tbuckley/cabot-search huggingface dataset:
Preliminary efficacy from an ongoing phase 1 dose escalation study of seclidemstat (SP-2577) in patients (pts) with advanced solid tumors (AST).
Authors: Sant P. Chawla, Victoria S. Chua-Alcala, Jasgit C. Sachdev, David S. Wages, David D. Stenehjem, Daniela Y. Santiesteban, Nadeem Q. Mirza, Michael S. Gordon
Journal: Journal of Clinical Oncology (2021)

3073 Background: Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that is aberrantly expressed in many solid tumors. High levels of LSD1 expression are often correlated with poor patient prognosis due to LSD1’s role in cancer cell proliferation, metastasis, and chemoresistance. Seclidemstat is a novel, selective, reversible and oral LSD1 inhibitor capable of inhibiting both LSD1’s catalytic and scaffolding functions. We report preliminary efficacy in AST from an ongoing phase 1 trial. Methods: SALA-003-AC19 (NCT03895684) is a phase 1 trial of single agent SP-2577 in pts with AST. All pts had progressive disease (PD) at time of study entry. Pts received oral SP-2577 twice a day under fasting condition, in 28-day cycles (C). The primary objective is safety and tolerability. Secondary objectives are to determine maximum-tolerated dose, preliminary efficacy, pharmacokinetics, and pharmacodynamics. Results: As of December 30, 2020, 19 pts with AST (10 sarcoma, 2 prostate, 2 ovarian, 2 pancreatic, 1 renal, 1 cervical, 1 breast) were enrolled. Pts received escalating doses of SP-2577 from 150 to 600 mg BID and the dose escalation is ongoing. The median age was 63 years (range, 21–79). 42% were male, and pts had received a median of 4 (range, 1–8) prior systemic therapies. The most common (&gt;5%) grade 3 treatment-related adverse events were GI related including diarrhea (5.3%) and abdominal pain (5.3%). No grade 4 events were reported and there were no treatment-related deaths. Safety data will be presented after completion of phase 1. Three pts had at least one dose reduction. Among the 13 pts who were evaluable for response at end of C2, 7 pts (54%) had best response of stable disease (SD) with median time to progression (TTP) of 4.3 months (range, 2.1–11.5). Four of the 7 pts had genetic abnormalities that may demonstrate increased sensitization to SP-2577 according to preclinical studies. Characteristics of 7 pts with SD at C2 and beyond are shown in the table. Conclusions: Seclidemstat has shown activity among advanced sarcoma pts with a manageable safety profile. The dose escalation is ongoing and preliminary clinical data supports further exploration in FET-translocated sarcoma as single agent and in combination therapy. Clinical trial information: NCT03895684. [Table: see text]
Effects of Qingre Huatan Huoxue prescription on biological characteristics and cell cycle proteins of esophageal cancer stem cells.
