bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of germline BRCA1/2 testing practices: A five-year comparative analysis among oncology providers and patients.
Authors: Effange Doreen , Buras Robert Richard , Gast Kelly C. , Larsen Haidle Joy , Shockney Lillie D. , Yung Rachel Lynn , Demirhan Kimberly , Kisiel Molly , Plotkin Elana 
Published: June 2024

e13172 Background: The Association of Cancer Care Centers (ACCC) launched a quality improvement initiative in 2018 to address suboptimal germline BRCA1/2 testing rates and identify barriers impeding testing for patients with early-stage or metastatic breast cancer. Between 2018 and 2023, changes in clinical guidelines led to expanded testing criteria and increased referrals for genetic testing. A follow-up survey in 2023 aimed to assess changes in testing practices and challenges faced by cancer care teams, considering the evolving landscape of genetic testing and the impact of the COVID-19 pandemic. Methods: In 2018, a survey of 95 oncology providers was conducted to explore provider characteristics, testing characteristics, and challenges/barriers to germline BRCA 1/2 testing. The survey was conducted again in 2023 for comparative analysis with a response of 115 oncology providers. The surveys explored provider characteristics, testing practices, and challenges/barriers to germline BRCA1/2 testing. To comprehensively understand the patient's perspective, an additional survey was conducted in October 2023, involving 61 individuals recently diagnosed with breast cancer to evaluate the patient experience with germline BRCA 1/2 testing and subsequent follow-up. Results: The adoption of expanded testing criteria, which influenced changes in clinical guidelines, has led to a substantial increase in referrals for genetic testing. The utilization of genetic testing by medical oncologists experienced a notable surge with 64% of survey respondents in 2023 reporting that medical oncologists most often initiated tests for germline BRCA1/2 mutations, compared to 29% in 2018. Patients’ awareness and engagement were high, with 82% undergoing germline BRCA1/2 testing, 48% undergoing testing at diagnosis, 33% before treatment, and 13% during treatment. In 2023, 23% of providers reported routinely ordering germline BRCA1/2 testing for patients with early-stage breast cancer, marking a threefold increase from the 2018 survey results. For patients with metastatic breast cancer, 41% of providers routinely ordered BRCA mutation testing, a threefold increase from 14% in 2018. While testing rates improved, challenges and barriers persist such as patient concerns (47%), access to genetic counselors (42%), turnaround time for test results (36%), and reimbursement issues (28%). Conclusions: The comparative analysis revealed a moderate improvement in germline BRCA1/2 testing practices, with increased provider engagement and patient awareness. Despite progress, challenges persist, needing multi-pronged efforts to enhance testing uptake and distribute critical information on testing to patients. The results indicate positive trends but underscore the importance of addressing barriers for comprehensive patient care.
Antibody-drug conjugates (ADC) in patients with advanced/metastatic HER2-low expressing breast cancer: A systematic review and meta-analysis.
Authors: Michelon Isabella , Dacoregio Maria Inez , Vilbert Maysa , N. Priantti Jonathan , Castro Caio , Vian Lucas , Cavalcante Ludimila 
Published: June 2024

e13174 Background: Historically, HER2-targeted therapies failed to improve survival of patients with HER2-low-expressing tumors. Recently, trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC), demonstrated superior outcomes compared with treatment of physician´s choice (TPC) in this population. Other ADCs have also shown encouraging results, including sacituzumab govitecan (SG), MRG002, and RC48-ADC. Hence, we performed a systematic review and meta-analysis to assess the effectiveness of ADCs in patients with HER2-low advanced/metastatic (a/m) breast cancer (BC). Methods: We searched PubMed, Embase, and Cochrane databases and ASCO, ESMO, and