tbuckley/cabot-search huggingface dataset:
High correlation between TMB, expressed TMB, and neoantigen load using tumor: Normal whole exome DNA and matched whole transcriptome RNA sequencing.
Authors: Christopher Szeto, Mrinal M. Gounder, Rahul Parulkar, Andrew Nguyen, Shahrooz Rabizadeh, Sandeep K. Reddy
Journal: Journal of Clinical Oncology (2020)

e15238 Background: Tumor Mutation Burden (TMB) has emerged as a biomarker of response to immune checkpoint inhibitor therapy, independent of PDL1 expression. The optimal cutoff for high versus low TMB is unknown and neoantigen load has been proposed as an alternative biomarker. We have previously described neoantigen silencing at the RNA level as potential means of immune escape. We hypothesized that expressed TMB (eTMB) and neoantigen load would differ from TMB. Methods: Using data from matched tumor:normal DNA, whole exome sequencing at 150x average depth, and whole RNA transcriptome at ~200x106 reads per tumor from a commercial database of 1395 heterogeneous cancer patient samples, we measured TMB and eTMB ( &gt; 2 alternate RNA reads supporting). Neoantigen load was measured as the count of unique 9mer peptides resulting from expressed somatic-specific variants with predicted binding affinity &lt; 500nM by NetMHC. Results: High correlation between TMB and eTMB was seen (R 2 = 0.94). No significant differences were seen between TMB, eTMB, and predicted neoantigen load. Using a cutoff of 200 non-synonymous variants (Rizvi 2015) to define TMB high versus highest quintile (TMB-20) (Samstein 2019) we saw high agreement of the 2 methods to assign TMB status as high v low. In the TMB-20 group with low TMB ( &lt; 200), most often reclassified were soft tissue sarcoma (18%) and pancreatic cancers (17%). Conclusions: Surprisingly, eTMB, TMB-20, and neoantigen load showed no significant difference from TMB using 200 variants as a cutoff for high. Tissue-specific TMB may be useful in patient with Sarcoma and Pancreatic cancers. Additional data inputs such as microbiome, chemokine expression, and TME cell phenotyping may be required to improve upon TMB as a biomarker of immunotherapy response.
Combination chemotherapy versus temozolomide (TMZ) for patients with MGMT methylated (m-MGMT) glioblastoma (GBM): Results of cellworks omics biosimulation—MyCare-015.
Authors: Michael Castro, Nirjhar Mundkur, Anusha Pampana, Aftab Alam, Aktar Alam, Rajan Parashar, Swaminathan Rajagopalan, Deepak Anil Lala, Kunal Ghosh Ghosh Roy, Sayani Basu, Annapoorna Prakash, Prashant Nair, Jim Christie, Vishwas Joseph, Ashish Agarwal, Poornachandra G, Liptimayee Behura, Shruthi Kulkarni, Nikita Ray Choudhary, Shweta Kapoor
Journal: Journal of Clinical Oncology (2020)

