tbuckley/cabot-search huggingface dataset:
Biomarker analysis of phase (Ph) IB trial of radium-223 (Rad) and niraparib (Nira) in patients (Pts) with metastatic castrate-resistant prostate cancer (mCRPC) (NiraRad).
Authors: Eddy Shih-Hsin Yang, Benjamin Leiby, Guru P. Sonpavde, David Johnson Einstein, Zachary L. Quinn, Russell Zelig Szmulewitz, A. Oliver Sartor, William Kevin Kelly
Journal: Journal of Clinical Oncology (2021)

5036 Background: Rad is an alpha particle emitter that causes DNA double strand breaks and has been FDA-approved for use in mCRPC pts with bone metastases. PARP-1 activity critically supports androgen receptor (AR) activity in mCRPC and potentiates AR-dependent DNA damage response pathways that promote prostate cancer cell survival. Nira is a potent and selective PARP-1/2 inhibitor that has shown single agent clinical activity in mCRPC. We previously reported the safety of targeting the PARP-1/AR axis with Nira in combination with Rad. Herein we describe the results of an exploratory biomarker analysis. Methods: The primary objective of NiraRad is to determine the optimum Ph II dose of Nira plus Rad (55 kBq/kg of body weight IV every 4 weeks (wks) x 6) in pts with and without prior chemotherapy (docetaxel). Pts were enrolled to one of three dose levels of Nira (100, 200, or 300 mg PO daily). All cohorts were combined for exploratory biomarker analysis using Nanostring PanCancer Driver and Immune Pathways panels and the nSolver Advanced analysis module was performed on blood obtained from 23 pts at baseline, cycle (C) 1 day (D) 15, and C3D15. A favorable response was defined as any PSA reduction at week 12 or treatment (tx) duration &gt; 18 wks, the median time on tx in the cohort of pts analyzed. A threshold of &gt; 2 fold (X) differentially expressed genes was used. Results: Of the 23 pts with biomarker data, 7 (30%) experienced PSA reductions and 11 (48%) received tx for &gt; 18 wks, 6 of which also had PSA reductions. Exploratory analysis revealed that the PI3K/Ras, MAPK, and transcriptional misregulation pathways were differentially regulated in pts who had favorable responses. The top downregulated gene, PAX5, which has been shown to promote prostate cancer growth, was decreased at C1D15 (2.7X, p &lt; 0.01) and C3D15 (4.8X, p &lt; 0.001) in pts with tx duration &gt; 18 wks and at baseline in pts who had PSA reductions (3.1X, p &lt; 0.05). Immune pathways analysis suggested downregulation of immunosuppressive B-cell (plasma cell) and upregulation of NK and T cell pathways in pts with tx duration &gt; 18 wks. Conclusions: Previously Nira and Rad have been shown to have acceptable tolerability in mCRPC pts. This exploratory analysis suggests potential response biomarkers that warrant further investigation. Managed by: the Prostate Cancer Clinical Trials Consortium; Funded by: Janssen Pharmaceuticals and Bayer Healthcare Pharmaceuticals, Inc. Clinical trial information: NCT03076203.
Effects of prognostic nutrition index on side effects and prognosis of radiotherapy and chemotherapy after radical gastrectomy.
