tbuckley/cabot-search huggingface dataset:
What happened to the preserved renal parenchyma after partial nephrectomy?
Authors: Steven Campbell, Longbin Xiong, Nguyen Jane, Fangjian Zhou, Zhiling Zhang, Yulu Peng
Journal: Journal of Clinical Oncology (2021)

e16581 Background: Partial nephrectomy (PN) is the standard therapy for small renal mass, despite various degree of ischemia reperfusion injury (IRI) is always inevitable as the renal artery is usually clamped during PN. In mouse IRI model, unilateral renal artery clamped for 21 minutes results to sever kidney fibrosis in one year. However, what happened to the preserved renal parenchyma after several years since PN is still a mystery. The aim of the study is to compare the pathological chronic kidney disease (CKD) score of normal renal parenchyma before and several years after PN, as well as to explore the factors that associated with CKD score increase and GFR decline. Methods: We retrospectively collected the clinicopathologic data of 114 renal cell carcinoma (RCC) patients who underwent PN and subsequent radical nephrectomy (RN) due to tumor recurrence in 19 Chinese centers and Cleveland clinic. Macroscopic normal renal parenchyma was sampled at least 5 mm away from the tumor border in PN specimen and at distal portion of the kidney in RN specimen. Pathological CKD score is a summary of glomerular, tubular, interstitial, and vascular score. MDRD2 equation was used to estimate the glomerular filtration rate (GFR). Predictive factors for CKD score increase were evaluated by logistic regression. Results: A total of 64 patients that have all the required data were included in the analysis. The median duration warm ischemia (n = 41) and hypothermia (n = 23) were both 23 min. In a median interval of 2.44 years, the CKD score arose in 73.4% (47/64) patients, with 45.3% (29/64) cases increased by ≥3. Even so, no kidney fibrosis was observed in this cohort including in those with extend warm ischemia (≥45min). There was no significant difference in the change of CKD score during patients with different ischemia time and type. However, patients with comorbidities such as hypertension, diabetes mellitus or CKD (HTN/DM/CKD) showed higher rate and extent of CKD score increase. In multivariate analysis, HTN/DM/CKD was found to be an independent predictor for the CKD score increase [OR:4.24 (1.23-14.64)]. However, the decline of GFR was mild and analogous between patients with or without CKD score increase (23.03±22.53ml/min/1.73m 2 vs. 24.27±21.79ml/min/1.73m 2 , p = 0.856). Conclusions: In majority, preserved renal parenchyma after PN suffered pathological deterioration. Ischemia time and type seem to have limited impact on the change of CKD score of preserved renal parenchyma during PN. Patients with HTN/DM/CKD have higher risk of CKD score increase in despite of similar mild GFR deterioration.
Chemotherapy at the end of life in colorectal and pancreatic cancer: Real-world data and trends over time.
Authors: Catherine Dunn, Belinda Lee, Jeremy David Shapiro, Rachel Wong, Grace Gard, Michael Michael, Wei Hong, Matthew E. Burge, Vanessa Wong, Ben Thomson, Sumitra Ananda, Sue-Anne McLachlan, Brett Knowles, Mehdrad Nikfarjam, Jeanne Tie, Ross Jennens, Joseph James McKendrick, Margaret Lee, Suzanne Kosmider, Peter Gibbs
Journal: Journal of Clinical Oncology (2021)

