tbuckley/cabot-search huggingface dataset:
The potential treatment of antroquinonol in adult patients with relapsed acute myeloid leukemia (AML).
Authors: Shou-Bao Wu, Elena Volodicheva, Olga Vinogradova, Today Su, Howard Cheng, Pei-Ni Chen, Shin-Shiou Lin
Journal: Journal of Clinical Oncology (2021)

e19001 Background: The prognosis of relapsed acute myeloid leukemia (R/R AML) remains poor and the management is challenging. Despite the increasing availability of targeted agents, the lower responses still represent a major obstacle to overcome. Antroquinonol is an isoprenyltransferase inhibitor with antitumor activity in vitro and xenograft models of AML. Our aim is to evaluate hematopoietic recovery with Antroquinonol in this phase IIa study. Here, the results from our phase IIa trial demonstrate the safety, tolerability, and activity of Antroquinonol in patients with relapsed AML. Methods: GHAML-2-001 is a phase IIa, open-label study in adult patients with relapsed acute myeloid leukemia or at initial diagnosis when no intensive treatment is possible. Antroquinonol 200 mg BID was administered in a 28-day cycle (up to six cycles). The primary endpoint is hematologic response rate. Secondary endpoints consist of 4-week survival, 24-week survival, duration of hematologic response and transfusion independence, and the response rates. Therapy was continued for as long as tolerated and there was continuing evidence of therapeutic benefit in the opinion of the investigator. Treatment response was assessed by the International Working Group (IWG) response criteria after each cycle. Results: Twelve eligible patients had a median age of 62.5 years (range, 42-69; 6 males, 6 females) and the whole process was conducted between March 2019 and February 2020. Of the two patients who did not complete the therapy period were due to the patient's decision to withdraw: One patient withdrew on day 7 and the other one withdrew on day 49. Among other ten patients who finished all six cycles (168 days), Antroquinonol showed excellent safety and favorable tolerability. At the end of the treatment, the rate of complete remission (CR/CRi) after 6-completed cycles was 50% (5/10) and the 24-week survival rate was 100%. Transfusion independence was achieved in 8 (80%) of 10 transfusion independence evaluable patients at the end of the 6th cycle treatment. Conclusions: In high-risk relapsed AML patients, orally administered Antroquinonol induced CRs and was well tolerated. This significant result suggests the potential of Antroquinonol for the therapy of this underserved population. Clinical trial information: NCT03823352. Clinical trial information: NCT03823352.
Deep-learning models for the detection and incidence prediction of chronic kidney disease and type 2 diabetes from retinal fundus images
Authors: Kang Zhang, Xiaohong Liu, Jie Xu, Jin Yuan, Wenjia Cai, Ting Chen, Kai Wang, Yuanxu Gao, Sheng Nie, Xiaodong Xu, Xiaoqi Qin, Yuandong Su, Wenqin Xu, Andrea Olvera, Kanmin Xue, Zhihuan Li, Meixia Zhang, Xiaoxi Zeng, Charlotte L. Zhang, Oulan Li, Edward E. Zhang, Jie Zhu, Yiming Xu, Daniel Kermany, Kaixin Zhou, Ying Pan, Shaoyun Li, Iat Fan Lai, Ying Chi, Changuang Wang, Michelle Pei, Guangxi Zang, Qi Zhang, Johnson Lau, Dennis Lam, Xiaoguang Zou, Aizezi Wumaier, Jianquan Wang, Yin Shen, Fan Fan Hou, Ping Zhang, Tao Xu, Yong Zhou, Guangyu Wang
Journal: Nature Biomedical Engineering (2021)
Impact of oncotype Dx score on treatment and long-term outcomes.
