tbuckley/cabot-search huggingface dataset:
Comparative efficacy of docetaxel versus novel hormonal agent in de novo metastatic hormone-sensitive prostate cancer: Real-world data curated by deidentified chart abstraction.
Authors: Bobby Chi-Hung Liaw, Sunny Guin, Tomi Jun, Kristin Ayers, Bonny Patel, Timmy O'Connell, Matthew Dietz, Michael Klein, Tony Prentice, Scott Newman, Marc Fink, Xiang Zhou, Eric Schadt, Rong Chen, William K. Oh
Journal: Journal of Clinical Oncology (2021)

e17047 Background: The addition of docetaxel or a novel hormonal agent (NHA), such as abiraterone acetate or enzalutamide, has become standard of care for mHSPC, but prospective data for comparative efficacy remains limited. Clinical variables abstracted through natural language processing of free text from patient charts can provide real-world data to answer important clinical questions. Methods: Using an innovative data abstraction process, we retrospectively identified men with de novo mHSPC within deidentified charts from the Mount Sinai Health System treated with either docetaxel or a NHA between January 1, 2014 and April 30, 2019. Dates were chosen to reflect the timeline for which these therapeutic agents received regulatory approval for mHSPC, but also to allow sufficient clinical follow up after treatment initiation. Primary outcome of failure-free survival (FFS), defined as the time to next treatment, was assessed using the Kaplan-Meier method and multivariable Cox proportional hazards models. We additionally performed multivariable analysis to evaluate the prognostic significance of post-treatment PSA nadir on FFS. Results: A total of 94 de novo mHSPC patients that received either docetaxel or an NHA were identified using proprietary Sema4 data abstraction process: 52 received docetaxel, 42 received an NHA. Use of an upfront NHA in mHSPC was associated with a significantly longer FFS compared to docetaxel (20.7 vs. 10.1 months, p = 0.023). While NHAs were associated with a significantly longer FFS than docetaxel in patients with high metastatic burden of disease (25.12 vs. 9.63 months, p = 0.014), this was not observed in low-volume disease (20.71 vs. 26.5 months, p = 0.9). In multivariable model analysis adjusting for age, baseline PSA, and metastasis burden, docetaxel remains independently associated with worse FFS compared to NHA (HR 1.96, 95% CI 1.12−3.45, p = 0.019). Irrespective of docetaxel or NHA use, lower post-treatment PSA nadir levels were associated with improved FFS (58.95 vs. 11.57 vs. 9.4 months for PSA ≤0.2, 0.2-0.4, &gt; 0.4ng/ml, respectively; p &lt; 0.001). Conclusions: Clinical variables abstracted from deidentified clinical documentation can efficiently provide relevant and reliable data upon which clinical research can be based. Comparative analysis of real-world data demonstrates superior FFS in de novo mHSPC treated with a NHA as compared to docetaxel. The depth of PSA response holds prognostic value for mHSPC outcomes, regardless of treatment used.
Major vault protein (MVP) negatively regulates osteoclastogenesis via calcineurin-NFATc1 pathway inhibition
Authors: Lichan Yuan, Na Zhao, Junyi Wang, Yuying Liu, Li Meng, Shuyu Guo, Erik A.C. Wiemer, Qi Chen, Yelin Mao, Jingjing Ben, Junqing Ma
Journal: Theranostics (2021)

Rationale: Bone homeostasis is maintained by a balanced interplay of osteoblasts and osteoclasts.Osteoclasts are derived from monocyte/macrophage lineage.Major vault protein (MVP) is known to promote apoptosis and prevent metabolic diseases in macrophage.However, whether MVP is involved in osteoclastogenesis is unknown.Here, we identified an important function of MVP as a negative regulator of osteoclastogenesis and its therapeutic potential in preventing bone loss.Methods: Expression of MVP in osteoclasts was investigated in human tumor tissues with immunohistochemical staining.Next, we generated total body (Mvp -/-) and monocyte-specific (Mvp f/f Lyz2-Cre) MVP gene knockout mice to observe bone phenotype and osteoclastogenesis using micro-CT and bone histomorphometry.Moreover, we examined the effects of MVP on osteoclast differentiation, bone resorption, NFATc1 activation and calcium oscillations in vitro.Finally, we explored the clinical potential of targeting MVP in two osteoporosis mouse models and used an adeno-associated virus (AAV) gene to overexpress MVP locally in mice.Results: We found that Mvp -/-and Mvp f/f Lyz2-Cre mice both exhibited osteoporosis-like phenotypes.MVP-deficiency also enhanced calcineurin-NFATc1 signaling and promoted NFATc1 activity, which led to enhanced osteoclastogenesis and bone resorption.Calcineurin inhibition using the small molecule inhibitor FK506 corrected the enhanced osteoclastogenesis in Mvp f/f Lyz2-Cre group.Additionally, MVP reexpression in Mvp f/f Lyz2-Cre group rescued calcineurin expression.MVP overexpression in wild-type mice prevented pathologic bone loss in mouse models of ovariectomized (OVX) and calvaria-adjacent lipopolysaccharide (LPS)-injected.Conclusions: Our data suggested that MVP negatively regulates osteoclast differentiation and bone resorption via inhibition of calcineurin-NFATc1 signaling.In osteoclast-related bone diseases such as osteoporosis, manipulation of MVP activity may be an attractive therapeutic target.
