tbuckley/cabot-search huggingface dataset:
Tumor-informed assessment of circulating tumor DNA and its incorporation into practice for patients with hepatobiliary cancers.
Authors: Pashtoon Murtaza Kasi, Griffin Budde, Farshid Dayyani, Gregory P. Botta, Adam Diehl, Gentry Teng King, Midhun Malla, Maen Abdelrahim, Diana L. Hanna, Liudmila N. Schafer, Mohamedtaki Abdulaziz Tejani, Michael Krainock, Paul R. Billings, Perry Olshan, Vasily N. Aushev, Alexey Aleshin
Journal: Journal of Clinical Oncology (2021)

4103 Background: Hepatocellular carcinoma (HCC) and biliary tract cancers [BTC - including cholangiocarcinoma (CCA) and gall bladder cancers (GBC)] represent a heterogeneous group of diseases. Glycoprotein-based tumor markers like alpha-fetoprotein (AFP) or carbohydrate antigen 19-9 (CA-19-9) though part of standard-of-care (SOC), lack sensitivity, and specificity. A fair proportion of these cancers do not produce these glycoproteins. Circulating tumor DNA (ctDNA) testing can fill this void and be used for the assessment of molecular residual disease (MRD), as well as for surveillance purposes in patients with HCC or BTC. Prospective evaluation of this methodology in clinical practice has been limited to date. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA. Serial time points were collected on a subset of patients to monitor their ctDNA levels in response to treatment. Results: Here we analyzed 200 plasma samples from a total of 90 patients with HCC (n=27) and BTC (n=63), comprising 46 patients with CCA and 17 patients with GBC. Sample-level ctDNA positivity rates, determined using a tumor-informed assay are presented in table. ctDNA detection was significantly associated with the stage of disease (Wilcoxon rank-sum test, p&lt;0.05). Serial time point analysis was performed on a subset of patients (n=56) that had 2-7 time points available and correlations between ctDNA levels and clinical response were noted and will be presented. Conclusions: Our study is the first to set the benchmark for the utility and feasibility of using a tumor-informed assay in this cohort of hepatobiliary cancers. With adjuvant chemotherapy already a SOC for BTC, and immunotherapy being studied for HCC alongside other novel agents for CCA and GBC, assessment of MRD or ctDNA clearance on therapy would be of value as an additional tool in identifying patients at high risk for recurrence/metastasis. The utility of this study would also lie in incorporation in clinical trials to enrich and study those who are at the highest risk of recurrence i.e. ctDNA positive.[Table: see text]
Fantasies of a Wounded Healer
Authors: Jessi Humphreys
Journal: Annals of Internal Medicine (2021)

On Being a DoctorJune 2021Fantasies of a Wounded HealerJessi Humphreys, MDJessi Humphreys, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M21-0438 Audio Reading - “Fantasies of a Wounded Healer” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads “Fantasies of a Wounded Healer” by Jessi Humphreys, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail On the way to a night shift during my intern year of medicine, I drove around a sharp bend. Had I been an hour earlier, the sun would have been setting over San Francisco, outlining the buildings in amber. Instead, it was dark and misty, and I already regretted my hasty evening “breakfast” of Sour Patch Kids. Silently, I thanked the coffee deities for the invention of caffeine.A fantasy came to me uninvited, catching me off-guard. I thought about turning the car wheel too quickly and skidding off the road. Maybe the bumper would collapse against a street lamp. ... Author, Article, and Disclosure InformationAffiliations: Corresponding Author: Jessi Humphreys, MD, 521 Parnassus Avenue, San Francisco, CA 94143; e-mail, Jessica.[email protected]edu. PreviousarticleNextarticle Advertisement Audio Reading - “Fantasies of a Wounded Healer” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads “Fantasies of a Wounded Healer” by Jessi Humphreys, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics June 2021Volume 174, Issue 6Page: 868-869 ePublished: 15 June 2021 Issue Published: June 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Concordance of DNA damage repair (DDR) gene mutations in paired primary and metastatic prostate cancer (PC) samples.
Authors: Michael Thomas Schweizer, Smruthy Sivakumar, Hanna Tukachinsky, Ilsa Coleman, Navonil De Sarkar, Evan Y. Yu, Eric Quentin Konnick, Peter Nelson, Colin C. Pritchard, Robert B. Montgomery
Journal: Journal of Clinical Oncology (2021)