Authors: Surbhi Warrior, Joshua Thomas, Elizabeth Behrens, Ruta D. Rao
Journal: Journal of Clinical Oncology (2021)

e12518 Background: Oncotype dx is a 21 gene breast cancer assay that helps predict benefit of chemotherapy in early-stage hormone receptor positive (HR+), HER2 negative, 0 to 3 node positive breast cancer as reported by TAILORx and RxPonder trials. Both trials found no benefit of adjuvant therapy in mid-range scores of 11-25 with the exception of some benefit in age under 50 or premenopausal status, no benefit if score was 0-10, and benefit of chemotherapy if &gt;25. Methods: All breast cancer patients between 2019-2020 were chart checked to evaluate oncotype dx scores. Patient characteristics were analyzed between oncotype dx scores of 0-10, 11-25, and &gt;25 using X square tests. 2000-2020 institutional cancer registry data was analyzed to understand recurrence and mortality in patients with oncotype dx testing. Results: 173 patients had oncotype dx testing between 2019-2020, and most were HR+, HER2-, and had 0-3 lymph nodes. There was no difference in race or ethnicity between the groups of oncotype dx scores (Table), and average age at diagnosis for all three groups was 58 years. More patients with lower oncotype dx score had hormone therapy, but this was not significant (0-10 at 93.6%, 11-25 at 90.8%, and &gt;25 at 82.1%, p=0.26). Patients with a higher oncotype score were significantly more likely to have chemotherapy (0-10 at 0%, 11-25 at 17.3%, and &gt;25 at 82.1%, p&lt;0.01). When looking at long term outcomes, the mortality rate was highest in the 11-25 score group at 9.5%, but was not significantly higher than 0-10 at 4.7% and &gt;25 at 2.1% (p=0.15). The recurrence was highest in the 0-10 group at 5.4%, but not significant compared to the 11-25 group at 4.1% and &gt;25 group at 4.2% (p=0.09). Conclusions: Race, ethnicity, and age does not impact predisposition to high oncotype dx score, which is interesting since literature shows minority women have higher mortality rates. This could be because oncotype dx looks at early-stage breast cancers and many minority women have later stages at diagnosis. There was no difference in which group received hormone therapy and there was significantly higher rate of chemotherapy administration in patients with scores &gt;25, which is consistent with prospective trial recommendations. When evaluating long term outcomes between oncotype dx groups over 20 years, there was no significant difference in recurrence of disease or mortality indicating that oncotype dx scoring accurately predicted overall benefit of chemotherapy.[Table: see text]
Adjuvant radiotherapy plus systemic chemotherapy in resected head and neck mucosal melanoma.
Authors: Rong Duan, Bixia Tang, Zhihong Chi, Chuanliang Cui, Bin Lian, Siming Li, Lili Mao, Xieqiao Yan, Xuan Wang, Xue Bai, Li Zhou, Xiaoting Wei, Jun Guo, Xinan Sheng
Journal: Journal of Clinical Oncology (2021)

e18042 Background: The median over survival (OS) of resected head and neck mucosal melanoma (HNMM) is 49.0 months. About 65% of patients experience local recurrence or distant metastasis after surgery. Therefore, adjuvant therapy is critical to improve the poor prognosis. Methods: Data regarding HNMMs with radical surgery (stage III-IVa, AJCC HNMM 8 th version) between September 1, 2006 and February 28, 2020 at Peking University Cancer Hospital was collected retrospectively. Postoperative radiotherapy was usually prescribed as GTV 60-70Gy/CTV 60Gy/30f. Patients were divided into four groups by the adjuvant regimens: radiotherapy+chemotherapy (RC), chemotherapy (C), radiotherapy (R) and observation (O). Results: In total, 368 patients were enrolled, including 104 RC,114 C, 53 R, 97 O, respectively. After median follow-up of 63.9 mo (range: 0.9-146.7), the median local relapse-free survival (LRFS) was 10.1 mo (95%CI: 6.7-13.6) in the O group, as compared with 65.9 mo (95%CI: 31.7-100.1, P＜0.001) in the R group, 75.6 mo (95%CI: 50.1-101.0, P＜0.001) in the C group, and 84.6 mo (95%CI: 48.5-120.8, P＜0.001) in the RC group. The median distant metastasis-free survival (DMFS) was 13.7 mo (95%CI: 8.0-19.5) in the O group, 15.3 mo (95%CI: 8.7-21.9, P = 0.898) in the R group, as compared with 25.7 mo (95%CI: 14.6-36.8, P = 0.001) in the C group, 49.3 mo (95%CI: 32.6-66.0, P＜0.001) in the RC group. Estimated OS was 36.4 mo (95%CI: 24.0-48.8) in the O group, as compared with 30.8 mo (95%CI: 23.0-38.6, P = 0.733) in the R group, 40.8 mo (95%CI: 34.8-46.8, P = 0.289) in the C group, 58.2 mp (95%CI: 36.4-79.9, P = 0.002) in the RC group. Primary location, age, gender, UICC staging and adjuvant regimens were included for multivariate Cox analysis. With regard to OS, UICC stage and RC were the prognostic factors. With regard to DMFS, UICC stage, RC and C were the prognostic factors. With regard to LRFS, UICC stage, RC, R, C were the prognostic factors. Conclusions: It is the largest study on the role of adjuvant radiotherapy and chemotherapy on HNMM till now. The results demonstrate that postoperative radiotherapy improves LRFS but has no impact on DMFS, while adjuvant radiotherapy plus chemotherapy prolongs OS. It further validates the clinical practice of UICC stage of HNMM, which might shed lights on the study of the whole mucosal melanoma.
