tbuckley/cabot-search huggingface dataset:
An open-label, fixed-sequence study to evaluate the effect of encequidar (HM30181) an oral P-gp inhibitor, on the pharmacokinetics of dabigatran etexilate (a P-gp substrate) in healthy male volunteers.
Authors: Christopher G. C. A. Jackson, Noelyn Anne Hung, David Cutler, Douglas Kramer, Jay Zhi, Wing Kai Chan, Min-Fun Rudolf Kwan, Tak Hung
Journal: Journal of Clinical Oncology (2021)

e15060 Background: Oral co-administration of encequidar (a selective, minimally absorbed oral P-gp inhibitor) 12.9 mg with paclitaxel (a P-gp substrate) 205 mg/m 2 for 3 consecutive days per week can achieve comparable AUC exposure to that of IV paclitaxel 80mg/m 2 with a significantly lowered C max and has been demonstrated its improved tumor response with reduced neuropathy compared to IV paclitaxel 175 mg/m 2 Q3W for the treatment of patients with metastatic breast cancer. Because of its pharmacology as an inhibitor of P-gp, encequidar may increase the bioavailability of orally administered drugs that are substrates of P-gp, such as dabigatran etexilate. Methods: To determine the effect of a therapeutic dose and regimen (3 once-daily 12.9 mg doses) of encequidar on the single dose PK of dabigatran etexilate, an open-label, fixed-sequence study was performed in 20 healthy male subjects. Participants received a single oral dose of dabigatran etexilate 75 mg on Day 1 of Treatment Period 1 (reference) and, after a washout period of at least 7 days, on Days 3, 17 and 31 of Treatment Period 2, after receiving once-daily oral doses 12.9 mg encequidar on Days 1 to 3 of Period 2. The PK sampling for determination of plasma concentrations of total and unconjugated dabigatran lasted up to 48 hours postdose of each dabigatran etexilate dosr. Results: Mean AUC and C max values for dabigatran were both increased ̃ 95% without changing t ½ when dabigatran etexilate was administered 1 hour post the 3 rd dose of 12.9 mg encequidar compared to when dabigatran etexilate was administered alone. When dabigatran etexilate was administered 2 weeks after encequidar administration, no apparent differences in dabigatran AUC or C max were detected compared to those of dabigatran etexilate alone. When administered 4 weeks after discontinuation of encequidar, dabigatran AUC and C max were both slightly lower than Reference dabigatran etexilate (̃ 25% lower for AUC and 34% lower for C max ). Both unconjugated and total dabigatran PK data were analyzed and shown to be similar. Encequidar and dabigatran etexilate were well tolerated and had acceptable safety findings in this healthy subject population. Conclusions: Concomitant dosing of encequidar with dabigatran etexilate resulted in &lt; 2-fold increase in exposure to dabigatran, which had abated by the time of the first re-test, 14 days after the last dose of encequidar. The observed changes do not warrant dose adjustment of dabigatran etexilate when administered with encequidar. Clinical trial information: ACTRN12618000791235.
The relationship between evolving sarcopenia and efficacy of immune checkpoint inhibitor in non-small cell lung cancer patients.
Authors: Tomonori Makiguchi, Hisashi Tanaka, Kageaki Taima, Soichiro Tatsuo, Saya Iida, Shingo Kakeda, Sadatomo Tasaka
Journal: Journal of Clinical Oncology (2021)

e21049 Background: Sarcopenia has been receiving attention due to its association with prognoses in patients with cancer. We investigated the association between evolving sarcopenia assessed with computed tomography (CT) and outcome of non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs). Methods: In this retrospective study, 47 NSCLC patients who received ICIs at our Hirosaki University Hospital were enrolled. Skeletal muscle area at the level of the third lumbar vertebra (L3-SMA) was measured from CT images before and 90 days after the ICI treatment. The factor related to the poor efficacy of ICIs was determined by logistic regression analysis. The prognostic cut-off value was estimated by a receiver operating characteristic (ROC) curve. As covariate factors, age, gender, smoking history, histology, performance status (PS), PD-L1 tumor proportion score (TPS), status of driver mutations, body mass index (BMI), serum protein and albumin levels, and lymphocyte count were included. Results: In the univariate analysis, reduction rate of L3-SMA, PS, BMI, serum protein and albumin levels, and lymphocyte count were significantly associated with efficacy. In the multivariate analysis, only reduction rate of L3-SMA was significant. The cut-off value was estimated to be 6%. The study subjects were divided into two groups by the cut-off value. In both of progression free and overall survival analysis, those with more than 6% of reduction had significantly shorter period being free of events than that of the other. Conclusions: Evolving sarcopenia assessed with CT images is promising as a prognostic factor in Japanese NSCLC patients receiving ICIs.
Lung cancer health services utilization and associated cost for the Colombian health system: A propensity score analysis of a national cohort of prevalent patients.
Authors: Giancarlo Buitrago, Javier Amaya-Nieto, Gabriel Fernando Torres
Journal: Journal of Clinical Oncology (2021)

