tbuckley/cabot-search huggingface dataset:
ctDNA resistance landscape of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI).
Authors: Ji-Youn Han, Myung-Ju Ahn, Sang-We Kim, Ki Hyeong Lee, Eun Kyung Cho, Yun-Gyoo Lee, Dong-Wan Kim, Joo-Hang Kim, Jong-Seok Lee, Gyeong-Won Lee, Byoung Yong Shim, Jin-Soo Kim, Sang Hoon Chun, Sung Sook Lee, Young Joo Min, Sang Won Shin, Arielle Yablonovitch, Carin R. Espenschied, Hyunwoo Jang, Byoung Chul Cho
Journal: Journal of Clinical Oncology (2020)

9601 Background: While EGFR mutant ( EGFRm) non-small cell lung cancer (NSCLC) patients usually experience improved clinical benefit with EGFR TKIs, most eventually progress. Understanding mechanisms of resistance (MoR) may allow for more personalized treatment. Lazertinib is an irreversible third generation EGFR TKI for which MoR are unknown. Obtaining sufficient tumor tissue for genotyping at progression is often difficult. Therefore, we utilized plasma ctDNA from patients treated with lazertinib to explore MoR. Methods: Plasma samples from 47 NSCLC patients in the phase 2 trial of lazertinib (NCT03046992) were collected at screening and progressive disease (PD) and underwent ctDNA NGS of 74 genes using Guarant360. All patients were positive for an EGFR Ex19del or L858R ( EGFRm) and T790M by tissue testing at screening. Acquired, nonsynonymous, characterized mutations detected in a PD sample but not in the screening sample from the respective patient were considered putative MoR, excluding aneuploidy. Patients with detectable plasma EGFRm and/or T790M at screening were evaluable. Results: ctDNA was detected in 47 (100%) screening samples and 43/45 (96%) PD samples (two failed sequencing). An EGFRm was detected in 85% of patients at screening (n = 40), 38 of which had PD ctDNA results and were included in analysis. T790M was detected in 30 patients at screening and subsequently not detected at PD in 21 of these patients, 55% of all 38 included patients. Among the ten patients with T790M detected at PD, on-target MoR were detected in 7 (18% of all included patients) including EGFR C797S (n = 3, 8%), EGFR amplification (n = 3, 8%), and EGFR T854A (n = 1, 3%). All C797S were in cis with T790M. No on-target MoR were detected in patients without T790M detected at PD. Off-target MoR were seen in 34% of patients (13/38) including mutations in PIK3CA (13%; 2 E545K, 2 E542K, 1 E81K), ERBB2 (5%; 1 D769H, 1 V777L), KRAS (3%; 1 G12C), and BRAF (3%; 1 G469A). Gene amplifications were detected in CCND1 (n = 1, 3%) , CCNE1 (n = 2, 5%) , ERBB2 (n = 1, 3%) , FGFR1 (n = 1, 3%) , MET (n = 4, 11%) , and PIK3CA (n = 1, 3%), with some patients having multiple MoR. Conclusions: The spectrum of MoR identified in this cohort of patients treated with lazertinib is similar to that reported in other third generation EGFR TKIs, but with some differences in frequencies. The most common resistance mechanisms are T790M loss and PIK3CA alterations which may address the mechanism of action. Our findings suggest putative MoR of lazertinib and show that ctDNA NGS is an effective way to identify MoR in patients progressing on targeted therapy. Clinical trial information: NCT03046992 .
Evaluating biomarkers in metastatic castration-resistant prostate cancer patients treated with enzalutamide: PSA, circulating tumor cell counts, AR-V7 status and radiographic progression.
Authors: Shruti U. Gandhy, Fatima Karzai, Jennifer L. Marte, Marijo Bilusic, Sheri McMahon, Julius Strauss, Anna Couvillon, Monique Williams, Amy Hankin, Seth M. Steinberg, Audrey Gill, Alisa Tubbs, Joseph Schonhoft, William Douglas Figg, Philip M. Arlen, William L. Dahut, James L. Gulley, Ravi Amrit Madan
Journal: Journal of Clinical Oncology (2020)