SABCS websites for studies evaluating ADCs on patients with HER2-low a/mBC. Outcomes of interest were objective response rate (ORR); disease control rate (DCR); clinical benefit rate (CBR); progression-free survival (PFS); and overall survival (OS). We used R software (v.4.2.2) and random effects models for all analyses. Heterogeneity was assessed using I2 test. Results: Overall, 12 studies were included (3 real-world studies and 9 clinical trials), with 1,292 HER2-low a/mBC patients, 378 received TPC, and 914 received ADCs. Most were treated with T-DXd (63%, n=572), SG (29%, n=268), MRG002 (6%, n=56), and RC48-ADC (2%, n=18). Median age ranged from 48.1 to 58 years, and follow-up from 9.5 to 18.4 months. Patients treated with T-DXd achieved a significantly higher ORR and DCR compared to those who received SG, RC48-ADC, and MRG002 (Table). CBR was numerically higher in patients on T-DXd than those on SG but did not reach a significant difference. Patients with HR-positive tumors treated with SG had an ORR of 45% (95% CI 23 – 67%), and patients with pure HER2-low treated with any ADC, had an ORR of 38% (95% CI 30 – 45%). In the pooled analysis of 3 RCTs, ADCs significantly prolonged PFS compared with TPC (n=963, HR: 0.44, 95% CI 0.32 – 0.61, I2 = 66%, p<0.001), and OS (n= 680, HR: 0.56, 95% CI 0.36 – 0.89, I2 = 73%, p=0.015). Patients on ADCs also achieved a greater anti-tumor response than TPC, including better ORR (OR: 4.18, 95% CI 2.40 - 7.28, I2 = 52%, p<0.001), DCR (OR: 2.82, 95% CI 2.06 - 3.85, I2 = 7%, p<0.001), and CBR (OR: 3.41, 95% CI 2.36 - 4.93, I2 = 25%, p<0.001). Conclusions: Our systematic review and meta-analysis supports the efficacy of ADCs in HER2-low a/mBC patients over TPC. Future studies should focus on bringing ADCs into earlier lines of therapy in this population.Anti-tumor activity of ADCs presented as overall % (95% CI). [Table: see text]
Low-dose radiation as a preconditioning regimen for dendritic cell vaccines.
Authors: Kwon Eric , Namen Shelby , Kang Solomon , Willoughby Colin , Zhang Kevin , Pandey Guarav , Yang Joanna Chensi , DeSelm Carl 
Published: June 2024

e14519 Background: Dendritic cells are potent antigen-presenting cells that induce the adaptive immune system to protect against cancer. While anti-tumor immunity can be improved with dendritic cell vaccines, it is not fully known what approved preconditioning agents, if any, improve dendritic cell vaccine-induced antitumor T-cell response and tumor elimination. We explored the effect of low-dose radiation (LDR), cyclophosphamide, and paclitaxel as preconditioning regiments for a dendritic cell vaccine. Methods: KP tumors were engineered with ovalbumin and orthotopically injected subcutaneously (SQ) into the flank of wild type B6 mice. Preconditioning regiments of a control, LDR (2 Gy), cyclophosphamide (20mg/kg), LDR (2 Gy) + cyclophosphamide (20mg/kg), and paclitaxel (20mg/kg) were given on day 4. Bone marrow dendritic cells (DCs) were electroporated with ovalbumin peptide SIINFEKL and then one million cells were injected i.v. on day 5 and 8. Blood collection was done and ovalbumin-specific T-cell populations were examined by tetramer staining for SIINFEKL-specific TCR over time. Tumor size was measured over time and survival data was analyzed accordingly. Results: LDR effectively produced a significant increase in CD8+ SIINFEKL tetramer+ T-cell count per uL of blood compared to the non-preconditioned group. In addition, this LDR preconditioning regiment produced a significantly improved tumor response over time. The overall survival rate of subjects receiving LDR was significantly improved compared to all other groups. Conclusions: Here, we find that LDR is most effective as a preconditioning regimen prior to dendritic cell vaccination for inducing an antitumor T-cell response and achieving tumor control over time. LDR provides a promising method to supplement dendritic cell vaccination and potentially improve patient outcomes. Further study is needed to confirm its efficacy.
Analysis of proteomics based on LC-MS detection on the efficacy of immunocombined therapy for hepatocellular carcinoma.
