bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of intensified preoperative management of locally advanced gastrorsophageal junction cancer (INPROVE).
Authors: Torresan Sara , Bortolot Martina , de Scordilli Marco , Innocente Roberto , Fumagalli Arianna , Foltran Luisa , Guardascione Michela , Di Nardo Paola , Ongaro Elena , Noto Claudia , Rota Simone , Pastò Brenno , Cannizzaro Renato , Navarria Federico , Vecchiato Massimo , Ubiali Paolo , Belluco Claudio , Petri Roberto , Guglielmi Alessandra , Puglisi Fabio
Published: July 2024

e16110

Background: The optimal management of locally advanced gastroesophageal junction adenocarcinoma (LAGEJad) is not fully established yet. Both neoadjuvant chemoradiotherapy (CRT) and perioperative taxane-based triplet chemotherapy (CT) are acknowledged treatment options for Siewert I and II cancers. In this retrospective study, we aimed to assess the safety and outcomes of an intensified preoperative regimen combining taxane-based triplet CT and CRT. Methods: We conducted a retrospective analysis of a cohort comprising 16 consecutive HER2 negative patients (pts) with LAGEJad treated at the Centro di Riferimento Oncologico of Aviano between 2019 and 2022. All pts received induction CT (iCT) consisting of fluoropyrimidine, oxaliplatin and docetaxel, followed by CRT (45Gy/25Fr) with simultaneous boost and concomitant CT. Surgery (Ivor-Lewis or McKeown) was performed 8 weeks post-CRT. Clinico-pathological (CP) and treatment features were analyzed using logistic regression to assess their association with response to iCT-CRT. The association of iCT-CRT with survival outcomes was investigated using the Kaplan-Meier method. Results: Key CP data are summarized in Table 1. Median age was 59 years, all pts were male. At diagnosis, 81.2% of pts exhibited cT3+ and cN+ disease. All pts received iCT and CRT. The rate of partial responses was 50% after iCT and 68.8% after CRT. Overall, 12 pts underwent surgery, all achieving R0 resections within a median timeframe of 9 [8.5;11] weeks post-CRT. Among them, 25% had a pathologic complete response, while 62.5% attained a Mandard tumor regression grade (TRG) of 1-2. No new safety signals emerged from iCT (only 2 pts had ≥G3 diarrhea) or CRT (≥G3 mucositis occurred in 6.2% and anemia in 6.2% of pts). No significant surgical delays were observed, although 5 pts experienced post-operative complications (4 grade I, 1 grade IIa). There were no statistically significant associations between CP variables and response to the iCT-CRT. Relapses were seen in 8 pts (2 locoregionally); 3-year survival was 46%. Median event-free survival was 5 [5;11] months, while median overall survival 34 [14;NR] months. Conclusions: The intensification of preoperative treatment in pts with LAGEJad is active and safe: the surgical schedule was not significantly delayed, and the safety profile remained comparable to standard regimens, with no major complications reported. Randomized clinical trials are ongoing to assess the clinical benefits of this approach. [Table: see text]
High versus standard radiation dose of definitive chemoradiotherapy combined with immunotherapy for inoperable esophageal squamous cell carcinoma: A multicenter propensity score matching analysis.
Authors: Chen Baoqing , Chen Biqi , Zhang Hao , Wang Bingyi , Cheng Qi , Chen Wenyan , Cheng Xingyuan , Cen Peiying , Liu Shiliang , Xi Mian , Li Qiaoqiao
Published: July 2024

e16118

Background: There is no consensus of the radiation dose for esophageal squamous cell carcinoma (ESCC) in the setting of definitive chemoradiotherapy (dCRT) combined with immunotherapy. This study aimed to compare the efficacy and safety of high-dose (HD) versus standard-dose radiotherapy (SD) for locally inoperable ESCC. Methods: Patients with locally advanced unresectable ESCC or advanced ESCC with supraclavicular lymph node metastases only who received high-dose (≥ 60Gy) or standard-dose (50-50.4Gy) radiation in dCRT combined with anti-PD-1 antibody as the first-line treatment from four academic cancer centers were enrolled. Propensity score matching (PSM) was conducted to minimize the potential confounding effects. Results: Between March 2019 and July 2022, 328 patients were enrolled from four cancer centers in China, with 163 patients in the HD and 165 patients in the SD groups, respectively. The median follow-up time in the HD and SD groups were 28.9 and 25.9 months, respectively. There was no significant difference in overall survival (OS) (median OS: not reached in both, P = 0.080), progression-free survival (PFS) (median PFS: not reached vs. 30.3 months, P = 0.073), locoregional progression-free survival (LRPFS) and distant metastasis survival (DM) between the HD and SD groups. After 1:2 PSM, 156 patients in the HD and 78 patients in the SD groups were selected for further analyses. The results remained consistent and showed that the HD group had no significant benefits in OS (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.50-1.51, P = 0.624), PFS (HR = 0.79, 95%CI = 0.51-1.23, P = 0.300), LRPFS (HR = 0.75, 95%CI = 0.47-1.19, P = 0.228) and DM (HR = 1.05, 95%CI = 0.64-1.73, P = 0.849), compared with the SD group. In terms of failure patterns, the incidences of locoregional failure only (13.5% vs. 16.7%, P = 0.512), distant failure only (10.9% vs. 9.0%, P = 0.648) and synchronous locoregional and distant failure (2.6% vs. 6.4%, P = 0.164) were similar between two groups. No significant difference was found in the incidences of hematological toxicities, esophagitis, pneumonia (12.2% vs. 10.3%, P = 0.664) and fistula (7.1% vs 9.0%, P = 0.603) between the HD and SD groups. Conclusions: Compared with a radiation dose of 50-50.4Gy, the increase in radiation dose (≥60Gy) did not result in survival benefits for inoperable ESCC patients receiving dCRT combined with immunotherapy. Furthermore, similar failure patterns and toxicities were observed between the two treatment groups.
Preclinical antitumor efficacy of ETN101, a novel oral anticancer agent with Wnt/ß-catenin signaling inhibition, TME modulation, and VEGFR2 targeting for advanced hepatocellular carcinoma treatment.
Authors: Yang HyeJin , Kim Yeoun-Hee , Choi Garam , Park Hyun Jin , Kim Yesl , Choi Min-Jin , Jang Eunbee , Jo Sang Heon , Kim Sarah , Hwang Seonghwan , Kwon Tae-Jun , Kim Dongkyu
Published: July 2024