e14501 Background: UKT-03 evaluated TMZ plus Lomustine in a single arm phase II trial in newly diagnosed GBM patients. An overall survival of 23 months was a substantial improvement over historical experience. Patients with m-MGMT v. unmethylated tumors had a 2-yr survival of 75% and median survival not reached compared to 20% and 12.5 months, respectively. These data formed the basis for NOA-9, a randomized phase III trial in newly diagnosed, m-MGMT GBM which randomized 141 patients to standard therapy or experimental therapy with Lomustine and TMZ every 6 weeks. A superiority for the combination was observed: 48.1 v. 31.4 months for the standard arm in the ITT analysis. Nevertheless, many neurooncologists are reluctant to adopt this approach. The current standard of care uses single biomarker, m-MGMT, in contrast to comprehensive pathway analysis (CPA). We sought to determine if CPA could discriminate more effectively among each patient’s likelihood of benefiting from combination treatment. Methods: Cellworks Singula employs a novel Cellworks Omics Biology Model (CBM) to predict patient-specific biomarker and phenotype response of personalized GBM avatars to drug agents, radiation, and targeted therapies. The CBM was developed and validated using PubMed to generate protein network maps of patient-specific activated and inactivated disease pathways. CBM was used to simulate the TMZ and TMZ-Lomustine therapies for each patient in a TCGA cohort of 368 GBM patients. Omics data including methylation, whole exome sequencing, and copy number alterations were input into CBM. The Singula Composite Inhibition Score (CIS) was calculated based on the measured quantitative drug effects. Results: Though incremental gain from the combination was seen in all patients, CIS varied across the population with relative scores ranging from 32-82, with best responders have more than twice the benefit. Conclusions: CPA shows that m-MGMT is an excellent biomarker for determining the likelihood of benefit from TMZ and lomustine, with the caveat that CBM identifies 18% could be spared from TMZ exposure and would benefit from Lomustine alone. Otherwise, these data lend support for evolving the standard of care with combination therapy for patients with m-MGMT GBM and should help overcome a reluctance to employing combination therapy. Additionally, CBM has utility to individualize clinical decision making. [Table: see text]
A phase II study of rh-endostatin in combination with chemotherapy in human epidermal growth factor receptor 2 (HER-2) negative advanced breast cancer (ABC).
Authors: Yuan Huang, Ya-bing Zheng, Wen-Ming Cao, Zhan-hong Chen, Jianfei Fu, Gang Li, Wang Xiao Jia
Journal: Journal of Clinical Oncology (2020)

1071 Background: There is an urgent need to improve the efficacy of chemotherapy for HER-2 negative patients (pts) who lack anti-HER-2 therapies. Rh-Endostatin (endostar), a recombinant human endostatin, is a potent inhibitor of angiogenesis. This single-arm multicenter phase 2 study was designed to assess the efficacy and safety of endostar combined with chemotherapy in HER-2 negative ABC. Methods: Eligible pts had HER-2 negative inoperable locoregionally recurrent or metastatic breast cancer and an ECOG PS of 0 or 1. Pts with either measurable or nonmeasurable disease were eligible. Endostar (15 mg/m 2 , continuous infusion, day 1-7) plus chemotherapy were administered every 21 days until disease progression, intolerable toxicity or other reasons. Chemotherapy regimens were selected by investigators based on clinical decision. Primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) and adverse events (AEs). Results: From August 2016 to December 2019, 40 female pts were enrolled in 3 centers. The median age was 52. Ten pts were previously untreated and 30 pts had at least 1 line of chemotherapy for advanced disease. 31 pts were triple negative BC (TNBC) and 9 pts were hormonal receptor positive (HR+). Platinum combined with paclitaxel or gemcitabine were administered with endostar in 55% of pts. Others received paclitaxel or gemcitabine combined with endostar. 12 pts achieved a best response of partial response (PR) and 13 pts had stable disease (SD). Among 30 pts with measurable disease, ORR was 40% and DCR was 83%. The ORR for patients treated as the first-line therapy was 75% while as the second line or beyond was 27%. For TNBC and HR+ BC pts, the ORR was 46% and 17% respectively. Median PFS was not reached after a median follow-up of 7.6 months. The most common Grade 3/4 AEs observed during this study were neutropenia (10%), leukopenia (10%) and thrombocytopenia (5%). Conclusions: Endostar combined with chemotherapy was effective and well tolerated for the treatment of HER-2 negative ABC, especially TNBC. Its efficacy and safety could be further studied in randomized trials. Clinical trial information: NCT03907098 .
Distribution of ACE2, CD147, CD26, and other SARS‐CoV‐2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID‐19 risk factors
Authors: Urszula Radzikowska, Mei Ding, Ge Tan, Damir Zhakparov, Yaqi Peng, Paulina Wawrzyniak, Ming Wang, Shuo Li, Hideaki Morita, Can Altunbulakli, Matthias Reiger, Avidan U. Neumann, Nonhlanhla Lunjani, Claudia Traidl‐Hoffmann, Kari C. Nadeau, Liam O’Mahony, Cezmi Akdis, Milena Sokolowska
Journal: Allergy (2020)