Author Correction: Delayed production of neutralizing antibodies correlates with fatal COVID-19
Authors: Carolina Lucas, Jon Klein, Maria E. Sundaram, Feimei Liu, Patrick Wong, Julio Silva, Tianyang Mao, Ji Eun Oh, Subhasis Mohanty, Jiefang Huang, Maria Tokuyama, Peiwen Lu, Arvind Venkataraman, Annsea Park, Benjamin Israelow, Chantal B. F. Vogels, M. Catherine Muenker, C-Hong Chang, Arnau Casanovas-Massana, Adam J. Moore, Joseph Zell, John B. Fournier, Abeer Obaid, Alexander James Robertson, Alice Lu-Culligan, Alice Zhao, Allison Nelson, Anderson Brito, Angela Nunez, Anjelica Martin, Anne E. Watkins, Bertie Geng, Caitlin J. Chun, Chaney C. Kalinich, Christina A. Harden, Codruta Todeasa, Cole Jensen, Coriann E. Dorgay, Daniel Kim, David McDonald, Denise Shepard, Edward Courchaine, Elizabeth B. White, Eric Song, Erin Silva, Eriko Kudo, Giuseppe DeIuliis, Harold Rahming, Hong-Jai Park, Irene Matos, Isabel Ott, Jessica Nouws, Jordan Valdez, Joseph Fauver, Joseph Lim, Kadi-Ann Rose, Kelly Anastasio, Kristina Brower, Laura Glick, Lokesh Sharma, Lorenzo Sewanan, Lynda Knaggs, Maksym Minasyan, Maria Batsu, Mary Petrone, Maxine Kuang, Maura Nakahata, Melissa Linehan, Michael H. Askenase, Michael Simonov, Mikhail Smolgovsky, Natasha C. Balkcom, Nicole Sonnert, Nida Naushad, Pavithra Vijayakumar, Rick Martinello, Rupak Datta, Ryan Handoko, Santos Bermejo, Sarah Prophet, Sean Bickerton, Sofia Velazquez, Tara Alpert, Tyler Rice, William Khoury-Hanold, Xiaohua Peng, Yexin Yang, Yiyun Cao, Yvette Strong, Zitong Lin, Anne L. Wyllie, Melissa Campbell, Alfred I. Lee, Hyung J. Chun, Nathan D. Grubaugh, Wade L. Schulz, Shelli Farhadian, Charles Dela Cruz, Aaron M. Ring, Albert C. Shaw, Adam V. Wisnewski, Inci Yildirim, Albert I. Ko, Saad B. Omer, Akiko Iwasaki
Journal: Nature Medicine (2021)
Similar decrease of proliferation employing Ki-67 after brief neoadjuvant hormonal treatment on invasive ductal carcinoma versus invasive lobular carcinoma.