e17569 Background: Enzalutamideis ahighly effective treatment in metastatic castration resistant prostate cancer (mCRPC). Although Prostate Cancer Working Group (PCWG) guidelines recommend continuing treatment until radiographic/clinical progression (rPD/cPD), many patients discontinue therapy for rising PSA alone. Methods: We conducted an open label, randomized phase 2 trial in mCRPC patients untreated with docetaxel, abiraterone, or enzalutamide, comparing enzalutamide alone or in combination with PROSTVAC, a therapeutic cancer vaccine designed to induce an anti-tumor immune response. The study discontinued accrual after planned interim analysis indicated no difference in progression between the two arms. Patients were followed beyond 1 st of 3 confirmed PSA rises until rPD. 49 patients were analyzed for Circulating Tumor Cell (CTC) count and AR-V7 status at 1 st PSA rise and at rPD/cPD or last follow up. Results: 57 patients were enrolled with median follow up time of 55.4 mo. 49/57 (86%) patients had rising PSA; median time to 1 st PSA rise for all patients was 6.4 mo (95% CI: 3.7-11.0 mo) after starting enzalutamide. 38/57 (67%) patients had progressive disease (majority with rPD; 1/38 (3%) with cPD); median time to progression for all patients was 23.3 mo (95% CI: 16.1-27.8 mo). 5 patients tested positive for AR-V7 within 30 days of rPD. In patients who experienced rPD/cPD, CTCs were detected in 11/24 (46%) samples taken at rPD vs. in only 3/24 (13%) samples taken at rising PSA. CTC counts were higher at rPD compared to samples taken at rising PSA (P = 0.004, Wilcoxon unpaired test). Of the 7 patients still being treated (median time on drug = 4.2 yrs), 2 experienced rising PSA; however none of the patients had detectable CTCs at a median of 30 days from last follow up. Conclusions: These data suggest that a rising PSA may not be a warning of near-term clinically significant disease progression in mCRPC patients treated with enzalutamide, given the 17-month difference between the first rise in PSA and ultimate rPD/cPD seen in this analysis. Further, CTCs and AR-V7 status associate strongly with rPD but not with rising PSA, adding biological rationale to the hypothesis that CTC counts and AR-V7 status are associated with disease progression. Collectively, these data highlight the need to continue to educate patients and providers on PCWG criteria for progression and appropriately-timed utilization of both therapies and diagnostic tests to maximize drug efficacy in mCRPC. Clinical trial information: NCT01867333 .
Real-world mutational profiling of Chinese non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) uncommon mutations acquired resistant to icotinib using next generation sequencing: A multicenter study.
Authors: Wen xian Wang, Chunwei Xu, Lei Lei, You-cai Zhu, Jinluan Li, Huafei Chen, Yong Fang, Hong Wang, Wu Zhuang, Meiyu Fang, Yinbin Zhang, Liping Wang, Huibao Zhang, Ying Zhou, Yu Zheng, Xugang Hu, Weiping Jiang, Gang Chen, Tangfeng Lv, Yong Song
Journal: Journal of Clinical Oncology (2020)