e16138

Background: Hepatocellular carcinoma (HCC) is an important cancer in worldwide with over 900,000 new cases and approximately 830,000 deaths were reported in 2020. It ranks sixth in global cancer incidence and third in mortality, highlighting its worldwide significance. The high frequency of occurrence and elevated mortality rates contribute to a significant socio-economic burden. However, most patients are diagnosed in the middle and late stages, missing the optimal treatment. Therefore, it is necessary to develop novel, safe, and effective drugs for HCC inhibition, elucidating their mechanisms of action. Methods: Evaluation of ETN101 was utilized in subcutaneous xenograft and orthotopic animal models with human HCC cell lines. ETN101 was administered orally. The tumor volume, tumor weight, and bodyweight were measured, and cancer cell proliferation and apoptosis were also analyzed. The toxicity of ETN101 was investigated through GOT/GPT and histological analysis in the liver and kidney. The signaling mechanism of ETN101 was analyzed through kinase analysis, phosphorylation, in silico docking analysis, and RNA sequencing, both in vitro and in vivo. Results: ETN101 demonstrated approximately 30% tumor inhibition at 10 mg/kg group compared to control. Moreover, 20 mg/kg treatment group also showed significant tumor reduction in all individuals with one complete response (CR). Interestingly, all individuals exhibited CR from 40 to 82 mg/kg treatment groups. During the 10 administrations of Nexavar and Lenvatinib, individuals who showed proliferated tumors persistently were selected, followed by the administration of ETN101. All individuals exhibited either CR or significant reduction in tumor volume upon ETN101. After tracking complete responders for two months, there were no signs of tumor recurrence or metastasis. These results suggested that ETN101 has anticancer effect by regulating Wnt/ß-catenin pathway in tumor microenvironment (TME) with increasing the infiltration of cytotoxic T cells into the tumor. Furthermore, it targets VEGFR2, blocking angiogenesis-related signals to improve therapeutic effects in advanced HCC. Conclusions: Due to lack of effective single drugs for advanced HCC patients, combination therapy is used clinically. We developed ETN101, a monotherapy that targets VEGFR2 and modulates the TME with the same mechanism as the combination therapy. ETN101 also showed excellent efficacy in preclinical study and secured a broad safety margin relative to the effective dose. In addition, ETN101 was effective in those who are not responded to conventional targeted cancer therapies. It is anticipated that ETN101 could serve as a novel therapeutic strategy for advanced HCC patients.
Efficacy and safety of regorafenib plus ICIs as second-line treatment in advanced HCC post-frontline treatment failure: A real-world study from a single center.
Authors: Meng Lingzhan , Li Hu , Yu Peng , Cao Li , Wang Zizheng , Yan Jin , Shao Yanling , Shi Bin , Zhu Zhenyu
Published: July 2024

