nodules still needs improvement. We aimed to validate a Pulmonary Nodules Artificial Intelligence Diagnostic System (PNAIDS) by analyzing computed tomography (CT) imaging data. Methods: This real-world, multicentre, diagnostic study was done in five different tier hospitals in China. The CT images of patients, who were aged over 18 years and never had previous anti-cancer treatments, were retrieved from participating hospitals. 534 eligible patients with 5-30mm diameter pulmonary nodules identified by CT were planning to confirm with histopathological diagnosis. The performance of PNAIDS was also compared with respiratory specialists and radiologists with expert or competent degrees of expertise as well as Mayo Clinic’s model by area under the curve (AUC) and evaluated differences by calculating the 95% CIs using the Z-test method. 11 selected participants were tested circulating genetically abnormal cells (CACs) before surgery with doctors suggested. Results: 611 lung CT images from 534 individuals were used to test PNAIDS. The diagnostic accuracy, valued by AUC, in identifying benign and malignant pulmonary nodules was 0.765 (95%CI [0.729 - 0.798]). The diagnostic sensitivity of PNAIDS is 0.630(0.579 – 0.679), specificity is 0.753 (0.693 – 0.807). PNAIDS achieved diagnostic accuracy similar to that of the expert respiratory specialists (AUC difference: 0.0036 [-0.0426 - 0.0497]; p = 0.8801) and superior when compared with Mayo Clinic’s model (0.120 [0.0649 - 0.176], p &lt; 0·0001), expert radiologists (0.0620 [0.0124 - 0.112], p = 0.0142) and competent radiologists (0.0751 [0.0248 - 0.125], p = 0.0034). 11 selected participants were suggested negative in AI results but positive in respiratory specialists’ result. 8 of them were malignant in histopathological diagnosis with tested more than 3 CACs in their blood. Conclusions: PNAIDS achieved high diagnostic accuracy in differential diagnoses between benign and malignant pulmonary nodules, with diagnostic accuracy similar to that of expert respiratory specialists and was superior to that of Mayo Clinic’s model and radiologists. CACs may be able to assist CT-based AI in improving their effectiveness but it still need more data to be proved. Clinical trial information: ChiCTR1900026233.
Subjective cognition in chimeric antigen receptor T-cell therapy recipients.
Authors: Anna Barata, Aasha Hoogland, Kelly Hyland, Anuhya Kommalapati, Reena Jayani, Nathalie E. Irizarry-Arroyo, Yvelise Rodriguez, Raviteja Alla, Brian James, Elizabeth Lafranchise, Michael D. Jain, Frederick Lundry Locke, Heather S.L. Jim
Journal: Journal of Clinical Oncology (2020)

7020 Background: Chimeric antigen receptor T-cell (CAR-T) therapy can lead to durable responses in chemorefractory patients with hematologic malignancies. CAR-T, however, can be associated with neurotoxicity. There is a significant body of literature describing patient-reported concerns with cognition in hematopoietic cell transplant (HCT) recipients, a similar treatment group. However, little is known about subjective cognition in CAR-T patients. This study examined changes in subjective cognition over time in CAR-T recipients and compared their outcomes with allogeneic HCT recipients. Methods: At baseline and 90 days after infusion, participants completed the Everyday Cognition Questionnaire (ECog). The ECog provides scores for total cognition, memory, language, visuospatial abilities, planning, organization, divided attention, and satisfaction with cognition. Comparison data from allogeneic HCT recipients came from a previous observational study. Linear mixed models compared changes in subjective cognition between recipients of CAR-T and allogeneic HCT over time. Models were adjusted by age, marital status, education, and Karnofsky performance status. Results: Participants were 111 CAR-T recipients (mean age 60 years, 37% female) and 190 allogeneic HCT recipients (mean age 53, 42% female). Linear mixed models indicated CAR-T recipients’ subjective cognition didn’t change within the 90 days after infusion (p’s &gt; .05). At baseline, there were no group differences between CAR-T and allogeneic HCT recipients in subjective cognition (p’s &gt; 0.05). Over time, however, subjective cognition between groups differed. Specifically, CAR-T recipients reported stable subjective cognition whereas allogeneic HCT recipients reported worsening total subjective cognition (p = 0.04), memory (p = 0.02), visuospatial abilities (p = 0.01), planning (p = 0.01), and divided attention (p = 0.01). At follow-up, CAR-T recipients reported better total subjective cognition (p &lt; 0.01), memory (p &lt; 0.01), language (p = 0.01), visuospatial abilities (p &lt; 0.01), planning (p &lt; 0.01), and divided attention (p &lt; 0.01) than allogeneic HCT recipients. Conclusions: Despite the neurotoxicity associated with CAR-T, patients can expect to perceive similar subjective cognition at day 90 compared to baseline. Future studies should also evaluate objective cognition in CAR-T recipients.
Single cell mapping of human brain tumors reveals tumor-specific education of tissue-invading leukocytes.
Authors: Ekaterina Friebel, Konstantina Kapolou, Susanne Unger, Nicolas Nunez, Sebastian Utz, Elisabeth Jane Rushing, Luca Regli, Michael Weller, Melanie Greter, Sonia Tugues, Marian Christoph Neidert, Burkhard Becher
Journal: Journal of Clinical Oncology (2020)