e21557 Background: Just like classical EGFR mutations, EGFR uncommon mutations non-small cell lung cancer (NSCLC) will still have acquired resistant problem to icotinib. The mechanism of icotinib resistance in such uncommon EGFR mutant patients has also risen to be a difficult question in lung cancer research. In order to explore the resistance mechanism in EGFR uncommon mutant NSCLC patients treated by icotinib, it is necessary to first identify the resistant gene profiles and clinic-pathologic characteristics of those patients. As far as we know that there is no large cohort of EGFR uncommon mutant NSCLC study in evaluating the efficacy and resistant genomic profiling of icotinib. Methods: We screened 3279 patients with NSCLC for EGFR uncommon mutations. Among them, 106 patients received icotinib treatment, and a total of 69 patients with stage IIIb-IV EGFR uncommon mutations NSCLC were undergoing tumor biopsies or blood withdrawing by the time of primary or acquiring to icotinib, in including formalin-fixed paraffin-embedded (FFPE) samples, serum samples and serous effusions. We used targeted next-generation sequencing to detect genes status of patients. Results: Among 69 patients treated with icotinib, 69.57% (48/69) developed acquired resistance, and 30.43% (21/69) had primary resistance. Using the specimens at the baseline, there were 39(81.25%) patients with EGFR T790M (including 7 patients with EGFR T790M, 32 patients with EGFR T790M plus EGFR amplification), 3(36.25%) patients with EGFR amplification, 1(2.08%) patient with BRAF mutation, 1(2.08%) patient with PIK3CA mutation, 1(2.08%) patient with CTNNB1 mutation, 1(2.08%) patient with ALK fusion, 1(2.08%) patient with ROS1 fusion, and 1(2.08%) patient with unknown status. Conclusions: EGFR T790M, EGFR amplification, BRAF mutation, PI3K-AKT-mTOR signaling pathway (PIK3CA mutations), CTNNB1 mutation, ALK fusion or ROS1 fusion might contribute to molecular mechanisms of acquired resistance to icotinib in EGFR uncommon mutations NSCLC. Our study uncovered EGFR uncommon mutational profiles of NSCLC patients with icotinib resistance with potential therapeutic implications.
两性畸形九例临床和超声诊断分析
Authors: 石华, 赵庆红, 张玉国, 胡佳琪, 郝力丹
Journal: BMJ (2011)

两性畸形(hermaphroditism)发病机制复杂,临床症状多样,仅靠临床表现确诊比较困难,超声检查可对两性畸形的诊断和临床治疗提供重要的影像学依据.现以9例性发育异常患者作为研究对象探讨两性畸形的临床及超声特点.一、资料与方法本院2009年12月至2010年12月收治的9例两性畸形患者,其中真两性畸形l例,男性假两性畸形4例,女性假两性畸形4例;社会性别男性2例,女性7例.平均年龄15.8岁(1.5 ～37.0岁).患者人院后均进行超声和染色体检查,手术切除的组织均送病理检查.超声采用彩色多普勒超声诊断仪器voluson730(美国GE公司),经腹部或直肠进行检查. 关键词：两性畸形
Time from diagnosis to 1<sup>st</sup> line immunotherapy (IOT) and its challenges, in a retrospective, multicenter study of Israeli patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Udi Shimony, Lior Hasid, Irad Deutsch, Eliran Malki, Daniel A. Vorobiof
Journal: Journal of Clinical Oncology (2020)

e19346 Background: The importance of timely treatment of advanced NSCLC and timeline measurements have been the subject of reported studies. Real world evidence data (RWED) via EHR and cutting-edge technology paired with Belong.life pts engagement platform, was evaluated in Israeli pts with NSCLC, members of Belong.life community. Timelines from diagnosis to start of IOT were analyzed by data scientists using AI and machine learning engines. Methods: 30 Israeli pts with advanced NSCLC, members of Belong.life, the largest global social media platform for cancer pts and caregivers, were screened during 2016-8. Demographics, time of diagnosis, time of starting IOT and reasons for treatment delays were documented. Results: 18 pts (60%) were males and 88% had Stage 4. Most pts (87%) were diagnosed during 2017-8. 46 % were &lt; 60 yrs and 54% &gt; 61 yrs. 18 (60%) pts received only pembrolizumab while 11 (37%) pts had it in combination with various chemotherapy drugs. 1 pt received single agent nivolumab. According to the dates reported by 22 (76%) pts, the median time from diagnosis to IOT initiation was 37 days( &lt; 20-96) with 13(59%) starting the treatment in &lt; 40 days. Most common delay causes were due to waiting for genetic tests to define targeted therapy (38%), protracted diagnostic phase (38%) and bureaucratic issues in 27%. Study limitations included its retrospective nature, a convenience sampling, and partial reliance on pts recall of dates. Conclusions: Healthcare systems are seeing an increase in the incidence of most cancers. We report marked variability in time to initiation of 1 st LOT therapy of Israeli pts with advanced NSCLC. The common reasons for the delays were obtaining the molecular tests results in order to define targeted drugs and as more targets and their therapies become available this period might increase. Treatment delays are likely to have a negative impact on pts well-being, quality of life and long-term prognosis. Speeding up diagnosis and treatment planning process could decrease pts waiting time, improve their quality of life and expectancy, therefore consideration to the development of a time to treatment protocol should be prioritized.
Adipophilin expression as an independent marker for poor prognosis of patients with triple-negative breast cancer.
Authors: Katsuhiro Yoshikawa, Mitsuaki Ishida, Hirotsugu Yanai, Koji Tsuta, Mitsugu Sekimoto, Tomoharu Sugie
Journal: Journal of Clinical Oncology (2020)