e18723 Background: Chemotherapy at the end of life (CEOL) is widely accepted as an indicator of aggressive care. However, the evidence is limited primarily to single-centre experiences, with no consensus regarding acceptable benchmarks for CEOL, nor how this may be changing over time and with novel treatment options. We describe ‘real world’ CEOL in two large, multisite Australian registries of metastatic colorectal cancer (mCRC) and both locally advanced and metastatic pancreatic cancer (PC). Methods: Data was analysed from the TRACC and PURPLE registries, two large prospective multisite Australian cancer registries collecting prospective demographic, tumour, treatment and outcome data for mCRC and PC respectively. We identified all decedents between May 2009 and November 2020, determined the proportion who died within 14 or 30 days of chemotherapy (14D / 30D), or within 30D after a new line of therapy, defined as the first cycle of a new treatment regimen. Using univariate analysis, we compared baseline demographic and clinicopathological variables and trends over time. Results: 1505 mCRC and 602 PC decedents were identified. 20.9% of decedents (21.6% mCRC and 19.3% PC) received chemotherapy within 30D, and 11.5% within 14D (12.3% mCRC and 9.6% PC). There were lower rates of 30D CEOL after the first cycle of a new line of therapy (4.3% mCRC and 5.7% PC). Rates of CEOL decreased over the study period for mCRC (median rate of initial 3-year period 28% versus 15% in last 3-year period), but remained largely static for PC (18.9% versus 17.9%). 30D CEOL was more likely with palliative than curative intent treatment (mCRC OR 1.6, 95% CI 1.14-2.25, p = 0.007, PC OR 5.3, 95% CI 1.6-17.8), and advanced rather than local disease in PC (PC OR 2.59, 95%CI 1.6-4.1, p &lt; 0.001). There was a trend towards CEOL and poorer performance status (ECOG) across all groups, only significant for 30D CEOL mCRC (OR 1.51, 95% CI 1.04-2.2). There was no association between CEOL and patient age, gender, Charlson comorbidity score or lines of therapy. Conclusions: Real-world rates of CEOL are higher in our cohorts of mCRC and PC patients than historical benchmarks but comparable to contemporary reports, which may be due to a wider array of available active treatments. Overall rates are decreasing over time for mCRC but static for PC, which may reflect the poorer overall survival for PC and lack of new effective therapies. The lower rates of death after new lines of therapy may signify that CEOL is more likely with existing treatment regimens and that clinicians are less likely to initiate a new chemotherapeutic regimen at EOL.
Tazemetostat (TAZ) in relapsed/refractory (R/R) follicular lymphoma (FL): Propensity-score matched analysis of E7438-G000-101 trial outcomes.
Authors: David Proudman, Deepshekhar Gupta, Dave Nellesen, Alex Wong, Jay Yang, Beth Kamp, Khalid Mamlouk
Journal: Journal of Clinical Oncology (2021)

e18627 Background: Oncology drug development often requires the use of non-randomized, open-label, phase 2 basket studies to better understand the early activity and safety of a potential new therapy. As such, baseline demographics and disease characteristics may differ between cohorts which can impact the perception of efficacy between cohorts. TAZ, a first-in-class, oral enhancer of zeste homolog 2 (EZH2) inhibitor was approved by the US FDA after demonstrating single-agent, antitumor activity in a phase 2 study in adults with wild-type (WT) or mutant (MT) EZH2 R/R FL who had received ≥2 prior systemic therapies (NCT01897571). Differences between the cohorts in baseline characteristics known to be prognostic for clinical outcomes were noted, with the WT EZH2 cohort enrolling more patients with poor-risk features. This analysis assessed outcomes in the 2 groups after minimizing differences in baseline characteristics by creating a matched sample of directly comparable WT and MT patients. Methods: Propensity scores for each WT (n = 54) and MT (n = 45) EZH2 patient in the study were generated, based on the likelihood of being selected given their baseline characteristics. Characteristics identified for inclusion in the model were chosen if they were prognostic based on peer-reviewed literature and where larger differences were observed between cohorts at baseline: ECOG performance status, number of prior lines of anticancer therapy, progression of disease within 24 months, double refractory status, and prior history of hematopoietic stem cell transplant. Patients were matched 1:1 on propensity score, using a nearest-neighbor approach with caliper restrictions. Baseline covariates between the two matched groups were found to be sufficiently balanced. Objective response rate (ORR) point estimates were measured for the matched WT and MT EZH2 groups, and progression-free survival (PFS) was described using Kaplan-Meier analyses. Results: The propensity-matched sample included 56 patients (28 WT and 28 MT). Prior to matching, ORR was 35% (95% CI [22%, 48%]) in the WT and 69% (95% CI [55%, 83%]) in MT EZH2 groups; after matching, the ORR was 50% (95% CI [31%, 69%]) and 71% (95% CI [54%, 88%]), respectively. Median PFS was 11.1 months (95% CI [5.4, 16.7]) in the WT and 13.8 months (95% CI [11.1, 22.1]) in the MT EZH2 groups prior to matching, and 14.3 months (95% CI [11.1, inf]) and 14.8 (95% CI [10.7, inf]) months in the WT and MT EZH2 matched groups, respectively. Conclusions: As expected, efficacy remained higher in the MT EZH2 group; however, after adjustment, the ORR and PFS improved in the WT EZH2 group. This hypothesis-generating analysis suggests that outcomes in patients with WT EZH2 R/R FL treated with TAZ may have been more similar to those in the MT EZH2 group in the phase 2 trial had the baseline disease characteristics been more equally matched.
Analysis of immune checkpoint blockade biomarkers in elderly patients using large-scale cancer genomics data.
Authors: Rossin Erbe, Zheyu Wang, Sharon Wu, Joanne Xiu, Neeha Zaidi, Marc E. Lippman, Claudine Isaacs, Reva K Basho, Heinz-Josef Lenz, Igor A. Astsaturov, John Marshall, Stephen Baylin, Elizabeth M. Jaffee, Evanthia T. Roussos Torres, Ashani Weeraratna, Hariharan Easwaran, Elana J. Fertig
Journal: Journal of Clinical Oncology (2021)