Authors: Jiyu Liu, Hongmin Dong, Wenling Wang, Gang Wang, Huan Pan, Weiwei Chen, Qian Wang, Ze-Jun Wang
Journal: Journal of Clinical Oncology (2021)

e16002 Background: To investigate the impact of preoperative prognostic nutritional index (PNI) on the severity of radiotherapy and chemotherapy toxicity and survival prognosis in patients with gastric cancer through retrospective analysis and research in order to guide clinical nutritional support treatment for patients with gastric cancer. Methods: Through a retrospective cohort study，we analyzed the data of 191 patients with gastric cancer in the Department of Gastrointestinal Surgery of the Affiliated Hospital of Guizhou Medical University and Guizhou Cancer Hospital from January 2008 to December 2018. According to the cut-off value, the patients were divided into high PNI group (PNI≥47.7) and low PNI group (PNI &lt; 47.7). We Compared the incidences of severe radiotherapy and chemotherapy toxicities and overall survival in high PNI group and low PNI group. and make Analysis of prognostic factors. Results: The low PNI group was more prone to severe radiochemotherapy hematological side effects than the high PNI group, and the postoperative survival time was shorter. Multivariate analysis showed that: TNM stage (P = 0.000) and PNI (P = 0.001) were Independent risk factors in predicting overall survival rate. Conclusions: The preoperative prognostic nutrition index is a useful factor for predicting the incidence of radiotherapy and chemotherapy toxicities in patients after gastric cancer surgery.It is one of the important factors affecting the prognosis of gastric cancer and helps to guide the nutritional support treatment of gastric cancer patients.
Immunological Microenvironment Predicts the Survival of the Patients with Hepatocellular Carcinoma Treated with Anti-PD-1 Antibody
Authors: Masahiro Morita, Naoshi Nishida, Kazuko Sakai, Tomoko Aoki, Hirokazu Chishina, Masahiro Takita, Hiroshi Ida, Satoru Hagiwara, Yasunori Minami, Kazuomi Ueshima, Kazuto Nishio, Yukari Kobayashi, Kazuhiro Kakimi, Masatoshi Kudo
Journal: Liver Cancer (2021)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Although immune checkpoint inhibitors (ICIs) have been considered as promising agents for the treatment of advanced hepatocellular carcinoma (HCC), previous clinical trials revealed that the response to anti-programmed cell death protein 1 (anti-PD-1) monotherapy was as low as 20%. Identifying subgroups that respond well to ICIs is clinically important. Here, we studied the prognostic factors for anti-PD-1 antibody treatment based on the molecular and immunological features of HCC. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Patients who were administered anti-PD1 antibody for advanced HCC at Kindai University Hospital were included. Clinicopathological backgrounds and antitumor responses were examined in 34 cases where tumor tissues before treatment were available. Transcriptome analysis was performed using 40 HCC samples obtained from surgical resection, and immune status was compared between 20 HCCs with activating mutations in β-catenin and those without the mutations using transcriptome-based immunogram. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Univariate analysis showed that the disease control rate was significantly better in patients with α-fetoprotein &amp;#x3c; 400 ng/mL, negative for β-catenin/glutamate synthetase (GS) staining, high combined positive score (CPS) of programmed death-ligand 1 (PD-L1), and increased infiltration of CD8&lt;sup&gt;+&lt;/sup&gt; cells in tumor tissues. Among them, negative staining of β-catenin/GS, CPS of PD-L1 ≥ 1, and high degree of CD8&lt;sup&gt;+&lt;/sup&gt; tumor-infiltrating lymphocytes (TILs) were significantly associated with longer survival in both progression-free survival (PFS) and overall survival (OS). The combination of these factors well stratified the survival of the patients on anti-PD-1 antibody in both PFS and OS (&lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.0001 and &lt;i&gt;p&lt;/i&gt; = 0.0048 for PFS and OS, respectively). In addition, the immunogram revealed that tumor-carrying mutations in β-catenin showed downregulation of immune-related genes, especially in those related to priming and activation by dendritic cells, interferon-γ response, inhibitory molecules, and regulatory T cells. &lt;b&gt;&lt;i&gt;Discussion/Conclusion:&lt;/i&gt;&lt;/b&gt; The combined score including Wnt/β-catenin activation, CPS of PD-L1, and degree of CD8&lt;sup&gt;+&lt;/sup&gt; TILs in HCC is informative for predicting the response to ICI in HCC cases. Constitutive activation of β-catenin can induce an immune cold phenotype with downregulation of immune-related genes, and immunohistochemistry-based evaluation is beneficial for identifying the subgroup that shows a good response to ICI.