만성 B형간염에서 클레부딘의 48주 치료 효과
Authors: 김민환, kyung-ah kim, 이준성, 이현웅, Kim Hyung Joon, 윤상구, Nam Hoon Kim, Won Ki Bae, 문영수
Journal: Clinical and Molecular Hepatology (2009)

목적: 클레부딘은 피리미딘 유사체로 실험실 및 동물실험에서 B형간염바이러스에 대해 강력한 억제 효과를 보여주었고, 만성 B형간염 환자를 대상으로 24주간 투여 효과를 평가한 3상 시험에서 강력하고 지속적인 항바이러스 효과를 나타내었다. 이번 연구에서는 48주 이상 클레부딘을 투여받은 만성 B형간염 환자 대상으로 클레부딘의 항바이러스 효과 및 바이러스 내성의 발생에 대해 알아보고자 하였다. 대상과 방법: 48주 이상 클레부딘을 투여받은 만성 B형간염 환자의 의무기록을 후향적으로 분석하였다. 3년 이내에 라미부딘 치료를 받은 적이 있는 환자는 제외하였다. 혈청 HBV DNA는 PCR hybridization 방법(검출 한계 316 copies/ mL)으로 측정하였다. 투여 24주와 48주째 혈청 HBV DNA, 혈청생화학검사 수치, 바이러스표지자 등을 분석하였다. 바이러스 돌파 현상 및 항바이러스 약제에 대한 내성의 발생 여부도 알아보았다. 결과: 총 74명의 만성 B형간염 환자가 포함되었으며(평균 연령 44세, 남:여=54:20, HBeAg 양성 환자 47명, HBeAg 음성 환자 27명), 이 중 10명은 라미부딘 치료를 받은 적이 있었다. 치료 전 혈청 HBV DNA 수치의 중앙값은 6.49 log10 copies/mL였다. 치료 48주째 혈청 HBV DNA 수치 감소폭의 중앙값은 전체 환자군에서 -4.34 log10 copies/mL, HBeAg 양성군에서 -4.84 log10 copies/mL, HBeAg 음성군에서 -3.74 log10 copies/mL였다. 치료 48주째 혈청 HBV DNA는 전체 환자 중 83.3%에서 검출되지 않았으며, 음전율은 HBeAg 양성군의 경우 76.6%, HBeAg 음성군의 경우 96.3%였다. 치료 48주째 84.7%의 환자에서 정상 혈청 ALT 수치를 보였다. 치료 48주째 두 명에서 바이러스 돌파 현상이 발생하였으며, 이전의 라미부딘 치료력과 간경변증의 존재가 내성 발생과 연관이 있었다. 결론: 만성 B형간염 환자를 대상으로 한 48주간의 클레부딘 치료는 효과적이었다. 그러나 이전 라미부딘 치료 경험자나 간경변이 동반된 경우 클레부딘에 대한 내성 발생의 위험이 증가한다.
Phase 1 first-in-human study of ABBV-184 monotherapy in adult patients with previously treated acute myeloid leukemia or non-small cell lung cancer.