2543 Background: Immune checkpoint blockade (ICB) immunotherapy in some cases elicits striking patient responses, but its efficacy appears to be dependent on several incompletely understood factors. Most studies of ICB therapies in elderly patients have concluded that they received no reduced benefit or even increased benefit compared to the younger patients analyzed, despite the systemic age-related immune changes that might be expected to produce a less effective immune response, such as loss of the capacity to generate new naive T cells. To understand and apply these results, it is necessary to investigate the relationship of age and the immune tumor microenvironment. Methods: We apply bioinformatics methods to genomic, transcriptomic, and clinical data from 9,523 patients across 31 cancer types from TCGA, 15,557 patients with breast, colon, or head and neck cancers from Caris Life Sciences, and 37,961 patients across 8 cancer types collected by GENIE. From these data we apply multivariate linear models across and within individual tumor types to estimate age-related associations to tumor mutational burden (TMB), T cell receptor diversity (miTCR), differential gene expression (edgeR), pathway enrichment (mSigDB and fgsea), and immune cell type infiltration (Quantiseq and MIXTURE). Results: Our analysis of large-scale molecular and clinical databases associates patient age with changes in several major biomarkers of ICB response. Notably, a robust correlation between increased tumor mutational burden and age was found across three different large cohorts (TCGA, Caris Life Sciences, and GENIE) in most ICB-approved cancer types. In the TCGA data, TMB increased with age pan-cancer (p &lt; 1x10 -16 ) and in 7 of 9 ICB-approved cancer types. These associations were validated in the larger cohort of patient samples in GENIE, which demonstrated correlations between increased TMB levels and patient age in all eight ICB-approved cancer types assayed (Table), as well as in the Caris colorectal (q &lt; 0.001) and breast (q &lt; 0.001) cancer cohorts. Significant associations of age to other biomarkers of ICB response (checkpoint gene expression, immune infiltration, and immune related pathway signaling) will be presented. Conclusions: These results provide context for the efficacy of ICB in elderly patients, highlight potential biomarkers for the treatment of elderly patients with immunotherapies, and strongly suggest the value of large-scale prospective study of elderly cancer patients treated with ICB.[Table: see text]
Abstract 15300: Angiopoietin-Like 4 Induces Cardiac Repair Through Inflammation Resolution Mediated by Skewed Polarization of Macrophage
Authors: Dong Im Cho, Yong Sook Kim, Youngkeun Ahn
Journal: Circulation (2018)

Introduction: Mesenchymal stem cells (MSCs) can suppress pathological inflammation. Hypothesis: However, the mechanisms underlying the association between MSCs and inflammation remain unclear. Meth...
Hyper-Activation of the Adenosinergic Axis in the Eμ-TCL1 Chronic Lymphocytic Leukemia Mouse Model Offers Therapeutic Opportunities
Authors: Tiziana Vaisitti, Sara Serra, Cinzia Bologna, Nicoletta Vitale, Stefania Gobessi, Dimitar G Efremov, Silvia Deaglio
Journal: Blood (2017)
GLIM versus ESPEN criteria for the diagnosis of early malnutrition in oncological outpatients.
Authors: Marta Gascon Ruiz, Diego Casas-Deza, Irene Torres, Maria Zapata-Garcia, Natalia Alonso Marin, Andrea Sesma Goñi, Julio Jose Lambea- Sorrosal, Maria Alvarez, Elisa Quilez, Maria Zurera Berjaga, Maitane Ocáriz, Alba Moratiel Pellitero, Ines Ruiz Moreno, Ana Goas Gomez, Maria Marti Pi, José Miguel Arbonés-Mainar, Dolores Isla
Journal: Journal of Clinical Oncology (2021)

