tbuckley/cabot-search huggingface dataset:
Population-based prostate cancer screening using a prospective, blinded, paired screen-positive comparison of PSA and fast MRI: The IP1-PROSTAGRAM study.
Authors: David Eldred-Evans, Paula Burak, Martin John Connor, Emily Day, Martin Evans, Francesca Fiorentino, Martin Gammon, Feargus Hosking-Jervis, Natalia Klimowska- Nassar, William McGuire, Anwar R Padhani, Derek Price, Toby Prevost, Heminder Sokhi, Henry Tam, Mathias Winkler, Hashim Uddin Ahmed
Journal: Journal of Clinical Oncology (2020)

5513 Background: The prostate-specific antigen (PSA) test can lead to under- and over-diagnosis of prostate cancer and has not been recommended for population screening. A fast MRI scan might overcome the limitations of PSA. IP1-PROSTAGRAM is the first study to evaluate the performance of a 15-minute non-contrast MRI for prostate cancer screening in comparison to PSA. Methods: IP1-PROSTAGRAM was a prospective, population-based, screen-positive paired-cohort study. Men aged 50-69 years in the UK were invited for prostate cancer screening through seven primary care practices or community-based recruitment. Participants underwent a PSA and MRI scan (T2-weighted and diffusion). MRI was scored using PIRADS version 2.0 without knowledge of PSA; screen-positive MRI (defined as either PIRADS score 3-5 or 4-5) were compared against a screen-positive PSA defined as ≥3ng/ml. If any test was screen-positive, a systematic 12-core biopsy was performed with MRI-ultrasound image-fusion targeted biopsy to MRI suspicious areas, as appropriate. Clinically-significant cancer was defined as any Gleason score ≥3+4. The primary outcome was the proportion of screen-positive MRI at different scores; important secondary outcomes were the number of clinically-significant and insignificant cancers detected. Results: 2034 men were invited to participate of whom 408 consented and 406 were screened by both PSA and MRI (10/Oct/2018-15/May/2019). The proportion with a screen-positive MRI (score 3-5) was higher than the proportion with a screen-positive PSA (17.7% [95%CI 14.3-21.8] vs. 9.9% [95%CI 7.3-13.2]; p &lt; 0.001). A screen-positive MRI (score 4-5) was similar to a screen-positive PSA (10.6% [95%CI 7.9-14.0] vs. 9.9% [95%CI 7.3-13.2], p = 0.71). An MRI score 3-5 or 4-5 used to denote a screen-positive MRI, compared to PSA alone, detected 14, 11 and 7 clinically-significant cancers, respectively. There were 7, 5 and 6 clinically-insignificant cancers detected, respectively. No serious adverse events occurred. Conclusions: When screening the general population for prostate cancer, MRI using a score of 4-5 to define a screen-positive test, compared to PSA alone at ≥3ng/ml, could lead to more men diagnosed with clinically-significant cancer without increasing the number of men biopsied or diagnosed with clinically-insignificant cancer. Clinical trial information: NCT03702439 .
Measurements of Mcl-1 protein dependencies using dimerization-specific antibodies as predictive biomarkers for BH-3 mimetic class therapies in AML.
Authors: Michael H. Cardone, Andrew Kinloch, Mine Canakci, Jingping Ge
Journal: Journal of Clinical Oncology (2020)