e16141

Background: Tyrosine kinase inhibitor or bevacizumab (TKI/Bev) combined with immune checkpoint inhibitors (ICIs) currently represent the preferred frontline therapy for patients with Hepatocellular Carcinoma (HCC). Despite this, clinical evidence guiding therapeutic choice for patients unresponsive to this initial immunotherapy regimen remains scarce. This real-world study aimed to assess the efficacy and safety of regorafenib combined with ICIs in patients with HCC who have exhibited disease progress during treatment with TKI/Bev plus ICIs. Methods: This retrospective analysis encompassed a cohort of patients who transitioned to a combined regimen of regorafenib and immune checkpoint inhibitors (ICIs) after the progression of hepatocellular carcinoma (HCC) following treatment with tyrosine kinase inhibitors (TKIs) or a combination of bevacizumab and ICIs, from January 2019 to November 2023. Key efficacy metrics included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The adverse events (AEs) were systematically classified in accordance with the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0). Results: A total of 37 patients were included; 56.8% were Child-Pugh A and 43.2% were Child-Pugh B. Treatment regimens prior to regorafenib and ICIs were lenvatinib plus ICIs in 83.8% of patients, sorafenib plus ICIs in three patients, apatinib plus ICIs, donafenib plus ICIs, and bevacizumab plus ICIs each in one patient. The ORR was 27.0% (10/37), and the DCR was 92.0% (28/37) according to mRECIST criteria. The median PFS was 7.8 months (95% CI, 6.0-9.6). The 6-month and 12-month PFS rates was 60.6% (95% CI, 46.4-79.2) and 40.0% (95% CI, 26.0%-61.6%). The median OS post-regorafenib and ICIs was 16.3 months, with 12-month and 24-month OS rates of 67.0% and 49.7%, respectively. The median OS since first-line treatment initiation was 35.8 months, with OS rates of 94.4% and 72.3% at 12-month and 24-month since first-line treatment initiation, respectively. Subgroup analysis indicated no statistical significance in median PFS between patients with lung metastasis and those without lung metastasis [3.9 months (95% CI, 3.0-4.8) vs 7.80 months (95% CI, 6.1-9.5); P=0.178], but there was a trend toward survival benefit in patients without lung metastasis. Grade 3-4 adverse events were reported in 16.22% of the patients, with no treatment-related fatalities. Conclusions: Regorafenib with ICIs is a promising and tolerable second-line treatment for advanced HCC after initial therapy failure.
CVM-1118: A potent oral anti-vasculogenic mimicry (VM) agent in combination with nivolumab in patients with unresectable advanced hepatocellular carcinoma (HCC)—A phase IIa study.
Authors: Yen Chia-Jui , Huang Yi-Hsiang , Yeh Kun-Yun , Chen Pei-Jer , Lu Sheng-Nan , Gutheil John , Melink Teresa J. , Chen Yen-Ling , Chen Chun-Man , Chao Ting-Yu , Chu Yi-Wen , Chien Du-Shieng
Published: July 2024

e16150

Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. This study evaluated the anti-tumor effect and safety profile of CVM-1118 plus nivolumab in patients with progressive unresectable advanced HCC following the first-line therapy with TKIs. Methods: Eligible pts had unresectable advanced HCC and were refractory to prior systemic therapy (e.g., sorafenib, lenvatinib, regorafenib, and/or ramucirumab), with the exception of prior immunotherapy. Patients received oral CVM-1118 at 200 mg BID (400 mg daily) in combination with intravenous nivolumab at 240 mg Q2W in 28-day cycles. The primary endpoint of objective response rate was evaluated using mRECIST. The secondary endpoints were overall response rate (ORR) (per RECIST 1.1), progression free survival (PFS), disease control rate (DCR), and duration of overall response (DoR). Results: A total of 31 evaluable pts were enrolled (25 M/6 F; median age 65 y, range 44–80 y). All patients were Child Pugh A, BCLC stage B (13%, n = 4) or C (87%, n = 27) at the start of treatment. The median number of prior lines of therapy was 1 (range 1–2). The duration of CVM-1118 and nivolumab treatment ranged from 1.5–15.0 mos (median 3.1 mos) with 5/31 (16%) pts remaining on treatment for ≥ 4.6 mos (range 4.67–15.0 mos). The best ORR was 19.4% (mRECIST) (2 CR (6%), 4 PR (13%)), with remaining responses including 11 SD (36%) and 14 PD (45%). The DCR was 54.8% (95% CI 37.3–72.3%), the median PFS was 3.53 mos (95% CI 1.9–5.4 mos) and the median DoR was 10.4 mos (95% CI 2.8–13.7 mos). The most common treatment-related AEs ³ grade 3 included AST increased (12.9%), neutrophil count decreased (9.7%), anemia (6.5%), and WBC decreased (6.5%). As opposed to therapy with atezolizumab plus bevacizumab, gastrointestinal hemorrhage and hypertension were not observed in this study. Pharmacokinetics data demonstrated that CVM-1118 was rapidly metabolized to CVM-1125 in all pts following administration. On Day 1, the mean drug exposure of CVM-1125 was Cmax 564 ng/mL and the AUC0-24 was 2154 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T1/2 of CVM-1125 was ~1.7 hr. Conclusions: CVM-1118 combined with nivolumab demonstrated clinical activity in advanced HCC pts with a safety profile that appears favorable compared to atezolizumab plus bevacizumab. These data support further development of the combination of CVM-1118 and nivolumab in pts with unresectable advanced HCC. Clinical trial information: NCT05257590 .
Transcatheter arterial chemoembolization combined with immune checkpoint inhibitors plus bevacizumab or lenvatinib in hepatocellular carcinoma: Results from a retrospective dual-center cohort study.
Authors: Jiang Yi , Shu Mingzhi , Yao Zheng , Liang Weiren , Sheng Jiayi , Ding Yinan , Zheng Jiaping , Shao Guoliang , Mao Junjie , Luo Jun
Published: July 2024