5020 Background: Mutations in DDR genes represent actionable alterations that can be used to guide precision medicine strategies in men with advanced PC. However, acquisition of contemporary tissue samples for advanced molecular testing can be a barrier to deploying precision medicine approaches. We hypothesized that most DDR alterations represent early truncal events in PC and that archival primary tissue would faithfully reflect mutations found in cell-free circulating tumor (ctDNA) and/or metastatic tissue. Methods: Patients were included in this study if a DDR pathway mutation was detected in metastatic tissue or ctDNA and primary tissue sequencing was available for comparison. Sequencing data from three cohorts were analyzed: 1) FoundationOne, 2) University of Washington (UW-OncoPlex or SU2C/PCF International Dream Team sequencing pipelines) and 3) University of Washington rapid autopsy series. Only pathogenic somatic mutations were included and we required ≥30 days between primary tumor tissue and ctDNA/tumor tissue acquisition. Clonal hematopoiesis of indeterminant potential (CHIP) and germline events were adjudicated by an expert molecular pathologist and excluded. Variants detected only in plasma were considered likely to be CHIP or low subclones if the variant fraction was &lt;1% and/or &gt;5-fold less than the estimate tumor content in plasma. Results: Paired primary and ctDNA/metastatic samples were sequenced from 72 individuals with known DDR alterations. After excluding ctDNA cases where only CHIP (N=13) and/or germline events (N=7) were observed, 51 subjects remained and were included in the final analysis. The median time from acquisition of primary tissue to acquisition of ctDNA or tumor tissue was 52 mos (range: 1 – 193 mos). Concordance in DDR genes across samples was 86% (95% CI: 74-93%). Rates of concordance between metastatic-primary and ctDNA-primary pairs were similar when CHIP cases were excluded (87% and 85%, respectively). BRCA2 reversion mutations associated with resistance to PARP inhibitors and platinum chemotherapy were detected in ctDNA from two subjects. Conclusions: These data provide evidence that primary prostate tissue accurately reflect the mutational status of actionable DDR genes in men with metastatic PC, supporting the hypothesis that DDR alterations are early truncal events. After excluding likely CHIP events, ctDNA profiling accurately captured these truncal DDR mutations, while also detecting reversion alterations that may suggest potential resistance mechanisms.[Table: see text]
Forecasting asparaginase quantity required to treat pediatric ALL in LMICs using ACCESS FORxECAST.
Authors: Terence M. Hughes, Brianna Empringham, Sumit Gupta, Zachary J. Ward, Jennifer Yeh, Anita K. Wagner, Lewis B. Silverman, Lindsay Lindsay Frazier, Avram Denburg
Journal: Journal of Clinical Oncology (2021)

10031 Background: Asparaginase (ASN) is a crucial component of pediatric acute lymphoblastic leukemia (ALL) protocols. ASN is available in three enzyme formulations: native from Escherichia Coli ( E. coli), PEGylated from E. coli (PEG), and native erwinia from Erwinia chrysanthemi (Erwinase). PEG is typically preferred in high-income countries, while E. coli is more accessible in low and middle income countries (LMICs). Erwinase is reserved for patients who develop hypersensitivity. Short shelf lives, high prices, intermittent availability, and concern for substandard formulations in LMICs have created a need for proactive ASN demand estimates, particularly in LMICs. Methods: We modified FORxECAST, a publicly available tool that forecasts pediatric cancer drug quantity and cost, to estimate ASN quantity required to treat pediatric ALL in 2021 across all LMICs. Incidence data is based on the Global Childhood Cancer microsimulation model, which extrapolates country registries to estimate diagnosed pediatric ALL patients. We forecast ASN quantity for both a base regimen (BR), recommended by the International Pediatric Oncology Society (SIOP), and a more aggressive regimen (AR) used in some LMICs with more advanced supportive care capacity. For both BR and AR, we estimate ASN quantity across four scenarios, outlining how quantity would vary based on formulation and ability to switch in cases of hypersensitivity. Results: The estimated quantity of ASN required to treat all children diagnosed with ALL in LMICs in 2021, across scenarios and regimens, is provided (Table). If E. coli were used to treat all diagnosed pediatric ALL patients across LMICs, required quantity would range from 1,198 M IU (BR) to 1,661 M IU (AR) (Scenario 1). If PEG were used, required quantity would range 150 M IU (BR) to 473 M IU (AR) (Scenario 2). Accounting for hypersensitivity would require 77 M IU (BR) to 137 M IU (AR) Erwinase (Scenarios 3 and 4). Conclusions: We adapted FORxECAST to be ASN-specific and estimated demand in LMICs for a range of scenarios, including for second line Erwinase; accounting for hypersensitivity is particularly important because discontinuation typically results in lower cure rates. We also estimated how quantity of ASN required would increase with treatment intensity. These results provide the first quantification of ASN need for pediatric ALL in LMICs, creating a demand estimate that can inform private and public efforts to produce a reliable supply of high quality ASN for all children with ALL.[Table: see text]
A randomized phase II trial of diffusion-weighted MR imaging-guided radiotherapy plus chemotherapy versus standard chemoradiotherapy in locoregional advanced nasopharyngeal carcinoma.
Authors: Feng Liu, Shengnan Fu, Yanzhu Chen, Ouying Yan, Lili He, Cuihong Jiang, Xiangwei Wu, Yaqian Han, Hui Wang
Journal: Journal of Clinical Oncology (2021)