e19505 Background: The anti-apoptotic Bcl-2 family proteins facilitate pro-survival and resistance to anti-cancer therapies. Measuring the function of these proteins has shown utility in predicting response to treatment. A biomarker platform that assesses the functionality of these proteins by measuring BH3 mediated signaling potential in individual patients’ cancers, could provide a potential guiding platform for treating AML. In AML venetoclax is becoming widely prescribed and highly effective in combination with other drugs. Recent data indicate that Mcl-1 dependence is a resistance factor to venetoclax and that methods for identifying this could provide guidance for combination treatments. We are developing a technology to directly measure the occurrence of heterodimers of Mcl-1, or Bcl-xL, bound to pro-apoptotic BH3-only protein Bim. These measurements are combined in algorithms developed to indicate the cancer cell apoptotic priming state and offer great potential for identifying best AML treatment options. Methods: Monoclonal antibodies against conformation-specific epitopes induced in Mcl-1/Bim and Bcl-xL/Bim protein complexes were made. Selective bonding of Heterodimer Specific Mcl-1 Bim (HSMCB) and Heterodimer Specific Bcl-xL Bim (HSBXB) mabs were confirmed using ELISA, fluorescence polarization, immunofluorescence microscopy and flow, and by immunohistochemistry in genetically defined cell lines and in AML patient biopsied samples. Results: We show that HSMCB signal depends on both Mcl-1 and Bim protein levels while HSBXB requires Bc-xL and Bim levels. The relative signals of HSMCB to unbound Mcl-1 signal ([HsMcB]/[Mcl-1]) provide a biomarker for Mcl-1 dependence. We carefully established binding metrics that correlate to drug response in cell lines. The pharmacological disruption of these complexes is monitored by the ratiometric readouts that serve as predictive biomarkers for BH-3 mimetic drugs in AML cells. Conclusions: Mcl-1 dependence is a predictive biomarker for venetoclax resistance and for response to Mcl-1 targeted therapies. Flow cytometric and IHC based measurements of a heterodimer complex offer a direct and simpler approach that harbors potential for use in clinical settings. Additional antibodies targeting Mcl-1/Bak and Bcl-2/Bim complexes are being tested.
A comparative study of PD-L1 IHC assays using immune cell scoring and CPS in breast cancer.
Authors: Bin Li, Lloye M. Dillon, Jennifer Jones, Keyur Desai, David Gold, Dimple Pandya, Mustimbo Roberts
Journal: Journal of Clinical Oncology (2020)

e15262 Background: The clinical benefit of immune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death ligand 1 (PD-L1) pathway has previously been demonstrated across a range of tumor types, including in PD-L1+ patients with metastatic triple-negative breast cancer (TNBC). Various PD-L1 immunohistochemistry (IHC) assays and scoring algorithms are being investigated to select patients with breast cancer (BC) most likely to respond to ICIs. Scoring algorithms include PD-L1 expression on tumor cells, immune cells (ICs), or both. We compared the analytical concordance of 3 PD-L1 IHC assays and evaluated PD-L1+ prevalence, using combined positive score (CPS) and % IC scoring algorithms in commercially procured TNBC and hormone receptor–positive, HER2-negative (HR+/HER2−) BC samples. Methods: PD-L1 expression was assessed by HistoGeneX (Naperville, IL) in 163 commercially procured, surgically resected, formalin-fixed, paraffin-embedded BC samples (mostly stage I–III) using the Ventana PD-L1 (SP142) and Dako PD-L1 IHC 28-8 and 22C3 pharmDx assays in conjunction with the CPS (28-8 and 22C3 assays) and % IC algorithms (SP142 and 28-8 assays). PD-L1+ prevalence with each assay and concordance between assays were calculated using CPS ≥ 1 and IC ≥ 1% cutoffs, with a single pathologist assigned to each scoring algorithm. Results: 93 HR+/HER2− BC and 70 TNBC samples were evaluable for PD-L1 expression across all assays and algorithms. Overall concordance was higher between the 28-8 and 22C3 assays (CPS cutoff of 1) than between the 28-8 and SP142 assays (IC cutoff of 1%). PD-L1+ prevalence was similar with the 28-8 and 22C3 assays (CPS ≥ 1) and higher with the 28-8 assay (IC ≥ 1%) than with the SP142 assay (IC ≥ 1%). PD-L1+ samples identified by the SP142 assay (IC ≥ 1%) were mostly included within PD-L1+ sample sets defined by the 28-8 assay (IC ≥ 1% and CPS ≥ 1). PD-L1+ prevalence was higher in TNBC vs HR+/HER2− BC for all assays (Table). No clear trend in PD-L1+ prevalence was observed across tumor grade and stage. Conclusions: High analytical concordance was observed between the 28-8 and 22C3 assays (CPS cutoff of 1) in both HR+/HER2− BC and TNBC samples. PD-L1+ prevalence varied according to IHC assay, scoring algorithm, and cutoff used. Further studies are needed to select the most appropriate PD-L1 assay and scoring algorithm for BC clinical trials. [Table: see text]
INDIGO: A global, randomized, double-blind, phase III study of vorasidenib (VOR; AG-881) vs placebo in patients (pts) with residual or recurrent grade II glioma with an isocitrate dehydrogenase 1/2 (IDH1/2) mutation.
Authors: Ingo K. Mellinghoff, Martin J. Van Den Bent, Jennifer Leigh Clarke, Elizabeth Anne Maher, Katherine B. Peters, Mehdi Touat, John Frederick De Groot, Macarena Ines De La Fuente, Isabel Arrillaga-Romany, Wolfgang Wick, Benjamin M. Ellingson, Steven Schoenfeld, Feng Tai, Kha Le, Min Lu, Lori Steelman, Islam Hassan, Shuchi Sumant Pandya, Patrick Y. Wen, Timothy Francis Cloughesy
Journal: Journal of Clinical Oncology (2020)

