tbuckley/cabot-search huggingface dataset:
Metastatic and sentinel lymph node mapping using intravenously delivered Panitumumab-IRDye800CW
Authors: Giri Krishnan, Nynke S van den Berg, Naoki Nishio, Georgina Juniper, Jaqueline Pei, Quan Zhou, Guolan Lu, Yu-Jin Lee, Kimberly Ramos, Andrei H Iagaru, Fred M Baik, Alexander D Colevas, Brock A Martin, Eben L Rosenthal
Journal: Theranostics (2021)

Rationale: Sentinel lymph node biopsy (SLNB) is a well-established minimally invasive staging procedure that maps the spread of tumour metastases from their primary site to the regional lymphatics. Currently, the procedure requires the local peri-tumoural injection of radiolabelled and/or optical agents, and is therefore operator dependent, disruptive to surgical workflow and restricted largely to a small subset of malignancies that can be readily accessed externally for local tracer injection. The present study set out to determine whether intravenous (IV) infusion of a tumor-targeted tracer could identify sentinel and metastatic lymph nodes (LNs) in order to overcome these limitations. Methods: We examined 27 patients with oral squamous cell carcinoma (OSCC), 18 of whom were clinically node negative (cN0). Patients were infused intravenously with 50mg of Panitumumab-IRDye800CW prior to surgical resection of their primary tumour with neck dissection and/or SLNB. Lymphadenectomy specimens underwent fluorescence molecular imaging to evaluate tracer distribution to LNs. Results: A total of 960 LNs were analysed, of which 34 (3.5%) contained metastatic disease. Panitumumab-IRDye800CW preferentially localized to metastatic and sentinel LNs as evidenced by a higher fluorescent signal relative to other lymph nodes. The median MFI of metastatic LNs was significantly higher than the median MFI of benign LNs (0.06 versus 0.02, p < 0.05). Furthermore, selecting the highest five fluorescence intensity LNs from individual specimens resulted in 100% sensitivity, 85.8% specificity and 100% negative predictive value (NPV) for the detection of occult metastases and 100% accuracy for clinically staging the neck. In the cN+ cohort, assessment of the highest 5 fluorescence LNs per patient had 87.5% sensitivity, 93.2% specificity and 99.1% NPV for the detection of metastatic nodes. Conclusion: When intravenously infused, a tumour-targeted tracer localized to sentinel and metastatic lymph nodes. Further validation of an IV tumor-targeted tracer delivery approach for SLNB could dramatically change the practice of SLNB, allowing its application to other malignancies where the primary tumour is not accessible for local tracer injection.
Clinical activity of durvalumab and savolitinib in MET-driven, metastatic papillary renal cancer.
Authors: Cristina Suarez Rodriguez, James Larkin, Poulam M. Patel, Begoña P. Valderrama, Alejo Rodriguez-Vida, Hilary Glen, Fiona Thistlethwaite, Christy Ralph, Gopalakrishnan Srinivasan, Maria Jose Mendez-Vidal, Abigail Carter, Charlotte Tyson, Aaron Prendergast, Kelly Mousa, Thomas Powles
Journal: Journal of Clinical Oncology (2021)

4511 Background: Savolitinib is a potent and selective MET inhibitor with activity in MET-driven papillary renal cancer (PRC). Durvalumab is a PD-L1 inhibitor which has been tested in combination with savolitinib in metastatic PRC with response rates of 29% (12/41). Here we describe the efficacy of this combination in MET-driven metastatic PRC. Methods: This single arm phase I/II trial explored durvalumab (1500mg Q4W) and savolitinib (600mg OD) together in metastatic PRC, with a 4wk savolitinib run in. Biomarker analysis results were compared with responses to treatment as planned in the protocol. The analysis presented here focuses on those patients with MET DNA alterations (central analysis:chromosome 7 gain/MET or HGF amplification/MET kinase domain mutations). Confirmed response rate (RR) (RECIST v1.1), progression-free survival (PFS), tolerability (CTCAE v4.03) and overall survival (OS) were analysed. Results: 42 patients were enrolled in the metastatic papillary cohort, of which 41 patients received treatment. The median follow up was 26.8 months. The confirmed RR was 29% (12/41) and median PFS was 4.9 months (95% CI 2.5-10.0). 14/41 (34%) of these patients had MET-driven disease. 71% (10/14) of MET-driven patients had not previously received systemic therapy and 7% (1/14) were PD-L1 positive. IMDC good, intermediate, and poor risk disease occurred in 36% (5/14), 57% (8/14), and 7% (1/14) of MET-driven patients respectively. Confirmed RR in MET-driven patients was 57% (8/14) with duration of response at 9.4 months (95% CI 3.9-Not reached [NR]). Median PFS and OS in MET-driven patients were 10.5 months (95% CI 2.9-15.7) and 27.4 months (95% CI 7.3-NR) respectively. No new safety signals were seen. Conclusions: The combination of savolitinib and durvalumab has clinical activity in MET-driven PRC. A randomised phase III study is planned based upon these data. Clinical trial information: NCT02819596.