Dermatologic adverse events of brentuximab vedotin: Characteristics, management, and their relationship with dose regimen.
Authors: Yuna Oh, Alexander Bang, Nicholas Kurtansky, Niloufer Khan, Melissa Pulitzer, Sarah Noor
Journal: Journal of Clinical Oncology (2021)

3049 Background: Owing to its high efficacy and tolerability, brentuximab vedotin (BV) is increasingly being favored over other aggressive systemic therapies for the treatment of various CD30+ Hodgkin and non-Hodgkin lymphomas, including peripheral T-cell lymphoma and cutaneous T-cell lymphomas. Dermatologic adverse events (dAE) are one of the most common toxicities associated with BV but data regarding their characteristics including correlation to dose, time to occurrence, and management is scarce. We aim to describe the clinical and pathologic characteristics of dAEs associated with BV, their relationship with administered dose regimen, and available management strategies. Methods: An IRB-approved retrospective analysis was conducted for all patients who had received at least one cycle of BV from Memorial Sloan Kettering Cancer Center in 2009-2020. Logistic regression, χ 2 , student’s t-test were performed for univariate analyses. Kaplan-Meier survival and multivariate Cox proportional hazard model evaluated dAE occurrence stratified by 5 major dose regimens (single cycle, 1.2mg q1w, 1.2mg q2w, 1.2mg q3w, 1.8mg q3w). Results: Of 611 patients, 201 experienced dAE with median time-to-event of 24 days and 29% experiencing &gt; 1 dAEs. Rash was the most common (62%; 142/230), followed by alopecia (20%) and xerosis (13%). For rash, 50% reported involvement of only the extremities and/or acral sites compared to 25% who had generalized rash. Of those reported (111), 68 patients had grade 1 dAE (61%), 38 grade 2 (34%), and 5 grade 3 (5%)-all grade 3 were rash (maculopapular/morbilliform). 14 cases (7%) resulted in treatment interruptions and 6 in discontinuations due to dAEs (3%). Pathology were often nonspecific consistent with a hypersensitivity reaction: spongiotic/psoriasiform dermatitis with perivascular lymphocytic infiltrates . Patients undergoing weekly regimen were at a statistically and clinically significantly higher risk of dAE during the first 100 days of BV treatment (p = 0.001). Between the two most frequently administered dose regimens (1.8mg vs. 1.2mg, q3w), the higher dose carried 105% higher risk for dAE (HR: 2.047, p = 0.053). Those who had received a single cycle of BV had the lowest risk compared to all other regimen (1/42, p = 0.001). Topical and/or systemic steroids were most frequently prescribed (43%) with 12% of patients requiring systemic steroids. Other treatments varied ranging from antihistamines to moisturizers. Conclusions: Understanding of the detailed characteristics, management strategies, dose-dependent effects associated with BV is critical to provide clinical guidance for primary providers and minimize treatment interruptions or discontinuations. The results overall suggest that the risk for dAEs is dose-dependent with those undergoing frequent dosing regimens having a greater risk, although most dAEs remain mild or low-grade.
Understanding factors associated with uptake of lung cancer screening among individuals at higher risk.