Authors: Martin Majer, Elizabeth Fauchier Little, Sarah Jones, Jasmine Dong, Karolina Bezdickova, David Hutton, Lucie Tomanova, John Promlap, Tien Promlap, Greg Schneringer, Steve DeMartini, Michael Russell, April Joyner, Susan Schmidt, Ravi Nagubandi, Randell Skau, Monica Swars, Megan Powell, Edward J. Ordorica
Journal: Journal of Clinical Oncology (2021)

e12606 Background: Invasive lobular carcinoma (ILC) differs from the more prevalent invasive ductal carcinoma (IDC) in histology, molecular underpinning, and biological responsiveness to cytotoxics. Patients diagnosed with IDC or ILC were evaluated in the clinical setting to determine if they differ in responsiveness to neoadjuvant hormone treatment. Methods: This is a retrospective observational study of an underserved, low income, rural population in Oroville, California. The data for this study was collected over ten years (2011-2021) from 58 estrogen receptor positive (ER+) breast cancer patients. The majority of these patients (48/58) were diagnosed with IDC with ages ranging from 35 to 91 (mean age is 66) and the remaining 10 were diagnosed with ILC with ages ranging from 58 to 85 (mean age is 64). Patients were given neoadjuvant hormone treatment starting after their initial biopsy confirming ER+ status until scheduled surgical removal by lumpectomy or mastectomy. Ki-67 was measured prior to treatment and then measured again after a minimum of 14 days on hormone therapy. The initial Ki-67 range for patients with IDC was 2%-75% (median of 15%). Ki-67 initial range for patients with ILC was 2%-30% (median of 11%). Positive response to treatment was set at &gt; 50% reduction in Ki-67, with no response set at &lt; 50% reduction in Ki-67. We compared the response rates of ILC and IDC patients using a chi-square test. Results: Chi-square analysis found no statistically significant difference between IDC and ILC response to hormone therapy. 34/48 (71%) patients with IDC responded to treatment, and 8/10 (80%) of ILC patients showed response. Incidentally, we noticed a higher prevalence of ILC in our community compared to expected numbers. Conclusions: When evaluating hormone therapy responsiveness in the neoadjuvant setting, there is no observable statistical difference in response rates between IDC and ILC. Neoadjuvant hormone testing employing Ki-67 response identifies subgroups of patients who benefit from the addition of new biologics (-ciclibs, mTOR inhibitors) in addition to hormone treatment. Our experience supports testing in this way to further individualize the care of patients unable to participate in clinical trials.
Abstract 10689: Does 3 Weeks of Anticoagulation With a Novel Oral Anticoagulant Obviate the Need for Transesophageal Echocardiography Before Cardioversion?
Authors: Carine Basmadjian, Mihir Jani, Zubair Khan, John Andriulli, Andrea M Russo, Matthew Ortman
Journal: Circulation (2019)

Introduction: The AHA, ACC, and HRS recommend anticoagulation with a novel oral anticoagulant (NOAC) for at least 3 weeks before direct current cardioversion (DCCV) of atrial fibrillation (AF) and ...
Multiomics analysis reveals high-immune infiltration in tumor-adjacent lung tissues affects the prognosis of stage I NSCLC.
Authors: Lisa Ying, Dan Su, Zhang Chunliu, Yiping Tian, Jing Bai, Canming Wang, Jianfei Fang, Andrew Futreal, Jianjun Zhang
Journal: Journal of Clinical Oncology (2021)

8540 Background: Along with the wide application of low-dose spiral CT in lung cancer screening, a large number of resectable patients with lung cancer are identified, especially stage I Non-Small Cell Lung Cancer (NSCLC). However, their prognosis varies greatly and 5-year recurrence rate of stage I NSCLC is around 30%. Therefore, it is crucial to explore the potential mechanism of recurrence of early NSCLC. Methods: Eighty-seven patients with stage I NSCLC were enrolled from April 2008 to July 2015, including 79 squamous carcinoma and 28 adenocarcinoma. Frozen tumor tissues and paired tumor-adjacent lung tissues were collected to employ targeted panel sequencing, RNA sequencing and TCR repertoire sequencing. Results: Ninety-five non-silent mutations were detected in tumor-adjacent lung tissues with a median tumor mutation burden of 1.5/Mb, significantly lower than that in tumor tissues (11/Mb), p &lt; 0.05. 42 mutations were specifically detected in the adjacent normal tissues, enriching in the immune response pathways. Comparing with paired tumors, tumor-adjacent lung tissues were found more favorable immune infiltration including higher immune cell activity like CD8+ T cell (0.50 vs 0.43, p &lt; 0.0001), up-regulated immune-associated pathways, higher TCR clonality (0.19 vs 0.18, p &lt; 0.05), less loss of heterozygosity (LOH) of human leukocyte antigen (HLA) (6.25% vs 50%, p &lt; 0.0001) and observed predicted neoantigens expression (1 vs 128, p &lt; 0.01). However, more shared viral-associated TCRs in tumor and tumor-adjacent tissues were found using the GLIPH algorithm. Prognostic analysis showed patients with higher overlap of TCR in tumors and tumor-adjacent lung tissues were prone to recur in five years. Furthermore, patients with higher immune infiltration in tumor-adjacent lung tissues had favorable outcomes than those with lower immune infiltration (HR: 0.37 for DFS, p &lt; 0.05, HR: 0.31 for OS, p &lt; 0.05), irrelevant of the infiltration level in tumor tissues. Conclusions: Immune microenvironment in tumor-adjacent lung tissues plays important roles in progress of stage I NSCLC.