Authors: Fuchun Si
Journal: Journal of Clinical Oncology (2021)

e16052 Background: Esophageal cancer (EC) stem cells characterized with immature differentiation, high invasion, high tumorigenesis and other biological characteristics, which are the root of the occurrence, development, recurrence, metastasis of EC. In this study, its purpose is to select and identify EC stem cells from serum-free cultured EC9706 cells, explore the effect of Chinese herbal prescription and its separated prescriptions on the biological characteristics of EC9706 stem cells, and to reveal the cytological and molecular mechanisms of Chinese herbal prescription anti-cancer. Methods: Firstly, MTT method was applied to explore the serum-free culture conditions of EC9706 stem cells in diameter of 60 mm low adhesion culture dish, at the same time, applying flow cytometry to identify the p75NTR mark ratio of each passage of cell to screenEC9706 stem cells. Next, Plotting the growth curve of EC9706 stem cells, detecting the proliferation inhibition rate EC9706 stem cells by cisplatin, soft agar clone formation, cell cycle to identify the characteristics of EC9706 stem cells by MTT method, soft agar assay, flow cytometry. Then applying MTT method and orthogonal test to screen and optimize Qingre Huatan Huoxue prescription (QHHP), using flow cytometry and western blot to test the effects of QHHP and its separated prescriptions on EC9706 stem cells appraisal indicators and Cell Cycle Proteins. Results: EC9706 cells with concentration of 8×10 4 cells/dish inoculateed on diameter of 60mm low adhesion culture dish, with adding 5 ml DMEM/F12 medium, a daily supplement of 20ng EGF, 10ng bFGF, per 10 to 14 days to passage one generation. After 5 generations of cell passage, the expression rate of p75NTR was 4-5%, was selected as the experimental object.EC9706 stem cells with the biological characteristics of slower adhesive growth, stronger cisplatin resistance, higher soft agar clone formation and p75NTR expression rate than that of EC9706 cells, and The cell cycle distribution was concentrated in the G0/G1 phase. 6 Chinese herbs were screened out ( Coptis coptidis, Rhizoma officinalis, Cucurbita pedicle, Toona bark, Cantharidopsis cantharidis, Augustia japonica) and compose QHHP. QHHP and its separated prescriptions could change the morphology, colony formation ability and cycle distribution of EC9706 stem cells in serum-free culture condition, which were related to the BMI1/CyclinB1 signaling pathway. Conclusions: Serum-free cell culture is a method to enrich stem cell-like cells in EC9706 cells. Qingre Huatan Huoxue prescription and its separated prescriptions inhibited the proliferation of EC9706 stem cells and change esophageal cancer stem cells characters. The mechanism of QHHP and its separated prescriptions on stem cells in EC9706 cells was related to BMI1 /CyclinB1 signaling pathway.
Anti-PD-L1 treatment to enhance the response of glioblastoma to radiation and produce long-term survival in mice.
Authors: Fei Wang, Nan Zhao, Chi Lin, Chi Zhang
Journal: Journal of Clinical Oncology (2021)

e14048 Background: Glioblastoma (GBM) is the most aggressive and most common primary central nervous system cancer in adults. Blocking the interaction between Programmed Cell Death Protein-1 (PD-1) and its ligand (PD-L1) has shown remarkable success in the treatment of several cancers. However, many challenges remain in improving the efficacy of using monoclonal antibodies (Ab) against the receptor PD-1 in GBM, mainly due to the “non-immunogenic” tumor characteristics of GBM. PD-L1 has been found to be overexpressed on the surface of human GBM tumor cells and tumor-associated macrophages (TAM). Radiotherapy (RT), as one of the standard therapy of GBM, could alter the tumor microenvironment and promote an antitumor immune response. We hypothesize that anti-PD-L1 therapy can enhance the RT effects and improve the outcome of treatment when combined. Methods: Using a preclinical orthotropic syngeneic CT-2A mouse GBM tumor model, we studied the efficacy of combined therapy with anti-PD-L1 and RT. Mice were stratified into four treatment groups: control, RT, anti-PD-L1 Ab, and anti-PD-L1 Ab plus RT. RT(8 Gy) was given one time simultaneously with the first dose of anti-PD-L1, followed by systemic anti-PD-L1 maintenance treatment to the mice. Overall survival and tumor growth were monitored. Immunohistochemistry on resected tumors during treatment was performed to characterize the immune response. Single-cell RNA sequencing (scRNA-seq) was also performed to further study the immunologic parameters in the mouse brain. Results: Our results showed that anti-PD-L1 Ab in combination with RT provided a remarkable antitumor immune response and improved overall survival, with 25.5, 34, and 30 days of median survival in control (no-treatment), RT, and anti-PD-L1 groups, respectively, and achieving long-term survival and complete tumor response in 80% of the mice in the anti-PD-L1+RT treatment group (median survival not reached) in GBM tumor-bearing mice. The combined therapy promoted the recruitment of tumor-infiltrating immune cells, reversed the hostile tumor immune environment with a higher M1/TAM ratio, CD8+ /CD4+ T cell ratio, and CD8+ T cell /Treg cell ratio in the tumor area comparing with those parameters in single modality treatment groups. Furthermore, scRNA-seq data demonstrated that anti-PD-L1 combined with RT resulted in robust higher CD8 effector T cells, while lower CD4 and CD8 exhausted T cells in the tumor region compared to other groups. Increased CD4 central memory T cells and CD8 central memory T cells were seen only in tumors treated with anti-PD-L1+RT providing immunologic explanations on the durable control of GBM achieved only by the combined therapy. Conclusions: The anti-PD-L1 therapy synergizes with RT by reversing the hostile tumor immune environment resulting in improved tumor control and long-term survival in the syngeneic mouse GBM model.