e16159

Background: Hepatocellular carcinoma (HCC) ranks as the sixth most prevalent cancer worldwide. Notably, over 80% of HCC cases are diagnosed at an intermediate to advanced stage. Transcatheter arterial chemoembolization (TACE) is globally acknowledged as the standard local treatment for intermediate HCC and remains the predominant care for advanced HCC, While lenvatinib (LEN) or the combination of bevacizumab (BEV) and atezolizumab is recognized as a first-line systemic therapy for HCC. Moreover, TACE+LEN+immune checkpoint inhibitors (ICIs) in the treatment of HCC significantly enhances OS and PFS compared to the TACE+LEN. However, comparative studies between TACE+ICI+BEV and TACE+ICI+LEN are still forthcoming. Methods: This retrospective study encompasses data from 64 patients diagnosed with intermediate to advanced unresectable HCC at two medical centers in China between January 2021 and June 2023. The study's primary outcomes were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included tumor response and conversion rates. Additionally, the study assessed the safety by adverse events (AE) across the two groups. Results: Of the 64 enrolled patients, 31 were treated with TACE+ICI+BEV and 33 with TACE+ICI+LEN. There was no significant difference in PFS between the two groups (5.7 months [95% confidence interval (CI) 5.2 to 7.9] versus 4.9 months [95% CI 4.5 to 7.7], P=0.404). The median OS for the TACE+ICI+LEN group was 21.3 months (95% CI 15.1 to 27.5), whereas the median OS in TACE+ICI+BEV group was not reached. A markedly higher proportion of patients in the TACE+ICI+BEV group achieved surgical conversion (22.6% versus 3.0%, P=0.047). Patients presenting with an alanine aminotransferase (ALT) level ≤40 u/L (hazard ratio [HR]=5.61, 95% CI 1.09-28.80, P=0.039) and without hepatic vein invasion (HR=31.6, 95% CI 1.03-9.68, P=0.044) appeared to derive greater benefit from the TACE+ICI+BEV regimen. Furthermore, patients with a Child-Pugh score of class A exhibited enhanced response to the triple-combination therapy (HR=6.17, 95% CI 1.86-20.53, P=0.003). Both therapeutic strategies were characterized by favorable safety profiles. Conclusions: TACE+ICI+BEV has demonstrated notable potential in increasing surgical conversion rate in the management of intermediate to advanced HCC, suggesting enhanced outcomes particularly in patients with superior liver function. [Table: see text]
Plasma growth hormone as a prognostic biomarker to durvalumab and tremelimumab in patients with advanced hepatocellular carcinoma.
Authors: Chamseddine Shadi , LaPelusa Michael Brian , Xiao Lianchun , Abugabal Yehia I. , Lee Sunyoung S. , Hu Zishuo Ian , Hu Zishuo Ian , Hatia Rikita , Hassan Manal , Yao James C. , Duda Dan G. , Datar Saumil , Amin Hesham M. , Kaseb Ahmed Omar
Published: July 2024

e16161

Background: In this study, we explored the potential of plasma growth hormone (GH) as a prognostic biomarker in patients with advanced HCC treated with durvalumab plus tremelimumab (D+T). Methods: In this study, we included 24 patients with advanced HCC who received D+T at MD Anderson Cancer Center between 2022 and 2023. Plasma GH levels were measured from prospectively collected blood samples from 16 of the 24 patients and were correlated with progression-free survival (PFS) and overall survival (OS). The cutoff for normal GH levels in women and men was defined as ≤3.7 μg/L and ≤0.9 μg/L, respectively. The Kaplan-Meier method was employed to compute the median OS and PFS, while the Log-rank test was applied to compare the survival outcomes between the GH-high and GH-low groups. Results: Twenty-four patients were included in this analysis, four female and twenty male, with a median age of 66.5 years. Of these 24 patients, 16 had GH levels available for analysis. At the time of the analysis, the 6-month OS rate was 100% among GH-low patients (6 patients) and 30% among GH-high patients (10 patients). OS was significantly longer in GH-low patients (not evaluable) compared to GH-high patients (3.94 months) (p = 0.030). PFS was also significantly longer in GH-low patients (not evaluable) compared to the GH-high patients (1.87 months) (p = 0.036). Conclusions: Plasma GH is a prognostic biomarker in patients with advanced HCC treated with D+T. Given the relatively small patient cohort size, this finding should be further validated in larger randomized clinical trials in advanced HCC patients.
Tislelizumab in combination with GEMOX and lenvatinib for conversion therapy of unresectable extrahepatic biliary tract carcinoma (eBTC): A prospective, single-arm, phase 2 study.
Authors: Liu Qu , Chang Zhengyu , Zhao Guodong , Gao Yuanxing , Tan Xianglong , Zhang Xuan , Jin Hailong , Liu Rong
Published: July 2024

