bluuebunny/crossref_metadata_2025 huggingface dataset:
The treatment outcomes of patients who failed to be randomly assigned after atezo/bev induction therapy in the Chinese TALENTop study.
Authors: Chen Yiwen , Sun Huichuan , Shen Feng , Chen Minshan , Huang Zhiyong , Song Tianqiang , Zeng Yongyi , Kuang Ming , Xiang Bangde , Liu Lianxin , Li Deyu , Wen Tianfu , Chen Yongjun , Peng Tao , Li Xiangcheng , Zhu Xiaodong , Zhou Jian , Fan Jia , Bai Xueli , Liang Tingbo
Published: July 2024

e16183

Background: Hepatocellular carcinoma (HCC) patients with macrovascular invasion (MVI) are considered to be at an advanced stage of disease with limited treatment options. The combination therapy of atezolizumab (atezo) plus bevacizumab (bev) has become a global standard of care for those patients and made conversion resection possible. The Chinese TALENTop study (NCT04649489) is aiming to clarify whether hepatic resection may provide additional benefit in HCC patients with MVI responding to atezo/bev. For patients without opportunity to receive hepatic resection, subsequent treatment outcomes will be reported. Methods: Potentially resectable HCC patients with MVI and without extrahepatic metastasis are eligible for this study. Eligible patients receive 3 cycles of atezo/bev and 1 cycle of atezo as primary systemic therapy (induction phase). Patients assessed as partial response (PR) or stable disease (SD) per RECIST v1.1 and considered suitable for R0 hepatic resection are randomized in a 1:1 ratio to either Arm A, hepatic resection followed by atezo/bev for 1 year, or Arm B, continuing atezo/bev therapy. The primary endpoint is the time to treatment failure. Patients failed to be randomized will enter the survival follow-up phase. After 296 patients entered induction phase, the patient profile, subsequent treatments per local standard of care and survival of patients who failed to be randomized were analyzed. Results: From Apr 2021 to Jun 2023, 296 patients were enrolled and entered induction phase and 175 patients failed to be randomized and were followed up until Sept 2023. The main reasons for failure to be randomized were disease progression (64.6%), investigator assessment of unsuitability for R0 hepatic resection (14.3%), and others. The 175 patients were characterized with a median age of 52 (26-76), and 166 (95%) had HBV infection. Among them, 165 (94%) had combined PVTT, 24 (14%) had combined HVTT and 5 (3%) had combined IVCTT. At a median follow-up time of 10.9 months (9.7-13.1), the median overall survival (mOS) is 13.8 months (8.9-15.8), 6- and 12-month survival rate were 71% and 53%, respectively. As the result of best response during induction phase, 3 patients (1.7%) achieved PR, 92 patients (52.6%) achieved SD and 65 patients (37.1%) were PD. 123 patients (70%) received subsequent therapy. The mOS of patients received different subsequent therapies was showed below. Conclusions: This study provides data on HCC patients with MVI after receiving atezo/bev. The result shows favorable survival even in patients failed to randomization to receive conversion resection, and subsequent treatment strategy may differ survival outcomes. Clinical trial information: NCT04649489 . [Table: see text]
Association between somatic mutation pathways and treatment response in patients with biliary tract cancers (BTCs).
Authors: Birda Vaibhav , Osataphan Soravis Alm , Lyon James , Paredes Rodrigo , Rattani Ahmed Anwer Ali , Peters Mary Linton Bounetheau
Published: July 2024

e16196

Background: Comprehensive somatic genomic profiling has become the standard of care for patients with BTCs, serving to identify targetable mutations and aiding in prognostication. While previous studies have identified individual somatic mutations such as TP53, CDKN1A, and KRAS as negative prognostic markers, little is known about their role as predictive biomarkers. This study aimed to investigate the predictive potential of somatic mutations and pathways using commercially available next-generation sequencing. Methods: We conducted a retrospective cohort study at Beth Israel Deaconess Medical Center (BIDMC) from January 2016 to January 2023, with data censoring in January 2024. Patient characteristics, including age, gender, race, stage, site of metastasis, performance status, and survival status, were collected. Somatic genomic alterations data were extracted from FoundationOneCDx, a commercially available NGS platform designed to capture 324 genetic alterations validated for therapy targets or unambiguous drivers of oncogenesis. Genetic alterations were classified into 14 oncogenic pathways constructed based on the TCGA and Reactome databases. Multivariate Cox proportional hazards regression analysis was performed between pathway alterations, progression-free survival and overall survival, accounting for selected covariates with p < 0.05 or potential known confounders. Results: Among 97 BTCs, 90 were successfully sequenced. Among these, 40 patients received gemcitabine and cisplatin, and 28 received fluorouracil and oxaliplatin (FOLFOX) therapy. Intrahepatic cholangiocarcinoma was present in 70% of cases, perihilar or distal cholangiocarcinoma in 27%, and gallbladder carcinoma in 3%. At presentation, 18% had stage I disease, and 44% had stage IV. The median follow-up time was 15 months. A total of 339 genomic alterations were identified, with 8% of samples harboring FGFR fusion or mutation, 9% IDH1 mutation, 6 % HER2 amplification, 30% KRAS mutation, and 32% with TP53 mutation. The most affected pathways were the cell cycle (66%) and DNA repair (50%). In multivariate regression analysis accounting for age, ECOG, and anatomical location, TP53 mutation was associated with shorter progression-free survival on gemcitabine and cisplatin treatment (n = 11, 2 vs. 6 months, HR 4.19, 95% CI 1.51 – 11.7, p < 0.01), whereas cell cycle pathway mutation was associated with longer progression-free survival (n = 14, 6 vs. 5 months, HR = 0.43, 95% CI 0.19-0.96, p < 0.05). No association was found between oncogenic pathways and treatment response to FOLFOX therapy. Conclusions: TP53 mutation is associated with a worse response, whereas cell cycle pathway mutations are associated with an improved response to gemcitabine and cisplatin therapy in patients with BTCs. Further research is needed to understand the mechanisms contributing to these observed effects.
Magnesium microspheres to enhance lipiodol-mediated transarterial chemo-embolization (TACE) of hepatocellular carcinoma: From bench to a pilot clinical study.
Authors: Zheng Liyun , Ji Jiansong
Published: July 2024