COVID-19 in Children—Not Just Little Adults
Authors: Jennifer E. Schuster, Annabelle de St Maurice
Journal: JAMA Network Open (2021)

Lyudmyla Kompaniyets, PhD; Nickolas T. Agathis, MD; Jennifer M. Nelson, MD; Leigh Ellyn Preston, DrPH; Jean Y. Ko, PhD; Brook Belay, MD; Audrey F. Pennington, PhD; Melissa L. Danielson, MSPH; Carla L. DeSisto, PhD; Jennifer R. Chevinsky, MD; Lyna Z. Schieber, DPhil, MD; Hussain Yusuf, MD; James Baggs, PhD; William R. Mac Kenzie, MD; Karen K. Wong, MD; Tegan K. Boehmer, PhD; Adi V. Gundlapalli, MD, PhD; Alyson B. Goodman, MD
Costs comparison of the immune check point inhibitors versus survival ratio in first-line non-small lung cancer.
Authors: Helmy M. Guirgis
Journal: Journal of Clinical Oncology (2021)

e21050 Background: Five-year overall survival (OS) was reported in 20% of patients treated by Pembrolizumab (Pembro) in 1st-line advanced/metastatic (a/m)-non-small lung cancer (nsLC). Costs of the immune check point inhibitors (ICI) are relatively high and bound to increase with extended use. We purposed to weigh and compare costs of ICI vs outcome. Methods: OS, hazard ratio (HR) and survival ratio (SR) defined as (1.0-HR) were used. Chemo-drug excluded; costs were calculated in US$. Results: Adjuvant Durv one-year costs in unresectable stage III were $130,956, OS gain 363 days and SR 0.47. Pembro one-year costs were $134,778. OS were 474 and SR 0.37 in programmed death receptor-ligand-1 &gt; 50%. At 5 years, costs were $673,890. Costs of 35-cycle Pembro combination were $336,945, OS 339 and SR 0.51. Costs increased with extended use. Atezolizumab/Bevacizumab-combination (Atezo/Bev) costs x 2-years were $492,114, OS 135 and SR 0.22. Using Biosimilar Bev costs dropped to $429,744. Ipilimumab/Nivolumab (Ipi/Nivo) costs x 2 were $544,696, OS 141 and SR 0.34. Costs of both Atezo/Bev and Ipi/Nivo increased by 50% with one year of extended use. Costs of Pembro-combination were 0.78 lower than Atezo/Bev and 0.62 than Ipi/Nivo. Pembro SR were 2.32 higher than Atezo/Bev and 1.65 than Ipi/Nivo. Absence of direct comparison, however, cast doubts on Pembro advantage. Conclusions: Costs of one-year adjuvant Durv, 3-year Pembro and 35-cycle Pembro-combination were considered fair and equitable with their corresponding SR. Pembro-combination costs were cheaper than Atezo/Bev and Nivo/Ipi. Costs of all drugs and combinations multiplied with extended use.
Comparison of 18F-AlF-NOTA-FAPI and 18F-FDG Imaging in a Patient With Gastric Signet-Ring Cell Carcinoma
Authors: Yue-Hong Guo, Min-Fu Yang
Journal: Clinical Nuclear Medicine (2021)

Abstract Several case reports have shown fibroblast activation protein inhibitor (FAPI) imaging to be superior to 18 F-FDG imaging in the delineation of primary gastric signet-ring cell carcinoma lesions. In this case, 18 F-AlF-NOTA-FAPI PET/CT showed more metastatic lesions that had more increased activity than 18 F-FDG PET/CT. However, neither 18 F-AlF-NOTA-FAPI nor 18 F-FDG imaging revealed any abnormal uptake in the primary gastric lesion, which was subsequently demonstrated to be the primary lesion by pathology.