e12552 Background: Adipophilin (ADP) is a lipid-regulating protein of the perilipin/adipophilin/tail interacting protein of 47 kDa (PAT) family that coats the surfaces of cytoplasmic lipid droplets. Lipids are essential for cellular proliferation in tumor cells, and ADP, which increases the efficiency of lipid use, may contribute to cancer growth. Some previous studies suggest that ADP expression can act as a prognostic marker for specific cancers. The aim of this study is to investigate the clinicopathological significance of ADP expression in patients with triple-negative breast cancer (TNBC). Methods: Using immunohistochemical staining and tissue microarrays, we analyzed the expression profiles of ADP, glutaminase, and glutamate dehydrogenase (key enzymes in glutamine metabolism) in 61 TNBC patients who underwent operation from January 2006–December 2018. Relapse-free survival (RFS) was compared based on ADP expression and the risk factors for RFS were analyzed. Results: Fourteen (23.0%) patients were ADP-positive. As compared to ADP-negative TNBC patients, ADP-positive TNBC patients correlated with poor RFS ( p = 0.032). Among the TNBC patients with high Ki-67 labeling index, those negative for ADP exhibited better RFS than those positive for ADP ( p = 0.049). Moreover, among the patients without adjuvant chemotherapy, those negative for ADP exhibited better RFS than those positive for ADP ( p = 0.080). ADP-positive patients correlated with a significantly higher recurrence based on multivariate analyses (hazard ratio, 4.89; 95% confidence interval, 1.04–23.0; p = 0.044). Moreover, ADP expression significantly correlated with the expression of glutaminase and glutaminate dehydrogenase ( p &lt; 0.001 and p = 0.029, respectively). Conclusions: ADP expression is a novel marker for poor prognosis of patients with TNBC and might be superior to Ki-67 as a prognostic marker. ADP expression may be related to upregulation of glutamine metabolism in cancer cells of TNBC.
Assessment of calcaneus bone strength in postmenopausal women with type 2 diabetes by quantitative ultrasonography
Authors: Zheng Xu, Hao Gu, Guanwu Li, Xuefeng Li
Journal: BMJ (2015)

The calcaneus bone strength was assessed by quantitative ultrasonography in 47 postmenopausal women with type 2 diabetes mellitus (T2DM group) and 30 healthy postmenopausal women (control group). Speed of sound (SOS), broadband ultrasound attenuation (BUA) and stiffness index (SI) in T2DM patients were (1 015±170)m/s, (84±14)dB/MHz and 45±8, respectively, which were significantly lower than those of control group (1 403±232)m/s, (111±18)dB/MHz and 66±12(all P<0.001). Stepwise multiple regression analysis showed that homeostasis model assessment of insulin resistance (IR) was independently correlated with the parameters of quantitative ultrasonography in T2DM patients. The results suggest that calcaneus bone strength is reduced in postmenopausal women with T2DM.


Key words: 
Diabetes mellitus, type 2; Ultrasonography, quantitative
Effect of type-A behavior pattern on intervention of benazepril in patients with essential hypertension
Authors: Xiao-hua Yuan, Shi-ying Liu, Li Cao, Yun Zhang, Li-li Liu
Journal: BMJ (2009)