e16204

Background: Transarterial chemoembolization (TACE) has been extensively used in clinic to treat unresectable hepatocellular carcinoma (HCC). However, arterial embolization would worsen the hostile physicochemical features in the tumor microenvironment (TME) by further reducing its pH and increasing hypoxia, leading to immunosuppressive TME and drug resistance. Methods: Magnesium microspheres (Mg MSs), acting as H2 donors and pH modulators, were prepared via gas atomization pulverization. Characterization included inverted optical microscopy, SEM, and XRD analysis. Their H2 generation and acid neutralization capabilities were confirmed. The Lip-Mg dispersion (Mg MSs dispersed in lipiodol) was tested for therapeutic efficacy in H22 murine liver tumor-bearing mice, 4T1, and CT26 subcutaneous tumor models, as well as in vivo interventional TAE therapy for rabbit orthotopic liver tumors. The modulated capacities of Lip-Mg in H2 gas generation, acid neutralization, and promotion of antitumor immune response were investigated in vivo. Finally, a single-center, single-arm, open-label trial (ChiCTR2200064999) evaluated the safety and efficacy of TACE treatment with Lip-Mg (M-TACE) in Chinese HCC patients. Results: Inverted optical microscopy and SEM images confirmed uniform, smooth Mg microspheres (~60 μm) with a grayish-white color. In acidic buffer (pH 6.4), Mg microspheres rapidly increased pH, as measured by pH meter or fluorescent probe. Lip-Mg treatment significantly inhibited tumor growth compared to controls, prolonging mouse survival by ~2-fold, validated in 4T1 and CT26 models. Ultrasonic and multispectral fluorescence imaging demonstrated Lip-Mg's ability to release H2 and neutralize pH in vivo, reversing the immunosuppressive tumor microenvironment. Clinical study showed manageable treatment-related adverse events, with no unexpected toxicities and negligible impact on serum magnesium levels, confirming the safety of Mg microspheres for M-TACE. According to mRECIST, M-TACE exhibited high CR (61.5%), PR (38.5%), and ORR (100%) rates, with an overall response rate and CR rate of 90% and 60%, respectively. Conclusions: Metallic Mg microspheres (~60 μm) were developed to enhance lipiodol-mediated TAE/TACE for HCC. When combined with lipiodol and injected, they neutralized the acidic TME, triggered hydrogen therapy, and reversed immunosuppression, effectively inhibiting tumor growth. Lip-Mg showed superior outcomes to lipiodol alone for TAE therapy, with M-TACE treatment exhibiting higher ORR and CR rates than cTACE. Post-M-TACE, adverse events were managed well without treatment discontinuations. Our study introduces Mg microspheres as a promising embolic device for M-TACE therapy, potentially improving TACE benefits. Clinical trial information: ChiCTR2100050327.
Stereotactic body radiation therapy combined with atezolizumab and bevacizumab for hepatocellular carcinoma with extrahepatic metastasis: Preliminary result of a single-arm study.
Authors: Wang Lu , Zhang Ti , Lin Zhenhai , Zhou Jiamin , Wan Juefeng , Pan Qi , Zhao Yiming , Zhu Weiping , Mao Anrong , Zhang Ning , Wang Longrong
Published: July 2024

e16205

Background: IMbrave150 study confirmed the clinical benefit of atezolizumab and bevacizumab in patients with advanced hepatocellular carcinoma (HCC). However, patients with extrahepatic metastasis (EHS) had a poorer prognosis. Studies suggested “abscopal effect” of synchronous radiotherapy and immunotherapy may improve antitumor activity. This study aimed to evaluate efficacy and safety of stereotactic body radiation therapy (SBRT) combined with atezolizumab and bevacizumab in HCC patients with EHS. Methods: This single-arm study included HCC patients with EHS from January 2022 to November 2023 in Fudan University Shanghai Cancer Center. Prior tyrosine kinase inhibitor and/or immune checkpoint inhibitor treatment were eligible. After first dose atezolizumab and bevacizumab, SBRT was performed with a total dose of 25-50 Gy. The primary endpoint was objective response rate (ORR). The secondary endpoints included overall survival (OS), disease control rate (DCR), progression-free survival (PFS), time to progression (TTP), and duration of response (DOR). Results: Thirty-nine patients were included. Fourteen patients were treated as first-line therapy and 25 patients were treated as later-line therapy. The mean age was 56.69±11.21 years and 89.7% were male. Of these patients, 66.7% had hepatitis viral infection and 25.6% had vascular invasion. 53.8% of patients had ≥2 extrahepatic spread lesions. In addition, 33.3% of patients had received prior immunotherapy and 23.1% of patients had received tyrosine kinase inhibitor therapy. The median follow-up was 6.50 (range: 1.43-22.17) months. The ORR and DCR were 43.6% and 92.3%, respectively. The ORR was 57.1% and 36.0% in first-line subgroup and later-line subgroup, respectively. The 12-month OS rates was 54.7%. The median PFS, median TTP and median DOR were 6.73 months, 8.67 months, and 7.17 months, respectively. The incidence of all grade TRAE and grade ≥3 TRAE were 38.5% and 12.8%, respectively. The most common grade ≥3 TRAEs were decreased platelet count (7.7%), decreased white blood cell count (2.6%), pruritus (2.6%) and rectal bleeding (2.6%). No serious adverse events occurred. Conclusions: SBRT combined with systemic atezolizumab and bevacizumab showed encouraging efficacy with manageable safety profile for HCC patients with EHS regardless of prior treatment. Further studies are warranted. Clinical trial information: NCT05396937 . [Table: see text]
Predictors of poor response to immune-checkpoint inhibitor (ICI) treatment among patient with hepatocellular carcinoma (HCC).
Authors: Das Parthib , Paul Samuel , Min Eric , Elsaid Mohamed I. , Mittra Arjun , Malalur Pannaga G. , Manne Ashish
Published: July 2024

