bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bruton's tyrosine kinase inhibitor zanubrutinib-based regimens in relapsed/refractory primary diffuse large B-cell lymphoma of central nervous system.
Authors: Wang Yali , Chen Feng , Li Wenbin 
Published: August 2024

30 Background: Patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) usually have a poor prognosis. Ibrutinib-based regimens revealed promising efficacy but showed off-target effects and drug resistance in some cases. Here, we conducted a retrospective study to evaluate the efficacy and safety of regimens based on second-generation bruton's tyrosine kinase (BTK) inhibitor zanubrutinib in R/R PCNSL. Methods: We respectively reviewed 23 patients with R/R PCNSL treated with zanubrutinib in our center from Apr. 2021 to Jan. 2024. The primary end points were overall response rate (ORR) and progression-free survival (PFS). Secondary end points included complete response rate (CRR), disease control rate (DCR), overall survival (OS) and adverse events (AEs). Response was assessed according to International Primary CNS Lymphoma Collaborative Group criteria. The severity of AEs was graded using the NCI Common Toxicity Criteria, version 5.0. Validated next-generation sequencing (NGS) panels were used to analyze the mutational status of the BCR pathway genes or other solid tumor-related genes. Results: The median follow-up at the cutoff date (15 Jan 2024) was 17.0 months (range, 2-33 months). The ORR, CRR and DCR were 78.3%, 39.1% and 91.3%. The median PFS was 31.0 months, but the median OS was not reached. Compared to germinal center B-cell like (GCB) group, non-GCB group showed a better ORR (76.9% vs 66.7%) and CRR (46.2% VS 33.3%). Multivariate analysis revealed that overall response (vs. no response, HR=0.20, P=0.027), long duration of zanubrutinib (≥6months vs. 2-5 months, HR=0.07, P=0.009) and refractory disease status (vs. relapse disease status, HR=0.12, P=0.014) were independent factors for longer PFS. The most commonly mutated genes are MYD88(15/17,88.2%), PIM1(9/17 52.9%), CD79B (8/17,47.1%), ETV6(7/17,41.2%), BTG1(5/17,29.4%) and GNA13(5/17,29.41%). The mutational status of MYD88/CD79B did not lead to any difference in PFS and OS. We obtained the Tumor Mutational Burden (TMB) information from 11 patients. The median TMB was 15.96 (range: 3.82-28.11) muts/Mb. Kaplan-Meier analysis demonstrated that PFS was significantly longer in patients with higher TMB (≥15.96 muts/Mb) after zanubrutinib-based treatment(P=0.005). Grade ≥3 and serious treatment-emergent AEs (TEAEs) were not found. The most commonly TEAEs were hematologic toxicity (8/23,34.8%) and skin rash (5/23,21.7%). Conclusions: Our study demonstrates that zanubrutinib-based therapy is effective and safe for the treatment of R/R PCNSL. We advocate for the prolonged administration of zanubrutinib to maintain treatment response. Patients with higher TMB derive greater benefits from zanubrutinib-based regimens.
Efficacy of combination of immune checkpoint inhibitors, chemotherapy, and targeted therapy in advanced/refractory cancer.
Authors: Salem Philip A. , Gensini Lorenzo , McCallum William G.B. , Hanna John , Wheeler Thomas M. , Stenoien Randall A. , Jabboury Khaled W. 