2509 Background: Brain tumors can be both of intracranial origin (e.g. gliomas) or spread from another location in the body (metastases). Tumor growth in the CNS is commonly favored by a highly immunosuppressive tumor microenvironment (TME). Whether the TME is predominantly shaped by the CNS microenvironment or by the nature of the malignancy is unknown, as is the origin and function of CNS tumor-associated macrophages (TAM). Methods: We have mapped the leukocyte landscape of brain tumors using high-dimensional profiling with mass cytometry (CyTOF). We designed two CyTOF panels (one lymphoid and one myeloid focused) measuring 74 parameters at the single-cell level and analyzed samples from 47 individuals with the most common tumor entities being glioblastoma and metastases from melanoma and lung cancer as well as control tissue from epilepsy surgery. Results: The heterogeneous composition of tissue-resident and invading immune cells within the TME alone permitted a clear distinction between glioblastoma and metastases. Tissue-invading leukocytes accumulate in metastases, whereas gliomas predominantly contain tissue-resident reactive microglia. In gliomas, isocitrate dehydrogenase 1 (IDH1) mutations are associated with minimal host responses whereas IDH1-wildtype gliomas comprise monocyte-derived macrophages (MDM) similar to metastases. These MDM show a distinctive signature trajectory indicative of tumor-driven education. Conclusions: The immune cell composition of the brain tumor TME is tumor entity-specific, rather than dictated by the CNS tissue. Defining the distinct immunological signature of brain tumors can facilitate the rational design of targeted immunotherapy strategies.
A multiparameter classifier to predict response to lapatinib plus trastuzumab (LT) without chemotherapy in HER2+ breast cancer (BC).
Authors: Jamunarani Veeraraghavan, Carolina Gutierrez, Carmine De Angelis, Tao Wang, Tomás Pascual, Britta Weigelt, Patricia Galvan, Brent Neil Rexer, Andres Forero-Torres, Antonio C. Wolff, Rita Nanda, Anna Maria Storniolo, Ian E. Krop, Matthew P. Goetz, Jorge S. Reis-Filho, Susan G. Hilsenbeck, Aleix Prat, C. Kent Osborne, Rachel Schiff, Mothaffar F. Rimawi
Journal: Journal of Clinical Oncology (2020)