Authors: Abraham Avigdor, Pierre Peterlin, Junichiro Yuda, Mor Tal Moskovitz, Nashat Y. Gabrail, Yakir Moshe, Bruno Quesnel, William R Henner, Edward B. Reilly, Donghui Huang, Maria Kovalenko, Apurvasena Parikh, Stacy Jaryno, Rachel S Leibman, Kevin J Freise, Esma Saada-Bouzid, Toshio Shimizu
Journal: Journal of Clinical Oncology (2021)

TPS2674 Background: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive therapeutic target in cancer, due to its broad expression in solid tumors and hematologic malignancies but limited expression in normal tissues. Elevated survivin expression is associated with an increased invasive phenotype and worse clinical outcomes. ABBV-184 is a first-in-class T-cell receptor (TCR)/anti-cluster of differentiation 3 (CD3) bispecific molecule. It is composed of a soluble TCR that binds to a survivin-derived peptide bound to the class I MHC allele HLA-A2:01 expressed on tumor cells and to the CD3 receptor on T cells. Preclinical data have demonstrated that treatment with ABBV-184 results in T-cell activation, proliferation, and redirected cytotoxicity of HLA-A2:01–positive target cell lines. This first-in-human trial evaluates ABBV-184 monotherapy in patients with previously treated acute myeloid leukemia (AML) or non-small cell lung cancer (NSCLC). Methods: Patients (≥18 years, Eastern Cooperative Oncology Group performance status ≤2, HLA-A2:01 restricted genotype) with relapsed or refractory AML or NSCLC are currently enrolling in this phase 1 multicenter, open-label trial (NCT04272203), which includes parallel dose-escalation and dose-expansion phases for both diseases. Primary objectives are to determine the recommended phase 2 dose (RP2D) of ABBV-184 (dose escalation) and to assess its preliminary efficacy (dose expansion). Secondary objectives include safety, tolerability, pharmacokinetics (PK), and immunogenicity assessments (dose escalation and dose expansion) and duration of response (dose expansion). Patients will receive intravenous infusion of ABBV-184 once weekly. Dose escalation of ABBV-184 is guided by a Bayesian optimal interval design and the RP2D will be determined on the basis of clinical safety, PK, and pharmacodynamic data. For patients with AML, disease assessment is performed according to modified European LeukemiaNet-International Working Group criteria. For patients with NSCLC, response will be assessed using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and immune RECIST. Treatment can continue until disease progression or intolerable toxicity. Biomarker assessments will include longitudinal profiling of peripheral blood immune cells and cytokines, analysis of HLA-A2 and survivin levels on AML bone marrow blasts and NSCLC tumor biopsies, and retrospective correlations of biomarker data with antitumor activity. Enrollment initiated in Sep 2020, with 7 patients enrolled as of Jan 2021. Clinical trial information: NCT04272203.
HGG-25. PRMT5 PROMOTES TUMOR GROWTH BY MAINTAINING STEMNESS OF PEDIATRIC HIGH-GRADE GLIOMA CELLS
Authors: John DeSisto, Aaron Knox, Hannah Chatwin, Ilango Balakrishnan, Sujatha Venkataraman, Rajeev Vibhakar, Adam Green
Journal: Neuro-Oncology (2021)

Abstract Background Pediatric high-grade gliomas (pHGG) are aggressive tumors that together constitute the most common cause of childhood cancer mortality. Tumor stem cells that drive proliferation of pHGG resist chemotherapy and radiation, complicating treatment. The arginine methyltransferase PRMT5 maintains self-renewal in neural stem cells through epigenetic modifications. We hypothesized that PRMT5, which we identified as a potential driver of diffuse midline glioma (DMG) through an shRNA screen, plays a similar role in pHGG. Methods Using lentiviral delivery of shRNA, we knocked down (KD) PRMT5 in cortical pHGG and DMG cell lines and performed phenotypic, mechanistic and self-renewal assays. We irradiated PRMT5 KD and control cells to study sensitization. We orthotopically injected mice with PRMT5 KD pHGG cells, and with DMG cells in which PRMT5 was knocked out (KO) using CRISPR-Cas. Results In cellular models of cortical pHGG and DMG, PRMT5 KD significantly reduced proliferation, inhibited cell cycle progression, increased apoptosis resistance, and decreased self-renewing cell frequency. A relative shift of PRMT5 from the cytoplasm to the nucleus accompanied differentiation induced by PRMT5 KD. Epigenetic changes accompanying PRMT5 KD included increased H3K27me3, a global transcription inhibitor, and decreased H3K27M expression in DMG. PRMT5 KD sensitized pHGG cells to radiation, increasing cell death 17–30%. PRMT5 KD/KO significantly increased survival in mice and decreased tumor aggressiveness and proliferation, but mice still died of tumor-related effects. Conclusions PRMT5 maintains self-renewal and drives proliferation in preclinical pHGG models. In cellular and in vivo models, PRMT5 KD/KO produces epigenetic changes, including increased H3K27me3 levels and diminished H3K27M, that may reduce proliferation and self-renewal. Future work includes elucidation of the mechanisms by which PRMT5 produces the observed changes. Because PRMT5 KD/KO does not eliminate tumor growth, we plan to further study combining PRMT5 KD/KO and clinical-grade small molecule PRMT5 inhibitors with radiation and chemotherapeutic agents.