血液疾患の強度が減少した幹細胞移植(RIST)に続く同時自己免疫性疾患の改良:移植片対自己免疫(GVA)効果
Authors: Yuji K, Kami M, Kato D, Miura Y, Myojo T, Kusumi E, Narimatsu H, Kishi Y, Hamaki T, Matsumura T, Miyakoshi S, Ueyama J, Morinaga S, Takaue Y, Taniguchi S
Journal: Blood (2004)
Genomic profiling by cell-free circulating tumor DNA in patients with recurrent adenoid cystic carcinoma (ACC) and the potential activity of selective fibroblast growth factor receptor (FGFR) inhibitors.
Authors: Cesar Augusto Perez, Giselle Dutcher, Zoukaa Sargi, Nelson Guevara, David Tse, Pasquale W. Benedetto
Journal: Journal of Clinical Oncology (2021)

e15018 Background: Few effective systemic therapies are available for adenoid cystic carcinoma (ACC). Multitargeted Tyrosine Kinase inhibitors (TKIs) as Lenvatinib and Rivoceranib can provide disease control and limited radiographic response in unselected ACC patients. Next-generation sequencing in tissue (tNGS) has identified MYB gene fusions in [patients with ACC but currently, only Notch1 mutations have an available targeted agent. The fibroblast growth factor receptor (FGFR) pathway is a downstream target of MYB. Methods: We retrospectively reviewed adult patients with a diagnosis of recurrent ACC seen at the University of Miami Sylvester Comprehensive Cancer Center between January 1, 2019 and October 31, 2020. Commercially available cell free DNA panel of 73 genes was used for analyzing circulating tumor DNA (ctDNA). Patients included had radiographically measurable disease and both tNGS and ctDNA data available. Results: Twelve patients were included. Median age at diagnosis was 54 years (28 - 68), and 69% were males. 83% of the patients had genomic abnormalities reported by tNGS, with the same number by ctDNA sequencing. Seven patients (58%) had genomic abnormalities in ctDNA of potentially therapeutic significance which were not found on tNGS, including FGFR1 amplification as well as FGFR2, BRAF, KRAS and JAK2 mutations. Three patients with FGFR genomic abnormalities only seen by ctDNA had been previously treated with Lenvatinib. One patient with primary lacrimal gland ACC metastatic to the liver and tNGS positive for NOTCH 1 had disease progression despite treatment with Lenvatinib and a NOTCH γ-secretase inhibitor. The patient’s ctDNA reported a FGFR2 mutation. The patient was started on Erdafitinib, an oral selective FGFR inhibitor, achieving a partial response at the primary site and metastatic liver lesions and remained on therapy for 7 months. Follow-up ctDNA after 3 months of therapy noted resolution of both FGFR and NOTCH abnormalities. Conclusions: Patients treated with lenvantinib or other TKIs may develop acquired resistance mutations and other genomic abnormalities. ctDNA can reveal additional therapeutic targets not present on tNGS and can be repeated serially. FGFR genomic abnormalities can be a driver mutation in patients with refractory advanced ACC and the activity of Erdafinib should be evaluated in this subset of patients with few therapeutic options.
Identification of predictive biomarker for immunotherapy by associating with CD8+T cell Infiltration in lung adenocarcinoma.