1011 Background: Several trials have shown 25-30% pathologic complete response (pCR) rates in patients with HER2+ BC treated with LT therapy (+ endocrine therapy if ER+), but no chemotherapy (CTX). We hypothesize that a multiparameter classifier, comprised of HER2 gene and protein levels, intratumor heterogeneity (ITH), HER2-enriched (E) subtype, and PIK3CA mutation status can identify patients whose tumors are “addicted” to HER2 signaling and are likely to achieve pCR from a CTX-sparing de-escalation strategy. Methods: Baseline specimens from 2 trials (TBCRC023 [NCT00999804] and PAMELA [NCT01973660]) of neoadjuvant CTX-sparing LT (+ endocrine therapy if ER+) in HER2+ BC were used. HER2 protein and ITH (scored for % 3+ by IHC), and gene amplification (HER2:CEP17 ratio and copy number (CN) by CISH) were measured on the same slide by the dual gene protein assay (GPA). HER2-E and PIK3CA mutation status were assessed by research-based PAM50 and MSK-IMPACT platforms, respectively. A decision tree algorithm was used to determine the GPA cutoffs and to construct the classifier of response (by pCR) in TBCRC023, which was then validated in PAMELA. Results: Of the evaluable patients from TBCRC023 (N = 130) and PAMELA (N = 151), GPA data were available for 121 and 94 cases, respectively. Both cohorts exhibited similar distributions for HER2 ratio, CN, and % 3+, and a strong correlation between HER2 ratio and CN (R &gt; 0.92). In TBCRC023, 73 cases had data from GPA, PAM50, and IMPACT, of which 15 had pCR. Recursive partitioning identified cutoffs of HER2 ratio &gt; 4.6 and % 3+ &gt; 97.5% in both the GPA data cohort (N = 121) and complete data cohort (N = 73). With PAM50 and IMPACT data, the model added HER2-E and PIK3CA wild-type (wt). For practical reasons, the classifier was locked as HER2 ratio ≥ 4.5 AND % 3+ ≥ 90% AND PIK3CA-wt AND HER2-E, which yielded a PPV of 55% and NPV of 94%. Validation in PAMELA using 45 cases with data for all 3 assays yielded PPV of 44% and NPV of 82%. 29 TBCRC023 cases without IMPACT data could be predicted to be non-pCR, of which 26 were correct (NPV = 89%). In PAMELA, 66 additional cases could be predicted to be non-pCR, of which 54 were correct (NPV = 81%). Conclusions: We have constructed a multiparameter classifier that can predict pCR with targeted therapy alone that compare to pCR rates of CTX + dual anti-HER2 in unselected patients. Prospective validation in a clinical trial is warranted. [Table: see text]
Comparison of the clinical interpretation of high-dimensional molecular data by two molecular tumor boards.
Authors: Damian Tobias Rieke, Till de Bortoli, Peter Horak, Mario Lamping, Ivan Jelas, Gina Rüter, Johannes Berger, Hanno Glimm, Benedikt Brors, Albrecht Stenzinger, Stefan Fröhling, Ulrich Keilholz
Journal: Journal of Clinical Oncology (2020)

3564 Background: The clinical interpretation of molecular data is a bottleneck of precision oncology. High-dimensional molecular data, such as RNA sequencing (RNA-seq) and whole-exome sequencing (WES), will likely increase the complexity of clinical interpretation. We compared the recommendations by two molecular tumor boards (MTBs) that independently interpreted the same high-dimensional molecular profiles. Methods: Patients with advanced solid tumors, no available standard therapy, an ECOG performance status of 0-1, and available fresh-frozen tissue underwent WES of tumor tissue and normal blood as well as RNA-seq of tumor tissue within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program of the German Cancer Consortium (DKTK). Data from 46 patients (WES and RNA-seq, n = 41; WES alone, n = 5) were independently discussed by two MTBs. Treatment recommendations were compared with regard to levels of evidence, therapeutic baskets, and types of biomarkers. Results: A total of 51,610 aberrations (median, 393 per patient) were considered for clinical interpretation (34,314 mutations/single-nucleotide variants, 7,115 mRNA expression changes, 6,144 DNA copy number variations, 4,037 gene fusions). 110 and 132 treatment options were identified by the two MTBs, respectively, with an overall agreement rate of 44.1%. The highest agreement rates were identified for treatment options based on clinical levels of evidence (Level 1, 60%; Level 2, 49.6%) and for poly(ADP-ribose)-polymerase inhibition (57.1%). The lowest agreement rates were identified when MTBs opted for traditional chemotherapy (0%), combination therapies (6.9%), therapies based on preclinical levels of evidence (Level 3, 35.9%; Level 4, 32%), and MAPK inhibition (35%). Similar agreement rates, ranging from 39% (gene fusions) to 54% (loss of heterozygosity), were observed for different types of biomarkers. Conclusions: Reproducible, evidence-based annotation of high-dimensional molecular data is feasible. Our experience provides a basis for ongoing harmonization and standardization efforts within the MTBs of the DKTK.
Identification of genetic alterations in childhood and adolescence glioblastoma (GBM) using next generation sequencing strategy.
Authors: Debora Cabral de Carvalho Corrêa, Indhira Dias-Oliveira, Maria Teresa de Seixas Alves, Nasjla Saba-Silva, Andrea Maria Capellano, Patrícia Dastoli, Sérgio Cavalheiro, Antonio Sergio Petrilli, Silvia Regina Caminada de Toledo
Journal: Journal of Clinical Oncology (2020)