e16212

Background: No established risk factors or toxicity biomarkers exist for HCCs treated with ICI, even though they are commonly used in clinical practice. The outcomes in real-world practice are worse than those reported in clinical trials. This retrospective review aims to identify HCC patients at high risk of failing ICI therapy. Methods: HCC patients who received at least one ICI dose between 1/1/2017 and 5/30/2023 (before tremelimumab/durvalumab approval) at the Ohio State University were included in this study. The patient's baseline (BL) characteristics (at the first dose of ICI) were extracted with immune-related adverse event (irAE) details and survival outcomes. We examined BL characteristics significantly different in poor (progression-free survival (PFS) ≤ median (m)) and worst (PFS ≤ 25% percentile) responders, and poor (overall survival (OS) ≤ m) and worst (OS ≤ 25% percentile) survivors. Chi-square test and logistic regression were performed using JMP Pro 17 (SAS Institute Inc., Cary, NC). Results: Our cohort included 53 HCC patients. The median age was 66 years (range 40-86), with 81% male and 85% White (13% African American and 2% other). The median OS and PFS were 19 months (m) (95% confidence interval [CI], 8-26) and 5m (95% CI, 2-9), respectively. The poor responders (PFS ≤5m, N = 30) had patients with significantly higher alcohol history (AHx, 90% vs. 70%) and mean alpha-fetoprotein (AFP, 44, 155 vs. 811 ng/mL) levels, a higher proportion of Child-Pugh (CP) C (A/B/C %, 53/27/20 vs. 53/47/0), and negligible bevacizumab (bev, 77 vs. 24) use, all (p < 0.05). The worst response group (PFS ≤2m, N = 16), furthermore, had significantly (p < 0.05) higher Albumin-bilirubin (ALBI) grade (G) 3 patients (50% vs. 16%), higher mean total bilirubin (2 vs. 1,2 ng/mL), lower tyrosine-kinase inhibitor (TKI, 7% vs. 46%), and lower mean albumin (Ab, 3 vs. 3.4) levels. A significantly (p < 0.05) higher fraction (fx) of poor survivors (OS ≤19m, N = 33) got ICI In the first or second line (85% vs. 45%) and did not receive any locoregional therapy (LRT, 66% vs. 35%). The worst survivors (OS ≤8m, N = 14) got ICI in the first line (100% vs. 59%, p = 0.04, and significantly (p < 0.05) lower Alb (3 vs. 3,4) and higher AFP (90620 vs. 3104) levels. The irAE group (N = 10, 19%) had higher AFP (115289 vs. 3482, p = 0.01) and a lower distant metastasis rate (20% vs. 58%, p = 0.02), and none of them received bev (0% vs. 30, p = 0.04). Conclusions: Response to ICI depends on BL liver function (AHx, ALBI, CP, Alb) and combination therapy (bev). Survival depends on HCC management up to the administration of ICI (LRT and TKI).
Targeting USP7 to induce ubiquitination degradation of oncogenic ATAD2 and effects on cholangiocarcinoma growth.
Authors: Zhang Peng , Zhang Chengsheng
Published: July 2024

e16215

Background: Cholangiocarcinoma (CCA) is a highly fatal disease due to limited therapeutic targets. Deubiquitinase USP7 is an oncogene and has been suggested to be deeply involved in regulating tumor initiation and progression, but its abundance and role in CCA still remain unclear. Methods: USP7 mRNA expression was performed using TCGA and GEO database. Survival analysis in CCA patients with high- and low-USP7 mRNA expression was performed using NODE database. CCK8, colony formation, flow cytometry and shRNA interference assay were used to evaluate the biological function of USP7-ATAD2 axis on CCA cancer cells in vitro. 4D label-free quantification proteomics was used to analyze the targets and networks regulated by USP7. The molecular mechanism of USP7 and ATAD2 in CCA was determined by conducting Western blot, co-immunoprecipitation, IHC and quantitative real-time PCR (qPCR) analyses. The CCA PDX model was used to evaluate the efficacy of targeting USP7 in the treatment of cholangiocarcinoma. Results: Here, we found USP7 is highly expressed in CAA, and is associated with poor outcomes of CCA patients. We show that USP7 depletion induces S phase arrest, and suppresses CCA tumor cells proliferation. Next, we provide a comprehensive understanding of targets and networks affected by USP7 depletion by performing a 4D label-free quantification proteomics analysis. We show that ATAD2 is a USP7 target, and USP7 interacts with and deubiquitinates ATAD2 to stabilize ATAD2 protein level. Ectopic expression of ATAD2 in USP7-depleted cells rescues the cell proliferation phenotype. Further, pharmacological blocking the activity of USP7 by P5091 inhibits tumor growth in CCA patient-derived xenograft (PDX) mouse model. Conclusions: This study uncovers the role of USP7-ATAD2 axis in regulating tumor growth, and targeting USP7 may provide a novel therapeutic strategy for CCA.
A prospective study of radiofrequency ablation combined with systematic neoadjuvant therapy in the treatment of recurrent hepatocellular carcinoma (RANT study).
Authors: Feng Kai , Ma Kuansheng , Wang Qiang , Xia Feng , Bi Huaqiang , Chen Zhiyu , Zhang Leida
Published: July 2024

