tbuckley/cabot-search huggingface dataset:
The impact of body weight and body mass index on outcomes of diffuse large B-cell lymphoma treated with axicabtagene ciloleucel.
Authors: Kitsada Wudhikarn, Radhika Bansal, Arushi Khurana, Matthew Hathcock, N. Nora Bennani, Jonas Paludo, Jose Caetano Villasboas, Yucai Wang, Patrick B. Johnston, Stephen M. Ansell, Yi Lin
Journal: Journal of Clinical Oncology (2021)

e19554 Background: Obesity is associated with a pro-inflammatory state and immune dysregulation. Retrospective studies indicate that obesity could affect toxicities and outcomes after immunotherapies including checkpoint inhibitors and allogeneic stem cell transplant. Currently, there are no data specifically on outcomes for obese patients who receive chimeric antigen receptor T (CAR-T) cells. We described the clinical outcome in obese patients with large B cell lymphoma (LBCL) who received axicabtagene ciloleucel (axi-cel). Methods: We analyzed the effect of body weight (BW) and body mass index (BMI) on toxicities and outcomes of 78 adults with LBCL who received axi-cel between June 2016 and October 2020 at Mayo Clinic. Obesity was defined as having BMI of 30 or higher. Results: Of 78 patients, 22 (28%) and 19 (24%) were classified as overweight (BMI 25-29.99 kg/m 2 ) and obese (BMI ≥30 kg/m 2 ), respectively. Baseline characteristics were not statistically significantly different between non-obese and obese patients. The median delivered dose of fludarabine was similar between non-obese and obese patients (89 [0-105] vs 88 [56-94] mg/m 2 , P=0.32) whereas the median delivered dose of cyclophosphamide was lower in non-obese patients (1503 [1077-1525] vs 1512 [1021-1660] mg/m 2 , P=0.01). The 30-days cumulative incidence of CRS and ICANS were similar between non-obese and obese patients. BW and BMI were not associated with CRS or ICANS. The overall response rate was 66% (CR 47%) and 68% (CR 53%) in non-obese and obese group, respectively ( P=0.83). The 1-year event free survival (EFS) and overall survival (OS) was 34.6% and 64.5%, neither were different between non-obese and obese patients (EFS 35.8% vs. 30.7%, P=0.60; OS 59.4% vs. 83.9%, P=0.18). The 1-year cumulative incidence of relapse and non-relapse mortality was comparable (60.8% vs. 69.0%, P=0.40 and 3.4% vs. 0%, P=0.42). In the Cox proportional hazards model, higher dose of fludarabine, but not cyclophosphamide, was associated with better EFS and OS; however, neither obesity nor BW were associated with toxicities and outcomes. Conclusions: In our study, Obesity was not associated with risk of toxicities or adverse survival outcomes. The effect of obesity on the pattern of LD chemotherapy dosing including toxicities and outcomes after CAR-T warrants further exploration. [Table: see text]
Tolerability of axitinib in advanced renal cell carcinoma: A meta-analysis.
Authors: Bareia Chaudhry, Shenhong Wu
Journal: Journal of Clinical Oncology (2021)

e16536 Background: Axitinib has been used extensively as a single agent or in combination with immunotherapy in the treatment of advanced renal cell carcinoma. It can be often discontinued due to adverse events. A meta-analysis of clinical trials was performed to evaluate the overall tolerability of axitinib in this setting. Methods: PubMed (Up to November 2020) was searched to identify clinical trials of axitinib in advanced or metastatic renal cell carcinoma. Reported data was collected to include axitinib and control discontinuation due to adverse events. A random or fixed effects model was used to determine summary incidences, relative risks, and 95% confidence intervals depending on the heterogeneity of included studies. Results: A total of 11 studies including 4,056 patients (axitinib alone n = 1384, axitinib combination n = 987, control n = 1685) were included for analysis. The summary discontinuation rate for axitinib due to adverse events was 13.4% (95% CI; 11.7-15.2%) with 8.9% (95% CI: 5.3-14.6%) as a single agent and 26.6% (95% CI:17.8 –37.8%) in combination with other agents. In comparison with controls based on randomized controlled studies, axitinib overall has similar discontinuation rate due to adverse events (RR: 1.18, 95% CI: 0.77-1.80). However, there was a significantly higher discontinuation rate with axitinib in combination with other agents including immunotherapeutic agents PD-L1 inhibitors than control treatment (RR: 1.52, 95% CI: 1.24-1.86). Conclusions: The tolerability of axitinib may vary significantly with its use as a single agent or in combination in the treatment of advanced renal cell carcinoma. Further studies are needed to improve its tolerability as a part of combination therapy.
Camrelizumab plus apatinib combined with TACE and cryoablation in the first-line treatment of advanced hepatocellular carcinoma.
Authors: Wenge Xing, Zhi Guo
Journal: Journal of Clinical Oncology (2021)