Tunicates Illuminate the Enigmatic Evolution of Chordate Metallothioneins by Gene Gains and Losses, Independent Modular Expansions, and Functional Convergences
Authors: Sara Calatayud, Mario Garcia-Risco, Òscar Palacios, Mercè Capdevila, Cristian Cañestro, Ricard Albalat
Journal: Molecular Biology and Evolution (2021)

To investigate novel patterns and processes of protein evolution, we have focused in the metallothioneins (MTs), a singular group of metal-binding, cysteine-rich proteins that, due to their high degree of sequence diversity, still represents a "black hole" in Evolutionary Biology. We have identified and analyzed more than 160 new MTs in nonvertebrate chordates (especially in 37 species of ascidians, 4 thaliaceans, and 3 appendicularians) showing that prototypic tunicate MTs are mono-modular proteins with a pervasive preference for cadmium ions, whereas vertebrate and cephalochordate MTs are bimodular proteins with diverse metal preferences. These structural and functional differences imply a complex evolutionary history of chordate MTs-including de novo emergence of genes and domains, processes of convergent evolution, events of gene gains and losses, and recurrent amplifications of functional domains-that would stand for an unprecedented case in the field of protein evolution.
Results from a phase II study of eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab in patients with PD-L1 unselected metastatic second-line squamous head and neck carcinoma.
Authors: Irene Brana, Martin Forster, Antonio Lopez-Pousa, Bernard Doger, Patricia Roxburgh, Pawan Bajaj, Daniela Urueta Portillo, Vanesa Quiroga, Matthew Krebs, Christian Mueller, Frederic Triebel
Journal: Journal of Clinical Oncology (2021)

6028 Background: Eftilagimod alpha (efti) is a soluble LAG-3 protein that binds to a subset of MHC class II molecules to mediate antigen presenting cell (APC) activation and CD8 T-cell activation. The stimulation of the dendritic cell network and subsequent T cell recruitment with efti may lead to stronger anti-tumor responses in combination than observed with pembrolizumab alone. We hereby report results of the 2 nd line metastatic squamous head and neck carcinoma (HNSCC) cohort (part C) of phase II trial (NCT03625323). Methods: Patients (pts) with HNSCC progressed on or after 1 st line platinum-based therapy and unselected for PD-L1 expression were recruited into part C. The study used a Simon's 2-stage design (18 pts planned for stage 1 and 19 for stage 2), with objective response rate (ORR) by iRECIST as the primary endpoint (EP). Secondary EPs include tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS), pharmacokinetics, pharmacodynamics and immunogenicity. Efti was administered as 30 mg subcutaneous injection every 2 wks for 8 cycles and then every 3 wks for 9 cycles with pembrolizumab (200 mg intravenous infusion every 3 wks for up to 2 yrs). Imaging was performed every 8 weeks. PD-L1 was assessed centrally (22C3 clone). The study was approved by ethics committees and institutional review boards. Results: In total 38 pts were enrolled. The median age was 62 yrs (range 37-84) and 89 % were male. The ECOG PS was 0 and 1 in 34% and 66%, respectively. Primary location at diagnosis was the oral cavity (29%), oropharynx (37%), hypopharynx (18%) and the larynx (16%). All PD-L1 subgroups (CPS &lt; 1 %, ≥ 1 to ≤19; ≥20) were included. All pts were pre-treated with platinum-based chemotherapy. Pts received a median of 3.0 (range 1 – 21) pembrolizumab and 5.0 (range 1-31) efti administrations. Thirty-five (35) pts were evaluated for response (cut-off Jan 2021) with 4 (11 %) pts showing CR, 7 (20 %) pts PR, 3 (9 %) pts SD, 16 (46 %) pts PD