e16240

Background: Radiofrequency ablation (RFA) is an important minimally invasive approach for recurrent HCC, but is hampered by the high recurrence rate and limited ablation volume for the tumor. This study aims to evaluate the efficacy and safety of systemic neoadjuvant therapy (tislelizumab combined with lenvatinib/bevacizumab) combined with RFA in the treatment of recurrent HCC. Methods: This prospective, single-arm, phase II trial enrolled patients with recurrent resectable HCC who has a history of liver resection or RFA (the number of lesions ≤ 3, the largest lesion ≤ 3 cm, as demonstrated by contrast enhanced CT/MRI). Prior to RFA, patients received tislelizumab (200 mg, q3w, iv) and lenvatinib (body weight≥60 kg, 12 mg; <60 kg, 8 mg, qd, po) or bevacizumab (15mg/kg) for two cycles. RFA was scheduled in one week after the systemic neoadjuvant therapy. After 4-8 weeks of surgery, patients continued to receive tislelizumab and lenvatinib /bevacizumab for 6 to 12 months. Primary endpoint was one-year relapse-free survival (RFS) rate and one-year overall survival (OS) rate. Secondary endpoints were objective response rate (ORR) by mRECIST, and adverse events (AE). Results: From November 2021 to October 2023, 20 patients (median age, 57 years) were enrolled, all Child-Pugh A and ECOG PS 0, mostly males (95%) and HBV infection (90.0%). 19 patients had received 2 cycles systemic neoadjuvant therapy and RFA was successfully performed, 1 patient achieved complete response after systemic treatment and didn't perform RFA. According to mRECIST, the ORR was 50% (95%CI: 27.20%-72.80%), and the DCR was 100 % (CR 1, PR 8, SD 11). After a median follow-up of 8.5 months (interquartile range 5-21 months), tumor recurrence was detected in 2 patients, 1 patient died of disease recurrence. The estimated 12-month RFS rate and OS rate were 76.9% (95%CI 31.2%, 94.3%) and 100%, respectively. Median RFS and OS were not reached. So far the safety of neoadjuvant treatment was satisfied, no grade 4 or above treatment-related-adverse events (TRAEs) were observed. Grade 3 TRAEs were reported in 3(13.04%) patients. Frequently occurring adverse eventswere grade 1-2, including total bilirubin increased (39.13%), elevated aspartate aminotransferase (30.43%), and elevated alanine aminotransferase (30.43%). Conclusions: Radiofrequency ablation combined with systematic neoadjuvant therapy exhibited promising efficacy and favorable safety for recurrent HCC. Clinical trial information: NCT05277675 .
Neoadjuvant tislelizumab combined with lenvatinib plus transcatheter arterial chemoembolization in resectable hepatocellular carcinoma with high-risk of recurrence: A prospective, single-arm, phase II trial.
Authors: Chen Zhiyu , Zhang Leida , Zhang Hui , Gong Yi , Feng Kai , Ma Kuansheng , Bi Huaqiang , Xia Feng , Dai Haisu
Published: July 2024

e16242

Background: Currently, more than 55% of liver cancer patients have recurrence within 1 years after radical surgery. However,there is no standard treatment of neoadjuvant therapy for resectable HCC patients. This study aimed to explore the efficacy and safety of the triple therapy [Tislelizumab combined with lenvatinib plus transcatheter arterial chemoembolization (TACE)] as neoadjuvant therapy in patients with resectable HCC with high-risk of recurrence. Methods: This prospective, single-arm, phase II trial (ChiCTR2200059574) enrolled patients with primary resectable HCC who had not received prior anti-tumor therapy. The recurrence rate was predicted to be > 50% according to the risk predictor ( http://www.asapcalculate.top/Cal2_ch.html ) of early recurrence before surgery. TACE will be performed once on Day 1. Tislelizumab (an anti-PD-1 antibody, 200 mg) intravenously once every 3 weeks and lenvatinib (body weight ≥ 60 kg, 12 mg;< 60 kg, 8 mg) orally daily was initiated 3 days after TACE treatment. Surgery was performed after two cycles of neoadjuvant treatment. After 4-6 weeks of surgery, patients continued to receive tislelizumab and lenvatinib for 6 months to 1 year. Primary endpoint was adverse events (AE) and major pathological reactions. Secondary endpoints were objective response rate (ORR) by mRECIST, relapse-free survival (RFS) and overall survival (OS). Results: From April 2022 to August 2023, 19 patients (median age, 55 years) were enrolled, all Child-Pugh A and ECOG PS 0, mostly males (89.5%) and HBV infection (94.7%). According to mRECIST, the ORR was 94.7% (18/19, CR 2, PR 16), and the DCR was 94.7% too (18/19, CR 2, PR 16, SD 0). In 19 patients, 14 patients had received surgical treatment (R0 resection rates were 100%), 12 patients (12/14, 85.7%) achieved major pathological reaction (necrosis≥90%), and 2 patients (2/14, 14.3%) achieved complete pathological response. For those patients who did not undergo surgery, 3 of them refused surgery, and 2 patients lost the chance of surgery because of disease progression and high ICG R-15, respectively. At the end of the last follow-up (January 20, 2024), tumor recurrence was detected in 2 patients after surgery. The 12-month RFS rate and OS rate were 80.2%(95% CI: 40.4%-94.8%)and 94.7%(95% CI: 68.1%-99.2%), respectively. Median RFS and OS were not reached. No grade 3 or above AE were observed. Conclusions: Tislelizumab, lenvatinib, and TACE were safe and showed promising efficacy as a neoadjuvant therapy for resectable HCC with high risk of recurrence. Clinical trial information: ChiCTR2200059574.
The safety and short-term efficacy of selective internal radiation therapy combined with systemic treatment for unresectable malignant hepatic tumors in Chinese patients.
Authors: Zhang Hui , Kong Mingxin , Tan BinBin , Shao MingHua , Fu Ying , Liu Ping , Fan Chao , Chen HaiLei
Published: July 2024