Authors: Puyuan Xing, Teng Li, Han Wang, Lin Yang, Guoqiang Wang, Shangli Cai, Li Junling
Journal: Journal of Clinical Oncology (2021)

e21177 Background: Tumor immune microenvironment (TIME) has been proved associated with response to immunotherapy(I/O). We hypothesized that screening potential mutation pattern which could significantly impact the tumor infiltrating lymphocytes(TILs) can help us to identify predictive biomarkers for I/O in Lung adenocarcinoma(LUAD). Methods: Multiple-dimensional data from The Cancer Genome Atlas LUAD cohort (n = 514) was used for building a mathematical model beween mutation signature and CD8+TIL score (based on MCP-counter). An independent public validation cohort (cohort 1: LUAD, n = 598) were used to assess the immunotherapeutic predictive performance of the potential mutation patterns. Results: Top 100 gene associated with CD8+TIL score were selected based on MC+ model which can provides the minimum non-convexity of the penalized loss given the level of bias. Seven TIME genes (SPTA1 coef 0.09; MET coef 0.02; HSD3B1 coef -0.00; STAT4 coef -0.01; EGFR coef -0.08; PIK3CB coef -0.08; KEAP1 coef -0.24) were generated by taking the intersection of the top 100 mutant genes and FoundationOne (F1) CDx NGS 315 genes panel and verified in cohort 1. Survival analysis showed that SPTA1 mt was the only one that associated with both significantly longer PFS (median PFS 3.15 vs 2.89 months; HR 0.65; 95% CI 0.45 to 0.93; p = 0.02) and OS (median PFS 15.08 vs 7.36 months; HR 0.59; 95% CI 0.40 to 0.88; p = 0.01) for patients who received I/O compared with chemotherapy(CT) among seven TIME genes. In order to test our hypothesis fully, a pooled analysis of SPTA1 mt (a core positive predictors of CD8+TILs) and KEAP1 mt (a core negative predictors for CD8+TILs ) were conducted and yielded that co occurrence of SPTA1 mt and KEAP1 mt had a compound effects for TIME. The validation showed that co mutation with SPTA1 mt was accompanied by an decrease HR for I/O vs. CT in both PFS (HR S+K vs. K only 0.59 vs 1.56) and OS (HR S+K vs. K only 0.39 vs 0.80) for KEAP1 mt patients. Conclusions: Our data show that it is feasible to identify individuals or groups of individual with specific mutations to immunotherapy responses from TIME view. SPTA1 mt was a core predictors for higher CD8+ TILs and can be identified as a predictive biomarker for benefit from I/O compared with CT. Prospective studies are warranted for further investigation.
肥満の代謝および認知合併症の効果的治療のための新規超長時間作用性エキセンディン-4キメラ蛋白質の遺伝子工学【JST・京大機械翻訳】
Authors: Lee Jong Youl, Park Taehoon, Hong Eunmi, Amatya Reeju, Park Kyung-Ah, Park Young-Hoon, Min Kyoung Ah, Jin Minki, Lee Sumi, Hwang Seungmi, Roh Gu Seob, Shin Meong Cheol
Journal: Biomaterials (2020)
Testing Mayo Clinic’s new 20/20/20 risk stratification model in another cohort of smoldering myeloma patients: A retrospective study.