Authors: Wang Nanya , Yan Yueqi , Wang Shibo , Liu Bo , Li Yu , Wang Ying 
Published: June 2024

e14549 Background: Combined immunotherapy has become the preferred treatment for HCC. However, it faces challenges: possible serious adverse reactions, the low objective response rate, and the median overall survival is about 20 months, which is far from meeting the clinical treatment needs. There is still a lack of effective predictive biomarkers in clinical practice to screen the dominant population of combined immunotherapy. The purpose of this study is to use LC-MS to screen and identify differential metabolites between patients with different efficacy to help screen the dominant population of clinical immunotherapy. Methods: 38 HCC patients were included who were treated in the Tumor Center of the First Hospital of Jilin University from June 2020 to March 2022 and received combined immunotherapy. Sample collection and follow· -up, and collect basic clinical data. The enrolled patients underwent enhanced CT examination every 3 treatment cycles, and the efficacy of the patients was evaluated according to the solid tumor efficacy evaluation standard 1.1 (RECIST V1.1). The serum of patients before treatment was detected by LC-MS, and the difference of mass spectrometry data between patients with different curative effects was compared, and the differential metabolites were explored by proteomics analysis. Results: The best of response was partial response in 7 patients (22.6 %), stable disease in 6 patients, and progressive disease in 18 patients (58.1 %). Based on LC-MS proteomics analysis, differential metabolites between patients with different therapeutic effects were screened and identified, namely Q9Y275, Q56UQ5, P13611, and P30530 (P < 0.05). The relative abundance of Q9Y275, Q56UQ5, P13611 and P30530 in the disease control rate group was higher than that in the PD group. Conclusions: Based on LC-MS proteomics analysis, four types of differential metabolites between different populations of PLC patients receiving combined immunotherapy were screened and identified, namely Q9Y275, Q56UQ5, P13611 and P30530.
Novel TROP2-targeted CAR T cells with high specificity and sustained efficacy for solid tumors in animal models.
Authors: Liu Chih-Chun , Kuo Tzer-Min , Lai Jiann-Shiun , Lai Ming-Tain 
Published: June 2024

e14563 Background: CAR T cell therapy, successful in hematological malignancies, encounters challenges against solid tumors due to immune exhaustion and senescence within the tumor microenvironment. The imperative need for an optimal tumor target antigen is evident in advancing CAR T therapy. TROP2, a membrane-associated glycoprotein, is highly expressed in diverse cancers, including cervical, bladder, esophageal, ovarian, and endometrial cancers. TROP2 overexpression, approaching 100% in cervical and hormone-resistant prostate cancer, correlates inversely with prognosis and survival, presenting TROP2 as a promising CAR T therapy target. This study engineered the novel TROP2 antibody R4702, featuring a distinct binding epitope from Sacituzumab and Datopotamab, to develop TROP2-specific CAR T cells and evaluated their efficacy against a spectrum of solid tumors. Methods: Expansion of CAR T Cells and Cytotoxicity: CAR T cells were created through lentivirus-mediated genetic engineering with the TROP2 antibody, followed by 10 days of expansion. T cell differentiation was evaluated, and luciferase-encoding target cells incubated with varying CAR T cell ratios overnight were quantified luciferase activity. In Vivo Efficacy and Persistence: CAR T cells were adoptively transferred into ASID mice with tumors. In vivo tumor imaging used luciferase activity, and calipers monitored tumor size weekly. CAR T cell persistence assessed their ability to suppress rechallenged tumor growth. Results: R4702, a novel TROP2-specific antibody, displayed high binding affinity to a distinct epitope. Post- ex vivo expansion, R4702 CAR T cells showed a substantial increase (100 to 200-fold) over 10 days, with a high expression level (50~80%) of R4702 CAR on T cells. Over 60% of R4702 CAR T cells displayed a less differentiated status, characterized by a CD62L+ population comprising TSCM and TCM. In vitro cytotoxicity revealed potent and specific efficacy against various TROP2-positive cancer cell lines, with no observed killing activity against TROP2-negative cells. In vivo efficacy of R4702 CAR T cells demonstrated 100% tumor growth inhibition within 30 days post-treatment across diverse xenograft models. Importantly, R4702 CAR T cells exhibited enduring anti-tumor efficacy against successive tumor challenges in xenograft models of pancreatic, gastric, NSCLC, TNBC, and ovarian cancers. In a head-to-head comparison with Sacituzumab and Datopotamab CAR T, R4702 demonstrated superior anti-tumor efficacy to Sacituzumab and comparable efficacy with Datopotamab in the BxPC-3 CDX model of pancreatic cancer. Conclusions: A novel TROP2-specific R4702 CAR T cell, developed, showcased robust tumor-killing capabilities. The anti-tumor activity persisted upon repeated tumor challenges across various xenograft models, underscoring the potential of R4702 CAR T cells as a promising therapeutic strategy.