e16247

Background: There are many systemic treatment options for patients with unresectable malignant hepatic tumors. In China, selective internal radiation therapy (SIRT) with yttrium-90 (Y90) resin microspheres was approved until 2022. The aim of this retrospective study was to investigate the safety and short-term efficacy of SIRT with Y90 resin microspheres followed by systemic treatment in Chinese patients. Methods: The study analyzed patients who received SIRT with Y90 combined with systemic treatment at our center between June 2022 and October 2023. The study's primary endpoint was to determine the objective response rate (ORR), while safety was the secondary endpoint. Response was measured based on modified Response Evaluation Criteria in Solid Tumors criteria (mRECIST) up to 90 days after the initial therapy. Safety was evaluated using the Common Terminology Criteria for Adverse Events Version 5.0. Results: 21 patients wereincluded, of whom 22 times of SIRT were performed. 18 patients had HCC, and 3 had mCRC.The baseline characteristics of the patients are shown in Table. The median age was 54 years (IQR, 48-59 years) and 90.5% of patients were male. According to Eastern Cooperative Oncology Group performance status, grade 0 and grade 1 were 81% and 19%, respectively, whereas Child-Pugh A represented 90.5% of cases. The proportion of patients with hepatitis B virus infection was 95.2%. Thirteen (61.9%) patients received different treatments before SIRT. The median number of tumors was 2.5 (IQR, 1-4.3), whereas the median diameter of the largest lesion was 100.4 mm (IQR, 68.3-127.7 mm). PVTT was classified as follows: Vp1 (n = 3), Vp2 (n = 2), Vp3 (n = 2) and Vp4 (n = 1). Median AFP was 33.2 ng/mL (IQR, 5.9-401 ng/mL). The median total radiation activity administered was 1.4 GBq (IQR, 0.9-2.7 GBq) and the median target tissue dose was 205 Gy (IQR, 155-242 Gy). Nine (43%) patients were downstaged to surgery. Four (19%) patients had a complete response, fifteen (71.4%) had a partial response and two (9.5%) had a progressive disease. ORR and disease control rate were 90.5% and 90.5%, respectively. None of the patients experienced grade 3 and higher adverse events. The most common treatment-related adverse events were fever and abdominal pain, which required no special treatment. Conclusions: SIRT with Y90 resin microspheres combined with systemic treatment is safe and effective in patients with unresectable malignant hepatic tumors, which resulted in encouraging ORR (90.5%) and a downstaging rate (43%). Clinical trial information: ChiCTR2300077524. [Table: see text]
Effect of regulatory B cell expansion on tissue-resident TPH cells immune evasion in hepatocellular carcinoma.
Authors: Li Siqi , Yu Haoyuan , Shi Mengchen , Liang Zhixing , Li Kun , Hu Yongwei , Zhang Mingshen , Yang Yang , Ye Linsen
Published: July 2024

e16252

Background: Within pathologically inflamed nonlymphoid tissues, TPH cells are uniquely positioned to stimulate B cell responses and antibody production. The phenotype, function and clinical relevance of TPH cells in hepatocellular carcinoma (HCC), however, are presently unknown. Methods: Flow cytometry was used to quantify the expression, phenotype and function of TPH cells. Log-rank tests were performed to evaluate disease-free survival and overall survival in samples from 39 patients and 101 patients with HCC. TPH cells, CD19+ B cells and TFH cells were cultured separately in vitro or isolated from C57/B6L mice in vivo for functional assays. Results: TPH cells highly infiltrated in tumor tissues, which influenced tumor sizes and early recurrence predictions and decreased survival times. The tumor-infiltrated TPH cells showed unique ICOShiCXCL13+IL-21-MAF+BCL-6- factors and triggered naïve B cell differentiation into regulatory B cells. Triggering PD-1 induced the production of CXCL13 by TPH cells, which then suppressed tumor-specific immunity and promoted disease progression. Conclusions: Our study reveals a novel regulatory mechanism of TPH cell-regulatory B cell mediated immunosuppression and provides an important perspective for the differentiation balance between protumorigenic TPH cells and antitumorigenic TFH cells in the HCC microenvironment.
Impact of preoperative frailty on outcomes of hepatic resection among elderly patients with hepatocellular carcinoma: A comprehensive multicenter cohort study.
Authors: Dan Li , Diao Yong-Kang , Wang Nanya , Yang Yi-Fan , Gu Wei-Min , Chen Ting-Hao , Li Jie , Wang Hong , Zhou Ya-Hao , Wang Xian-Ming , Zeng Yong-Yi , Pawlik Timothy M. , Fan Zhong-Qi , Lau Wan Yee , Shen Feng , Lv Guo-Yue , Yang Tian
Published: July 2024