e24065 Background: Malnutrition is one of the most prevalent problems among oncological patients. It reduces the response to treatments and negatively impacts survival. In 2019, a consensus criteria for diagnosing malnutrition (GLIM criteria) were proposed by most scientific nutrition societies. The objective of our work is 1) to assess the diagnostic capacity of the GLIM criteria in ambulatory patients with cancer and 2) to compare the GLIM with the ESPEN criteria to evaluate the contributions of these new criteria with respect to the existing ones. Methods: Observational, cross-sectional, and single-center study carried out at the Medical Oncology Department in the Lozano Blesa Clinical Hospital in Zaragoza (Spain). One hundred and sixty-five outpatients with tumors in the upper gastrointestinal tract, head and neck, and colorectal locations were recruited. All of them received the MST, MUST, and Nutriscore screening tools along with the ESPEN and GLIM diagnostic criteria. Results: The prevalence of malnutrition was 46.7% according to the GLIM criteria and 21.2% using the ESPEN tool. Patients diagnosed by GLIM had a higher body mass index (BMI, 24.3 kg/m 2 ) and muscle mass (MM, 16.1 kg/m 2 ) than those diagnosed by ESPEN (21.2 kg/m² and 14.3 kg/m 2 respectively, both p = 0.001). The MST, MUST, and Nutriscore tools had a higher degree of concordance with GLIM compared to ESPEN (MST 0.53 vs 0.26; MUST 0.36 vs 0.66; Nutriscore 0.28 vs 0.54). Conclusions: The found prevalence of malnutrition in cancer patients is higher using the GLIM instead of ESPEN criteria. This disparity can be explained at least in part by the difficulty of the ESPEN criteria for malnutrition to diagnose patients with high baseline BMI or MM. The use of criteria with greater sensitivity, such as the new GLIM criteria, could help early diagnosis and thus early intervention in cancer patients. [Table: see text]
Genetically-engineered “all-in-one” vaccine platform for cancer immunotherapy
Authors: Aihua Wu, Yingzhi Chen, Hairui Wang, Ya Chang, Meng Zhang, Pengfei Zhao, Yisi Tang, Qin Xu, Zhuangzhi Zhu, Yang Cao, Yongzhuo Huang
Journal: Acta Pharmaceutica Sinica B (2021)

An essential step for cancer vaccination is to break the immunosuppression and elicit a tumor-specific immunity. A major hurdle against cancer therapeutic vaccination is the insufficient immune stimulation of the cancer vaccines and lack of a safe and efficient adjuvant for human use. We discovered a novel cancer immunostimulant, trichosanthin (TCS), that is a clinically used protein drug in China, and developed a well-adaptable protein-engineering method for making recombinant protein vaccines by fusion of an antigenic peptide, TCS, and a cell-penetrating peptide (CPP), termed an "all-in-one" vaccine, for transcutaneous cancer immunization. The TCS adjuvant effect on antigen presentation was investigated and the antitumor immunity of the vaccines was investigated using the different tumor models. The vaccines were prepared via a facile recombinant method. The vaccines induced the maturation of DCs that subsequently primed CD8+ T cells. The TCS-based immunostimulation was associated with the STING pathway. The general applicability of this genetic engineering strategy was demonstrated with various tumor antigens (i.e., legumain and TRP2 antigenic peptides) and tumor models (i.e., colon tumor and melanoma). These findings represent a useful protocol for developing cancer vaccines at low cost and time-saving, and demonstrates the adjuvant application of TCS-an old drug for a new application.
TIVO-3: Age-related tolerability outcomes of tivozanib versus sorafenib in metastatic relapsed or refractory renal cell carcinoma, a subgroup analysis of the TIVO-3 clinical trial.
Authors: Bernard Escudier, Brian I. Rini, Sumanta K. Pal, David F. McDermott, Camillo Porta, Elena Verzoni, Michael B. Atkins, Michael N. Needle, Thomas E. Hutson
Journal: Journal of Clinical Oncology (2021)