TPS4160 Background: Hepatocellular carcinoma (HCC) is a common cancer in the world, a leading cause of cancer-related death, and especially in China. Most of the HCC patients are diagnosed at an advanced stage and require a multidisciplinary approach. The IMbrave 50 trial has reported the successful efficacy of atezolizumab and bevacizumab combination therapy in advanced hepatocellular carcinoma, which indicate the potential efficacy of combination of immunotherapy and antiangiogenesis therapy in HCC patients. In some studies, the combinatorial approaches with immunotherapy and liver directed therapies such as transarterial chemoembolization (TACE), radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation are explored. Most combined interventional therapies reveal their enormous advantages as compared with any single therapeutic regimen alone, which may result from the immunologic enhancement effect of the multimodel therapy. In this study, we evaluated the efficacy and safety of combined therapy with camrelizumab plus apatinib mesylate and TACE plus cryoablation in patients with advanced HCC. Methods: This study was an open-label, single-arm, single centre, phase 2 trial in patients who were diagnosed with advanced HCC. Patients who meet the following criterias will be enrolled: (1) 18 - 75 years old; (2) Child-Pugh classification A or B(≤7);(3) Barcelona Clinic Liver Cancer stage B or C, or China liver cancer staging (CNLC) stage IIb̃IIIa; (4) Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0–1; (5) no history of previous systematic treatment; (6) expected life expectancy of more than 12 weeks; (7) adequate organs function. The key exclusion criteria were history of active autoimmune disease, or concurrent medical use of immunosuppressive medications or immunosuppressive doses of systemic corticosteroids. Eligible patients received camrelizumab 200 mg intravenously every 2 weeks and apatinib 250 mg orally once per day continuously in a treatment cycle of 4 weeks, treatment continued until 1 year or development of unacceptable toxicity or progression of disease. TACE was administrated at the first treatment cycles on day 1or 2, the chemotherapy regimens included 100-150mg oxaliplatin, 750-1000mg fluorouracil, or 30-50 mg lobaplatin, raltitrexed 2-4mg, and epirubicin 40-80 mg. Two or three weeks after the TACE, percutaneous cryoablation was performed under CT guidance. TACE and cryoablation was given as combination therapy and the periods were assessed by the investigator. The primary endpoint is objective response rate (complete or partial response according to mRECIST) and Progression-Free-Survival (Time ranges from random to the first occurrence of disease progression or death from any cause). This trial is registered with Chinese Clinical Trials Registry, ChiCTR2100043044, and is ongoing. Clinical trial information: ChiCTR2100043044.
Triptolide: pharmacological spectrum, biosynthesis, chemical synthesis and derivatives
Authors: Jie Gao, Yifeng Zhang, Xihong Liu, Xiayi Wu, Luqi Huang, Wei Gao
Journal: Theranostics (2021)

Triptolide, an abietane-type diterpenoid isolated from Tripterygium wilfordii Hook. F., has significant pharmacological activity. Research results show that triptolide has obvious inhibitory effects on many solid tumors. Therefore, triptolide has become one of the lead compounds candidates for being the next "blockbuster" drug, and multiple triptolide derivatives have entered clinical research. An increasing number of researchers have developed triptolide synthesis methods to meet the clinical need. To provide new ideas for researchers in different disciplines and connect different disciplines with researchers aiming to solve scientific problems more efficiently, this article reviews the research progress made with analyzes of triptolide pharmacological activity, biosynthetic pathways, and chemical synthesis pathways and reported in toxicological and clinical studies of derivatives over the past 20 years, which have laid the foundation for subsequent researchers to study triptolide in many ways.
Targeting immunodominant Bet v 1 epitopes with monoclonal antibodies prevents the birch allergic response
Authors: Amanda Atanasio, Matthew C. Franklin, Vishal Kamat, Annabel Romero Hernandez, Ashok Badithe, Li-Hong Ben, Jennifer Jones, Joannie Bautista, George D. Yancopoulos, William Olson, Andrew J. Murphy, Matthew A. Sleeman, Jamie M. Orengo
Journal: Journal of Allergy and Clinical Immunology (2021)
Impact of medical mistrust (MM) on perceptions of tumor genomic profiling (TGP) among African American (AA) cancer patients: Application of perceptual mapping (PM).
Authors: Michael J. Hall, Paul D'Avanzo, Yana Chertock, Jesse A Brajuha, Sarah Bauerle Bass
Journal: Journal of Clinical Oncology (2021)