Morbidity and mortality from COVID-19 caused by novel coronavirus SARS-CoV-2 is accelerating worldwide, and novel clinical presentations of COVID-19 are often reported. The range of human cells and tissues targeted by SARS-CoV-2, its potential receptors and associated regulating factors are still largely unknown. The aim of our study was to analyze the expression of known and potential SARS-CoV-2 receptors and related molecules in the extensive collection of primary human cells and tissues from healthy subjects of different age and from patients with risk factors and known comorbidities of COVID-19.We performed RNA sequencing and explored available RNA-Seq databases to study gene expression and co-expression of ACE2, CD147 (BSG), and CD26 (DPP4) and their direct and indirect molecular partners in primary human bronchial epithelial cells, bronchial and skin biopsies, bronchoalveolar lavage fluid, whole blood, peripheral blood mononuclear cells (PBMCs), monocytes, neutrophils, DCs, NK cells, ILC1, ILC2, ILC3, CD4+ and CD8+ T cells, B cells, and plasmablasts. We analyzed the material from healthy children and adults, and from adults in relation to their disease or COVID-19 risk factor status.ACE2 and TMPRSS2 were coexpressed at the epithelial sites of the lung and skin, whereas CD147 (BSG), cyclophilins (PPIA andPPIB), CD26 (DPP4), and related molecules were expressed in both epithelium and in immune cells. We also observed a distinct age-related expression profile of these genes in the PBMCs and T cells from healthy children and adults. Asthma, COPD, hypertension, smoking, obesity, and male gender status generally led to the higher expression of ACE2- and CD147-related genes in the bronchial biopsy, BAL, or blood. Additionally, CD147-related genes correlated positively with age and BMI. Interestingly, we also observed higher expression of CD147-related genes in the lesional skin of patients with atopic dermatitis.Our data suggest different receptor repertoire potentially involved in the SARS-CoV-2 infection at the epithelial barriers and in the immune cells. Altered expression of these receptors related to age, gender, obesity and smoking, as well as with the disease status, might contribute to COVID-19 morbidity and severity patterns.
双皮层综合征误诊为脑白质发育不良一例
Authors: 王加强, 殷明岗, 李世绰
Journal: BMJ (2007)

患者女,10岁,主因发作性意识丧失伴右侧肢体抖动4年就诊.曾查头颅MRI诊断为可疑脑白质发育不良,癫痫.既往史、个人史无特殊.母孕期体健,否认毒物、X线接触史.查体:神志清楚,语速慢.定向力可,理解力、判断力、计算力差,余未见异常。
Effects of pegylated interferon plus ribavirin on naive and retreat chronic hepatitis C patients: a retrospective study
Authors: Zong-guo Yang, Pei-yan Ye, Xiao-rong Chen, Cheng Liu
Journal: BMJ (2012)

Objective To evaluate the effects of pegylated interferon plus ribavirin on naive and retreated chronic hepatitis C (CHC) patients.Methods A total of 67 CHC patients were divided into naive group (n =35) and retreat group (n =32) based on their treatment history.And their virological responses [rapid virological response (RVR),early virological response (EVR),virological response to etravirine (ETR) and sustained virological response (SVR)] and risk factors were analyzed.Results ①RVR and EVR of naive group were 60％ (n =21) and 77％ (n =27),respectively,and the retreat group were 28％ (n =9),53％ (n =17).The differences between the two groups were significant (both P ＜ 0.05).On the contrary,CHC patients in both groups might achieve similar ETR and SVR rates (P ＞ 0.05) ; ② The relapse rate in the retreat group was higher than that in the naive group (22％ vs.10％).But the differences had no statistical significance (P ＞ 0.05) ; ③ CHC patients in the retreat group could achieve similar responses,including RVR,EVR,ETR and SVR (P ＞ 0.05) whether treated previously with standard interferon or pegylated interferon; ④ According to muhivariable logistic regression analysis,the retreated genotype 1 CHC patients has a lower SVR rate compared with naive genotype non-1 counterparts (OR =0.29 and 0.26,all P ＜ 0.05).Conclusions CHC patients in the naive group could achieve higher virological responses and a lower relapse rate compared to those in the retreat group.The previous treatment regimeu has no significant effect on virological responses of CHC patients retreated with Peg-IFN plus ribavirin.Genotype 1 and retreatment are both risk factors of achieving SVR.