6018 Background: We hypothesized that diffusion-weighted MR imaging (DWI) guided dose-painting radiotherapy (DP-RT) was associated with improved tumor control and survival compared with standard CT-based radiotherapy in locoregionally advanced nasopharyngeal carcinoma (NPC). The purpose of this randomized phase II trial was to compare the efficacy and toxicity of DWI guided DP-RT plus chemotherapy versus standard CT-based radiotherapy plus chemotherapy in locoregionally advanced NPC. Methods: Two hundred and fifty-six patients with stage III-IVa (8th AJCC) NPC were randomly assigned to receive DWI-guided dose-painting radiotherapy plus chemotherapy (DP-RT group, n = 128) or standard CT-based radiotherapy plus chemotherapy (CT-based RT group, n = 128). Patients in both groups received 3 cycles of induction chemotherapy followed by cisplatin-based concurrent chemoradiotherapy. In DP-RT group, subvolume GTVnx-DWI (gross tumor volume of nasopharynx in DWI) was defined as the areas within the GTVnx (gross tumor volume of nasopharynx) with an apparent diffusion coefficient (ADC) below the mean ADC (ADC &lt; mean). The dose to GTVnx-DWI was escalated to DT 75.2 Gy/32 Fx in patients with T1-2 disease, and DT 77.55 Gy/33 Fx in those with T3-4 disease, in 2.35 Gy per fraction. In CT-based RT group (n = 128), PGTVnx was irradiated at DT 70.4-72.6 Gy/32-33 Fx in 2.2 Gy per fraction. This trial is registered with chictr.org.cn, number ChiCTR1800015779. Results: Compared with standard CT-based radiotherapy, DWI-guided DP-RT significantly improved 2-year local recurrence-free survival (LRFS, 100% vs. 95.4%; P = 0.024), distant metastasis-free survival (DMFS, 97.9% vs. 90.6%; P = 0.006), disease free survival (DFS, 93.2% vs. 86.8%; P = 0.021), and overall survival (OS, 100% vs. 95.2%; P = 0.038). No statistically significant differences in acute and late toxic effects were observed. Multivariate analysis showed that dose painting (DWI-guided DP-RT vs CT-based RT without DP) was a significant independent prognostic factor for DMFS and DFS (P = 0.021 and P = 0.020, respectively). Conclusions: Diffusion-weighted MR imaging guided dose-painting radiotherapy plus chemotherapy is associated with a considerable survival benefit, without increasing toxicity, as compared with standard CT-based radiotherapy plus chemotherapy, among patients with locoregionally advanced nasopharyngeal carcinoma. Clinical trial information: ChiCTR1800015779.
Epidemiology of Peripheral Artery Disease and Polyvascular Disease
Authors: Aaron W. Aday, Kunihiro Matsushita
Journal: Circulation Research (2021)