Published: August 2024

41 Background: The treatment of advanced/refractory malignancies continues to pose a major challenge, and it is associated with poor outcome. It has been shown that in some cancers, the combination of chemotherapy (CT) with immune checkpoint inhibitors (ICIs), or CT with targeted therapy (TT), are superior to chemotherapy alone. Consequently, in our treatment program (ICTriplex), TT was added to CT plus ICIs. These three modalities have convergent efficacy with divergent toxicity. Our prior data were previously reported (1-3). Methods: Treatment with ICTriplex was highly personalized and was tailored to the individual patient and their specific cancer. It was designed based on diagnosis, prior therapy, and genomic profiling. Between March 2017 and January 2024, 56 patients (pts) with advanced malignancies were treated: 31 females and 25 males, with a median age of 58. Tumor types included: lung (12), pancreas (8), colorectal (8), biliary tract (5), breast (4), stomach (4), melanoma (3), ovary (3), sarcoma (3), cervix (2), glioblastoma (2), Hodgkin’s (1), and thymoma (1). 43 pts received prior therapy: 14 received ICIs, 23 TT, and 42 CT. The agents used in ICTriplex were: 6 ICIs primarily nivolumab and pembrolizumab, 12 CT primarily taxanes, gemcitabine, and platinum, and 23 TT, primarily bevacizumab and erlotinib. Response was evaluated by both PET/CT and CT scans. A complete remission was achieved when metabolic activity completely resolved on PET/CT. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier estimator. Results: The overall response rate (ORR) was 88%. A complete remission (CR) occurred in 29 pts (52%), and a partial remission (PR) in 20 pts (36%). Of the 12 pts with lung cancer, 9 (75%) achieved CR and of these, 4 pts had brain metastases that completely resolved without radiation. Of the 8 pts with pancreatic cancer, 4 (50%) achieved CR. 4 of 5 pts with biliary tract cancer achieved CR. Toxicity was reasonable in all pts except for 3 who died from complications possibly related to ICIs. The median PFS was 11 months, and the median OS was 15 months. The achievement of CR and the PD-L1 + status, resulted in a statistically significant better PFS (p= 0.00; p= 0.02) and OS (p=0.00; p= 0.005). Patients with lung cancer showed a better PFS (p= 0.02) with the median at 19 months, and the median OS was 36 months. Potential predictors of unfavorable prognosis, such as receiving prior treatment, did not impact patients' clinical outcome. Conclusions: ICTriplex is a very effective treatment for advanced cancer that has become resistant to conventional therapy or with no available standard therapy. We strongly recommend this therapeutic approach for the treatment of such patients. 1. ASCO 2019 (e14254) 2. ASCO 2020 (e15150) 3. ASCO 2022 (e14590).
Targeted degradation of undruggable proteins using a novel heterobifunctional proteomimetic platform.
Authors: Wang Max Mu 
Published: August 2024

47 Background: Of the ~20,000 proteins in the human genome, only a subset can be modulated via traditional pharmacological approaches. “Undruggable” targets currently include proteins with pivotal roles in cancer pathogenesis. Our work aims to introduce a new paradigm for engaging these clinically relevant proteins using a modular platform we term the HYbrid DegRAding Copolymers (HYDRACs). HYDRACs multiplex targeting warheads with degradation inducers and have long circulation times plus high cell uptake. Preliminary studies on MYC and RAS, targets of great pharmaceutical interest, highlight the potential of this platform to revolutionize drug design. Methods: HYDRACs containing MYC or RAS targeting peptides randomly copolymerized with degrons were synthesized using ROMP. Fluorescent and biotin-tags were incorporated for use in uptake and pull-down assays. Viability following treatment with MYC-HYDRACs was performed in multiple cell lines with both cellular (MYC-independent lines) and polymer composition controls. Target engagement was assessed via immunoprecipitation and circular dichroism with protein degradation monitored by WB. Unbiased whole proteome analysis and RNAseq were done to confirm observed effects were selectively on-target. In vivo efficacy and biodistribution was assessed in tumor-bearing mice. Results: HYDRACs show high levels of cell uptake and antiproliferative effects at sub-micromolar concentrations in a formulation- and target-dependent manner. Cells treated with MYC-HYDRACs displayed reduced MYC protein levels, which were rescued by proteasome or neddylation inhibition. Swapping out the degron for various validated E3 ligase recruiters maintained MYC degradation, highlighting the “plug-and-play” nature of this approach. On-target activity was confirmed via RNAseq. Biophysical analysis showed strong HYDRAC-protein interactions, orthogonally supported by the presence of target protein following pull-down of biotin-terminated HYDRACs. Target protein degradation only occurred following treatment with an intact HYDRAC compound. Mice bearing MYC-CaP tumors showed delayed tumor growth following treatment with MYC-HYDRACs, with compound accumulation in the tumor for up to 72 h following a single injection. Generalizability was demonstrated against RAS, with RAS-HYDRACs capable of degrading KRAS across multiple different alleles, acting as a pan-KRAS degrader. Conclusions: We present a novel platform technology that addresses the challenges inherent to peptide delivery approaches. HYDRACs have the potential to dramatically alter the drug discovery landscape, allowing for the development of cancer-relevant target modulators for which there are no current viable therapies. We envision the HYDRAC platform as a generalizable approach to designing degraders of proteins of interest, greatly expanding the therapeutic armamentarium for TPD.
Multiinstitutional cohort study of patient outcomes in Child-Pugh (CP) B liver function treated with atezolizumab plus bevacizumab (A+B) for hepatocellular carcinoma (HCC).