Effect of RIPK3 on non-canonical PANoptosis to suppress anti-tumor immunity in lung cancer.
Authors: Zhong Hua , Yang Yv , Wang Yue , Wu Erpeng 
Published: June 2024

e14565 Background: Hypoxia and glucose deprivation are common features of solid malignancies and considered the causes of tumor necrosis, while the molecular mechanisms of tumor cell death and its impact on tumor progression are not yet clear. PANoptosis is a newly recognized programmed cell death pathway, characterized by the simultaneous activation of necroptosis, apoptosis and pyroptosis. The canonical PANoptosis is controlled by an ASC-dependent multimeric protein complex named the PANoptosome. Methods: Using immunoblot and immunofluorescent analysis, we described the RIPK3 expression patterns and detected the programmed cell death markers in lung cancer tissues. We built a RIPK32×Fv-Flag-expressing PKLC cell line and identified the key molecules involved in tumor cell death by using MS analysis of RIPK3-immunoprecipitate. These molecules were confirmed by CRISPR-Cas9 mediated gene knockout. Then we analyzed the secretome by 4D-diaXLMS of cell death conditioned medium and identified a variety of DAMPs and cytokines released by PANoptotic tumor cells. Last, the differences of tumor growth and the immune microenvironment between wild-type and Ripk3 KO PKLC-CDX were compared. Results: Hypoxia and glucose deprivation could induce over expression of RIPK3 and mediated PANoptosis of tumor cells. The oligomerized RIPK3 rapidly recruits MLKL and mediates MLKL phosphorylation to induce necroptosis. Further aggregated RIPK3 can recruit RIPK1 and assembles with FADD and Caspase-8, causing Caspase-8 auto-cleavage. Active Caspase-8 can directly cleave caspase-3 and GSDMD to induce apoptosis and pyroptosis. The PANoptosis we described is initiated by RIPK3 and independent of ASC, which we termed non-canonical PANoptosis. We also found that Caspase-3, as an executor of apoptosis, is able to cleave RIPK3, RIPK1 and truncated GSDMD, negatively regulating PANoptotic cell death. Finally, we identified a variety of DAMPs released by PANoptotic tumor cells, which facilitate neutrophil differentiation and activation, promoting tumor progression by suppressing anti-tumor immunity. Conclusions: Hypoxia and glucose deprivation induce non-canonical PANoptosis that is initiated by RIPK3 and independent of ASC. The PANoptotic tumor cells suppress anti-tumor immunity through releasing DAMPs and cytokines to mediate neutrophil differentiation and activation, which promote lung cancer progression.
Pre-clinical safety and efficacy evaluation of sodium chloride nanoparticles for treating non-muscle invasive bladder cancer.
Authors: Gdowski Andrew , Kim Lucia , Lai Xining , Ma Xinrui , Raupp John , Zhan Shuyue , Beckabir Wolfgang , Sturdivant Michael , Wobker Sara Elizabeth , Li Zibo , Xie Jin , Kim William Y. 