Phase I dose escalation of KD033, a PDL1-IL15 bispecific molecule, in advanced solid tumors.
Authors: Jason J. Luke, Anthony J. Olszanski, Igor Puzanov, Dan Lu, Adrian Hackett, Stella Martomo, Jeegar Patel, Olivier Schueller, Alessandro Mora, Miranda Schlitt, Linghui Li
Journal: Journal of Clinical Oncology (2021)

2568 Background: IL-2 and IL-15 signal through the shared IL-2/15 βγ receptor, but unlike IL-2, IL-15 does not expand regulatory T cells (Tregs), does not mediate activation-induced cell death and may have an improved therapeutic index. KD033 is a fusion antibody combining a fully human, high affinity anti-human Programmed Death Ligand 1 (PD-L1) IgG1 antibody with the human IL-15 receptor alpha (IL15Rα) sushi domain and human IL-15 (IL-15). KD033 (or its mouse cross reactive surrogate molecule, srKD033) has been extensively characterized in multiple in vitro and in vivo nonclinical studies. The fusion of anti-PD-L1 antibody to IL-15 significantly increases the maximal-tolerated dose (MTD) of srKD033 in mice compared to free IL-15. In addition, srKD033 has exhibited increased efficacy in rejecting tumors in mice as compared to the combination of its individual components, anti-PD-L1 antibody and IL-15. Methods: This is a phase 1, open-label, multiple ascending dose, multi-center clinical trial being conducted in patients with metastatic or locally advanced solid tumors (NCT04242147). The primary objective is to determine the safety and tolerability and the MTD of KD033. Secondary objectives include characterization of PK and immunogenicity, evaluation of CD8 T and NK cell activation and assessment of best overall response and duration of response. KD033 is administered by IV infusion over 30 minutes every 14 days. Accelerated intra-patient dose escalation across the initial three dose levels, followed by 3+3 escalation thereafter, is investigating dose ranges from 3 µg/kg to 600 µg/kg. Efficacy evaluation is planned in an expansion cohort of patients with PD-1/L1 refractory tumors. Results: A total of 7 patients have received treatment. Three patients were dosed in Cohort 1 and four patients were dosed in Cohort 2. Through two dose escalation cohorts (3 µg/kg – 25 µg/kg), no dose-limiting toxicities have been reported. Grade 1-2 treatment-related toxicities, when observed, resolved within 24 hours with supportive management. 6 patients are evaluable for treatment response with one patient (adenoid cystic carcinoma) in the first cohort having stable disease for more than 6 months. Conclusions: KD033 has been well tolerated early in dose escalation with on-mechanism pharmacodynamics consistent with IL-15 agonism. Clinical trial information: NCT04242147.