Authors: Mahipal Amit , Zemla Tyler J. , Patell Kanchi , Naleid Nikolas , Gile Jennifer , Jin Zhaohui , Tran Nguyen H. , Borad Mitesh , Chakrabarti Sakti , Storandt Michael H. 
Published: August 2024

50 Background: A+B is commonly used as first line systemic therapy in HCC patients with CP-B liver function, although in the IMbrave150 clinical trial, its efficacy was only assessed in patients with CP-A liver function. We evaluated outcomes in patients with CP-B liver function and compared to those with CP-A. Methods: We completed a multi-institution, retrospective review of patients with HCC from Mayo Clinic and University Hospitals Seidman Cancer Center, who had received A+B in the first line setting between March 2018 and November 2023. CP score was calculated at time of treatment, response was assessed, and progression free (PFS) and overall (OS) survival were determined using the Kaplan Meier method. Results: Among 322 patients with HCC, median age was 66.5 years, 78.6% were male, and 82.6% were white. Eighty-six patients (27%) had CP-B liver function, while 226 (70%) had CP-A and 10 (3%) had CP-C. Etiology of liver disease in patients with CP-B included hepatitis B in 7.0%, hepatitis C in 38.4%, alcohol use in 30.2%, and metabolic associated steatohepatitis in 20.9%. Median OS in patients with CP-B liver function was 6.4 months, while mOS was 21.6 months for those with CP-A ( p<0.0001). Further stratifying, mOS in those with CP-B7 was 9.1 months, CP-B8 was 5.5 months, and CP-B9 was 4.0 months. 12-month OS in patients with CP-B was 32.4%, compared to 69.3% in CP-A. Median PFS was 4.8 months in those with CP-B and 8.9 months in those with CP-A. Median PFS in those with CP-B7, -B8, and -B9 was 6.4 months, 2.7 months, and 2.7 months, respectively. Among those with CP-B, 1 patient had a complete response, 17 (19.8%) had a partial response, 29 (33.7%) had stable disease, and 37 (43.0%) had progressive disease. Adverse events in CP-B patients included hypertension in 14.0% (grade 3 in 1 patient), bleeding in 16.3% (grade 3 or greater in 11.6%), fatigue in 38.4%, and an immune-related adverse event in 17.4% (grade 3 in 5.8%). Conclusions: Patients with advanced HCC and CP-B7 liver function may still benefit from A+B. Importantly, no additional safety risks were identified in this subgroup. Those with CP-B8 and CP-B9 have significantly worse survival than those with CP-B7 and the likelihood of benefit from systemic therapy is minimal. It is important for providers to address the impact of baseline liver function on expected outcomes in patient with HCC.
Cryoablation versus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma with lenvatinib from a real-world study.
Authors: Chang Xiujuan , Wang Di , Zhang Wei , Huang Jiagan , Zeng Zhen 
Published: August 2024

54 Background: Hepatocellular carcinoma (HCC) is characterized by hypovascularity, the efficacy of transcatheter arterial chemoembolization (TACE) has been suboptimal. This study sought to evaluate and compare the efficacy and safety profiles of cryoablation (CRYO) plus lenvatinib (LEN) against TACE plus LEN for unresectable hepatocellular carcinoma (u-HCC) patients within a real-world clinical practice. Methods: A prospective study was conducted involving 234 patients with u-HCC who underwent treatment with LEN plus either CRYO or TACE at the Fifth Medical Center of the Chinese PLA General Hospital from October 2018 to May 2023. Treatment selection was determined through multidisciplinary discussions among a liver cancer board, weighing the pros and cons. The final decision was made by the patients and clinicians based on consensus. Clinical characteristics were balanced using propensity score matching (PSM). The primary endpoint was overall survival (OS), while secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Tumor response was based on RECIST v1.1 and mRECIST by blinded independent imaging review, AEs by CTCAE v5.0. Results: In this study, 212 (90.6%) were male, with an average age of 56 years. 206 (88%) patients were infected with hepatitis B virus (HBV), and 178 (76.1%) and 77 (32.9%) patients were classified as Child-Pugh A and BCLC B. After PSM, the clinical characteristics were comparable between the CRYO plus LEN and the TACE plus LEN group. Over a median follow-up of 31.8 months, 124 patients (53%) died. The CRYO plus LEN group demonstrated similar OS (24.2 vs. 22.0 months, P = 0.64), PFS (8.7 vs. 11.9 months, P = 0.48), ORR (53.1% vs. 53.1%, P = 1.00), and DCR (86.5% vs. 78.1%, P = 0.19) compared to the TACE plus LEN group after PSM, with consistent results observed before PSM. The two groups exhibited comparable AEs. In addition to similar LEN-related AEs, the most common CRYO-related AEs included 50% elevated ALT, 50% elevated AST, and 38.5% fever, which were consistent with the TACE related AEs. Notably, the incidence of abdominal pain was higher in the TACE plus LEN group compared to the CRYO plus LEN group (7.5% vs. 0.8%, P = 0.021), while pleural effusion was more prevalent in the CRYO plus LEN group than that in the TACE plus LEN group (6.2% vs. 0, P = 0.038). Conclusions: The CRYO plus LEN group exhibited comparable efficacy and well-tolerated safety with TACE plus LEN for u-HCC patients within a real-world clinical setting. It offers a viable alternative for HCC characterized by hypovascularity, presenting a promising therapeutic approach in the clinical management of u-HCC. Clinical trial information: ChiCTR2200058643 .