e18784 Background: There is need for high quality data about the economic burden of disease in low- and middle-income countries. We aimed to determine the annual incremental cost of health care services utilized by lung cancer patients in the Colombian health system. Methods: We conducted a national cohort study of prevalent patients with lung cancer in Jan-2017 and followed-up until Dec-2017. We used two electronic algorithms to identify all lung cancer prevalent patients in the Contributory regime, using national health claims databases ( Base de datos de suficiencia de la Unidad de Pago por Capitación and Base de Datos Única de Afiliados), based on identification of ICD-10 codes for 4 months or more during the previous 3 years (sensitive algorithm) and adding the presence of at least one oncological procedure (specific algorithm). We identified all health services cost from the health system perspective (2017 USD). We performed a propensity score analysis to estimate the annual incremental cost of care of patients with lung cancer compared to those without the disease. Standardized differences lower than 0.1 were used to measure the balance of baseline variables. We used generalized linear models as a sensitivity analysis. Results: We identified 4,827 and 3,238 lung cancer prevalent patient using the sensitive and specific algorithm, respectively. Each cohort was matched 1:1 with a no-exposed cohort of 14,968,202 individuals without a diagnosis of lung cancer using a caliper of 0.0001. Matched samples showed good balance on baseline characteristics. Annual incremental cost for patients diagnosed with lung cancer in Colombia ranged between USD $ 3,146.92 and USD $ 4,156.23. We also estimated incremental cost for outpatient and inpatient healthcare services as shown in table. Conclusions: In 2017, each patient with lung cancer represented an incremental cost to the Colombian health system between 49.35% and 65.19% of GDP per capita. This information is paramount to understand lung cancer spending in Colombia and for other low- and middle-income countries. [Table: see text]
Postoperative low molecular weight heparin bridging treatment for patients at high risk of arterial thromboembolism (PERIOP2): double blind randomised controlled trial
Authors: Michael J Kovacs, Philip S Wells, David R Anderson, Alejandro Lazo-Langner, Clive Kearon, Shannon M Bates, Mark Blostein, Susan R Kahn, Sam Schulman, Elham Sabri, Susan Solymoss, Tim Ramsay, Erik Yeo, Marc A Rodger
Journal: BMJ (2021)

Abstract Objective To determine the efficacy and safety of dalteparin postoperative bridging treatment versus placebo for patients with atrial fibrillation or mechanical heart valves when warfarin is temporarily interrupted for a planned procedure. Design Prospective, double blind, randomised controlled trial. Setting 10 thrombosis research sites in Canada and India between February 2007 and March 2016. Participants 1471 patients aged 18 years or older with atrial fibrillation or mechanical heart valves who required temporary interruption of warfarin for a procedure. Intervention Random assignment to dalteparin (n=821; one patient withdrew consent immediately after randomisation) or placebo (n=650) after the procedure. Main outcome measures Major thromboembolism (stroke, transient ischaemic attack, proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, peripheral embolism, or vascular death) and major bleeding according to the International Society on Thrombosis and Haemostasis criteria within 90 days of the procedure. Results The rate of major thromboembolism within 90 days was 1.2% (eight events in 650 patients) for placebo and 1.0% (eight events in 820 patients) for dalteparin (P=0.64, risk difference −0.3%, 95% confidence interval −1.3 to 0.8). The rate of major bleeding was 2.0% (13 events in 650 patients) for placebo and 1.3% (11 events in 820 patients) for dalteparin (P=0.32, risk difference −0.7, 95% confidence interval −2.0 to 0.7). The results were consistent for the atrial fibrillation and mechanical heart valves groups. Conclusions In patients with atrial fibrillation or mechanical heart valves who had warfarin interrupted for a procedure, no significant benefit was found for postoperative dalteparin bridging to prevent major thromboembolism. Trial registration Clinicaltrials.gov NCT00432796 .
Whole-genome sequencing to improve sarcoma diagnosis and patient care.
Authors: Luuk J. Schipper, Kim Monkhorst, Kris Samsom, Petur Snaebjornsson, Hester Van Boven, Paul Roepman, Lizet Van Der Kolk, Linda J.W. Bosch, Winan J. van Houdt, Winette T.A. Van Der Graaf, Gerrit A. Meijer, Emile E. Voest
Journal: Journal of Clinical Oncology (2021)