Objective To investigate the effects of type-A behavior pattern on intervention of benasepril in patients with essential hypertension.Methods According to the type-A behavior score patients with essential hypertension were divided into two groups:type-A group(n=80)and non-type-A group(n=80).Benazepfil was given to all patients for 3 months with gradual increase of dosage till the blood pressure (Bp)was controlled under 140/90 nlln Hg(1 mm Hg=0.133 kPa).The plasma levels of angiotensin II (Ang Ⅱ)was measured by radioimmunoassay and left yentrieular mass index(LVMI)was examined by ultrasonic echoeardiography(UCG)before and after treatmenL Results Before benazepril treatment.plasma AngⅡ levels and LVMI in type-A group were higher than those in non-type-A group(P＜0.05),but there was no difference in Bp between two groups.Type-A behavior value were positively correlated with Ang Ⅱ and LVMI in two groups,but only Ang Ⅱ level was independent risk factor.Ang II levels were positively correlated with LVMI in two groups and that was more significantly in type-A group(P＜0.05-0.01).After treatment,Bp,plasma Ang Ⅱ and LVMI were all decreased significantly in two groups(P＜0.05-0.01)and Ang Ⅱ and LVMI were decreased more markedly in type-A group(P＜0.05).The variations of Ang Ⅱ and LVMI before and after treatment were positively correlated in two groups.but more markedly in type.A group (P＜0.05-0.01).Condusion Characters may affect left ventricular hypertrophy in patients with essential hypertension through some stress factors and benazepril has better intervening effect on it.

Key words: 
Character; Hypertension; Hypertrophy,left ventricular
Rechallenging with immune checkpoint inhibition after a treatment-limiting immune-related adverse event.
Authors: Richard Lee O'Neal, Kandice Roberts, Zhonglin Hao, Susanne M. Arnold
Journal: Journal of Clinical Oncology (2020)

3053 Background: Immune checkpoint inhibition (ICI) with cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), or programmed death ligand-1 (PD-L1) blockade can be associated with the development of immune related adverse events (irAE), many of which can be treatment-limiting. Due to an absence of randomized controlled trials, the current approach in regards to ICI discontinuation versus rechallenging remains controversial. Methods: We assessed all patients who had received ICI at a single academic institution from 5/2015 to 1/2019, identifying those who had delays in their treatment. Retrospective chart review was performed to determine type of ICI, type and grade of irAE, treatment of irAE, and recurrence and grades of irAE if ICI was resumed, as well as to assess overall survival (OS). Results: 562 patients received ICI (lung cancer [232, 41%], melanoma [66, 12%], kidney cancer [43, 8%], bladder cancer [27, 5%], and other cancers [194, 34.5%]) from 5/2015 – 1/2019. Of these, 121 (22%) had a treatment-limiting irAE (most commonly dermatitis [24%], colitis [17%], pneumonitis [14%], and hepatitis [12%]). Of the patients who had ICI held, 80/121 (66%) were eventually rechallenged, while 41/121 (34%) discontinued permanently. When rechallenged with ICI, 47/80 (59%) had no further treatment-limiting irAEs, 16/80 (20%) had a recurrence of the same irAE, and 17/80 (21%) developed a different irAE. Of those who were rechallenged, only 17/80 (21%) ultimately had to discontinue because of a second irAE. At a median follow up time of 12.1 months, median OS was not reached in those patients who experienced a treatment limiting irAE and was 8.1 months in those who did not (hazard ratio [HR] for death, 0.33; 95% CI 0.23 – 0.48; p &lt; 0.001). At 12 months from initiation of ICI, 77.0% of patients who had a treatment-limiting irAE were alive, compared to 39.6% of those who did not have an event. Restarting ICI after a treatment-limiting irAE was not associated with a change in OS (HR 0.66 [95% CI 0.27 – 1.66], p = 0.38). Conclusions: Patients who discontinued ICI secondary to irAEs had relatively low rates of recurrent toxicity when rechallenged with treatment. These patients were just as likely to develop a new toxicity as a recurrence of the original irAE, and relatively few had to discontinue permanently. Development of a treatment-limiting irAE was associated with improved OS compared to those who did not. This study suggests that rechallenging with ICI may be safe in selected patients, though this did not have an impact on OS.
Effectiveness of community-hospital-based integrated management of diabetes patients in Xiamen, Fujian province
Authors: 唐国宝, 张民福, 王秀琴
Journal: BMJ (2011)