Risk of Atrial Fibrillation According to Cancer Type
Authors: Jun Pil Yun, Eue-Keun Choi, Kyung-Do Han, Sang Hyun Park, Jin-Hyung Jung, Sang Hyeon Park, Hyo-Jeong Ahn, Jae-Hyun Lim, So-Ryoung Lee, Seil Oh
Journal: JACC CardioOncology (2021)

Patients with cancer have an increased risk of atrial fibrillation (AF). However, there is a paucity of information regarding the association between cancer type and risk of AF.This study sought to evaluate the risk of AF according to the type of cancer.We enrolled 816,811 patients who were diagnosed with cancer from the Korean National Health Insurance Service database between 2009 and 2016. Age- and sex-matched noncancer control subjects (1:2; n = 1,633,663) were also selected. Newly diagnosed AF was identified based on the type of cancer.During a median follow-up of 4.5 years, AF was newly diagnosed in 25,356 patients with cancer (6.6 per 1,000 person-years). In multivariable Fine and Gray's regression analysis, cancer was an independent risk factor for incident AF (adjusted subdistribution hazard ratio [aHR]: 1.63; 95% confidence interval [CI]: 1.61 to 1.66). Multiple myeloma showed a higher association with incident AF (aHR: 3.34; 95% CI: 2.98 to 3.75). Esophageal cancer showed the highest risk among solid cancers (aHR: 2.69; 95% CI: 2.45 to 2.95), and stomach cancer showed the lowest association with AF risk (aHR: 1.27; 95% CI 1.23 to 1.32).Although patients with cancer were found to have a higher risk of AF, the impact on AF development varied by cancer type.
Imaging determinants of early progression in relapsed and refractory Hodgkin and diffuse large B cell lymphoma.
Authors: Surabhi Bajpai, Manish Sharma, Shweta Narang, Ravikanth Mankala, Usha Lalchandani, Jayant Narang, Rudresh Jarecha, Oliver Bohnsack
Journal: Journal of Clinical Oncology (2021)

e19522 Background: Diffuse Large B-cell Lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma with over 18,000 new cases diagnosed each year in the United States and approximately 7-8 cases per 100.000 people globally. Hodgkin’s Lymphoma (HL) is less common accounting for approximately 9,000 new cases each year. However, their imaging manifestations overlap; with both the diseases demonstrating extensive lymph nodal and extra-nodal involvement along with intense uptake on 18 FDG-PET. Novel targeted therapies have been developed to improve survival in patients with DLBCL and HL. The purpose of this study analysis was to determine if there was a correlation between the baseline tumor burden and early tumor progression based on imaging. Methods: This retrospective study involved the analysis of baseline imaging data (CT, MRI and PET) of 469 patients enrolled in multiple phase II/III clinical trials involving a diagnosis of DLBCL and HL. Image analysis was performed utilizing the IWG criteria Lugano 2014 modification. The staging of the baseline disease burden was performed as per the Revised Staging System for Primary Nodal Lymphomas. In addition to the staging, the sum of the product of perpendicular diameters of all target lesions (SPD), and spleen size at baseline were recorded. The time point of disease progression was also captured in this analysis for each patient. These baseline imaging parameters were compared among patients with early progression (≤6 months following onset of therapy). Results: Out of the 469 patients, 61.4% of patients (n = 288/469) demonstrated disease progression during treatment and/or follow up phase of the trial. In this cohort, 64.5% (n = 186/288) of patients showed early progression. Patients with advanced stage disease at baseline (Stage II bulky, III and IV) showed a higher rate of early progression compared to those with limited baseline disease burden (Stage I and II) (47.1% vs 32.9%). The occurrence of early progression was similar in patients with normal spleen size at baseline compared to those with an enlarged spleen at baseline (39.3% vs 41%). There was a trend towards higher baseline SPD in patients with early progression (3204mm 2 , +12.5%) and late progression (3185mm 2 , +12%) compared to patients who did not demonstrate progression during the trial phase (2804mm 2 , p = 0.23-0.45). Conclusions: Baseline disease staging is an important determinant of early progression in patients with DLBCL and HL. Baseline tumor burden is potentially a predictive marker of disease progression. Therefore, precise staging along with accurate recording of baseline tumor burden have important prognostic and subsequent therapeutic strategy implications for prospective decision making in the era of precision medicine. Further prospective studies may be needed to validate our results.