11540 Background: With more than 70 different histological subtypes, accurate classification sarcomas is challenging. Although pathognomonic genetic events aid accurate classification, large-scale molecular profiling is generally not incorporated in regular diagnostic workflows for sarcoma patients. We hypothesized that whole genome sequencing (WGS) optimizes clinical care of sarcoma patients by detection of pathognomonic and actionable variants, and of underlying hereditary conditions. Methods: WGS of tumor and germline DNA was incorporated in the diagnostic work-up of 83 patients with a (presumed) sarcoma as part of the WIDE (Whole genome sequencing Implementation in standard Diagnostics for Every cancer patient) study in a tertiary referral center. WGS results were reported back to the pathologist and treating clinician. Clinical follow-up data were collected prospectively to assess impact of WGS on clinical decision making. Results: WGS analysis had impact on multiple levels. First, in 14% of cases (12/83 patients), the genomic profile led to a revision of the diagnosis (table). All patients had undergone multiple diagnostic procedures (mean number: 4) and pathologist assessments (mean: 6) before WGS analysis was performed. Secondly, actionable biomarkers with therapeutic potential were detected for 36/83 patients and finally, 8 pathogenic germline variants were present. Taken together, WGS had implications for clinical decision making in 52% of patients with (presumed) sarcomas. Conclusions: WGS is an important extension of the diagnostic arsenal of pathologists and has contributed to change of care in 52% of patients with sarcomas. Given the diagnostic complexity and high unmet need for new treatment opportunities in sarcomas we advocate the use of WGS for sarcoma patients early in the disease course. Clinical trial information: NL68609.031.18. [Table: see text]
Role of biogenetic markers in differentiation and prognosis of giant cell tumor: A systemic review.
Authors: Muhammad Taqi, Mobeen Zaka Haider, Mishaal Tariq, Syed Faraz-ul-Hassan Shah Gillani, Munawar Ali, Zarlakhta Zamani, Muhammad Haseeb ul Rasool, Moazzam Shahzad, Muhammad Umair Mushtaq
Journal: Journal of Clinical Oncology (2021)

e23514 Background: Giant cell tumor (GCT) is a locally aggressive bone tumor. Early diagnosis and potential for recurrence are often difficult to assess due to a lack of bio-genetic markers and radiographic findings overlap with other osteolytic lesions. The purpose of this study is to explore biological and genetic markers that can be used for detection, differentiation, recurrence, and prognosis of GCT. Methods: We conducted a literature review including 24 articles out of 1568 articles, summarizing the role of biogenetic markers in the prognosis of GCT. Results: P63 is 98.6% sensitive and relatively specific for GCT as compared to other multinucleated giant cells containing neoplasms. MDM2(Mouse double minute 2 homolog), IGF1(Insulin-like growth factor 1), STAT1(Signal transducer and activator of transcription 1), and RAC1(Ras-related C3 botulinum toxin substrate 1) are associated with GCT recurrence. Increased expression of proteins like STAT5B, GRB2, and OXSR1 are related to a higher probability of metastasis. Neutrophil to lymphocyte ratio &gt; 2.70, platelets to lymphocyte &gt; 215.80, lymphocyte to monocyte ≤ 2.80, and AGR albumin to globulin &lt; 1.50 ratio were significantly associated with decreased disease-free survival (DFS) (p &lt; 0.05). Large amounts of osteoclast-related mRNA in GCTs (P &lt; 0.05) are associated with the grade of bone resorption. We propose that subarticular primary malignant bone sarcoma with H3.3 mutations represent true malignant GCTB. IMP3 and IGF2 might be potential biomarkers in regulating the angiogenesis of GCT spine and predicting the patients’ prognosis. Conclusions: This review study has shown serological markers are significant in determining the diagnosis, differentiation, prognosis, and recurrence of GCT, which can be added to tumor work-up for definitive diagnosis and prognosis. [Table: see text]
HGG-17. FOCUSED ULTRASOUND-ENHANCED DELIVERY OF RADIOLABELED AGENTS TO DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Dezhuang Ye, Xiaohui Zhang, Lihua Yang, Yimei Yue, Yuan-chuan Tai, Joshua B Rubin, Yongjian Liu, Hong Chen
Journal: Neuro-Oncology (2021)