e22527 Background: TGP is widely used to identify targetable mutations for precision cancer treatment and clinical trials. Many patients have poor understanding of TGP and are unaware of possible secondary hereditary risks. Lack of clarity regarding the relevance of informed consent and genetic counseling further magnify risks for patients. AA patients have lower genetic knowledge and health literacy and higher MM than Caucasian patients, making them especially vulnerable in the clinical setting. Perceptions of TGP in AA cancer patients have not been well-characterized. Methods: 120 AA pts from 1 suburban and 1 urban site (Fox Chase Cancer Center[FCCC] and Temple University Hospital[TUH]) were surveyed. A k-means cluster analysis using a modified MM scale was conducted; chi-square analysis assessed demographic differences. Perceptual mapping (PM)/multidimensional scaling and vector modeling was used to create 3-dimensional maps to study how TGP barriers/facilitators differed by MM group and how message strategies for communicating about TGP may also differ. Results: Data from 112 analyzable patients from FCCC (55%) and TUH (45%) were parsed into less MM (MM-L, n = 42, 37.5%) and more MM (MM-H, n = 70, 72.5%) clusters. MM-L and MM-H clusters were demographically indistinct with no significant associations by sex (p = 0.49), education (p = 0.3), income (p = 0.65), or location (p = 0.43); only age was significant (older = higher MM, p = 0.006). Patients in the MM-H cluster reported higher concerns about TGP, including cost (p &lt; 0.001), insurance discrimination (p &lt; 0.001), privacy breaches (p = 0.001), test performance/accuracy (p = 0.001), secondary gain by providers (p &lt; 0.001) and provider ability to explain results (p = 0.04). Perceptual mapping identified both shared and contrasting barriers between MM clusters (Table). Conclusions: More than 2/3 of AA patients comprised a MM-H cluster. Communication strategies should focus on concerns about family and how to discuss TGP with an oncologist. PM can identify distinct and shared information needs of vulnerable populations undergoing TGP. [Table: see text]
Racial/ethnic disparities in oropharyngeal cancer outcomes among males in the United States (2005-2016): A population-based retrospective cohort study.
Authors: Seiichi Villalona, Antoinette Stroup, Satsuki Villalona, Jeanne Ferrante
Journal: Journal of Clinical Oncology (2021)

e18576 Background: The incidence of male oropharyngeal cancers (OPCa) has increased rapidly during the past two decades in the United States. Little is known regarding differences in OPCa incidence and outcomes by race/ethnicity and human papillomavirus (HPV) status. Methods: Population-based retrospective cohort study of 175,843 males diagnosed in U.S. with OPCa from 2005-2016 in the North American Association of Central Cancer Registries. Outcomes included: incidence trends of OPCa by race/ethnicity [Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Hispanic, Other] and histology-based HPV status; late-stage diagnosis; 5-year cumulative and mean survival; and mortality (cause-specific, all cause). Results: The majority of male OPCa were HPV-related (92.2%) and in NHW (83.6%), with marked increase in late-stage HPV-related OPCa among NHW. No difference in late-stage diagnosis was observed between NHW, NHB (aOR, 0.99, 95% CI, 0.94-1.04), and Hispanics (aOR, 0.98, 95% CI, 0.92-1.04), while other race had lower odds of late-stage diagnosis (aOR 0.87, 95% CI, 0.79-1.01). HPV-related cancers (aOR, 3.47, 95% CI, 3.33-3.62), Medicaid (aOR, 1.37, 95% CI, 1.28-1.46) and no insurance (aOR, 1.44, 95% CI, 1.32-1.56) were independent predictors of late-stage diagnosis. NHB (69.72 months, 95% CI, 68.14-71.31) and Hispanics (91.89 months, 95% CI, 89.87-93.91) had lower unadjusted mean survival in HPV-related OPCa relative to NHW (99.63 months, 95% CI, 99.18-100.07; p &lt; 0.01). Higher cancer-specific mortality was observed among NHB (aHR, 1.79, 95% CI, 1.71-1.86), Hispanics (aHR, 1.07, 95% CI, 1.01-1.14), HPV-related OPCa (aHR, 1.17, 95% CI, 1.11-1.24), age &gt; 54 years, insurances other than private, residence in counties with higher poverty, and geographic regions other than the Northeast. Adjusting for treatment attenuated associations but did not eliminate the observed cancer-specific mortality, except in Hispanics and residence in the South. Conclusions: There has been a sharp increase in HPV-related late-stage OPCa among NHW males over the past decade. Despite no racial/ethnic differences in late-stage diagnosis, NHB had highest mortality that was not explained by treatment. HPV vaccination and possibly, oral cancer screening should be promoted, especially in NHW males. Further research is needed to elucidate comorbidities and possible biologic mechanisms responsible for the higher OPCa mortality among NHB males.
Nano-hydroxyapatite accelerates vascular calcification via lysosome impairment and autophagy dysfunction in smooth muscle cells
Authors: Qi Liu, Yi Luo, Yun Zhao, Pingping Xiang, Jinyun Zhu, Wangwei Jing, Wenjing Jin, Mingyao Chen, Ruikang Tang, Hong Yu
Journal: Bioactive Materials (2021)