e16163

Background: Resection is the only possibility for cure but only less than 1/3 patients with BTC are diagnosed at resectable stages. PD-1 monoclonal antibody plus GEMOX and Lenvatinib regimens have shown promising efficacy for intrahepatic cholangiocarcinoma. However, owing to the extrahepatic and intrahepatic BTC are highly heterogeneous, the efficacy of combination regimen on eBTC is not clear. In this study, we explored the efficacy and safety of Tislelizumab plus GEMOX and Lenvatinib for conversion therapy of unresectable eBTC. Methods: In this prospective, single-arm phase 2 study, major eligible criteria were unresectable locally advanced or metastatic extrahepatic BTC, no previous systemic treatment, ECOG PS 0 or 1. Patients received tislelizumab (200 mg, iv, d1, every 3 weeks) in combination with GEMOX (gemcitabine: 1000 mg/m2, iv, d1,d8, every 3 weeks; oxaliplatin: 85 mg/m2, iv, d1, every 3 weeks) and Lenvatinib (bodyweight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day, po) until disease progression, intolerable toxicity or surgery. Surgery was performed after treatment response was assessed to meet the criteria of resection. Primary endpoint was the rate of radical resection. Second endpoints included ORR, DCR per RECIST 1.1, and safety, major pathologic response (MPR), PFS, OS. Results: Between Mar 1st 2022 and Feb 1st 2024, 35 patients were enrolled with a median age of 57.5 years (range 52-65); 20 males (57.1%), 15 females (42.9%); ECOG PS 0 (n = 13, 37.1%) or 1 (n = 17, 62.9%); 7 distal cholangiocarcinoma (20.0%), 16 hilar cholangiocarcinoma (45.7%), 12 gallbladder carcinoma (34.3%). 30 patients were evaluated for tumor response. The best overall responses were 2 complete response (6.7%), 16 partial response (53.3%), 9 stable disease (30.0%) and 3 progressive disease (10.0%). The ORR was 60.0% and DCR was 90.0%. 7 patients (20.0%) received radical resection and the complete pathological response (pCR) rate was 42.9% (n = 3). Any-grade adverse events (AEs) occurred in 91.4% (n = 32) patients. Grade 3-4 AEs occurred in 20.0% (n = 7) patients. The most frequent grade 3-4 AEs (incidence > 5%) were thrombocytopenia (8.6%), elevated AST/ALT (8.6%), neutropenia (5.7%) and leukopenia (5.7%). No grade 5 AEs. Conclusions: Tislelizumab plus GEMOX and Lenvatinib showed promising efficacy with manageable safety profile for conversion therapy of unresectable extrahepatic BTC. More patients were recruiting to further prove these results. Clinical trial information: ChiCTR2200056808.
A retrospective analysis of efficacy and safety of lenvatinib combined with PD-1 inhibitor and chemotherapy in advanced biliary tract cancer (BTC).
Authors: Li Hu , Meng Lingzhan , Yu Peng , Cao Li , Wang Zizheng , Yan Jin , Shao Yanling , Shi Bin , Zhu Zhenyu
Published: July 2024

e16173

Background: Lenvatinib combined with PD-1 inhibitor and chemotherapy has showed a relatively high antitumor activity for ICC in phase 2 clinical trials. This study retrospectively analyzes the efficacy and safety of real-world lenvatinib combined with PD-1 inhibitor and chemotherapy in BTC. Methods: Patients with advanced BTC who received lenvatinib combined with PD-1 inhibitor plus oxaliplatin and gemcitabine (Gemox) chemotherapy were retrospectively screened. The overall survival, progression-free survival, objective response rate, disease control rate and safety were evaluated. Results: From Jan 2021 to Apr 2023, 27 pathologically-confirmed advanced BTC pts were enrolled. The median age is 61 (range, 39-74) years, 18 (66.7%) were male. Fourteen patients had TNM stage Ⅳdisease, and 7 patients had stage III. Twenty-six (96.3%) patients had an ECOG performance status of 1. All patients were child-pugh A. Fourteen patients had metastasis, 8 patients with lymph node metastasis, 4 with bone metastasis. 11 (40.7%) had positive PD-L1 expression. At baseline, 18 (66.7%) patients had a CA19-9 level > 200 U/mL. The median CEA level was 3.56 ng/mL; 48.1% of the patients had a level > 5 ng/mL. At the date cut off (Dec 15, 2023), the median follow-up time was 10.4 months (range: 4.8-25.7). ORR was 70.4% (19/27), and disease control rate (DCR) was 85.2% (23/27). Three pts with locally advanced disease were down-staged and then underwent resection. They remained disease-free survival at the end of last follow-up. The median PFS was 9.0 months (95% CI: 4.0-14.0) and median duration of response (DOR) was 9.8 months. The median OS was 20.4 months (95% CI: 13.6-27.2). 12-months OS rate was 73.3% (95% CI: 57.5%-89.2%).20/27 pts experienced treatment-related adverse events (AE). No grade 5 AE was observed. The most common AE was fatigue 66.7% (18/27), headache 7.4% (2/27). Grade 3 fatigue and grade 3 kidney injury occurred in 1 patient separately. Conclusions: Lenvatinib combined with PD-1 inhibitor and Gemox chemotherapy provided remarkable efficacy with reasonable tolerability in advanced BTC patients.
Liquid biopsy-based prediction of clinical benefit from immune checkpoint inhibitors in advanced biliary tract cancer.
Authors: Zhang Nan , Wang Yunchao , Yuan Mingming , Shao Jing , Chen Rongrong , Piao Mingjian , Li Jiongyuan , Li Chengjie , Zhang Longhao , Xue Jingnan , Wang Yanyu , Xun Ziyu , Wang Shanshan , Li Yiran , Sun Huishan , Wang Hanping , Zhao Hai-Tao
Published: July 2024