Key words: 
Hepatitis C,chronic;  Interferon alfa-2a;  Ribavirin
Neuromuscular dysfunction and associated health/socioeconomic outcomes: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Rozalyn L Rodwin, Yan Chen, Yutaka Yasui, Wendy M. Leisenring, Todd M. Gibson, Paul C. Nathan, Rebecca M. Howell, Kevin R. Krull, Caroline Mohrmann, Robert J. Hayashi, Eric Jessen Chow, Kevin C. Oeffinger, Gregory T. Armstrong, Kirsten K. Ness, Nina S. Kadan-Lottick
Journal: Journal of Clinical Oncology (2020)

10546 Background: Childhood cancer survivors are at risk for neuromuscular dysfunction. We estimated the prevalence and cumulative incidence of neuromuscular dysfunction in a cohort of childhood cancer survivors and examined associations with treatment exposures and health/socioeconomic outcomes. Methods: CCSS participants ≥5 years from cancer diagnosed between 1970-1999 (n = 25,583, 46.5% female, median [range] age 54.4 [15.1-57.6] years) and siblings (n = 5,044, 52.3% female, median [range] age 54.1 [32.5-57.0] years) were included. Neuromuscular dysfunction was identified by self-report of 1) motor dysfunction: impaired balance, tremor, or extremity weakness; 2) sensory dysfunction: impaired touch sensation. Multivariable analyses examined predictors of dysfunction by diagnosis. Results: Cumulative incidence of neuromuscular dysfunction was elevated at 20 years from diagnosis in survivors (24.3%, 95% CI 23.8-24.8; motor 18.2%, sensory 13.5%) versus siblings (8.9%, 95% CI 8.1-9.7). In survivors five years from diagnosis, motor dysfunction was associated with exposure to cytarabine (OR = 1.39, 95% CI 1.10-1.77) and spinal radiation (OR = 2.11, 95% CI 1.31-3.41) in acute lymphoblastic leukemia/non-hodgkin lymphoma (ALL/NHL), vinca alkaloids (OR 1.29, 95% CI 1.03-1.60) and brain radiation (OR = 1.58, 95% CI 1.35-1.85) in central nervous system tumors, and cytarabine (OR = 3.73, 95% CI 1.62-8.57) and non-brain/spine radiation (OR = 1.84, 95% CI 1.42-2.40) in bone/soft tissue tumors. Sensory dysfunction was associated with exposure to vinca alkaloids (OR = 3.45, 95% CI 1.06-11.22) in ALL/NHL, and platinum agents (OR = 1.31, 95% CI 1.03-1.67) and spinal radiation (OR = 3.71, 95% CI 1.24-11.11) in bone/soft tissue tumors. Survivors with neuromuscular dysfunction were at increased risk for adverse health/socioeconomic outcomes (Table). Conclusions: Neuromuscular dysfunction is a prevalent morbidity in childhood cancer survivors, associated with specific therapies within a particular diagnosis. Interventions are needed to identify and improve neuromuscular dysfunction given its association with adverse health/socioeconomic outcomes. [Table: see text]
Breast cancer index (BCI) predicts benefit of two-and-a-half versus five years of extended endocrine therapy in HR+ breast cancer patients treated in the ideal trial.
Authors: Gerrit-Jan Liefers, Iris Noordhoek, Kai Treuner, Hein Putter, Yi Zhang, Elma Meershoek – Klein Kranenbarg, Jenna Wong, Cornelis J. H. Van De Velde, Catherine A. Schnabel
Journal: Journal of Clinical Oncology (2020)