During 2004 to 2009, 701 patients with diabetes were under community-hospital-based integrated management at Zhonghua and Xiagang community health-care service centers, Xiamen, Fujian.Changes of clinical indicators, life-style and frequency of checks for its complications in them were compared before and after the management. All clinical indicators decreased with length of management, with fasting blood glucose from ( 7. 6 ± 2. 3 ) mmol/L before management to ( 7. 3 ± 2. 0) mmol/L half a year after management, (7. 2 ± 2. 1 ) mmol/L one year after management, (6. 9 ± 1.7 ) mmol/L two years after management. Their life-style also improved significantly and frequency of checks for complications increased with: 54. 4% for retinopathy, 52. 5% for diabetic foot, and 51.8% for neuropathy after management (P ＜0. 05).

Key words: 
Community health services ;  Evaluation studies ;
First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).
Authors: Paul G. Richardson, Annette J. Vangsted, Karthik Ramasamy, Suzanne Trudel, Joaquín Martínez, Maria-Victoria Mateos, Paula Rodríguez Otero, Sagar Lonial, Rakesh Popat, Albert Oriol, Chatchada Karanes, Robert Z. Orlowski, Jesus G. Berdeja, Lilly Wong, Chenyang Shi, Manisha Lamba, Evelyn Barnett, Daniel W. Pierce, Michael Pourdehnad, Nizar J. Bahlis
Journal: Journal of Clinical Oncology (2020)

8500 Background: CC-92480 is a novel cereblon E3 ligase modulator (CELMoD) agent designed for rapid, maximal degradation of Ikaros and Aiolos. In vitro, it has enhanced antiproliferative and tumoricidal activity in MM cell lines, including those resistant to lenalidomide (LEN) and pomalidomide (POM), with strong immune stimulatory activity. Methods: A phase 1, multicenter, dose-escalation study evaluated the maximum tolerated dose (MTD), recommended phase 2 dose, safety, tolerability, and pharmacokinetics of CC-92480 + DEX in heavily pretreated RRMM pts. Eligible pts had progression on or within 60 days of their last MM therapy and were either resistant or intolerant to, or not otherwise candidates for currently available therapies. Several treatment schedules tested escalating doses of CC-92480 + DEX (40 mg; 20 mg if ≥75 yrs). Results: As of Dec 24, 2019, 66 pts had received CC-92480 + DEX. Median age was 67 yrs (range 40–78), median number of prior regimens was 6 (range 2–13). Prior therapies included stem cell transplantation (67%), bortezomib (92%), LEN (89%), POM (83%), and anti-CD38 antibodies (78%). CC-92480 doses explored included 0.1–1.0 mg QD (10/14 days × 2), 0.8–1.0 mg QD (21/28 days), 0.2–0.8 mg BID (3/14 days × 2), and 1.6–2.0 mg QD (7/14 days × 2). MTD was 1.0 mg for both 10/14 × 2 and 21/28 schedules. Grade 3–4 treatment-emergent adverse events (TEAEs) were reported in 58 (88%) pts. Most frequent grade 3–4 TEAEs included neutropenia (53%), infections (30%), anemia (29%), and thrombocytopenia (17%), with 9% grade 3 fatigue. Among different cohorts,10 pts had dose-limiting toxicities (the majority related to neutropenia). Overall response rate (ORR) was 21% (9 very good partial responses [VGPRs]; 5 PRs) for efficacy evaluable population (n = 66). Efficacy was dose and schedule dependent; across two 1.0 mg QD schedules (10/14 × 2 and 21/28), 10 of 21 (48%) pts responded (7 VGPR and 3 PR), with response independent of immunomodulatory drug (IMiD) refractoriness. Plasma exposure increase and peripheral blood Ikaros and Aiolos degradation were dose dependent. Ikaros and Aiolos significantly decreased in bone marrow plasma cells of LEN- and POM-refractory pts. Conclusions: TEAEs of CC-92480 were mainly related to myelosuppression in heavily pretreated, including triple-class-refractory, RRMM pts. Promising activity with 48% ORR at therapeutic doses was observed. The study is ongoing to further optimize dose and schedule, with combination studies underway and dose expansion cohorts planned. Clinical trial information: NCT03374085 .