EPCT-04. RESULTS OF A PHASE 1 STUDY OF THE ONCOLYTIC ADENOVIRUS DNX-2401 WITH RADIOTHERAPY FOR NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Marc Garcia-Moure, Jaime Gállego Pérez-Larraya, Ana Patiño, Marisol Gonzalez-Huarriz, Chris Jones, Alan MacKay, Jasper Van der Lugt, Esther Hulleman, Carlos de Andrea, Itziar Astigarraga, Miguel García-Ariza, Blanca Lopez-Ibor, Maria Villalba, Frederick F Lang, Juan Fueyo, Candelaria Gomez-Manzano, Jessica Dobbs, Ricardo Diez-Valle, Marta M Alonso, Sonia Tejada
Journal: Neuro-Oncology (2021)

Abstract Background A Phase 1, single center study is ongoing to evaluate the conditionally replicative oncolytic adenovirus, DNX-2401 (tasadenoturev), followed by radiotherapy (RT) in pediatric patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Methods Patients 1–18 years with newly diagnosed DIPG with no prior treatment, Lansky/Karnofsky performance score ≥ 70, and adequate organ function were enrolled. A tumor biopsy was performed followed by a single intratumoral injection of 1e10-5e10 virus particles (vp) DNX-2401. Conventional radiotherapy was initiated within 1 month of DNX-2401 administration. Results Enrolled subjects (n=12) had a median age of 9 (range 3–18) and performance scores of 90–100 (n=4; 33%) or 70–80 (n=8; 67%). As part of a dose escalation design, subjects were treated with 1e10 vp (n=4) or 5e10 vp DNX-2401 (n=8), which was then followed by standard RT in 11 of 12 subjects (92%). No dose-limiting toxicities were observed and the treatment regimen was well-tolerated. Adverse events (AEs) have been primarily mild to moderate and consistent with underlying disease. The most commonly reported AEs (≥ 5 subjects), regardless of study drug relationship, include headache, asthenia, vomiting, anemia, leukocytosis, and fever. Two SAEs have been reported including grade 3 lymphopenia and grade 3 abdominal pain. Tumor reductions have been observed and efficacy evaluations are ongoing. As of 09Dec2020, 12-month survival (OS-12) was 71% and 4 of 12 patients had survived &amp;gt; 20 months. Four subjects continue to be followed for survival. Correlative analysis of tumor biopsy and peripheral samples is ongoing. Conclusions DNX-2401 followed by RT can be safely administered to pediatric subjects with newly diagnosed DIPG; clinical activity and preliminary survival are encouraging.
Analysis of a Naturally Occurring PAR4 Variant By Hydrogen/Deuterium Exchange Reveals Its Structural Rearrangement upon Activation By Thrombin and the Molecular Basis for Altered Reactivity
Authors: Xu Han, Lukas Hofmann, Maria de la Fuente, Tivadar Orban, Nathan Alexander, Krzysztof Palczewski, Marvin T Nieman
Journal: Blood (2017)
Molecular characterization of luminal breast tumors in African American women.