Abstract Diffuse intrinsic pontine glioma (DIPG) arising in the brainstem is the deadliest pediatric brain cancer with nearly 100% fatality and a median survival of &amp;lt;1 year. The critical location in the brainstem and the often intact blood-brain barrier (BBB) pose significant challenges in the treatment of DIPG. The objective of this study was to demonstrate the potential for focused ultrasound-induced BBB disruption (FUS-BBBD) to improve DIPG treatment by enhancing the safe and efficient delivery of drugs. A genetically engineered mouse model of DIPG was generated using the RCAS (replication-competent avian sarcoma-leucosis virus long-terminal repeat with splice acceptor)/tumor virus A modeling system. A magnetic resonance-guided FUS (MRgFUS) system was used to induce BBB disruption in these mice with the FUS targeted at the center of the tumor. Two radiolabeled agents with different sizes were used to evaluate the delivery efficiency of the FUS-BBBD technique in DIPG mice: a small-molecular radiotracer, 68Ga-DOTA-ECL1i, and a radiolabeled nanoparticle, 64Cu-labeled copper nanoparticles (64Cu-CuNCs, ~ 5 nm in diameter). 68Ga-DOTA-ECL1i (half-life ~ 1 h) and 64Cu-CuNCs (half-life ~13 h) were intravenously injected into the mice after FUS sonication, and microPET/CT imaging was performed at 1 h and 24 h, respectively, to evaluate the spatial-temporal distribution of these two agents in the brain and quantify the delivery outcome. FUS treatment increased the uptake of 68Ga-DOTA-ECL1i and 64Cu-CuNCs to the DIPG tumor by 3.25 folds and 4.07 folds on average, respectively. These findings demonstrated, for the first time, that FUS can increase BBB permeability in a murine model of DIPG and significantly enhance the delivery of agents of different sizes into the DIPG tumor.
Diabetes is the strongest risk factor of hepatic fibrosis in lean patients with non-alcoholic fatty liver disease
Authors: Huiyul Park, Eileen L Yoon, Seon Cho, Dae Won Jun, Eun-Hee Nah
Journal: Gut (2021)

We read the commentary by Francque and Wong1 with great interest. They pointed out that metabolic dysfunction could be the main factor associated with an increased risk of hepatic fibrosis among lean patients with non-alcoholic fatty liver disease (NAFLD). However, it is unclear whether the definition of metabolic dysfunction would also fit lean patients, who are less likely to have metabolic risks.2 Herein, we evaluated the fibrosis burden in lean patients with NAFLD according to the presence of each metabolic dysfunction component.

We analysed participants in a community-based cohort, all of whom have undergone magnetic resonance elastography (MRE) for their health check-up (N=6775, 100% single ethnic Korean). Fatty liver was diagnosed by ultrasonography. The prevalence of NAFLD and lean (body mass index <23) NAFLD in all subjects was 35.2% and 3.7%, respectively. The mean liver stiffness value was lower in lean patients with NAFLD than in non-lean patients (2.26±0.55 vs 2.39±0.53, p<0.001) (online supplemental table 1). However, there was no difference in the prevalence of both significant (MRE …
The IMMULAB trial: A phase II trial of immunotherapy with pembrolizumab in combination with local ablation for patients with early stage hepatocellular carcinoma (HCC).
Authors: Arndt Vogel, Thorsten Oliver Goetze, Guido Hausner, Michael Geißler, Gabriele Margareta Siegler, Ludwig Fischer von Weikersthal, Angelika M. R. Kestler, Matthias Kleiß, Tobias Müller, Andreas Teufel, Jens Marquardt, Maria A Gonzalez-Carmona, Daniel Wilhelm Mueller, Regina Eickhoff, Enrico N. de Toni, Oliver Waidmann, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2021)