Atherosclerotic lower extremity peripheral artery disease (PAD) is increasingly recognized as an important cause of cardiovascular morbidity and mortality that affects >230 million people worldwide. Traditional cardiovascular risk factors, including advanced age, smoking, and diabetes, are strongly linked to an increase risk of PAD. Although PAD has been historically underappreciated compared with coronary artery disease and stroke, greater attention on PAD in recent years has led to important new epidemiological insights in the areas of thrombosis, inflammation, dyslipidemia, and microvascular disease. In addition, the concept of polyvascular disease, or clinically evident atherosclerosis in multiple arterial beds, is increasingly identified as a particularly malignant cardiovascular disease worthy of special clinical attention and further study. It is noteworthy that PAD may increase the risk of adverse outcomes in similar or even greater magnitude than coronary disease or stroke. In this review, we highlight important new advances in the epidemiology of PAD with a particular focus on polyvascular disease, emerging biomarkers, and differential risk pathways for PAD compared with other atherosclerotic diseases.
The efficacy and safety of lenvatinib for advanced hepatocellular carcinoma in China: A retrospective, real-world study.
Authors: Xin-Rong Yang, De-Zhen Guo, Fei-Yu Chen, Jia Fan, Zhou Jian
Journal: Journal of Clinical Oncology (2021)

e16182 Background: Hepatocellular carcinoma (HCC) is one of the most common malignancy with dismal outcomes. Recently, lenvatinib have been approved as the first-line therapy for unresectable HCC. However, the efficacy and safety of lenvatinib with the combination of other therapy such as transarterial chemoembolization (TACE) and immune checkpoint inhibitor (ICI) therapy was still unclear. Methods: A multicenter retrospective study was conducted and 158 HCC patients treated with lenvatinib from four medical centers were enrolled between November 2018 and December 2020. According to the treatment combined with lenvatinib, all patients were classified into four groups, including lenvatinib monotherapy (LEN) group, combined ICI (c-ICI) group, combined TACE (c-TACE) group and combined ICI and TACE (c-ICI-TACE) group. Objective response rate (ORR) and disease control rate (DCR) were assessed. Overall survival (OS) and time to progression (TTP) were calculated and compared among different groups. Results: All patients (n = 158) were classified into LEN group (n = 40), c-ICI group (n = 42), c-TACE group (n = 39) and c-TACE-ICI group (n = 37). In all patients, the ORR and DCR was 29.1% and 74.1%. The median OS and TTP were 21.8 and 6.2 months, respectively. Four groups showed significant differences in ORR and DCR rates. Specifically, c-ICI-TACE group have significantly higher ORR and DCR rate compared with LEN group (ORR: 12% vs. 38%, P = 0.002; DCR: 60% vs. 89%, P = 0.004). Kaplan-Meier analysis identified that LEN group, c-ICI group, c-TACE group and c-TACE-ICI group showed significantly different TTP (median TTP: 5.0 vs. 6.6 vs. 4.9 vs. 9.5 months; P = 0.021), but similar OS (median OS: 21.8 vs. 19.6 vs. 17.5 months vs. unreached; P = 0.180). Further investigation revealed lenvatinib combined with ICI could prolong TTP compare with lenvatinib without ICI (median TTP: 8.4 vs. 5.0 months; P = 0.019), but it had no significant impact on OS (median OS: unreached vs. 20.1 months; P = 0.300). c-ICI-TACE group showed both better TTP and improved OS compared with other three groups (median TTP: 9.5 vs. 5.2 months; P = 0.004; median OS: unreached vs. 20.1 months; P = 0.034). Univariate and multivariate analysis confirmed that c-ICI-TACE was an independent protective factor for OS (hazard ratio: 0.226; 95% confidence interval: 0.10-0.50; P &lt; 0.001) and TTP (hazard ratio: 0.55; 95% confidence interval: 0.32-0.95; P = 0.032). Most patients (152/158, 96.2%) showed adverse events (AEs) during lenvatinib treatment and the grade 3 AE occurred in 45 patients (28.5%). No significant difference of AE (P = 0.569) and grade 3 AE (P = 0.572) was found among four groups. Conclusions: Lenvatinib was an effective treatment for patients with HCC. Lenvatinib combined ICI could prolong the TTP, while lenvatinib combined ICI and TACE could improve both TTP and OS. Combined therapy wouldn’t escalate the AE and grade 3 AE rates.
The Influence of Timing in Critical Care Nutrition
Authors: Liam McKeever, Sarah J. Peterson, Omar Lateef, Carol Braunschweig
Journal: Annual Review of Nutrition (2021)