Authors: Yael Simons, Mohamed Hassan, George Chlipala, Oana Cristina Danciu, Vijayakrishna K. Gadi, Manmeet Singh, Gayatry Mohapatra, Kent Hoskins
Journal: Journal of Clinical Oncology (2021)

550 Background: Racial disparities in breast cancer (BC) mortality are attributed to later stage diagnoses and a higher incidence of triple-negative BC among African American (AA) women. In previous work, we showed that AA women with ER+ BC are more likely to develop biologically aggressive disease and are more likely to die from early stage, ER+ BC than non-Hispanic White women (Hoskins et al, JAMA Oncol, 2021). The underlying molecular drivers of this disparity are unknown. Here we report the molecular characterization of a series of luminal BC from AA women. Methods: Consecutive breast tumor specimens received in the Pathology Department underwent next generation sequencing (NGS). Unstained FFPE tissue sections were macro-dissected to isolate tumor cells, and nucleic acids were extracted using commercially available kits. DNA and RNA sequencing libraries were prepared with the Oncomine Comprehensive Assay v3 (OCAv3) (Thermo Fisher), which includes 161 driver genes and detects SNVs, CNVs, INDELs and gene fusions. Sequencing was performed on the Ion S5XL sequencer. Sequencing reads were mapped to the UCSC human genome build GRCh37/hg19 using Torrent Suite™ software (version 5.10; Thermo Fisher). Data analysis and variant calling was performed using the Ion Reporter analysis tool. Results: We identified 60 somatic driver gene alterations in luminal tumors from 35 AA patients (primary tumors, n = 26; metastatic tumors, n = 9). Recurrently altered genes identified in &gt; 5% of tumors are listed in the Table. The most frequently altered gene was PIK3CA (42% of tumors). ESR1 gene fusions were seen in 25% of tumors. Interestingly, an equal frequency of ESR1 fusions were detected in primary (27%) and metastatic (22%) tumors, in contrast to activating mutations which are found in recurrent tumors following treatment with aromatase inhibitors. ARID1A alterations were identified in 17% of primary tumors. ARID1A encodes a subunit of the SWI/SNF chromatin remodeling complex. Alterations in ARID1A confer endocrine resistance, and are enriched in recurrent tumors in the literature. We also found a high number of CNVs in members of the FGF gene family (36% of tumors), which are also associated with resistance to endocrine therapy. An in silico analysis comparing our findings with publicly available datasets will be presented. Conclusions: This study of somatic driver gene alterations in a consecutive series of luminal breast tumors from AA patients found a higher than expected frequency of alterations in genes associated with endocrine resistance in untreated primary tumors, suggesting a partial explanation for racial disparities in survival.[Table: see text]
Programmed death ligand-1 (PD-L1) expression in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with nivolumab (NIVO) in combination with stereotactic body radiotherapy (SBRT) in NIVES study.
Authors: Cristina Masini, Gabriele Carlinfante, Cinzia Iotti, Ugo De Giorgi, Roberto Salvatore Bellia, Sebastiano Buti, Francesco Salaroli, Ilaria Zampiva, Renzo Mazzarotto, Claudia Mucciarini, Maria Giuseppa Vitale, Alessio Bruni, Giuseppe Procopio, Stefania Kinspergher, Valentina Vanoni, Franco Nole, Franco Morelli, Susanne Baier, Consuelo Buttigliero, Carmine Pinto
Journal: Journal of Clinical Oncology (2021)

4558 Background: The NIVES study represents the first prospective trial with NIVO in combination with SBRT in pre-treated mRCC patients. This study did not meet the primary endpoint in terms of objective response rate (ORR) as previously reported. However this combination showed a faster time to treatment response, a long progression free survival and median duration of response without increasing toxicities. Here we have tested with an exploratory analysis the correlation between PD-L1 expression and clinical outcomes in pts treated with NIVO plus SBRT. Methods: PD-L1 expression was assessed in archival collected tumour samples in our central laboratory using 4 commercial kits for immunoistochemical (ICH) analysis (clone 22C3 pharm DX Dako Agilent, 28.8 Abcam and SP142 and SP263 Ventana Medical System). A tumor cell was considered positive if any membranous staining was found regardless of the intensity. In particular the immunostaining was scored 0 when all tumor cells were unstained (PD-L1-negative), 1+ when &lt; 1% positive tumor cells were counted, 2+ when the percentage was between 1% and 50%,3+ when the number of stained cells was more than 50%. ORR and overall survival (OS) were correlated with PD-L1 staining. Results: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 44 of 69 pts enrolled in the NIVES study. Twenty-two pts of 44 (50%) were considered PD-L1-negative using all the 4 commercial kits for ICH analysis, while 14 of 44 pts (31,8%) were defined PD-L1 weakly positive (positive tumor cells &lt; 1% at least in one kit for ICH). Eight of 44 pts (18.1%) were defined PD-L1 strong positive when at least one kit for ICH scored 2+ or 3+. About the correlation between ORR and PDL1 staining in the 42 pts (2/44 pts are not evaluable for ORR), ORR was 18.2% (95% CI, 5.2% to 40.3%) in the PD-L1-negative group vs 20% (95% CI, 5.7% to 43.7%) in weakly/strongly PD-L1 positive (p = 1.00). Among the 44 pts in the intention-to-treat population with available PD-L1 status, median OS was not significantly different between pts with PD-L1 negative (20.56 months, 95% CI, 7.16 to NR) and PD-L1 positive (18.33 months, 95% CI, 6.83 to NR) (p = 0.56). Conclusions: For the first time four commercial kits for ICH analysis were used to test PD-L1 expression in pretreated mRCC pts. Data from these small sample size seem to confirm that PD-L1 in pre-treated mRCC cancer is not a predictive biomarker for selecting pts to receive NIVO-based treatment. Clinical trial information: NCT03469713.