TPS2574 Background: Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options consist of surgery followed by observation (“watch and wait”) for pts with lower risk for disease progression or post-operative chemo-radiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (m IDH1/2) occur in approximately 70% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate (2-HG). VOR, an oral, potent, reversible, brain-penetrant inhibitor of mIDH1/2, was evaluated in 76 pts with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at doses of &lt; 100 mg daily. Preliminary clinical activity was observed in non-enhancing glioma pts in both studies, most recently with an objective response rate (ORR) of 30.8% at 50 mg QD in the perioperative study and &gt; 90% 2-HG suppression at this dose level relative to untreated control samples (Mellinghoff et al., J Clin Oncol 2019). Methods: Approximately 366 pts will be randomized 1:1 to VOR (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria include: age ≥12 years; grade 2 oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed m IDH1/2 status; ≥1 prior surgery for glioma within the previous 5 years but no other anticancer therapy; Karnofsky performance status ≥80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the VOR arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint is progression-free survival assessed by independent review. Secondary endpoints include safety and tolerability, tumor growth rate assessed by volume, time to next intervention, ORR, overall survival, quality of life assessed by the Functional Assessment of Cancer Therapy–Brain questionnaire, and plasma pharmacokinetics. Exploratory endpoints include seizure activity and neuro-cognitive function. Clinical data will be reviewed regularly throughout the study by an independent data monitoring committee. The study is currently enrolling pts in the US, with additional countries planned (NCT04164901). Clinical trial information: NCT04164901 .
Effect of music therapy on symptoms, adverse events, and quality of life of breast cancer patients undergoing chemotherapy: A randomized clinical trial.
Authors: Rachel Jorge Dino Cossetti Leal, Talita Uchoa Lima, Emanuel Cabral Pereira, Raniere Victor Braga Nascimento, Eduardo José Silva Gomes Oliveira, Caio Marcio Barros Oliveira, Ed Carlos Rey Moura, Joao Nogueira Neto, Plinio da Cunha Leal
Journal: Journal of Clinical Oncology (2020)

e24140 Background: Music can influence human behavior and may be used as complementary therapy in health care. Objective: To assess the effect of music therapy on symptoms, adverse events and quality of life (QoL) of breast cancer patients undergoing chemotherapy (CT). Methods: Non-blinded, randomized clinical trial. Patients were randomized into two groups: musical group (MG) or control group (CG), and followed during the first 3 cycles of CT. Sociodemographic data, WHOQOL-BREF, BDI-II, BAI and Chemotherapy Toxicity Scale were assessed. Patients were evaluated after each of the first three CT cycles. MG underwent a 30-minute musical intervention prior to CT. There was no intervention in the CG. Results: Higher QoL scores on functional scales were observed for the MG in comparison to the CG after the first and third sessions of chemotherapy. Depression (p &lt; 0.001) and anxiety scores (p &lt; 0.001) and vomiting (p 0.01) incidence were lower for the MG in the third CT session. All participants in the MG reported positive changes in life in the Subjective Impression of the Subject questionnaire, as well as improvement in fatigue and reduced stress levels. Conclusions: Improvements in QoL, anxiety, depression, and incidence of vomiting were associated with music therapy intervention, suggesting a positive effect of music therapy on adverse events of cancer CT. Clinical trial information: RBR-88r347 .
Interferon gamma resistance in setting of LKB1 loss: Phenotypic characterization and investigation of mechanism.
Authors: Jacob Kaufman
Journal: Journal of Clinical Oncology (2020)