Published: June 2024

e14591 Background: Non-muscle invasive bladder cancer (NMIBC) presents a significant therapeutic challenge. Current treatment modalities such as BCG and intravesical chemotherapy given after transurethral resection of bladder tumors (TURBT), while effective, are associated with high cost burdens and are difficult for patients to tolerate due to side effects. This ultimately limits treatment regimen duration and decreases the effectiveness of the therapy which frequently leads to local recurrence. Sodium Chloride Nanoparticles (NaCl-NPs) have previously shown promise in preclinical models of intra-tumoral injection of various tumor types but has not been tested in more clinically relevant models of bladder cancer. In this study, we evaluate the safety and efficacy of NaCl-NPs as a local intravesical therapy for preventing tumor development in a preclinical murine model of bladder cancer. Methods: We conducted a dose escalation experiment via intravesical instillation of increasing doses of NaCl-NPs (300 ug/ml-2700 ug/ml, n=3 mice per group) to identify the maximum tolerated dose. Mice were treated on a weekly dosing schedule and toxicity was evaluated at day 35 as a composite of: evaluation of bladder histology with Hematoxylin and Eosin (H&E) staining by a board-certified pathologist, blood chemistry measurements, complete blood counts, as well as body weight measurement. Secondly, we assessed the efficacy of the nanoparticles through a tumor prevention experiment where MB49 bladder cancer cells were instilled in the murine bladder and shortly after treated with intravesical: 1.) Saline, 2.) Gemcitabine, or 3.) NaCl-NPs for 1 hour (n=18 per group). Mice were monitored for tumor development with 3D bladder ultrasound. In additional, overall survival (OS) was assessed. Results: The dose escalation study showed that there was no local or systemic toxicity in the NaCl-NP treated mice, even at the highest concentration (2700ug/ml). The tumor prevention study showed that mice treated with NaCl-NPs had a significant 2.55 fold reduction in tumors that developed at 4 weeks compared to saline (22% vs 56% respectively, p <0.05). This reduction was similar to that seen with intravesical gemcitabine, which is clinically, a standard of care intravesical chemotherapy. We also found an improvement in overall survival in the NaCl NP group with 70% of mice alive at 60 days compared to the other treatment groups (65% gemcitabine; 40% saline). Conclusions: Our findings suggest that NaCl-NPs could provide a safe and effective alternative therapy for preventing recurrence of NMIBC following transurethral resection of bladder tumors. This opens avenues for safer treatment protocols that can mitigate the side effects commonly seen in the management of early-stage bladder cancer.
Envafolimab plus chemotherapy as neoadjuvant therapy for resectable esophageal squamous cell carcinoma (ESCC): A prospective, single-arm, phase II study.
Authors: Zhao Jinbo , Yan Xiaolong , Bai Yuquan , Duan Hongtao , Jiang Tao 
Published: June 2024

e14633 Background: Currently, chemotherapy plus PD-1 inhibitor immunotherapy has become a promising option in the neoadjuvant setting of resectable ESCC, nevertheless, the PD-ligand 1 (PD-L1) blockade-based combination has rarely been investigated to date. Envafolimab is the first and only globally approved subcutaneous (SC) PD-L1 inhibitor, which has shown satisfactory efficacy and safety profile in tumors. This Simon’s two-stage, phase II study explored the safety and feasibility of SC administration of envafolimab as an alternative to intravenous (IV) administration of PD-1/PD-L1 inhibitors in the neoadjuvant therapy of resectable ESCC. Here, we reported the results of the stage 1. Methods: In this Simon’s two-stage, phase II study, patients initially treated with locally advanced and resectable (stage II-IVA) ESCC were enrolled and received envafolimab (300mg, SC, day 1), albumin-bound paclitaxel (130mg/m2, IV, days 1 and 8), and carboplatin (AUC = 5, day 1) every 3 weeks for 3 cycles. The primary endpoints were safety and pathological complete response (pCR). A Simon’s two-stage design was utilized with following assumptions. Target accrual was 13 patients in the first stage (If 3 or more patients had pCR in stage 1, study could continue in stage 2), total 34 patients were enrolled in the stage 2. Secondary endpoints were major pathological response (MPR). Safety was assessed by adverse events (AEs) and postoperative complications. Results: Between October 2022 and April 2023, 13 (81.3%) of 16 enrolled patients completed neoadjuvant therapy and underwent surgery. All 13 (100%) surgical patients underwent successful R0 resection; of whom, 8 (61.5%) achieved pCR and 9 (69.2%) achieved MPR, respectively. Downstaging occurred in 10 (76.9%) of 13 patients. pCR and MPR were identified to be associated with tumor downstaging but not with PD-L1 expression. CPS levels in MPR and pCR group were significantly higher than that in Non- MPR and Non-pCR group. Grade 3-4 treatment-related AEs (TRAEs) and immune-related AEs (IrAEs) occurred in 12.5% and 37.5% of 16 patients, respectively. 10 (76.9%) of 13 patients reported postoperative complications. No treatment-related surgical delay or death occurred. Conclusions: Envafolimab plus chemotherapy as neoadjuvant therapy demonstrated promising antitumor activity for resectable ESCC with high rates of pCR, MPR and R0 resection, as well as acceptable tolerability. Based on the encouraging efficacy of our regimen in the first stage, we will continue the enrollment of patients in stage 2. Keywords: Esophageal squamous cell carcinoma; Envafolimab; Neoadjuvant therapy; Chemotherapy Clinical trial information: NCT05552651 .