Clinical determinants of survival in patients with stage II-III pancreatic cancer.
Authors: Itakura Haruka , Xu Qinmei , Toesca Diego , Vitzthum Lucas , Jamalian Arash , Schueler Emil , Alkim Emel , Baclay J Richelcyn , Chang Daniel Tandel , Fisher George A. 
Published: August 2024

56 Background: We sought to identify the clinical determinants of overall survival (OS) in patients diagnosed with stage II-III pancreatic cancer not undergoing surgery. We curated a relatively homogenous cohort of patients who did not undergo surgical resection, but instead underwent chemotherapy in sequence with stereotactic body radiation therapy (SBRT) to examine the features that differentiated those with poor OS. Methods: In a retrospective study, we examined a cohort of 259 patients with stage II-III pancreatic cancer who underwent chemotherapy in sequence with SBRT without surgery at a single institution (Stanford Health Care). We conducted both univariate and multivariate Cox regression analyses to assess the relationships between OS and individual clinical and tumoral variables, including: age, sex, stage, Karnofsky performance status (KPS), body mass index, vessel involvement, tumor location, and biological equivalent dose [BED] of SBRT as potential determinants. Results: The study cohort consisted of 136 men (52.5%) and 123 women (47.5%) with a median age of 69 (range 38-94). Tumor histology was predominantly ductal adenocarcinoma (n=249, 96.1%), with tumor sites of involvement spanning: uncinate (n=35, 13.5%), head (n=160, 61.8%), body (n=59, 22.8%), and tail (n=5,1.9%). More patients had stage III (n=171, 66%) than stage II (n=88, 34%) disease, and their tumor resectability by NCCN criteria were rated as: unresectable (n=145, 56%), borderline (n=28, 10.8%), resectable (n=11, 4.2%), or unrecorded (n=75, 29%). Tumor progression was observed in local (n=71, 27.4%), regional (n=29, 11.2%), and distant (n=150, 57.9%) sites during the median follow up period of 17 months (range 15-18 months) from diagnosis and 12 months (10-13 months) from SBRT. Death (n=213, 82.2%) during this period was more common than survival (n=46, 17.8%). In univariate analyses, clinical features impacting OS included: KPS (hazard ratio [HR] 0.14, p=0.007); male sex (HR 1.44, p=0.01), pancreatic head tumors (HR 1.44, p=0.011), BED (HR 1.33, p=0.035), and age (HR 1.013, p=0.044). In the multivariate analysis, which incorporated only features significant in the univariate analyses, tumor location at the pancreatic head (HR 1.412, p=0.021) and male sex (HR 1.360, p=0.03) conferred the highest risks for poor OS, with BED bordering on significance (p=0.059) (Table). Conclusions: Among patients with stage II-III pancreatic cancer who underwent chemotherapy in sequence with SBRT, but not surgery, the most significant clinical determinants of poor OS were location of the tumor in the pancreatic head and male sex. Prioritizing additional disease monitoring and alternative therapies for this subset of patients at higher risk of poor survival may be warranted. [Table: see text]
Effect of impaired autophagic flux on breast carcinogenesis through the enhanced LC3-p62-NRF2 feedback loop.