e21015 Background: NSCLC Patients with LKB1 loss respond poorly to immune checkpoint inhibitors (ICI). Determining mechanisms of the underlying immune resistance and strategies to overcome it are urgent and unmet clinical needs. Methods: We re-expressed WT LKB1 into LKB1 mutant NSCLC cell lines and measured effects on immune associated phenotypes in vitro. Specifically, we evaluated response to exogenous interferon gamma (IFNG), as well T-cell mediated cytotoxicity using a T-cell co-culture assay. To identify IFNG signaling changes influenced by LKB1, we evaluated the differential effects of LKB1 on IFNG induced gene expression using RNAseq. Finally, we performed a whole genome loss of function screen using CRISPR-Cas9 library (TKOv3) to identify genes and pathways that modify susceptibility to IFNG in the LKB1 mutant and LKB1 WT state in the A549 cell line. Results: Across multiple LKB1 mutant cell lines, restoration of WT LKB1 enhanced anti-proliferative effects of IFNG in vitro. Furthermore, WT LKB1 enhanced T-cell mediated cytotoxicity in T-cell co-culture assays using anti-NY-ESO TCR and expression of NY-ESO antigen into an HLA matched NSCLC cell line, H2023 (17% vs 40% cell death; P &lt; 0.01). IFNG treatment induced expression of a core set of interferon-driven genes in both the mutant and LKB1 WT state. However, differentially expressed gene classes included downregulation of proliferation-associated genes in the LKB1 WT state, as well as upregulation of ferroptosis genes, and enhanced IFNG-driven expression of immune evasion genes including PDL1, PDL2, TRAF1, and IDO1 in the LKB1 WT state. PDL1 expression was assessed by flow cytometry and found to be upregulated upon expression of LKB1. Our functional genomics screen identified genes whose inhibition enhanced IFNG susceptibility in the A549 mutant state, and genes whose inhibition restored IFNG resistance in the A549 LKB1 WT state. Preliminary analysis identifies candidate signaling and metabolic pathways that appear to confer IFNG sensitivity in the mutant state without significant effect on IFNG sensitivity after LKB1 add-back. These include modifiers of the Hippo/YAP pathway as well as modifiers of ferroptosis, which will form the basis for further mechanistic experiments. Conclusions: ICI resistance caused by LKB1 loss is associated with insensitivity to IFNG, and can be modified in vitro by re-expression of WT LKB1. An integrated approach to evaluate modifiers of IFNG effects identifies resistance mechanisms that may be potential therapeutic targets.
A prospective, open-label, multicenter, phase IV clinical study on the safety and efficacy of lobaplatin in the treatment of metastatic breast cancer.
Authors: Binghe Xu, Min Yan, Quchang Ouyang, Guohui Han, Ying Cheng, Dewei Wang, Ran Li, Da Zhao, Tao Sun, Yuju Bai, Hao Yu
Journal: Journal of Clinical Oncology (2020)