e16254

Background: With the increasing prevalence of hepatic resection for hepatocellular carcinoma (HCC) in the elderly, understanding the impact of preoperative frailty on surgical outcomes is crucial. This multicenter cohort study investigates the association between frailty and both short- and long-term outcomes post-hepatic resection in elderly HCC patients. Methods: This multicenter study involved elderly HCC patients (≥ 70 years) undergoing curative-intent resection at 10 hospitals in China from 2012 to 2021. Frailty was assessed using the Clinical Frailty Scale (CFS), with a score of ≥5 indicating frailty. The primary outcomes were overall survival (OS) and recurrence-free survival (RFS), while secondary outcomes included postoperative 30-day morbidity and mortality, and 90-day mortality. Comparisons were made between patients with and without preoperative frailty. Results: Out of 488 elderly patients, 148 (30.3%) were classified as frail. Frail patients had significantly higher rates of 30-day morbidity (68.9% vs. 43.2%), 30-day mortality (4.1% vs. 0.6%), and 90-day mortality (6.1% vs. 0.9%) compared to non-frail patients (all P < 0.05). Over a median follow-up of 37.7 months, frail patients showed markedly lower median OS (41.6 months [95% CI, 32.0-51.2] vs. 69.7 months [55.6-83.8]) and RFS (27.6 months [23.1-32.1] vs. 42.7 months [34.6-50.8]) than non-frail patients (both P < 0.01). Multivariable Cox regression analysis identified frailty as an independent risk factor for decreased OS (HR 1.61, P = 0.001) and RFS (HR 1.32, P = 0.028). Conclusions: Preoperative frailty is significantly associated with worse short-term and long-term outcomes following hepatic resection in elderly HCC patients. These findings underscore the importance of incorporating frailty assessment into the perioperative and postoperative care of elderly patients undergoing HCC resection.
Inpatient mortality outcomes of patients with hepatocellular carcinoma with congestive heart failure: A nationwide retrospective cohort study.
Authors: Adegbite Benjamin Olufemi
Published: July 2024

e16256

Background: Chronic conditions create challenges in improving outcomes and treatment strategies for cancer patients. In the general population, for example, congestive heart failure (CHF) has been associated with poor cardiovascular health and thus increased mortality. However, its prognostic implications in patients with hepatocellular carcinoma (HCC) are less clear despite the physiological connection of the cardiohepatic system. This study aims to elucidate the relationship between CHF and mortality among HCC patients, offering insights that could inform clinical management strategies and improve care. Methods: The 2017 – 2019 versions of the National Inpatient Sample (NIS) database from the Healthcare Cost and Utilization Project (HCUP) were used to acquire the sample population. ICD-10 codes were used to identify diagnoses and procedures. The main sample population consisted of all patients diagnosed with HCC. A multivariate regression model was used (adjusted for age, sex, race, median household income based on patient ZIP code, Charleston Comorbidity Index score, hospital region, hospital teaching status based on rural/urban setting) to calculate the adjusted odds ratio (aOR) for outcomes. First, the association between CHF and inpatient outcomes was examined. Then mortality was calculated for HCC patients receiving therapeutic interventions (chemoradiation, liver transplant, radiation, or immunotherapy) based on CHF status. Results: There were 29,396 patients with HCC. Of this amount, 3,810 patients (13%) had CHF diagnoses. For inpatient procedures, 1,120 patients (3.8%) underwent a liver transplant, 265 (0.9%) received chemotherapy, 2 (0.01%) received immunotherapy, and 5 (0.02%) received radiation therapy. The cohort of CHF patients was found to be older than non-CHF patients (70.2 ± 0.3 years and 64.3 ± 0.2 years, respectively, with p < 0.001). The multivariate regression analysis for the entire sample showed that the adjusted odds of mortality for HCC patients with CHF was 0.92 times that of not having CHF but not significant (95% CI 0.8 – 1.07, p = 0.3). The analysis was then applied to HCC patients receiving one of the four treatments during their hospitalization. Results showed that the CHF cohorts had increased odds of mortality if they received a liver transplant (aOR 20.3, 95% CI 2.5 – 165.7; p = 0.005) or chemotherapy (aOR 338.4, 95% CI 10.0 – 11428.9; p = 0.001). Conclusions: Having CHF is not a significant predictor of mortality in patients with HCC. However, when considering HCC patients undergoing liver transplantation, having comorbid CHF significantly carried about a 20-fold odds in mortality. In addition, HCC patients receiving chemotherapy had a 338-fold odds of death if they have CHF. Thus, careful consideration and planning must be taken into account to optimize patients’ cardiac status when considering treatment options.
Identification of immune biomarkers in treatment-naive patients with metastatic pancreatic cancer treated with the GSK-3 inhibitor elraglusib (9-ING-41) in combination with gemcitabine/nab-paclitaxel in the 1801 phase 2 study.
Authors: Weiskittel Taylor , Koukol Austin , Kellinger Caroline , Zhang Leiqing , Carneiro Benedito A. , Li Hu , Ugolkov Andrey , El-Deiry Wafik S. , Mazar Andrew Paul
Published: July 2024