Authors: Abdi Gudina, Anapaula Cupertino, Charles Stewart Kamen, David Adler, Elizabeth Belcher, Nikesha Gilmore, Amber Kleckner, Evelyn Arana, Lee Kehoe, Sara Hardy, Michelle Christine Janelsins, Gary R. Morrow
Journal: Journal of Clinical Oncology (2021)

10559 Background: Lung cancer is the leading cause of cancer death in the U.S, accounting for about 25% of all cancer mortality. The U.S Preventive Services Task Force has recommended annual screening for lung cancer using low-dose computed tomography (LDCT) scanning for individuals at higher risk (aged 55-80 years with a &gt;30 pack-year smoking history). Early detection using LDCT scanning reduces lung cancer specific mortality by 20%. Despite its efficacy, the uptake of annual lung cancer screening among high-risk individuals remains low ( &lt; 18%). The purpose of this study was to identify factors associated with the uptake of lung cancer screening in high-risk individuals in the U.S population. Methods: Data for this study were obtained from the 2017-2019 Behavioral Risk Factor Surveillance System (BRFSS), a population-based survey conducted annually by the Centers for Disease Control and Prevention (CDC) in collaboration with health departments in all 50 states, Washington, DC, and the U.S territories. We restricted our sample to high-risk individuals aged 55-80 years with a &gt;30 pack-year smoking history. Only subjects with complete data on all predictor variables (age, gender, race/ethnicity, marital status, education, income, insurance, COPD, current smoking status, primary care provider) and the outcome variable (uptake of lung cancer screening) (n = 11, 714) were included in the final analysis. Chi-square tests were used to compare the uptake of lung cancer screening by demographic and socioeconomic factors. Multivariable logistic regression models were used to model the association between the predictors and the outcome variable. Results: Individuals with no health insurance (OR: 0.64; 95%CI: 0.46-0.90), no primary healthcare provider (OR: 0.40; 95%CI: 0.31-0.52), no chronic obstructive pulmonary disease (COPD) (OR: 0.35; 95%CI: 0.31-0.0.40) and who were females (OR: 0.86; 95%CI: 0.76-0.96) were less likely to participate in annual lung cancer screening. Individuals aged 65–69 years (OR: 1.65; 95%CI: 1.38-1.97), 70–74 years (OR: 1.77; 95%CI: 1.46-2.14) or 75–80 years (OR: 1.42; 95%CI: 1.16-1.76) were more likely to receive annual lung cancer screening compared with those aged 55-59 years. Race/ethnicity, level of education, level of income, marital status, and current smoking status had no significant association with the uptake of annual lung cancer screening. Conclusions: Our study identifies factors associated with lower uptake of annual lung cancer screening (no health insurance coverage, no primary healthcare provider, no COPD, and female gender). The findings from this study have important implications for the design of more effective interventions to target specific subgroups for the uptake of annual lung cancer screening.
Outpatient practice pattern and remote patient monitoring for axicabtagene ciloleucel CAR-T therapy in patients with aggressive lymphoma.
Authors: Radhika Bansal, Jonas Paludo, Adam Holland, Spychalla Megan, McClanahan Alli, Matthew Hathcock, Hassan Alkhateeb, David Dingli, Yucai Wang, Saad Kenderian, Shaji Kumar, Mithun Vinod Shah, Siddiqui Mustaqeem, Rahma M. Warsame, Jose Caetano Villasboas, Nabila Nora Bennani, Patrick B. Johnston, Stephen M. Ansell, Tufia C. Haddad, Yi Lin
Journal: Journal of Clinical Oncology (2021)

7554 Background: Chimeric antigen receptor T-cell therapy (CAR-T) are commonly administered inpatient due to concern for early onset cytokine release syndrome (CRS), especially with axicabtagene ciloleucel (axi-cel). We report Mayo Clinic Rochester experience for hospital-based outpatient (HBO) management of patients (pts) receiving axi-cel and identify opportunities for improvement. HBO is closely integrated with inpatient practice and includes the same specialty trained clinical team. It is the first point of contact 24/7 for pts and triage evaluations. Lymphodepletion chemotherapy and CAR-T infusion is given on HBO followed by daily monitoring till day 8 and thereafter, as clinically needed until admission criteria is met. Methods: We retrospectively analyzed database of pts who received axi-cel between 1/2018 and 1/2021. After 06/2020, remote patient monitoring (RPM) tools were implemented to collect patient-reported neurologic symptoms and vital signs via bluetooth-enabled devices 4 