with 5 (14 %) pts being not evaluable as per iRECIST. ORR was reported with 31.4 % (95 % CI 16.9 % - 49.3 %) and DCR 40 %Median PFS was 2.1 months and 35 % were progression free at 6 months. Median OS (46 % events) was 12.6 months. There were no adverse reactions leading to treatment discontinuation. The most common ( &gt; 10 %) treatment emergent adverse events were cough (18 %), asthenia (16 %), dyspnea (11 %), fatigue (13 %), diarrhea (11 %), hypothyroidism (11%), upper respiratory tract infection (11%) and back pain (11%). Conclusions: Efti in combination with pembrolizumab is safe and shows encouraging antitumor activity in platinum pre-treated 2 nd line HNSCC patients. Clinical trial information: NCT03625323.
Prospective correlation between the patient microbiome with response to and development of immune-mediated adverse effects to immunotherapy in lung cancer.
Authors: Justin Chau, Meeta Yadav, Ben Liu, Muhammad Furqan, Qun Dai, Shailesh Shahi, Arnav Gupta, Keri Nace Mercer, Evan Eastman, Taher Abu Hejleh, Carlos Hou Fai Chan, George J. Weiner, Catherine Cherwin, Sonny T.M. Lee, Cuncong Zhong, Ashutosh Mangalam, Jun Zhang
Journal: Journal of Clinical Oncology (2021)

e21024 Background: Though the gut microbiome has been associated with immunotherapy (ICI) efficacy in certain cancers, similar correlations between microbiomes at other body sites with treatment response and immune related adverse events (irAEs) in lung cancer (LC) patients receiving ICIs have not been made. We designed a prospective cohort study conducted from 2018-2020 at a single-center academic institution to assess for correlations between the microbiome in various body sites with treatment response and development of irAEs in LC patients treated with ICIs. Methods: Patients with histopathologically confirmed, unresectable/advanced/metastatic LC planned to undergo ICI-based therapy were enrolled between September 2018 and June 2019. Patients must have had measurable disease, ECOG 0-2, and good organ function to be included. Data was collected for analysis from January 2019 to October 2020. Nasal, buccal and gut microbiome samples were obtained prior to ICI initiation, at development of irAEs, improvement of irAEs to grade 1 or less, and at disease progression. 16S rRNA sequenced data was mapped to the SILVA 13.2 database; operational taxonomic unit clusters were analyzed using MicrobiomeAnalyst and METAGENassist. Results: 37 patients were enrolled, and 34 patients were evaluable for this report. 32 healthy controls (HC) from the same geographic region were included to compare baseline gut microbiota. Compared to HC, LC gut microbiota exhibited significantly lower α-diversity. The gut microbiome of patients who did not suffer irAEs were found to have relative enrichment of Bifidobacterium ( p = 0.001) and Desulfovibrio ( p = 0.0002). Responders to combined chemoimmunotherapy exhibited increased Clostridiales ( p = 0.018) but reduced Rikenellaceae ( p = 0.016). In responders to chemoimmunotherapy we also observed enrichment of Finegoldia in nasal microbiome, and increased Megasphaera but reduced Actinobacillus in buccal samples. Longitudinal samples exhibited a trend of α-diversity and certain microbial changes during the development and resolution of irAEs. Conclusions: This pilot study identified significant differences in the gut microbiome between HC and LC patients, and correlates specific bacterial genera to ICI response and irAEs in LC. In addition, it suggests potential predictive utility in nasal and buccal microbiomes, warranting further validation with a larger cohort and mechanistic dissection using preclinical models. Clinical trial information: NCT03688347.