Authors: Aftab Mehreen , Waidha Kamran , Gopas Jacob , Hussain Showket 
Published: August 2024

6 Background: Breast cancer affects more women worldwide than any other type of cancer. Although some genes have been identified as potential causes, the exact molecular mechanism of the disease is still unknown. In our study, we aimed to investigate the role of NRF2 and the autophagy markers p62 and LC3 in breast cancer cell lines that have different Tp53 status using a new compound called 6,6'dihydroxythiobinupharidine (DTBN). In our previous research, we have shown that DTBN modulates key cellular signal transduction pathways that are relevant to disease biology, including cancer. Furthermore, we analyzed online databases to determine the correlation between NRF2, p62, LC3, and Tp53 in breast cancer patients. Methods: To evaluate the effect of DTBN on NRF2, p62 and LC3 in different types of breast cancer cell lines with varying TP53 status, we conducted molecular studies by inhibiting NRF2 activity. We synthesized the correlation between NRF2, p62, LC3 and TP53 expression and clinical parameters by analyzing TCGA and GEO datasets. Results: Our findings suggest that DTBN induces cell death and autophagy in all breast cancer cell lines, regardless of their Tp53 status. However, they also led us to hypothesize that NRF2 may hinder the sensitivity of cancer cells to DTBN-induced cell death and autophagy. To test this hypothesis, we inhibited NRF2 activity using an NRF2 inhibitor called brusatol. The results of the study indicate that the inhibition of NRF2 significantly increased cell death and autophagy in DTBN-treated cells. We observed a decrease in the expression of the autophagy marker p62, while an increase in the expression of another autophagy marker LC3. These findings suggest that the interaction between NRF2, LC3 and p62, which is activated in response to DTBN treatment, may serve as a potential anticancer drug target. We have validated the positive correlation between NRF2 and the autophagic gene p62 and LC3, in different Tp53 status breast cancer cell lines by analyzing TCGA and GEO data. Conclusions: Our study shows that high levels of Nrf2, LC3 and p62 expression are significantly associated with increased breast cancer cell proliferation and migration. This implies that patients with breast cancer have lower overall survival and a higher rate of recurrence. Our findings highlight the role of DTBN-induced NRF2 and LC3 expression and reduced p62 expression in breast cancer cells with varying Tp53 status. These results may represent a paradigm for better understanding the cancer cell response to therapies and designing more efficient combined anticancer therapies targeting NRF2, LC3 p62, and Tp53.
68Ga-FAPI-04 positron emission tomography/computed tomography (PET/CT) for detecting occult peritoneal metastasis in locally advanced gastric cancer: A single-center prospective cohort study.
Authors: Hu Qiancheng , Zhang Shunyu , Su Ming Gang , Yang Kun , Gou Hongfeng , Hu Jiankun 
Published: August 2024

61 Background: Occult peritoneal metastasis (OPM) is a common finding in patients diagnosed with advanced gastric cancer. Preoperative diagnosis of OPM is crucial for developing treatment strategies and for evaluating the prognosis of patients with locally advanced gastric cancer. To evaluate the accuracy of 68Ga-FAPI-04 PET/CT in diagnosing OPM in locally advanced gastric cancer. Methods: This was a prospective, observational, single-center, single-blind, cohort study. Patients with histologically proven locally advanced gastric or gastroesophageal junction adenocarcinoma on initial staging evaluation were recruited. Laparoscopic staging and cytological analysis of peritoneal washing served as reference standards for the final diagnosis. The primary outcome was the proportion of participants changing treatment strategy from curative to palliative treatment. Results: A total of 49 patients were recruited between November 2022 and July 2023 . Nine of the 49 patients were diagnosed with OPM following 68Ga-FAPI-04 PET/CT examinations. A total of 18.4% (n=9) of patients with locally advanced disease on initial staging evaluation by contrast-enhanced CT were upstaged to stage IV for peritoneal metastasis on 68Ga-FAPI-04 PET/CT. The sensitivity of 68Ga-FAPI-04 PET/CT in detecting OPM was 85.7%, and the specificity was 92.3%. The overall diagnostic accuracy of 68Ga-FAPI-04 PET/CT was 91.8%. Based on ROC curve analysis, the area under the curve (AUC) was 0.893 (95% CI: 0.734–1). Conclusions: The findings of this study suggest a significantly additional value of 68Ga-FAPI-04 PET/CT in detecting OPM. Thus, it would be useful to include 68Ga-FAPI-04 PET/CT in the guidelines for staging locally advanced gastric cancer, instead of laparoscopic staging. Clinical trial information: ChiCTR2300067591 .