e16331

Background: Elraglusib (9-ING-41), a potent and selective GSK-3 inhibitor, is a targeted anticancer agent with clinical activity in phase 1 trial and undergoing clinical development for the treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC). Elraglusib (9-ING-41) displayed immune-modulatory activity in preclinical models and modulation of serum cytokine profile in clinical specimens. Here, we investigated the correlation between plasma levels of cytokines/chemokines/soluble cell receptors/growth factors (CCSG) and clinical outcomes of patients with mPDAC treated with elraglusib and gemcitabine/nab-paclitaxel (GnP) in an exploratory study. Methods: CCSGs were evaluated in the pre-dose plasma samples of patients with newly diagnosed mPDAC enrolled in the 1801 phase 2 study (NCT03678883) treated with GnP (n = 13) or elraglusib/GnP (n = 32). Using a Luminex immunoassay, 40 CCSGs were screened as predictive biomarkers of median overall survival (mOS) in the elraglusib/GnP arm using 5-fold cross-validation and maximally selected rank statistic cutpoint determination. A subset of CCSGs (n = 10) was remeasured using an MSD immunoassay with greater sensitivity. Maximally selected rank statistic cutpoint determinations were conducted using MSD results for elraglusib/GnP samples with mOS and median progression free survival (mPFS). P values < 0.05 were considered statistically significant. Results: Luminex screening revealed several CCSGs significantly stratified elraglusib/GnP patients by mOS. IL-6 and IL-8 were identified as top candidates with stable and significant results on cross-validation. Using the MSD assay, both were confirmed to stratify elraglusib/GnP patients by OS and extended to analyze PFS. Low level of IL-8 conferred a better OS prognosis (HR: 0.0919, 95%, CI: 0.0205-0.411, P < 0.001) than low IL-6 (HR: 0.205, 95%, CI: 0.063-0.665, P = 0.005) in the elraglusib/GnP treated patients. Correlations with mPFS were similar in the elraglusib/GnP patients for IL-6 (HR: 0.248, 95% CI: 0.072-0.848, P = 0.02) and IL-8 (HR: 0.297, 95%, CI: 0.111-0.743, P = 0.01). Conclusions: Preliminary results of our exploratory study identified low plasma levels of IL-6 and IL-8 prior to elraglusib/GnP treatment as potential predictive biomarkers associated with improved outcomes in previously untreated patients with mPDAC. The 1801 Part 3 Arm B clinical trial recruitment has been completed. We plan to analyze additional pre-dose plasma samples obtained from approximately 200 patients by April 2024. These will be analyzed using interim OS data available by April 2024 and included in the final presentation. Clinical trial information: NCT03678883 .
Impact of treatment setting on survival outcomes in undifferentiated pancreatic carcinoma: An analysis of the National Cancer Database.
Authors: Braun John Paul , Bine Christopher Reese , Silberstein Peter T.
Published: July 2024

e16333

Background: Undifferentiated carcinoma of the pancreas is a rare and highly aggressive form of pancreatic cancer, characterized by its low degree of cellular differentiation. The prognosis for this condition remains poor, with median survival times typically not exceeding one year. While existing research indicates that treatment at academic institutions may lead to improved survival outcomes compared to non-academic settings, there is scant research on this topic in the context of undifferentiated carcinoma of the pancreas. Addressing this research gap, this study analyzes data from the National Cancer Database (NCDB) to compare long-term survival rates between patients treated at academic institutions and those at other facilities. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with undifferentiated carcinoma of the pancreas from 2004 to 2019 using the histology code 8020 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA, and Chi-Square tests were performed. Data was analyzed using SPSS version 27 and statistical significance was set at α = 0.05. Results: In this analysis of 284 patients, 124 (43.7%) received care at academic centers, while 160 (56.3%) were treated at non-academic institutions. Individuals treated at academic centers had a significantly extended mean overall survival of 27 months compared to 13.9 months for those treated elsewhere (p < 0.05). Additionally, patients at academic centers were more likely to be insured, undergo surgical interventions, receive chemotherapy, and be initially diagnosed at a different facility (p < 0.05). Conversely, patients at non-academic centers were more likely to be white, live closer to their care facility, and exhibit greater metastatic regional lymph nodes (p < 0.05). However, there was no significant association between treatment at academic centers and variables such as median income, cancer grade, and Charlson-Deyo Comorbidity Index (CDCI) (p > 0.05). Conclusions: This study revealed that individuals with undifferentiated carcinoma of the pancreas receiving treatment at academic centers exhibit a significantly improved overall survival rate compared to those treated at non-academic centers. This disparity in survival rates might be attributed to the higher prevalence of chemotherapeutic treatments and surgical interventions at academic institutions. While these observations are based on correlational data, they underscore the necessity for further investigation to establish causality.
Molecular and clinical features of pancreatic acinar cell carcinoma: A single institutional experience.
Authors: Balachandran Pillai Ashwathy , Yousef Mahmoud M.G. , Yousef Abdelrahman M.G. , Hurd Mark W. , Wang Huamin , Maitra Anirban , Willis Jason , Shen John Paul Y.C. , Pant Shubham , Smaglo Brandon George , Wolff Robert A. , Zhao Dan
Published: July 2024

e16335

Background: Acinar Cell Carcinoma (ACC) accounts for around 1% of pancreatic cancer. The molecular and clinical features of acinar cell carcinoma are less characterized. We sought to evaluate the clinical and molecular features of patients with ACC at MD Anderson Cancer Center. Methods: Patients with ACC who had germline and/or somatic molecular testing at MD Anderson Cancer Center from 2008 to 2022 were identified retrospectively. After obtaining approval of approval of the institutional review board genomic alterations including germline or somatic BRCA mutations, KRAS mutation, demographic, clinical, and pathological information were extracted from institutional databases using the Palantir Foundry software platform (Syntropy); this included natural language processing with subsequent validation by manual chart review. Overall Survival (OS) was calculated from the date of diagnosis to death or last follow-up. The Kaplan-Meier method was used for survival analysis. Results: 16 patients were identified with molecular testing results available. There were 13 males and 3 females. The median age of diagnosis was 62.5 years (range 49 -72). 14/16 patients (87.5%) had metastatic disease, one (6.25%) patient had borderline resectable disease and one (6.25%) had localized resectable disease at initial diagnosis. Median OS was for 24 months for patients with metastatic disease. There were 2 patients with mixed pathology, 1 with acinar cell carcinoma with neuroendocrine features and the 2nd had mixed acinar cell-ductal carcinoma. 15/16 (93.75%) patients were tested for KRAS and all 15 were KRAS wildtype. Somatic mutations in DNA damage repair genes (BRCA2, PALB2) were present in 3 patients (25%) and 2 patients had germline mutation (BRCA and ATM) (16%) out of 12 patients tested for those genes. 6/16 (37.5%) patients were treated with FOLFIRINOX at first line. 3/6 (50%) of these patients had partial response, 2/6 (33%) had stable disease and only 1/6 (16%) had progression. 5 patients were treated with FOLFOX based regimen and 1/5 (20%) had response, 2/5 (40%) had stable disease and 2/5 (40%) had progression of disease. 5 patients were treated with gemcitabine-based regimen and only 1 had response which received gemcitabine/nab-paclitaxel combined with cisplatin. Conclusions: ACC were KRAS wild type and had higher rates of germline/somatic mutations in DNA damage repair genes. Better treatment outcome of FOLFIRNIOX/ platinum-based regimens was suggested based on this limited patient dataset. Larger studies are needed to further understand the molecular features of ACC and guide the treatment of this rare entity of pancreatic cancer.
Correlation of significant delays and ethnic disparities in the receipt of treatment, palliative care, and supportive care interventions in pancreatic adenocarcinoma.
Authors: Gupta Aakash Rai , Richards Jefferson , Sakai Leo , Al-Manaseer Farris , Nguyen Brian , Miles Ethan , Cote Gregory Michael , Ferrell Betty R. , Joachim-Celestin Maud , Montgomery Susanne , Saumoy Monica , Reeves Mark Evan , Thiruvengadam Nikhil Ravi
Published: July 2024