e14547 Background: Glioblastoma (GBM) is the most aggressive brain malignancy with a heterogeneity molecular profile and accounts for no more than 3-5% of Central Nervous System tumors in children. Despite its rarity, pediatric GBM pertain different molecular genetics, outcome and effectiveness to therapies and remains an equally lethal tumor in children. Identification of genetic alterations in GBM of childhood and adolescence is important to refine molecular classification, define prognosis and therapeutic strategies. We aimed to detect and investigate molecular changes with potential prognostic marker and therapeutic target in GBM, using next generation sequencing (NGS) strategy. Methods: We selected 41 GBM samples from patients treated at Pediatric Oncology Institute/GRAACC. NGS was performed to identified genetic alterations in tumor samples using Oncomine Childhood Cancer Research Assay (OCCRA) panel, specific genetic panel for childhood and adolescence neoplasms. Results: We selected 41 GBM samples and identified 33 mutated genes. The most commonly detected genetic alterations were involving TP53, PDGFRA, PIK3CA, NF1, MYC, MET and genes with histone-related functions, including H3F3A and ATRX. Mutations in H3F3A K28M, ATRX and TP53 were most recurrent. ATRX alterations, either nonsense substitution or frameshift deletion, were exclusively found in patients with H3F3A K28M mutations. TP53 loss-of-function was exclusive in 9 of 41 (22%) tumors. In 7 of 9 cases (78%) harboring both H3F3A and TP53 mutations, patients died due to disease progression . In these patients, H3F3A-TP53 mutation is suggested to be unfavorable prognostic factor. Copy number alterations were found in 30% of GBM cases and PDGFRA-amplifications were the most frequent. PDGFRA-amplification was exclusively found in patients with H3F3A K28M mutations and 75% of these patients did not survived longer than two years. Conclusions: Molecular profiling based on NGS genetic panel, specific for pediatric tumors, can provide information about potential prognostic biomarkers for GBM of childhood and adolescence. Thus, wider understanding about GBM biologic heterogeneity may lead to personalized therapeutic strategies for pediatric patients.
Lymphocyte-activation gene 3 (LAG-3) expression in the inflammatory microenvironment of glioma.
Authors: Maximilian Mair, Barbara Kiesel, Katharina Feldmann, Georg Widhalm, Karin Dieckmann, Adelheid Woehrer, Leonhard Muellauer, Matthias Preusser, Anna Sophie Berghoff
Journal: Journal of Clinical Oncology (2020)

2553 Background: The blockade of lymphocyte-activation gene 3 (LAG-3), an inhibitory receptor on tumor-infiltrating lymphocytes, is currently under investigation in many extracranial tumor entities. Methods: 54 patients with diffuse glioma were included: 35 patients with glioblastoma (GBM, median age at diagnosis: 61 years) as well as 14 with WHO grade II and 5 with WHO grade III glioma (lower-grade glioma, LGG, median age at diagnosis: 45 years). Isocitrate dehydrogenase 1/2 mutations (IDH-mt) were present in 17/54 patients and 37/54 patients had IDH wildtype (IDH-wt) tumors. LAG-3 expression on tumor-infiltrating lymphocytes (TILs) was analyzed by immunohistochemistry (monoclonal anti-LAG-3 antibody, clone 17B4, LSBio Inc.). Results: LAG-3 + TILs could be observed in 5/54 (9.3%) samples, while CD3 + TILs were present in 32/54 (59.3%) and CD8 + TILs in 24/54 (44.4%) samples. Only IDH-wt glioma presented with LAG-3 + TILs (p = 0.168). Samples with LAG-3 + TILs presented with a numerical trend towards higher presence of CD3 + (5/27 CD3 + vs. 0/22 CD3 − , p = 0.072) and CD8 + TILs (4/24 CD8 + vs. 1/30 CD8 − , p = 0.159). 4/7 (57.1%) samples presenting with PD-1 + TILs also presented with LAG-3 + TILs (p = 0.001). Furthermore, glioma samples with LAG3 + TILs presented with higher expression of PD-L1 (median: 1% vs. 0%; p = 0.166). There was no difference in overall survival (OS) according to LAG-3 + TIL infiltration (median OS in LAG-3 + : 21.7 months vs. LAG-3 − : 41.4 months, p &gt; 0.05). Conclusions: LAG-3 + TILs are rarely observed in IDH-wt and absent in IDH-mt glioma. Gliomas with an active inflammatory microenvironment present more frequently with LAG3 + TILs. The diverse composition of the inflammatory microenvironment and particular inflammatory subgroups should be considered in future clinical trials on immune-modulating therapies in glioma.
A case of lupus nephritis complicated with bilateral herpes zoster
Authors: Xue Cao
Journal: BMJ (2020)