Vascular calcification (VC) is a common characteristic of aging, diabetes, chronic renal failure, and atherosclerosis. The basic component of VC is hydroxyapatite (HAp). Nano-sized HAp (nHAp) has been identified to play an essential role in the development of pathological calcification of vasculature. However, whether nHAp can induce calcification in vivo and the mechanism of nHAp in the progression of VC remains unclear. We discovered that nHAp existed both in vascular smooth muscle cells (VSMCs) and their extracellular matrix (ECM) in the calcified arteries from patients. Synthetic nHAp had similar morphological and chemical properties as natural nHAp recovered from calcified artery. nHAp stimulated osteogenic differentiation and accelerated mineralization of VSMCs in vitro. Synthetic nHAp could also directly induce VC in vivo. Mechanistically, nHAp was internalized into lysosome, which impaired lysosome vacuolar H+-ATPase for its acidification, therefore blocked autophagic flux in VSMCs. Lysosomal re-acidification by cyclic-3′,5′-adenosine monophosphate (cAMP) significantly enhanced autophagic degradation and attenuated nHAp-induced calcification. The accumulated autophagosomes and autolysosomes were converted into calcium-containing exosomes which were secreted into ECM and accelerated vascular calcium deposit. Inhibition of exosome release in VSMCs decreased calcium deposition. Altogether, our results demonstrated a repressive effect of nHAp on lysosomal acidification, which inhibited autophagic degradation and promoted a conversion of the accumulated autophagic vacuoles into exosomes that were loaded with undissolved nHAp, Ca2+, Pi and ALP. These exosomes bud off the plasma membrane, deposit within ECM, and form calcium nodules. Vascular calcification was thus accelerated by nHAP through blockage of autophagic flux in VSMCs.
Spectrum of <i>BRAF</i> mutations in Indian patients with NSCLC: A molecular kaleidoscope.
Authors: Mansi Sharma, Shrinidhi Nathany, Satyajeet Soni, Arpit Jain, Anurag Mehta, Parveen Jain, Ullas Batra
Journal: Journal of Clinical Oncology (2021)