Authors: Camille Tessier, Thomas Allard, Jean-Samuel Boudreault, Rayan Kaedbey, Flechere Fortin, Vincent Ethier, Michel Pavic
Journal: Journal of Clinical Oncology (2021)

e20005 Background: Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder associated with a high risk of transformation to symptomatic multiple myeloma (MM). SMM risk of progression to MM is highly heterogeneous and several models have been suggested to predict this risk, but none have yet been adopted internationally. Lakshman et al. recently proposed a risk stratification model based on three markers: bone marrow plasma cell (BMPC) percentage &gt; 20%, free light chain ratio (FLCr) &gt; 20 and serum M protein &gt; 20 g/L. In this “20/20/20” model, patients with 0, 1 or ≥ 2 risk factors are respectively considered at low, intermediate and high-risk of progression. The goal of our study was to test this risk model in our population and to determine if similar results could be obtained in another cohort of SMM patients. Methods: We conducted a retrospective, single center study with 89 patients diagnosed with SMM between January 2008 and December 2019. Patients were identified by query of the electronic medical records and the 2014 International Myeloma Working Group (IMWG) diagnostic criteria for SMM were used to determine eligibility. The main endpoint was progression to symptomatic multiple myeloma or amyloidosis. Results: All three markers proposed by Lakshman et al. were associated with an increased risk of progression: BMPC percentage ≥ 20% (hazard ratio [HR]: 4.28 [95% C.I., 1.90 – 9.61]; p &lt; 0.001), serum M protein ≥ 20g/L (HR: 4.20 [95% C.I., 1.90 – 15.53]; p = 0.032) and FLCr ≥ 20 (HR: 3.25 [95% C.I., 1.09 – 9.71]; p = 0.035). Immunoparesis (HR: 2.61 [95% C.I., 1.07 – 6.41]; p = 0.036) was also an independent risk factor in our population. The estimated median time to progression (TTP) was not reached for the low and intermediate risk groups and was 29.1 months (95% C.I., 3.9 – 54.4) in the high-risk group (p = 0.006). The estimated mean TTP for the low-risk group, the intermediate-risk group and the high-risk group were respectively 78.4 months (95% C.I., 68.3 – 88.5), 48.3 months (95% C.I., 31.9 – 64.8) and 35.2 months (95% C.I., 19.1 – 51.2). Sex, IgA isotype, positive Bence-Jones, abnormal β2-microglobulin and MGUS prior to SMM did not result in an increased risk of progression. The estimated proportion of progression-free patients at 1, 2 and 5 years were 96.8%, 93.4% and 77.5% for the low-risk group, 80.0%, 80.0% and 62.2% for the intermediate risk group and 70.0%, 58.3% and 29.2% for the high-risk group. Conclusions: When Mayo Clinic’s new 20/20/20 risk model was applied to our population, it adequately predicted the risk of progression to symptomatic disease at 2 years. As it relies on readily available biological parameters, this model is easy to use and can be applied in most clinical settings. We believe this model could be used to further study therapeutic approaches in higher risk SMM.
Adverse effects of adjuvant tamoxifen treatment on bone mineral density in premenopausal breast cancer patients: A systematic review and meta-analysis.
Authors: Chihwan Cha, Soo Jin Lee, Hanpyo Hong, Yun Young Choi, Min Sung Chung
Journal: Journal of Clinical Oncology (2021)

e12500 Background: It is well known that adjuvant tamoxifen treatment for breast cancer in postmenopausal women decreases bone loss. However, the adverse effect of adjuvant tamoxifen therapy for bone mineral density (BMD) in premenopausal breast cancer patients remains uncertain. This meta-analysis aimed to assess the effects of adjuvant tamoxifen therapy on BMD changes in premenopausal women with primary breast cancer. Methods: Through April 2020, studies reporting BMD changes of lumbar spine or hip in premenopausal women with primary breast cancer treated with adjuvant tamoxifen were collected from EMBASE and PubMed. The pooled analysis was performed using random effects model of the standardized mean difference (SMD) of BMD in patients. Results: A total of 1,432 premenopausal patients from eight studies were included in the pooled analysis. After 3 years of median follow up, adjuvant tamoxifen therapy decreased BMD by as much as SMD of -0.79 [95% confidence interval (CI); -1.25 to -0.33, P &lt; 0.01] at lumbar spines and -0.38 at hip (95%CI; -0.88 to 0.12, P &gt; 0.05). Compared with patients received tamoxifen alone, patients who received combination therapy with chemotherapy or ovarian function suppression (OFS) showed decreased bone loss at lumbar spine (SMD -1.17 with 95%CI -1.59 to -0.75, -0.43 with 95%CI -2.26 to 1.40, and -0.75 with 95%CI -1.38 to -0.13, respectively). Conclusions: Our meta-analysis revealed that premenopausal women who received adjuvant tamoxifen treatment showed significant bone loss over a period of time, especially at lumbar spine. However, tamoxifen attenuated bone loss in those who received tamoxifen after chemotherapy or along with OFS.[Table: see text]