Does aggressive surgery only benefit patients with less advanced ovarian cancer?
Authors: Shinichi Tate, Kyoko Nishikimi, Ayumu Matsuoka, Satoyo Otsuka, Makio Shozu
Journal: Journal of Clinical Oncology (2021)

5556 Background: The recent SCORPION trial showed that aggressive primary debulking surgery (PDS) did not improve survival outcomes in patients with advanced ovarian cancer and was associated with a high incidence of perioperative morbidity. We compared survival outcomes and morbidity between patients who underwent highly aggressive and less aggressive surgery at our hospital; patients with high tumor loads were treated with neoadjuvant chemotherapy (NACT), followed by aggressive surgery. Methods: This retrospective study included 209 patients with a surgical complexity score (SCS) ≥8, who underwent aggressive surgery between January 2008 and December 2018. PDS, followed by chemotherapy was performed in this study, and NACT followed by interval debulking surgery (IDS) was performed in patients with excessively high tumor loads, a poor general condition, or unresectable lesions in whom PDS was contraindicated. Based on the median SCS, patients were categorized into highly aggressive surgery and less aggressive surgery groups, and we performed an intergroup comparison of progression-free survival (PFS), overall survival (OS), and perioperative morbidity. Results: The median SCS was 13 in all cohorts. The less aggressive surgery group (SCS &lt; 13) and the highly aggressive surgery group (SCS≥13) included 83 and 126 patients, respectively. The peritoneal cancer index in the highly aggressive surgery group was higher than that in the less aggressive surgery group (20 vs. 9). Notably, 52 patients (63%) underwent PDS in the less aggressive surgery group, and 104 patients (83%) underwent IDS after NACT in the highly aggressive surgery group. No intergroup difference was observed in patients without any residual disease (less aggressive surgery group: 74 patients [89%] vs. highly aggressive surgery group: 118 patients [94%], p = 0.245). The median PFS in the less- and highly aggressive surgery groups was 32 months (95% confidence interval [CI] 24–45) and 31 months (95% CI 27–34) (log-rank test, p = 0.622; Wilcoxon test, p = 0.926), respectively. The median OS in the less- and highly aggressive surgery groups was 99 months (95% CI 59–not reached) and 75 months (95% CI 56–106) (log-rank test, p = 0.390; Wilcoxon test, p = 0.799), respectively. Severe perioperative complications (Clavien-Dindo grade ≥IIIb) occurred in 4 patients (4.8%) and 8 patients (6.4%) in the less- and highly aggressive surgery groups, respectively (p = 0.767). Conclusions: Aggressive surgery benefits both patients with less advanced and advanced ovarian cancer. Selection of the optimal timing of debulking surgery may lead to better survival outcomes without an increase in perioperative morbidity in patients with high tumor loads, who undergo highly aggressive surgery.
Exploring the applicability of immunotherapy in different EGFR mutation subgroups based on data analysis of 9,659 Chinese patients with NSCLC.