Proper timing of critical care nutrition has long been a matter of controversy. Critical illness waxes and wanes in stages, creating a dynamic flux in energy needs that we have only begun to examine. Furthermore, response to nutrition support likely differs greatly at the level of the individual patient in regard to genetic status, disease stage, comorbidities, and more. We review the observational and randomized literature concerning timing in nutrition support, discuss mechanisms of harm in feeding critically ill patients, and highlight the role of precision nutrition for moving the literature beyond the realm of blunt population averages into one that accounts for the patient-specific complexities of critical illness and host genetics.
Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study
Authors: Chung-Han Lee, Amishi Yogesh Shah, Drew Rasco, Arpit Rao, Matthew H Taylor, Christopher Di Simone, James J Hsieh, Alvaro Pinto, David R Shaffer, Regina Girones Sarrio, Allen Lee Cohn, Nicholas J Vogelzang, Mehmet Asim Bilen, Sara Gunnestad Ribe, Musaberk Goksel, Øyvind Krohn Tennøe, Donald Richards, Randy F Sweis, Jay Courtright, Daniel Heinrich, Sharad Jain, Jane Wu, Emmett V Schmidt, Rodolfo F Perini, Peter Kubiak, Chinyere E Okpara, Alan D Smith, Robert J Motzer
Journal: The Lancet Oncology (2021)
Late immune-related adverse events with immune checkpoint inhibitors.
Authors: Andrew Ip, Shuo Wang, Divya Cheruku, Kanchi Krishnamurthy, Melinda Weber, Brittany Sinclaire, Elli Gourna Paleoudis, Adil Alaoui, Shaked lev-Ari, Michael T Serzan, Shari Adams, Jordan Kaufman, Sahil B. Parikh, Emily Tonti, Eric Muller, Aquino Williams, Jaeil Ahn, Andrew Pecora, Michael B. Atkins, Neil J. Shah
Journal: Journal of Clinical Oncology (2021)

2635 Background: Immune Checkpoint Inhibitors (ICIs) are associated with unique immune-related adverse events (irAEs). IrAEs can occur at any timepoint of ICI treatment. Late irAEs are not well reported in the literature. Herein, we attempt to characterize irAEs that occur 6-month, one year and two years after ICI treatment initiation. Methods: We identified patients treated with ICIs (anti-CTLA-4, anti-PD(L)-1 either alone or in combination or with chemotherapy) across Hackensack Meridian Health hospital and MedStar Georgetown University Health systems from 12011 to 4/2018. Patients' baseline demographics, treatment history, and irAEs were collected from EHR. CTCAE V4.03 was used to grade irAEs. Results: We identified 1332 patients treated with 1443 unique ICIs. The ICI therapies were nivolumab 38% (543), pembrolizumab 23% (332), ipilimumab plus nivolumab 12% (180), ipilimumab 11% (161), Atezolizumab 3% (47) and others 13% (180). Tumor types were lung cancer 34% (496), melanoma 27% (389), GI cancers 6% (92), kidney cancer 6% (87), and other cancers 26% (379). The median age was 66 (21-87), age &gt;75 37% (541), Caucasian 67% (970). We identified a total of 911 any grade irAEs among 37% (552) therapies. Among, 911 irAEs, grade 1-2, grade ≥3 and unknown grade irAEs were 39% (572), 12% (182) and 11% (157), respectively. The most common any grade irAEs were skin rash 22% (202), colitis 13% (120), and hepatitis 12% (108). 84% of all irAEs and 85% of ≥ Grade 3 irAEs occurred within 6 months of treatment initiation. Of the 350, patients on active treatment at six months, 37 % (132) and 7% (26) developed any grade and grade ≥3 irAEs, respectively. irAEs that had &gt; 10% of their occurrences after six months were skin rash and colitis 14% each. Other common irAEs were hypothyroidism, hepatitis, joint pain, pruritis and pneumonitis at 7% each. Among 170 patients on active treatment at one year, 37% (62) and 7% (12) developed any grade and grade ≥3 irAEs respectively. irAEs with &gt;10% incidence after one year of treatment were rash 19% and hepatitis 13%. Conclusions: Our RWE findings suggest although 85% irAEs occurs within the first six months of treatment, late irAEs can occur with ICI treatment. The incidence and pattern of late irAEs appears similar to early irAEs, (e.g., skin rash, colitis, hypothyroidism and hepatitis) with pneumonitis being a notable exception. It is uncertain if these results will be influenced by changing patterns of ICI use (e.g. different diseases and/or regimens) over time.[Table: see text]