512 Background: For postmenopausal women with hormone receptor positive (HR+) breast cancer, the optimal duration of extended endocrine therapy (EET), after completing 5 years of initial aromatase inhibitor (AI)–based adjuvant therapy, remains unclear. BCI [HOXB13/IL17BR (H/I)] is a gene expression-based biomarker that has been demonstrated to predict EET benefit in the MA.17 and Trans-aTTom studies in patients treated with adjuvant tamoxifen. The current study examined the ability of BCI (H/I) to predict endocrine benefit from 2.5 vs. 5 years of extended letrozole in the IDEAL trial. Methods: All patients with available tumor specimens were eligible for this blinded prospective-retrospective study. The primary endpoint was Recurrence-Free Interval (RFI). Median follow-up was 9.1 years from randomization. Kaplan-Meier and Cox proportional hazards regression analysis were used to analyze the differential benefit of EET with statistical significance of the interaction between BCI (H/I) and treatment assessed by likelihood ratio test. Results: 908 HR+ patients (73% pN+, median 59y, 45% pT1, 48% pT2, disease free at 2.5 years) were included, with 88% and 68% receiving prior treatment with an AI or chemotherapy, respectively. BCI by H/I status (High vs. Low) was significantly predictive of response from extended letrozole in the overall (N = 908) and pN+ (N = 664) cohorts. Notably, BCI (H/I) predicted EET benefit in patients that received any primary adjuvant therapy with an AI (N = 794). Treatment to biomarker interaction was significant in the overall (p = 0.045), pN+ (p = 0.029) and any prior AI (p = 0.025) cohorts, adjusted for age, pT stage, grade, nodal status, prior endocrine therapy and prior chemotherapy. Conclusions: Novel findings from this study demonstrate that BCI predicts endocrine benefit from extended letrozole in postmenopausal patients treated with primary adjuvant AI. These results support the growing body of evidence that BCI by H/I status predicts preferential endocrine response in distinct subgroups of patients, and further support its role as an important genomic tool to inform the risk-benefit regarding duration of extended endocrine therapy. Clinical trial information: NTR3077, BOOG 2006-05, Eudra-CT 2006-003958-16 . [Table: see text]
Eradication of medulloblastoma by NKG2D-specific CAR T-cells.
Authors: Hong-jiu Dai, Bin Sun, Dong Yang, Hui Xu, Jingjing Zhu, Jia Wei, Xudong Zhao
Journal: Journal of Clinical Oncology (2020)