e16179

Background: Immune checkpoint inhibitors (ICIs) show promising efficacy as first-line therapy for advanced biliary tract cancer (aBTC), but validated predictive biomarkers are lacking. Here, we identified liquid biopsy-based biomarkers and developed a prediction model. Methods: aBTC patients who received ICIs-based combination therapy as the first-line treatment were prospectively enrolled in this study (NCT06074029). Plasma samples were collected before the first and second immunotherapy infusion to perform cell-free DNA (cfDNA) sequencing of 1021 genes. Circulating tumor DNA (ctDNA) concentration was calculated by multiplying the mean variant allele frequency by the cfDNA concentration and ctDNA fold change was calculated by dividing on-treatment ctDNA concentration by the pre-treatment ctDNA concentration. Tumor mutation burden (TMB) was normalized using the cfDNA concentration. In addition, RNA was extracted from peripheral blood mononuclear cells to profile the leukocyte transcriptome using whole transcriptome sequencing, and the relative proportions of immune cells in leukocytes was deconvoluted using CIBERSORT algorithm. Log-rank and univariate Cox regression were used to evaluate the relationship between features and progression-free survival (PFS). Results: 37 patients were enrolled, with 62.2% having intrahepatic cholangiocarcinoma. The median age was 61 years and 54.1% of patients were females. The median PFS was 4.4 months. Variables related to PFS with the log-rank p value smaller than 0.05 (Table) were entered into a multivariate Cox regression using a stepwise approach for final variable selection. As a result, ctDNA fold change, KRAS mutation, and resting memory CD4 T cell level were used to construct a COX regression model to predict clinical benefit from ICIs. The model predicting 6-month PFS demonstrated an AUC of 0.909 (95% CI, 0.795-1.024). Internal validation, performed through a bootstrap analysis with 100 iterations, yielded an optimism-adjusted AUC estimate of 0.859. Conclusions: Our preliminary results support the excellent performance of this liquid biopsy-based multivariable model to early predict durable benefit from ICIs in aBTC. A large sample size and verifying this model with internal and external data are warranted. Clinical trial information: NCT06074029 . [Table: see text]
Effect of immune checkpoint inhibitor administration timing on survival outcomes in advanced biliary tract cancers: A single-center propensity score matching analysis.
Authors: Zheng Yichen , Shi Fanfan , Peng Wei , Ma Ji
Published: July 2024

e16186

Background: Circadian rhythms in the immune system and anti-tumor immune responses have not received adequate attention in terms of their impact on cancer immunotherapy. Recent advances in immune checkpoint inhibitors (ICIs) have marked a significant breakthrough in the treatment of advanced biliary tract cancer (BTC), but not all patients benefit from this therapy. Our study aimed to investigate whether the timing of ICI administration affects the treatment outcomes in BTC patients. Methods: We included patients with advanced BTC patients at West China Hospital of Sichuan University who received at least two ICI treatments from October 2019 to May 2023, with follow-up until December 2023. The primary outcome was overall survival (OS), with secondary outcomes including progression-free survival (PFS), objective response rate (ORR), and adverse event incidence. Propensity score matching (1:2 ratio, nearest-neighbor caliper width of 0.1) and COX regression were used to analyze the relationship between the proportion of ICI administrations after 16:30 and both OS and PFS, while the Chi-square test was used to compare the ORR and adverse event rates between groups. Results: A total of 207 patients were eligible for analysis. Before matching, 37 patients had more than 20% of their ICI administrations after 16:30, and 170 had less than 20%. After matching, 34 patients receiving more than 20% of ICIs after 16:30 were compared with 65 who did not. The former group showed significantly shorter OS (median 10 months [95%CI: 8-14 months] vs. 17 months [95%CI: 12-20 months], HR = 2.067 [95%CI: 1.226-3.485, P = 0.00645]) and PFS (median 5 months [95%CI: 4-7 months] vs. 9 months [95%CI: 8-12 months], HR = 2.093 [95%CI: 1.315-3.331, P = 0.00183]), with these results remaining robust after multivariate Cox regression analysis. No significant difference in ORR (χ^2 = 2.287, p = 0.131) was observed. Safety analysis showed no difference in the incidence of adverse events, including Grade 3/4 adverse events, immune-related adverse events, and medication discontinuation due to adverse events (all p > 0.050). Sensitivity analyses in patients receiving at least three ICI treatments revealed similar results. Conclusions: The timing of ICI administration influences the efficacy of immunotherapy in advanced biliary cancer, with administrations before 16:30 associated with better survival outcomes. Further research with larger sample sizes and prospective studies is needed to validate these findings.
A prospective cohort study on the improvement of disease-free progression survival in patients with hepatocellular carcinoma by combining Sophora japonica granules with targeted and immune checkpoint inhibitors.
Authors: Li Hui , Zhang Hongliang , Zhang Tong , He Wenting
Published: July 2024