e16553 Background: Tivozanib (TIVO) is a potent and selective VEGF receptor (R) tyrosine kinase inhibitor with a long half-life designed to optimize the VEGF blockade while minimizing off-target toxicities. The TIVO-3 trial demonstrated improved progression-free survival (PFS) when compared to sorafenib (SOR; 5.6 mo. vs 3.9 mo., respectively) with a hazard ratio (HR) of 0.73. TIVO showed better tolerability with reduced need for dose interruptions (p = 0.0164) and dose reductions (p = 0.0147) as compared to SOR. Methods: Data was analyzed to identify relationships between and age or prior use of immune checkpoint inhibitors (CPI). Results: Of the 343 patients treated on study, 120 (35%) were between age 65 and 75 and 34 (10%) were over 75. Adverse events were less frequent for TIVO compared to SOR in all age groups and drug exposure was consistently greater in the TIVO arm. Of particular interest, the tolerability advantages noted in the total population are also observed in the patients 75 and over with almost half the rate of the adverse drug reactions leading to dose reduction or discontinuation compared to SOR. Patients treated with prior CPI had an increased need for dose adjustment, but dose adjustments were less common with TIVO than SOR in CPI exposed and naïve patients. Conclusions: Tivozanib was better tolerated than sorafenib regardless of age or prior CPI treatment. Dose adjustments and interruptions are more common after prior CPI. Clinical trial information: NCT02627963. [Table: see text]
Clinical Evidence That Deficiency of the Methylcytosine Dioxygenase TET2 Gene Promotes the Clonal Expansion and Therapeutic Efficacy of CD19-Directed T Cells
Authors: Joseph A Fraietta, Christopher L Nobles, Morgan A Sammons, Shannon A. Carty, Stefan M Lundh, Tyler Reich, Alexandria P Cogdill, Mercy Gohil, Jennifer J.D. Morrissette, Irina Kulikovskaya, Farzana Nazimuddin, Minnal Gupta, Yan Wang, Xiaojun Liu, Regina M Young, David E Ambrose, Martha S Jordan, Katherine T Marcucci, Bruce L Levine, Yangbing Zhao, Michael Kalos, David L Porter, Simon F Lacey, Shelley L Berger, Frederic D Bushman, Carl H June, J. Joseph Melenhorst
Journal: Blood (2017)
Efficacy and safety of the PI3Kδ inhibitor zandelisib (ME-401) on an intermittent schedule (IS) in patients with relapsed/refractory follicular lymphoma (FL) with progression of disease within 24 months of first-line chemoimmunotherapy (POD24).
Authors: John M. Pagel, Nishitha Reddy, Deepa Jagadeesh, Anastasios Stathis, Adam Steven Asch, Huda S. Salman, Vaishalee Padgaonkar Kenkre, Jacob Drobnyk Soumerai, Judith Llorin-Sangalang, Igor Gorbatchevsky, Joanne Li, Andrew David Zelenetz
Journal: Journal of Clinical Oncology (2021)

7550 Background: FL patients (pts) with POD24 have poorer survival and may benefit from novel therapies at relapse. Zandelisib, a potent, selective, and structurally differentiated oral PI3kδ inhibitor was evaluated in a dose escalation/expansion Phase 1b study for FL demonstrating a high objective response rate (ORR) and well tolerated when given on IS (J Clin Oncol 2020;38:#8016). We report here results based on POD24 status (NCT02914938). Methods: Eligible pts had ≥1 prior therapy, adequate bone marrow and organ function, ECOG performance status ≤2, and no prior PI3K therapy. Zandelisib was administered at 60 mg once daily for 8 weeks followed by IS on days 1-7 of each subsequent 28-day cycle, either as monotherapy or with rituximab at 375 mg/m 2 for 8 doses in Cycles 1-6. Treatment was continued until disease progression, intolerance, or withdrawal of consent. Imaging scans were obtained after 2 and 6 cycles, and then every 6 cycles. Response was reported based on Lugano criteria. Results: 37 FL pts were enrolled and received zandelisib on IS as monotherapy (N = 18) or in combination with rituximab (N = 19). Median number of prior therapies = 2 (range, 1-5). The ORR was 86.5% (32/37) with 27% CR (complete response). In the monotherapy group the ORR and CR were 77.8 % (14/18) and 27.8% and with rituximab 94.7% (18/19) and 26.3% respectively. Median duration of response (DOR) among all pts was not reached with a median follow-up of 16.9 months (mos) (1.2-33.1+). 22 pts (59%) were POD24, of which 15 (68%) had ≥2 prior lines of therapy. Despite more refractory disease, ORR among the POD24 pts was 81.8% (Table). Zandelisib on IS was well tolerated. 3 pts (8%) discontinued therapy due to an adverse event (AE) for any cause. Grade (Gr) 3 AE of special interest (AESI) were 2 (5.4%) diarrhea, 2 (5.4%) colitis, 3 (8.1%) rash, 3 (8.1%) ALT elevation, 1 (2.7%) AST elevation and no pulmonary infection. Conclusions: Zandelisib administered on IS as monotherapy or with rituximab resulted in a high-rate of durable responses in FL, both in POD24 and non-POD24 groups and therapy was well-tolerated with low rate of Gr 3 class-related AESI and discontinuation rate due to AE’s. Zandelisib as monotherapy is being evaluated in a global Phase 2 study in FL and MZL after failure of 2 prior therapies (NCT03768505). A Phase 3 study of zandelisib plus rituximab in FL and MZL after failure of prior immunochemotherapy will begin enrollment in 2021. Clinical trial information: NCT02914938. [Table: see text]