TPS4159 Background: The investigator-initiated IMMULAB study investigates the clinical activity of peri-interventional treatment with the anti-PD1 antibody pembrolizumab in HCC patients who are candidates for local ablation via either radiofrequency ablation (RFA), microwave ablation (MWA) or brachytherapy, or - as recommended for tumor larger than 3 cm – by combination with TACE. Patients with extrahepatic disease are excluded. Local ablation is known to induce tumor destruction with subsequent antigen release resulting in host adaptive immune responses. However, tumors could quickly overcome the immune responses by upregulating PD-L1/PD-1 expression and inhibiting the function of CD8 + and CD4 + T cells. Thus, combination of local ablation with an anti-PD1 antibody might display interesting effects by activating immune cells and disabling immune inhibitory mechanisms at the same time. Methods: This is a prospective investigator initiated single-arm multicenter phase II trial investigating immunotherapy with the PD-1 inhibitor pembrolizumab in combination with local ablation in early stage hepatocellular carcinoma (HCC). Patients with a child-pugh classification score ≤ 6, including high risk candidates for local ablation (defined as patients having ≤ 5 tumor nodules with diameters ≤ 7cm [longest axis] each OR patients with vascular infiltration) receive 200mg pembrolizumab i.v. q3w for 2 cycles. Thereafter, radiologic imaging is followed by local ablation on day 1 of cycle 3. Further pembrolizumab (200mg) is applied 2 days after ablation and thereafter every 3 weeks (q3w) for a total treatment duration of up to 12 months. It is planned to enroll 30 pts. Primary efficacy endpoint is the overall response rate (RECIST 1.1) after 2 cycles of pembrolizumab and before performing local ablation aiming in the conversion / downstaging of borderline candidates by pre-interventional treatment with pembrolizumab. Overall recruitment has started; currently (Feb 2021) 18 of 30 planned patients have been enrolled. Clinical trial information: NCT03753659.
Clinical characteristics of SF3B1 mutant (mut) uveal melanoma (UM) and response to immune checkpoint inhibition (ICI).
Authors: Joe Grimes, Alexander Noor Shoushtari, Marlana Orloff, Shaheer Khan, Cody Chiuzan, Susan Jean Hsiao, Diana McDonnell, Brian P. Marr, Richard D. Carvajal
Journal: Journal of Clinical Oncology (2021)

9535 Background: Metastatic UM is associated with a median overall survival (OS) &lt; 1 year (yr) and overall response rate (RR) to ICI &lt; 18%. SF3B1 mut UM represent a clinically unique subset of UM, distinct from BAP1 mut disease, characterized by aberrant spliceosome machinery which may result in increased neoantigen presentation, increased immunogenicity, and sensitivity to ICI. To assess these hypotheses, we performed a multicenter retrospective analysis to assess the natural history and response to ICI in patients (pts) with SF3B1 mut UM. Methods: Patients were identified from institutional databases and the AACR Project GENIE Consortium. Data collected included: baseline and recurrent disease characteristics, molecular characteristics, treatments received, treatment response, and vital status. Efficacy endpoints included investigator assessed RECIST RR and OS. Results: 58 pts with deleterious SF3B1 mutations were identified: 56 R625; 1 D781G; 1 G742D. Median age at diagnosis (dx) was 52 (range, 14-87). 50% were female. 49 pts developed distant metastases. The median time from initial dx to metastasis was 6.1 years (yrs; range, 0.9 to 26.7). Initial metastatic sites (n = 48) were: liver-only (52%); non-liver-only (29%); mixed liver and non-liver disease (19%). The most common initial metastatic sites were: liver (71%), lung (29%), soft tissue (13%), lymph node (8%), and bone (4%). The median OS for all pts from time of metastasis was 3.9 years (95% confidence interval (CI), 2.3-6.2) with OS for pts with non-liver only disease at 6.2 yrs vs those with liver-only or mixed disease at 3.4 yrs (hazard ratio = 2.12, p = 0.14). 1-year OS rate from time of metastasis was 94% (95% CI, 0.86-0.99). 34 pts received ICI for metastatic disease at which time 27% had received a prior systemic therapy (median, 0; range, 0-3) and 35% had received a prior hepatic regional therapy (median, 0; range, 0-6). 15 pts received single-agent anti-PD1; 4 received ipilimumab alone; 15 received dual ICI. 10 pts received ICI with concurrent hepatic regional tx. Best response among 33 evaluable pts were: 9% partial response; 39% stable disease; 52% progressive disease. Median OS from ICI initiation was 20.2 months (95% CI, 13.1-27.4). 1-year OS from ICI initiation was 74% (95% CI, 0.59-0.90). Conclusions: SF3B1 mut UM is characterized by later development of metastases, more common involvement of extrahepatic sites, and longer OS when compared with historical datasets of molecularly unselected UM. Although a modest RR to ICI was observed, the median OS and 1-year survival rate post-ICI are numerically superior to historical controls. Given the more indolent course of SF3B1 mut UM, stratification by SF3B1 status should be included in future clinical trials.