e13062 Background: Platinum-based chemotherapy is an important treatment for anthracycline- and taxane-resistant metastatic breast cancer(MBC), especially for triple-negative breast cancer(TNBC). Here, we presented the results of a phase IV clinical study of the third-generation platinum compound lobaplatin (LBP) in the treatment of MBC. Methods: Patients(Pts) diagnosed with MBC who had previously received chemotherapies containing anthracycline and/or taxane were recruited. The chemotherapy regimen was decided by the investigator but must include LBP. The primary endpoint was safety, the secondary study endpoints included PFS, OS, ORR, and DCR. Results: 1181 pts were enrolled from 34 research centers, 252 pts of them were TNBC. The main treatment regimens included LBP plus paclitaxel (134, 11.4%), LBP plus docetaxel(263,22.3%), LBP plus gemcitabine(235,19.9%) and LBP plus vinorelbine (404, 34.3%).The overall incidence of AE and grade III/IV(G3-4) incidence of AE were 95.00% and 58.10%, respectively. The most common AE were leukopenia (79.9%, G3-4: 39.5%), neutropenia(75.4%, G3-4: 43.8%), anemia(67.4%, G3-4: 17.8%), and thrombocytopenia(51.1%, G3-4: 17.8%). Creatinine clearance rate (Ccr) was the main influence factor for thrombocytopenia, the incidence of G3-4 thrombocytopenia in pts with Ccr &lt; 60 ml/min were higher than that in pts with Ccr≥60 ml/min. Median follow-up was 36 months. The ORR and DCR were 36.8% and 76.9%, respectively. The mPFS and mOS were 5.5 months and 15.4 months, respectively. The efficacy of LBP combined with taxanes was significantly better than that of other regimens. Different sites of metastasis, ECOG score, clinical stage and age were the main factors influencing for efficacy. Conclusions: LBP-based regimens are effective and safe, and these regimens provide an alternatively treatment option for Chinese MBC pts. Clinical trial information: ChiCTR-ONC-13003471. Clinical trial information: ChiCTR-ONC-13003471 .
Mutation of DNA damage repair genes confers an immune-privileged tumor microenvironment in colorectal cancer with a prognostic value.
Authors: Dandan Liang, Huan Chen, Ying Yang, Guanxiong Zhang, Jiao Zhang, Henghui Zhang
Journal: Journal of Clinical Oncology (2020)

4080 Background: Microsatellite instability high (MSI-H)/mismatch-repair-deficient (dMMR) has been proved as a validated biomarker in solid tumors receiving immune checkpoint inhibitors (ICIs). Recently, mutational status of the DNA damage repair (DDR) genes has been linked to anti-tumor immune response in bladder cancer. Therefore, it would be of great interest to unravel the implications of DDR in shaping the immune responsiveness in CRC. Methods: The genomic correlates were examined in a publicly available cohort from Memorial Sloan Kettering Cancer Center (MSK ICI cohort). To explore the associations between DDR mutation and immune features, the genomic data of The Cancer Genome Atlas (TCGA) colorectal adenocarcinoma (COADREAD) dataset was analyzed. Further, we determined DDR mutation and MSI status in a Chinese CRC cohort via a 543-gene panel sequencing. Results: First, we observed that DDR pathway was commonly mutated (21.79%) in the multi-cancer MSK ICI cohort, with the highest frequency of 36.36% in CRCs. Second, survival analysis revealed that the median overall survival (mOS) in patients with DDR mutations was significantly longer than that in the DDR wild-type subgroup, in both pan-cancer (P = 0.0008; mOS 31 vs 16 months) and CRC patients (P = 0.016; mOS 34 vs 13 months) in the MSK ICI cohort. However, in the TCGA COADREAD dataset, there was no significant difference in OS or progression free survival (PFS) between DDR mutant and DDR wild-type subgroups. These observation indicated a specific prognostic value for DDR mutation in patients with ICI treatment while not conventional treatment. Third, in the TCGA COADREAD dataset, DDR mutations were associated with increased TMB, enrichment of immune cell infiltration and immune checkpoint molecule expression, suggesting an improvement of various steps of the cancer immunity cycles in DDR mutant CRCs. Lastly, we investigated the DDR mutational pattern, and its associations with MSI-H and other genomic features in a Chinese CRC cohort. Notably, MSI-H and DDR mutation account for 5.7% and 13.4% respectively, suggesting that DDR may identify a higher proportion of potential responders than MSI-H. Conclusions: Our data suggest that DDR mutation is a potential prognostic biomarker for ICI-treated CRCs. Functional analysis in TCGA dataset revealed that DDR mutation might be an indication of enhanced cancer immunity. The higher incidence of DDR mutation in Chinese CRCs emphasized the future utility of panel-based DDR evaluation in guiding ICI treatment.
Updates from a phase Ib study of isatuximab (Isa), bortezomib (V) and dexamethasone (D) plus cyclophosphamide (C) or lenalidomide (R) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM).
Authors: Enrique M. Ocio, Paula Rodríguez Otero, Sara Bringhen, Stefania Oliva, Axel Nogai, Michel Attal, Philippe Moreau, Joaquin Martinez-Lopez, Nadia Le Roux, Sandrine Macé, Marie-Claude Rouchon, Qiuyan Wang, Maria-Victoria Mateos
Journal: Journal of Clinical Oncology (2020)