Profiling plasma angiogenesis factors after use of biologics in metastatic colorectal cancer (mCRC): Update results from GI-SCREEN CRC Ukit study.
Authors: Yu Sunakawa, Satoshi Yuki, Manabu Shiozawa, Toshiki Masuishi, Tomohiro Nishina, Hisateru Yasui, Takashi Ohta, Naoki Takahashi, Hironaga Satake, Akiyoshi Kanazawa, Masahiro Goto, Hideaki Bando, Hiroya Taniguchi, Yoshinaga Okugawa, Kentaro Yamazaki, Hiromichi Ebi, Yukiko Abe, Shogo Nomura, Chiharu Asano, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2021)

3529 Background: No predictive biomarkers have been validated to determine which patients (pts) with metastatic colorectal cancer (mCRC) benefit the most from angiogenesis inhibitors. Recent studies suggest that plasma angiogenesis factors and their dynamics may have some prognostic or predictive value. Methods: In this prospective longitudinal study, serial plasma sample collections were done at the time points of pre- and post-treatments in mCRC pts receiving biologics in either first- or second-line chemotherapy (chemo). Comprehensive measurements of 17 factors were performed by the multiplex assay with Luminex technology. Statistical analyses were conducted by using the Brunner-Munzel and Jonckheere-Terpstra test. Results: From Sep 2017 to Dec 2020, 789 plasma samples were collected from 498 enrolled pts [first-line chemo plus bevacizumab (BEV, n=102), first-line chemo plus anti-EGFR antibody (aEGFR, n=100), second-line chemo plus BEV (n=100), second-line FOLFIRI plus ramucirumab (RAM, n=99), second-line FOLFIRI plus aflibercept (AFL, n=85) and other treatment (n=7)]. 789 samples were evaluable for this analysis. In the analysis of first-line, level of VEGF-D was significantly higher in both post-BEV and post-aEGFR comparing with pre-first-line [pre-first-line; 264 pg/ml, post-first-line BEV; 354 pg/ml (p&lt;0.001), post-first-line aEGFR; 380.5 pg/ml (p&lt;0.001)], while PlGF was significantly higher only in post-BEV [pre-first-line; 6.7 pg/ml, post-first-line BEV; 23.4 pg/ml (p&lt;0.001), post-first-line EGFR; 7.4 pg/ml (p=0.650)]. These dynamics were also observed in pts with paired samples (Table). In pts with paired samples who received second-line treatment, level of VEGF-A was significantly decreased in post-BEV, while it significantly increased in post-RAM and AFL. A significant elevation of VEGF-D level was observed in only post-RAM. PlGF level significantly increased in post all second-line angiogenesis inhibitors. In the distribution analysis of angiogenesis factors, there were no or weak correlations between VEGF-D and PlGF at the time points of all post-treatments (r = 0.09-0.26). Conclusions: Plasma levels of VEGF-D, VEGF-A and PlGF were independently changed by angiogenesis inhibitors as well as anti-EGFR therapy, suggesting the possibility of usefulness for selecting better biologics by measuring baseline angiogenesis-related factors in first- and second-line chemo. Clinical trial information: UMIN000028616. [Table: see text]