2522 Background: Medulloblastoma (MB) is a cancerous malignant brain tumor, that most often occurs in young children. Standard-of-care therapies for treating pediatric MB have long-term side effects, even in children who are cured. Recently people are exploring the potential of chimeric antigen receptor T (CAR-T) cell therapy in brain tumor, yet the clinical outcome is limited. It's reported that NKG2D ligands are wildly expressed in MB cells, which supports NKG2D system might play an important role in MB therapy. Here, we take advantage of NKG2D-specific CAR-T cells (KD-025) for MB treatment. Methods: HTB186, HTB185 and HTB187 MB cell lines as well as MB cancer patient samples were evaluated for NKG2D ligands expression. The KD-025 showed antigen-specific stimulation by cytokine secretion and target cell lysis. HTB186 cells, which stably express luciferase protein, were used to establish in vivo subcutaneous and xenograft models in NSG mice. Mice received a single treatment of 10 million KD-025 intravenously. Results: NKG2D ligands were detected on HTB186 and HTB187 cells and most of screened BM patient samples. The KD-025 was generated with CD8 hinge region and transmembrane region, 4-1BB costimulatory region and CD3 zeta region. The KD-025 expression was &gt; 50% on the surface of T cells confirmed by flow cytometry. Co-incubation of KD-025 with HTB186 cells specifically upregulates TNF-α, IFN-γ, IL-10 and IL-2 cytokines and strongly lysis tumor cells even at low E:T ratio (70-80% at 8:1). Strikingly, KD-025 markedly eliminated xenograft tumors in vivo and did not exhibit significant treatment-related toxicity in the treated mice. Regarding to T cell persistence, the CAR-T cells are barely detectable 24 days after injection, which is comparable with CD19 CAR in our experiments as well as published data. No obvious pathological changes were found in the tested organs. Conclusions: Our work with the KD-025 contributes to the growing body of research committed to discovering a novel therapy for MB. NKG2D ligands are highly expressed on human MB samples. KD-025 potently respond to MB and eliminate tumor in a xenograft mouse model with no obvious safety issues. The results support future clinical trial of KD-025 in patients with MB, where the need for effective treatment is great.
CDK 4/6 drug target activation mapping of HR+/HER2- metastatic breast cancer for treatment selection and response prediction.
Authors: Maysa M. Abu-Khalaf, Christos Hatzis, K. Alex Hodge, Frances Valdes, William M. Sikov, Monica M. Mita, Neelima Denduluri, Kris Awerkamp, Rita Murphy, Daniel Zelterman, Bryant Dunetz, Emanuel Petricoin, Mariaelena Pierobon
Journal: Journal of Clinical Oncology (2020)

e13029 Background: Despite the fact that a number of CDK 4/6 inhibitors have become FDA approved as the main frontline therapy for HR+/HER2- metastatic breast cancer (MBC), there are no validated predictive markers of response to this class of drugs. Additionally, approximately 30-40% of patients (pts) have little to no response to these agents, with disease progression occurring in weeks to a few months after therapy initiation. We have initiated a clinical trial (NCT03195192) to utilize cutting edge proteomic technologies to map the functional activation of the signaling architecture of tumors taken from HR+/HER2- MBC pts at diagnosis. We plan to correlate these functional phosphoprotein-based signaling patterns with PFS intervals to identify candidate markers associated with response to CDK 4/6 inhibitor therapy. Methods: Pre-treatment diagnostic FFPE biopsy material from 26 individuals enrolled on study were analyzed by an LCM- reverse phase protein array workflow. Quantitative measurements of a focused set of 8 qualifying (pre-hypothesized) protein/phosphoprotein CDK 4/6 kinase pathway biomarkers, total Rb, Rb (S780), total Cyclin D1, Cyclin D1 (S286), total pI6INK, total p27, p27 (T187), FoxM1 (T600) were measured. Results: Baseline tumor tissue was successfully analyzed for 26 pts, 17 (65%) White, 8 (31%) African American, and 1 (4%) Asian; average age 62 (range 36-79); 4 pts (15%) had prior endocrine therapy and 4 (15 %) had chemotherapy in the adjuvant setting. Seven pts remain on study treatment. Unsupervised analysis revealed substantial concordance between a number of the total-phosphoprotein paired biomarkers, with 8/26 (31%) patients having relatively low activation/expression pattern (within the bottom quartile of the data range of the 8 markers) and 6/26 (23%) having relatively high activation/expression pattern within the top quartile of the data range of the 8 markers). Conclusions: Functional CDK 4/6 drug target pathway mapping analysis is possible from the pre-treatment diagnostic FFPE material and revealed sub-populations of patients who had systematically low and high levels of CDK 4/6 kinase substrate proteins and phosphoproteins that indicate overall drug target activity. Correlations of those patterns with PFS outcome data is ongoing with final analysis planned for Summer 2020. Clinical trial information: NCT03195192 .