8529 Background: We report updated data from a Phase Ib study of Isa, a CD38 monoclonal antibody, plus VCd or VRd in transplant ineligible patients (pts) with NDMM (NCT02513186). Methods: Isa-VCd: Isa (10 or 20 mg/kg; weekly [QW] cycle 1 [C1], then Q2W), V (1.3 mg/m 2 ; twice weekly C1, then QW), C (300 mg/m 2 ; QW C1, then Days [D] 1, 8, 15 to C12), d (20 mg; twice weekly C1, then D1, 2, 8, 9, 15, 16, 22, 23 to C12). Isa-VRd: Isa (10 mg/kg), V and d as described above; R (25 mg/day; D1–14 and D22–35). Efficacy and safety were evaluated. Conventional (M-protein levels) and minimal residual disease (MRD) IMWG response assessments were compared. MRD negativity was assessed at 10 −5 by next-generation sequencing and flow. Mass Spectrometry (MS) negativity (no detectable serum M-protein) was assessed for 13 pts by Immuno-Capture and Liquid Chromatography coupled to High Resolution MS. Results: As of Nov 18, 2019, 17 pts were treated with Isa-VCd (10 mg/kg, n = 13; 20 mg/kg, n = 4), 27 with Isa-VRd; 53% and 63% remained on treatment, respectively. Infusion reactions were seen in 53% of Isa-VCd and 63% of Isa-VRd pts; Grade ≥3 infections in 23% and 37%; serious adverse events in 47% and 52%. See table for efficacy. 3 MRD positive pts were MS positive with persistent detectable M-protein ( &gt; 10 µg/mL). 8/10 MRD negative pts were MS positive (4 at 5-10 µg/mL; 4 at &gt; 10 µg/mL) and 2/10 were MS negative ( &lt; 5 µg/mL). Stable residual M-protein was observed by MS up to 23 months post-MRD negativity. All pts tested by MS are still progression-free. Conclusions: Isa-VCd/VRd shows encouraging efficacy and tolerability in NDMM. MS seems to be more sensitive than MRD; low levels of M-protein were detectable even in MRD negative pts. Clinical trial information: NCT02513186 . [Table: see text]
RAAS antagonist therapy for prevention of atrial fibrillation in hypertension
Authors: Li Li, Yanming Li, Weihua Guo, Changsheng Ma
Journal: BMJ (2019)

Hypertension is the most common and controlable risk factor of atrial fibrillation (AF). Resin-angiotensin-aldosterone system (RAAS) antagonist therapy may reduce atrial remodeling and hold promise as upstream therapy for AF, especially for the patients with left ventricular hypertrophy and left ventricular dysfunction. The RAAS antagonist therapy for prevention of AF in hypertensive patients needs to be further explored in large scale randomized studies.


Key words: 
Hypertension; Atrial fibrillation; Renin-angiotensin-aldosterone system(RAAS)
羟基脲致小腿皮肤溃疡一例
Authors: 胡妮妮, 肖青, 戴勤
Journal: BMJ (2004)

患者男,64岁.1997年10月检查发现外周血白细胞为270×109/L,骨髓增生极度活跃,粒系增生明显,以中性中幼、晚幼、杆状核粒细胞为主,PH染色体阳性,诊断为慢性粒细胞白血病(CGL).予口服羟基脲(Hu)3 g/d,肌肉注射干扰素α-2b(300万单位,隔日1次).以后根据白细胞下降的程度改Hu为1～1.5 g/d,长期坚持治疗。