Authors: Hao Peng, Hushan Zhang, Libin Zhang, Yang Wang, Xudong Shen, Depei Huang, Zheyuan Xu, Han Wang
Journal: Journal of Clinical Oncology (2021)

e21020 Background: Here we assessed TMB level, PD-L1 expression, and their correlation in 9649 Chinese NSCLC patients with or without EGFR mutation, and different subtypes of EGFR mutations, to find out the underlying mechanisms that different outcomes of ICI for EGFR wild type and EGFR mutation NSCLC patients, and the possibility of ICI therapy for NSCLC patients of different EGFR mutation subtypes. Methods: Tumor tissue samples of 9649 NSCLC patients were collected from Janary 2018, expression of PD-L1 were detected by using Dako PD-L1 IHC 22C3 pharmDx, Tumor Proportion Score (TPS) was used to determine expression of PD-L1. Gene mutation was detected by means of next generation sequencing (NGS). Performed Whole-Exome Sequencing (WES) on 70 tissue samples and corresponding White Blood Cells (WBCs) as matched control. Other samples were detected with panel covering whole exon regions of 733 cancer related genes. All these detections were performed in a College of American Pathologists (CAP)-certified and Clinical Laboratory Improvement Amendments (CLIA)-accredited lab for gene mutation analysis (3D Medicines Inc.,Shanghai, China). Statistical analysis was performed using GraphPad Prism (version 7.01) and SPSS version 21.0 (SPSS,Inc.). Results: Results showed that the proportion of EGFR mutation in Chinese patients with NSCLC was 51.3%, and the proportion of EGFR mutation subtypes were 42.6% L858R, 39.5% exon 19del, 2.3% exon 20in, 4.3% T790M. These samples were divided into different groups according to EGFR mutation, both WES based and panel-based results showed that EGFR wild type group displayed higher TMB level than EGFR mutation group (P &lt; 0.05). However, except for exon 19del, L858R, exon 20in, no significant differences were found between wild type and other EGFR mutation subtypes. Furthermore, results of IHC revealed that, higher proportion of strong positive PD-L1 expression (TPS≥50) were found in EGFR wild type than exon 19del, L858R and exon 20in, no significant correlation was found between TMB level and PD-L1 expression. Conclusions: EGFR mutations account for half of Chinese NSCLC patients. The biomarkers of immune checkpoint inhibitors (such as TMB and PD-L1) are different in various EGFR mutation subtypes, which may indicate that for some NSCLC patients with EGFR mutation subtypes, they may also respond to ICI treatment as wild-type.
Phase II trial of neoadjuvant mFOLFOX 6 with panitumumab (P) in T3 rectal cancer with clear mesorectal fascia (MRF) and <i>KRAS</i>, <i>NRAS</i>, <i>BRAF</i>, <i>PI3KCA</i> wild type (4WT). GEMCAD 1601 PIER trial.
Authors: Carlos Fernandez-Martos, Carles Pericay, Joan Maurel, Ana Virgili, Jaume Capdevila, Javier Gallego, Ruth Vera, Nuria Rodriguez-Salas, Ferran Losa, Manuel Valladares, Ana Vivancos, Juan Ayuso, Monique Maas, Fernando Martínez, Marcos Melian, Xabier García de Albéniz
Journal: Journal of Clinical Oncology (2021)

3512 Background: Patients with advanced colorectal cancer with 4WT tumors achieve increased response rates with chemotherapy and anti-EGFR therapy as compared with chemotherapy alone. In clinically staged (c) T3 rectal cancer neoadjuvant oxaliplatin/fluoropyrimidine combination has shown to induce encouraging pathological complete response (pCR). We hypothesize that combining FOLFOX and P could improve outcomes in 4WT tumors. Methods: PIER was an investigator-initiated phase II, single-arm, multicentre clinical trial to evaluate the safety and efficacy of neoadjuvant mFOLFOX6 with P in pts &lt; 75-y, with 4WT rectal cancer of the middle third staged as T3 by centrally-reviewed magnetic resonance imaging (MRI) and clear MRF, who were candidate for a R0 resection with sphincter preservation surgery. Pts received 6 cycles and underwent re-staging with MRI and sigmoidoscopy. Pts without progression underwent total mesorectal excision 4 weeks after the last cycle. Patients with progression were treated with pre-op chemoradiotherapy. The primary endpoint was pCR. The study followed a 2-Stage Simon’s MiniMax design (P0 of 16%, P1 of 35%, alpha and beta of 0.1). The target sample size was 35 patients and if 9 or more achieved a pCR, the results would be compatible with efficacy. We present primary and early secondary endpoints. Results: Between 9/2017 and 6/2020, 90 patients were screened (56 excluded; 42 were excluded due to mutations, 12 were excluded due to discrepancies with central review of radiology) of whom 34 were enrolled. In the ITT population a pCR was observed in 11 pts (32.3%; [95% CI 17.39-50.53]) and a near-complete pathological response (Mandard 1+2) was observed 17 pts (52.9%). Clinical complete or near complete response was achieved in 50% and there were no progressions. R0 resection rate and pathological circumferential resection margin neg- were 100%. Full compliance with induction was 88%. Neoadjuvant G3/4 toxicity occurred in 54% and was consistent with FOLFOX/P safety profile. G3/4 postoperative related toxicity was 19% with one reoperation. Conclusions: The study met the threshold for efficacy. mFOLFOX6 with P as neoadjuvant therapy can be effective and safe without unexpected toxicities in mrT3, clear MRF and 4WT rectal cancer and resulted in a higher rate of pCR compared with our previous series (GEMCAD 0801; The Oncologist 2014) in a similar molecular-unselected population. This study was funded by Amgen S.A. Clinical trial information: NCT03000374.