患者女性、22岁，因双侧同时出现红斑、簇集性水疱伴疼痛4 d就诊。既往狼疮性肾炎病史2个月余，现口服醋酸泼尼松35 mg/d维持治疗。查体：左上肢和右下肢带状排列红斑基础上簇集分布的水疱、丘疱疹。实验室检查异常：单核细胞数1.0×109/L，单核细胞百分比11.98%，余未见明显异常；尿蛋白（++）、潜血（-）；补体C3 0.60 g/L、补体C4 0.11 g/L。诊断狼疮性肾炎并发双侧带状疱疹，经口服伐昔洛韦、维生素B1和B12、普瑞巴林胶囊，湿敷康复新液、喷昔洛韦软膏治疗10 d皮疹明显好转，疼痛消失。
Abstract 15492: Non-Invasive Radiation Therapy of Ventricular Tachycardia Storm Guided by Computerized 12-Lead ECG-Based Mapping
Authors: Gordon Ho, Todd Atwood, Kevin Murphy, Andrew Bruggeman, Elliot R McVeigh, Andrew Kahn, Gregory K Feld, Christopher Villongco, David E Krummen
Journal: Circulation (2019)

Introduction: Stereotactic radioablation of ventricular tachycardia (VT) guided by epicardial body surface imaging (ECGi) has been performed in a few patients with promising results. Hypothesis: We...
Association between serum uric acid levels and lipid profile in elderly Chinese: the Guangzhou Biobank Cohort Study
Authors: Yi-ping Ba, Ya-li Jin, Lin Xu, Chao-qiang Jiang, Bin Liu, Wei-sen Zhang, Keung Cheng Kar
Journal: BMJ (2013)

The associations between serum uric acid (UA) levels and lipid profile in 3061 men and 7338 women aged 50+ years from Phase 1 of the Guangzhou Biobank Cohort Study were investigated. Based on the results, prevalence of hyperuricemia in men (UA>420 μmol/L) and women (>360 μmol/L) were 32.5% (996/3061) and 31.5% (2310/7338), respectively. The levels of total cholesterol (TC), triglyceride (TG) and low-density lipoprotein-cholesterol(LDL-C)in those with hyperuricemia were all significantly higher than those without (P<0.01). After adjustment for age, sex, smoking, waist circumference, body mass index, diastolic blood pressure and systolic blood pressure, UA level was positively associated with TC, TG and LDL-C, and was negatively associated with high-density lipoprotein-cholesterol (HDL-C) (P<0.01). Multivariate regression analysis also showed positive association of UA level with TC, TG and LDL-C and negative association with HDL-C (P<0.01). The results suggest that early treatment of hyperuricemia may be benefit in preventing further cardiovascular events.


Key words: 
Uric acid; Lipid profile
由病例分析看强直性脊柱炎的诊断和治疗
Authors: 张洁, 黄烽
Journal: BMJ (2006)

强直性脊柱炎(ankylosing spondylitis,AS)是一种慢性进行性疾病,主要侵犯骶髂关节、脊柱骨突、脊柱旁软组织及外周关节.病因目前尚未完全明确.流行病学统计,我国患病率为0.26%～0.35%,男女之比为5:1,好发于13～31岁.由于AS常导致青壮年疼痛、致残,影响生活和工作,故科学的诊治十分重要。