e21199 Background: Mutations in the BRAF gene (0.8%-8% cases of NSCLC) comprise a molecularly heterogeneous group, with the canonical V600E mutation as well as myriad variants. Traditionally, diagnostics utilize modalities like mutation specific IHC or allele specific real-time PCR for detection of V600E variant and may underestimate the true prevalence of non-V600E variants. Broader panel next generation sequencing (NGS) testing may be a better modality for detecting them and this may have potential therapeutic implications. This retrospective study of patients with BRAF mutated NSCLC looked at their molecular and clinicopathologic spectrum. Methods: 260 patients underwent panel based NGS testing between 2017-2020. BRAF mutant cases, detected at any point during the course of their disease, were reviewed for clinical, pathologic, molecular features; as well as associated treatment and outcomes. Results: BRAF alterations were seen in 14/260 (5.38%) patients. Median age of the cohort was 62 years (range: 39-86 years) with a female predilection (8/14, 57.1%). BRAF V600E mutation was seen in 6 (42.9%) patients and 8 (57.1%) harbored a non-V600E alteration; the spectrum of which included G466E, G469A, N581I, V600_K601delins, D594G, L597Q, G649V and a TRIM24-BRAF fusion. All patients were never smokers with an adenocarcinoma histology.11 (78.6%) patients had extra thoracic metastases, and 2 (14.3%) cases had metastases to the brain at diagnosis. 11/14 (78.6%) patients had presence of liver metastases (V600E vs non V600E: 43% vs 57%, p = 0.09). 11 patients took treatment at our centre and two patients received anti-BRAF therapy. One patient with V600E mutation received vemurafenib. The other patient with a nonV600E mutation (V600_601delins, detected on NGS) received combination dabrafenib-trametinib with an ongoing partial response at 6 months. 8 patients received chemotherapy and median PFS was 4.8 months, similar for all mutation types. Median OS for the entire cohort was not reached owing to high censorship. Conclusions: This single centre study depicts distinct clinicopathologic features in Indian patients with BRAF mutant NSCLC. The higher prevalence of non-V600E mutation may be attributed to increased use of broader panel based NGS testing as opposed to sequential single gene testing. One of the patients with a non-V600E mutation responded to targeted therapy, hence clinicians should be aware of this spectrum of potentially targetable BRAF mutations.
Phase I study of H3B-6527 in hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC).
Authors: Teresa Macarulla, Victor Moreno, Li-Tzong Chen, Michael B. Sawyer, Lipika Goyal, Andres J. Muñoz Martín, Yang Sheng-Shun, Samuel Le Sourd, John Morris, Michael Fuchs, Thomas Benjamin Karasic, Yoon-Koo Kang, Wei-Peng Yong, Anand Selvaraj, Benoit Destenaves, Jianjun Alan Xiao, Ronald Gomez, Antonio Gualberto, J. Marc Marc Pipas, Richard S. Finn
Journal: Journal of Clinical Oncology (2021)

4090 Background: Evidence suggests that hyperactivated fibroblast growth factor 4 (FGFR4) signaling pathway leads to enhanced tumor growth. Targeting FGFR4 may have therapeutic benefit in tumors with altered FGF19 signaling. A phase I study (NCT02834780) was undertaken to assess H3B-6527, a highly selective covalent FGFR4 inhibitor, in patients with HCC/ICC. Methods: Adults with advanced HCC/ICC, ECOG PS 0-1, well compensated liver function, who progressed after &gt; one prior therapy, received H3B-6527 po daily (QD) or twice-daily (bid) on a 21-day cycle following a 3+3 design. Doses ranged from 300-2000mg QD or 500-700mg BID. Patients in dose escalation were treated regardless of FGF19 status. Patients in expansion had FGF19+ tumors by mRNA testing. Adverse events (AEs), and pharmacokinetics (PK) were assessed. Response was determined by RECIST 1.1/mRECIST imaging every 6 weeks. Results: Study enrollment is complete at 128 patients. Ninety HCC patients were treated (QD = 48, bid = 42). ICC enrollment was suspended after 38 patients due to limited efficacy. No dose-limiting toxicities were seen and no grade 4-5 treatment related AEs have been observed. Recommended Phase II dose for H3B-6527 is 1000mg QD based upon safety, efficacy, and PK data. Grade 3 TEAEs have occurred in 12.5% of patients on QD dosing. Treatment related TEAEs were seen in 62.5% of patients on the QD schedule, with diarrhea (45.8%), fatigue (12.5%), and nausea (12.5%) most frequent. Drug discontinuation due to AEs for QD dosing was 8.3%. Interim data analysis shows that, for HCC patients with &gt;2 prior lines of therapy treated on QD schedule, overall survival was 10.6m, progression-free survival 4.1m, overall response rate 16.7% (all partial responses), and clinical benefit rate 45.8% (responders + durable stable disease &gt;17 weeks). H3B-6527 Cmax and AUC were lower at 300 mg dose but then similar across 500–2000 mg doses. Following oral administration of 1000 mg fasted, H3B-6527 plasma concentration reached peak at a Tmax of ̃2-3 hours and then decayed exponentially, with terminal half-life of ̃4-5 hours. There was no accumulation following QD dose. Dosing with food did not meaningfully change H3B-6527 plasma exposure. Conclusions: H3B-6527 was well tolerated and demonstrated a favorable toxicity and safety profile and encouraging clinical activity in heavily pretreated HCC patients. Final trial results will be presented at conference. Clinical trial information: NCT02834780.