e16355

Background: In patients with pancreatic adenocarcinoma (PDAC), immediate treatment initiation is preferred. Early palliative care initiation has also improved quality of life and symptom burden. However, the timing of real-world treatment and palliative care initiation and possible ethnic disparities are not well understood. The objective of this study was to evaluate the timing of care initiation in a mainly Hispanic population of PDAC patients. Methods: We conducted a retrospective cohort study that included patients diagnosed with PDAC from 2014 to 2023 at Loma Linda University Health (the only tertiary care center for two large Hispanic-majority counties with large rural populations). Data were obtained on the presence and timing of appropriate provider referrals, care establishment, treatment, advanced care planning, and hospital admissions. We used a Wilcoxon rank-sum test to compare Hispanic and non-Hispanic patients regarding the time to treatment initiation and palliative care initiation. Results: 263 PDAC patients were identified (mean age 66, 57% female, 47% Hispanic, 67% head tumor, 78% stage III/IV). After diagnosis, 93% of patients were referred to medical oncology, 82% to surgical oncology, 61% to palliative care, and 30% to genetic testing. An advanced directive or physician orders for life-sustaining treatment was completed for 24% of patients. The time to care initiation is as follows: a median of 23 days (IQR 14, 54) from diagnosis to the first medical oncology visit, 13 days (IQR 6, 37) to the first surgical oncology visit, 73 days (IQR 24, 132) to the first palliative care visit and 133 days (IQR 47, 329) to hospice referral. 64% of hospice referrals were placed within the last two weeks of life. Hispanic patients had a significantly longer time to treatment initiation (68 days vs. 48 days, p= 0.008) but similar times to palliative care initiation (73 vs 74 days, p= 0.64). Hispanics also had a lower rate of completing genetic testing (45% to 66%, p= 0.07). Conclusions: In our retrospective cohort study, significant delays in establishing care with oncology, palliative care, and hospice initiation in patients with PDAC were noted. Low rates of advanced care planning were also noted despite guideline recommendations for early-focused symptomatic interventions and advanced care planning. Hispanic patients had significantly longer time to treatment initiation and lower rates of genetic testing. These results indicate a need for improved targeted patient care navigation for multidisciplinary PDAC management, particularly in Hispanic patients.
An NCDB analysis of the predictive factors associated with the receival of tumor resection in mucinous cystadenoma of the pancreas.
Authors: Devireddy Shalika , Silberstein Peter T. , Chaddha Jasleen Kaur
Published: July 2024

e16356

Background: Mucinous cystadenoma (MCN) of the pancreas is characterized by mucin-producing cystic tumors that may lead to pancreatic ductal obstruction. While many of these cystic lesions are benign, there exists a notable risk for malignancy. Presently, the standard approach to managing MCN involves surveillance. Surgical resection is considered after evaluating histological features, the patient's age, surgical risk, and tumor size. Previous studies have linked surgical resection to favorable overall outcomes. However, no studies have investigated the predictive factors correlated to receiving surgery in MCN patients. This study aims to utilize the National Cancer Database (NCDB) to analyze factors that determine receival of tumor resection in patients with MCN of the pancreas. Methods: The NCDB was used to identify patients diagnosed with MCN of the pancreas from 2004 to 2019 using the histology codes 8470 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA Chi-Square, and Multilevel Logistic Regression were performed, and data were analyzed using SPSS version 27. Statistical significance was set at α = 0.05. Results: 827 patients with MCN of the pancreas formed the initial sample. 552 patients received a tumor resection whereas 274 patients did not receive surgery ( 66.7% vs 33.1%, respectively). Surgical patients experienced significantly longer overall survival than nonsurgical patients ( 111.2 months vs. 20.1 months, p < 0.001). Complete tumor resection with no residual tumor cells was associated with improved outcomes in MCN( p < 0.001). Metastasis to distant sites was associated with decreased likelihood of receiving surgery ( p < 0.001). Well and moderately differentiated disease, stage I, II, and II disease, treatment at an academic facility, and private insurance status were associated with increased likelihood of receiving tumor resection ( p < 0.001). Income status and race did not appear to impact overall survival of these patients. Adjuvant therapies did not appear to impact overall survival of these patients. Conclusions: The results of this research align with other studies, affirming that surgical resection yields superior outcomes in patients with MCN of the pancreas. Factors such as well or moderately differentiated disease, early-stage diagnosis, treatment at academic facilities, and private insurance status increased the likelihood of tumor resection. Distant metastasis reduced the likelihood of receiving surgery. Complete tumor removal without presence of residual tumor cells post-surgery is correlated with improved survival. Income status and race did not appear to impact overall survival, and adjuvant therapies showed no discernible effect. To improve current treatment protocols for patients with MCN of the pancreas, more research needs to be conducted on the predictive factors of receiving surgery.