times daily through month 1. Adverse data trends are addressed by the HBO team. Results: Among 72 recipients, 89% received their cells outpatient; 8% remained outpatient for the entire month. CRS and neurotoxicity incidence were comparable to those reported from CIBMTR. Median time to first admission was 2 days (Table). Use of bridging therapy, increased CRP and LDH were associated with early admission (≤3 days). Median time to tocilizumab, steroid, oxygen support, vasopressor was 4 days after admission. Half of HBO visits required intervention such as blood transfusions, IV medications through the first month. Nine pts had enrolled in RPM to date; with 8 having evaluable data. With 4 scheduled entries/day, a median of 1 entry/day was skipped and 2 entries/day were answered incompletely. An average of 57 additional unscheduled entries were generated per pt. Among a median of 373 (range 91-522) readings per pt over the first month, 4% (2%-20%) of the readings generated alerts. An average of 4 alerts were seen within 48 hours prior to admission. Data including additional subjects will be presented at ASCO meeting. Conclusions: We report a feasible outpatient care model for management of axi-cel recipients with safe outcomes. Clinical characteristics associated with more aggressive disease are associated with likelihood of early admission. Early RPM experience suggest use of digital tools could improve monitoring compliance and may predict evolution to symptoms requiring escalation of care.[Table: see text]
RARE-14. DISRUPTION OF GEMC1-MCIDAS MULTICILIOGENESIS PROGRAM PROMOTES CHOROID PLEXUS CARCINOMA
Authors: Navleen Singh, Tamanna Sarowar, Tasneerm Zahran, Haotian Zhao
Journal: Neuro-Oncology (2021)

Abstract Tumors of the choroid plexus (CP) are rare primary brain neoplasms mostly found in children. CP tumors exist in three forms: CP papilloma (CPP), atypical CPP, and CP carcinoma (CPC). Though CPP is more benign, CPC is a highly lethal and little understood cancer with poor survival rate and a tendency for recurrence and metastasis. CP tumors are thought to arise from CP epithelial cells that secrets cerebral spinal fluid and generate multiple cilia on their apical surface. Here we show that aberrant NOTCH and Sonic Hedgehog signaling in mice drive tumors that resemble CPC in humans. In contrast to CP epithelial cells with clusters of multiple cilia, NOTCH-driven CP tumors were monociliated, and disruption of the NOTCH complex restored multiciliation and decreased tumor growth. NOTCH suppressed multiciliation in tumor cells by inhibiting the expression of Geminin Coiled-Coil Domain Containing 1 (GEMC1), and multiciliate differentiation and DNA synthesis associated cell cycle protein (MCIDAS), early transcriptional regulators of multiciliated cell (MCC) differentiation. Consistently, Gemc1-Mcidas deficiency led to a lack of MCCs in the CP, and impaired the correction of the multiciliation defect in tumor cells by a NOTCH inhibitor. Disturbances to the GEMC1 program are commonly observed in human CPCs characterized by solitary cilia and frequent somatic TP53 mutations. Accordingly, CPC driven by deletion of tumor suppressors Trp53 and Rb1 in mice exhibits a cilia deficit consequent to loss of Gemc1-Mcidas expression. Taken together, these findings reveal that the GEMC1-MCIDAS multiciliogenesis program in the CP is critical for inhibiting tumorigenesis, whereas a defective multiciliation program promotes CPC and may represent a therapeutic avenue for this cancer.
Antibody-drug conjugates for the treatment of lymphoma: clinical advances and latest progress
Authors: Yurou Chu, Xiangxiang Zhou, Xin Wang
Journal: Journal of Hematology & Oncology (2021)

Antibody-drug conjugates (ADCs) are a promising class of immunotherapies with the potential to specifically target tumor cells and ameliorate the therapeutic index of cytotoxic drugs. ADCs comprise monoclonal antibodies, cytotoxic payloads with inherent antitumor activity, and specialized linkers connecting the two. In recent years, three ADCs, brentuximab vedotin, polatuzumab vedotin, and loncastuximab tesirine, have been approved and are already establishing their place in lymphoma treatment. As the efficacy and safety of ADCs have moved in synchrony with advances in their design, a plethora of novel ADCs have garnered growing interest as treatments. In this review, we provide an overview of the essential elements of ADC strategies in lymphoma and elucidate the up-to-date progress, current challenges, and novel targets of ADCs in this rapidly evolving field.