e16187

Background: To evaluate the clinical efficacy of combining Sophora japonica granules with targeted therapy and immune checkpoint inhibitors (ICIs) in patients with unresectable hepatocellular carcinoma (HCC) who had not undergone systemic treatment. Methods: A prospective cohort study design was adopted (ChiCTR2400079626), collecting HCC patients visited the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region from July 1, 2019, to July 1, 2023. All patients received targeted therapy and ICIs treatment. "Whether Sophora japonica granules were combined during treatment" was considered as the exposure factor. Patients who met this exposure factor were included in the exposure group (n = 48), and those who did not meet this factor were included in the non-exposure group (n = 44). The disease-free survival (PFS), six-month PFS rate, and subgroup analysis between two groups. Results: The PFS of the exposure group was 8.9 months (m), and that of the non-exposure group was 5m(P = 0.001 HR = 0.50, 95%CI (0.32~0.78)). The six-month PFS rates were 66.7% compared to 34.1%(P = 0.001). Subgroup analysis showed that in subgroups with hepatitis, cirrhosis, vascular invasion, extrahepatic metastasis, tumor maximum diameter ≥5cm, combined TKI, the exposure group had significantly longer PFS than the non-exposure group (respectively: 9m VS 5m, 10m VS 4m, 13m VS 3m, 8.3m VS 4m, 9m VS 4m, 9m VS 5m),(P < 0.05). In the subgroup with a history of alcohol consumption, the exposure group's PFS was extended by 9 m (14m VS 5m; P = 0.010); in the subgroup with baseline AFP ≥400ng/ml, PFS was extended by 6m (9m VS 3m; P = 0.017), and in the subgroup with baseline AFP < 400ng/ml, PFS was also extended by 2.9m (8.9m VS 6m; P = 0.024), with all differences being statistically significant. Multivariate analysis showed that extrahepatic metastasis was an independent prognostic factor, with a disease progression risk 1.77 times higher than that of patients without extrahepatic metastasis [HR = 1.77, 95%CI (1.11~2.81), P = 0.016]. Combining Sophora japonica granules was a protective factor [HR = 0.53, 95%CI (0.33~0.84), P = 0.006], reducing the risk of disease progression in HCC patients treated with targeted therapy and ICIs by 47%. Conclusions: Combining Sophora japonica granules can extend the progression-free survival of HCC patients treated with targeted therapy and ICIs, increase the six-month PFS rate, and significantly reduce the risk of disease progression. The survival benefit was more pronounced in subgroups with vascular invasion and a history of alcohol consumption, with PFS exceeding one year. After combining Sophora japonica granules, the survival benefit improved more in the ICIs + TKI subgroup compared to the ICIs + bevacizumab subgroup. Clinical trial information: ChiCTR2400079626.
A retrospective study of PD-1/PD-L1 combination therapy versus TKI monotherapy in elderly patients with uHCC.
Authors: Wang Nanya , Li Yu , Wang Ying , Liu Bo , Wang Shibo
Published: July 2024

e16191

Background: The rising elderly population worldwide has led to an increase in cases of liver cancer among individuals aged ≥65 years. With the advancement of medical treatments, the management of unresectable hepatocellular carcinoma (uHCC) now predominantly involves immunotherapy combination therapy. However, existing data in elderly patients are limited. Therefore, we conducted a retrospective analysis on the efficacy and safety of immune combination therapy compared with TKI monotherapy in elderly uHCC patients. Methods: A retrospective analysis was conducted on uHCC patients aged ≥65 years at the First Hospital of Jilin University between March 2019 and July 2023. The targeted therapy used in this study included, but not limited to, sorafenib, lenvatinib. PD-1/PD-L1 inhibitors such as pembrolizumab and atezolizumab were also utilized. Follow-up was conducted until death, loss to follow-up, or December 2023. The primary endpoint was overall survival (OS), while the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), adverse events (AEs) and immune-related AEs (irAEs). Results: A total of 70 patients were included in this study, with 33 patients receiving monotherapy, and 37 patients receiving immune combination therapy. The median age was 68 years old, with 78.8% being male. The combination therapy group had a higher ORR (10.8% vs. 3.0%) DCR (48.5% vs. 45.9%) compared to the monotherapy group. However, there were no statistically significant differences in median PFS (7.0 vs. 12.0 months) and median OS (9.8 vs. 17.5 months) between the two groups. Among the subgroups, combination therapy showed better results except for patients with ascites. Immune combination therapy appeared to be superior to monotherapy in terms of both PFS (6.2 vs. 6.8 months, P = 0.888) and OS (6.8 vs. 10.2 months, P = 0.888). Multivariate analysis showed that elevated total bilirubin may be a risk factor for OS in patients ≥65 years old. Regarding safety, the adverse event (AE) rate was 39.3% in the monotherapy group. The most common AEs reported were abdominal distension (18.2%), fatigue (15.2%), and proteinuria (6.1%). In the combination therapy group, the AE rate was higher at 59.4%, with the most common AEs being thyroid function abnormalities (24.3%), fatigue(24.3%), decreased appetite(18.9%), and hypertension(18.9%). The rate of drug withdrawal due to adverse reactions was significantly higher in patients receiving combination therapy compared to those receiving monotherapy (40.5% vs. 12.1%, P = 0.008). Conclusions: In elderly uHCC patients (≥65 years old), immune combination therapy shows a higher ORR and potentially longer PFS and OS except patients with ascites. AEs and drug withdrawal rates are higher in the combination therapy group. Further discussions are needed to determine the optimal treatment strategy for elderly uHCC patients.
Role of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte-ratio (PLR) in unresectable hepatocellular carcinoma (uHCC): Subgroup analysis of patients treated with camrelizumab (cam) + rivoceranib (rivo) in the CARES-310 trial.
Authors: Burgoyne Adam , Kaseb Ahmed Omar , Shi Wei , Alexander Laura , Meng Xianzhang , Ryan Kristin , Galloway Chris , Neubach Will , Vogel Arndt , Chan Stephen Lam
Published: July 2024