Efficacy of first-line treatments for patients (pts) with advanced EGFR mutated NSCLC: Network meta-analysis of TKI monotherapy and combinations trials.
Authors: Alexey Bogdanov, Fedor Vladimirovich Moiseenko, Albina Zhabina, Nikita Volkov, Elizaveta Artem'eva, Mikhail Fedyanin
Journal: Journal of Clinical Oncology (2021)

e21120 Background: Various EGFR TKIs and several combinations are the standard of initial treatment for NSCLC with EGFR mutations. For this moment one size fits all approach is used. Due to the limited nature of this subgroup direct prospective survival comparison of various options is time and resource consuming. The main objective of this study was to compare available prospective trials in a network meta-analysis in order to determine the overall survival (OS) advantage. Methods: Using frequentist approach (netmeta R package) we performed a network meta-analysis of prospective randomized trials comparing having platinum doublet or 1G TKI as a control arm and 1G TKI, 2G TKI, 3G TKI, combination of chemotherapy (CT)+1G TKI, combination anti-VEGF/R+1G TKI as investigation arm in pts with EGFRmut NSCLC. Between trials we compared OS and progression free survival (PFS ) for overall population and subgroups by mutation, sex, age, smoking status. Results: 17 trials involved 4671 pts were considered eligible for meta-analysis. Trials investigated various combinations of TKIs in untreated EGFR mutated NSCLC: 8 had chemotherapy (CT) as control arm (ENSURE, EURTAC, IPASS, NEJ002, OPTIMAL CTONG-0802, WJTOG3405, LUX-Lung-3/6) and 9 with 1G TKIs as control arm (JO25567, NEJ026, 14034 H3E-CR-JIMIT, NEJ009, Noronha et. al, LUX-LUNG7, ARCHER1050, SWOGS1403, FLAURA). Compared to 1G TKIs improved OS was observed for combination of 1G TKI and CT (HR 0.64 (0.53– 0.78)), 3G TKIs (HR 0.80 (0.64-1.00)), 2G TKIs (HR 0.83 (0.72-0.96)) (The OS benefit was ranked No.1 for TKI+chemo (P-score – 0.96), No.2 – 3G TKI (P-score – 0.68), No.3 – 2G TKI (P-score – 0.64)) Addition of anti-VEGF/R therapy did not improve OS (HR 0.91 (0.68-1.21) over 1G TKIs alone. Importantly OS advantage remained significant in a subgroup of ex19del only for 2G TKIs (HR 0.71 (0.53-0.96)). No advantage for particular regimen was seen for L858R subgroup. 3G TKIs (HR 0.46 (0.27-0.78)), combinations with CT (HR 0.55 (0.40-0.75)) and anti-angiogenic agents (HR 0.57 (0.37-0.89), improved PFS over 1GTKIs, while 2G TKIs had a tendency for improving (HR 0.78 (0.58-1.06)). Conclusions: Our network meta-analysis showed that compared to initial treatment with 1G TKI monotherapy - 1G combination with CT, monotherapy with 3G and 2G may provide OS advantage. Still for ex19del subgroup OS benefit was significant only for 2G TKI. The availability of multiple first line options force the importance of stratification of patients for particular treatment type.