Influence of study discontinuation during the run‐in period on the estimated efficacy of sacubitril/valsartan in the <scp>PARAGON‐HF</scp> trial
Authors: Kota Suzuki, Brian Claggett, Masatoshi Minamisawa, Milton Packer, Michael R. Zile, Marc A. Pfeffer, Lu‐May Chiang, Martin Lefkowitz, John J.V. McMurray, Scott D. Solomon, Akshay S. Desai
Journal: European Journal of Heart Failure (2021)
RAMucirumab in combination with TAS102 versus TAS102 monotherapy in metastatic colorectal cancer: Safety results from the phase IIb part of the RAMTAS phase II/III trial of the German AIO (AIO-KRK-0316).
Authors: Stefan Kasper, Thorsten Oliver Goetze, Sebastian Stintzing, Ralf Dieter Hofheinz, Marianne Sinn, Tobias Nicolaas Dechow, Thomas Jens Ettrich, Verena Keitel, Ullrich Graeven, Ludwig Fischer von Weikersthal, Alexander Kolov, Thomas Edelmann, Alexander Stein, Tanja Trarbach, Sabine Junge, Claudia Pauligk, Isabel Virchow, Jens T Siveke, Salah-Eddin Al-Batran, Martin H. Schuler
Journal: Journal of Clinical Oncology (2021)

3566 Background: Patients (pts) with mCRC progressing on standard chemotherapy have limited therapeutic options. Trifluridine/tipiracil (TAS102) significantly improved survival in patients with refractory mCRC. Ramucirumab (ram) is approved in combination with FOLFIRI for second-line treatment. There is a strong rationale to evaluate the efficacy and safety of ram in combination with TAS102 in pts with refractory mCRC. Methods: This is a randomized, open-label, multicenter, starting as phase IIb and extended to a phase III study in pts with advanced mCRC. Eligible pts were randomized to receive either ram (8 mg/kg on d1+15, q4w) and TAS102 (35 mg/m² on d1-5 and d8-12, q4w, arm A) or TAS102 alone (arm B). The primary endpoint is overall survival. A total of 145 pts were enrolled into phase IIb. Here, we present the data from an interim safety analysis comprising the first 80 treated pts. The trial was extended to phase III including a total of 426 pts. Enrolment of additional 281 pts started in Dec 2020. The trial endpoints remained unchanged. Results: Pts (40 arm A, 40 arm B) received a median of 2.5 treatment cycles in arm A and 2 cycles in arm B; 31 pts in treatment arm A and 32 pts in arm B discontinued participation prematurely, mainly due to cancer progression. Most patients developed adverse events (AEs): grade 3 AEs were observed in 28 pts (70%) in arm A (24 treatment-related) and 27 pts (67%, 17 treatment-related) in arm B. More grade 4 AEs were seen in arm A (13 pts, 32.5%) than in arm B (5 pts, 12.5%). In total, 46 Serious AEs (SAEs) occurred, 27 in arm A (10 treatment-related) and 19 in Arm B (2 treatment-related). Five SAEs (3 in arm A, 2 in arm B) had a fatal outcome (one in arm A treatment-related). Within the analyzed population, no SUSAR occurred. Conclusions: This safety analysis demonstrates a minor increase in AEs in the experimental arm but no unexpected events. There were no excessive toxicity or unacceptable risks. In summary, a favorable risk-benefit-profile was confirmed. Based on these safety results and the ongoing need for efficient treatment in the tested population, the trial was extended to phase III. Clinical trial information: NCT03520946.