e16197

Background: CARES-310 (NCT03764293) evaluated the combination of the PD-1 inhibitor, cam, and the VEGFR-2 tyrosine kinase inhibitor, rivo, compared to sorafenib (sor) for the treatment of 543 patients (pts) with uHCC. Cam + rivo significantly improved mOS (22.1 months [mo] [95% CI 19.1-27.2] vs 15.2 mo [13.0-18.5] HR 0.62 [95% CI 0.49-0.80]; one-sided p < 0.0001) and mPFS (5.6 mo [95% CI 5.5-6.3] vs 3.7 mo [2.8-3.7]; HR 0.54 [95% CI 0.44-0.67]; one-sided p < 0.0001) compared to sor. The most common (≥20%) grade ≥3 treatment-related adverse events (TRAEs) for cam + rivo were hypertension (37.5%) and increased AST (16.5%) vs palmar-plantar erythrodysesthesia syndrome (15.2%) for sor. An elevated level of inflammation, including NLR and PLR, have been associated with poor survival outcomes in pts with HCC (Lin S, et al. Trans Cancer Res. 2021). Here, we present a subgroup analysis of the CARES-310 trial evaluating the impact of baseline (BL) NLR and PLR status on pt outcomes. Methods: The subgroup of pts treated with cam+rivo and BL NLR < 5 or ≥5 and PLR < 300 or ≥300 were evaluated for mOS, mPFS, overall response rate (ORR), disease control rate (DCR), and safety. Results: Of 272 pts treated with cam+rivo, 64.3% of pts had extrahepatic spread, median AFP was 84.1 ng/mL, 86.8% were Child-Pugh (CP) class A5, 13.2% were CP class A6, 73.5% were ALBI grade 1, 26.5% were ALBI grade 2. Additionally, 249 pts had NLR < 5, 10 pts had NLR ≥5, 252 pts had PLR < 300, and 7 pts had PLR ≥300. Pts with BL NLR < 5 and PLR < 300 demonstrated improved outcomes in mOS, mPFS, ORR, and DCR vs pts with BL NLR ≥5 and PLR ≥300 (Table). Rates of any grade TRAEs and grade ≥ 3 TRAEs were comparable between pts with BL NLR < 5 and ≥5 and PLR < 300 and ≥300 (Table). Conclusions: These results suggest that NLR and PLR may serve as a prognostic marker in patients with uHCC, but larger studies are needed to validate these findings. Clinical trial information: NCT03764293 . [Table: see text]
Hepatic artery infusion of FOLFOX chemotherapy and camrelizumab combined with sorafenib for advanced stage hepatocellular carcinoma (Double-IA-001): A phase II trial.
Authors: Nuerhashi Gulijiayina , Shen Lujun , Fan Weijun
Published: July 2024

e16199

Background: Hepatic arterial infusion chemotherapy (HAIC) using a combination of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) has shown excellent local control for hepatocellular carcinoma (HCC) patients classified under Barcelona Clinic Liver Cancer (BCLC) stage C. In China, both camrelizumab (a PD-1 inhibitor) and sorafenib were approved first-line approach for advanced stage HCC. This study (ChiCTR2100041874) aimed to the efficacy of combined hepatic artery infusion of FOLFOX chemotherapy and camrelizumab, together with sorafenib in BCLC stage C. Methods: Eligible patients were given a maximum of six cycles of hepatic artery infusion of HAIC-FOLFOX and camrelizumab, along with sorafenib, until either disease progression, intolerable toxicities emerged or disease downstaged and converted to received surgical resection. The primary outcome measured was the objective response rate (ORR) based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results: Twenty-five patients were enrolled. Based on mRECIST criteria, by the end of Feb 4, 2024, the confirmed ORR stood at 44.0%, with a disease control rate of 60.0%. The median progression-free survival was 3.33 months. Patient quality of life had a transient deterioration within four cycles of treatment, and generally recovered thereafter. A total of 28.0% of patients had grade ≥3 or above treatment-related adverse events, which could be alleviated after symptomatic treatment. Conclusions: The combination of double intrahepatic infusion of FOLFOX and camrelizumab with sorafenib demonstrated encouraging results and manageable safety concerns for BCLC stage C HCC. Clinical trial information: ChiCTR2100041874.
Impact of cholangiocarcinoma on the severity of acute cholangitis: A nationwide sample analysis.
Authors: Khan Shahryar , Amin Muhammad Kashif , Khan Muhammad Atif , Asif Samia , Khan Mashal Alam
Published: July 2024

e16200

Background: Acute cholangitis (AC) is a clinical entity caused by bacterial infection of the hepatobiliary system, commonly secondary to obstruction of the bile duct or hepatic ducts. The outcomes are poor if not treated promptly. Cholangiocarcinoma (CC) is a group of heterogeneous cancers of the intrahepatic or extrahepatic bile ducts with a guarded prognosis. Our study aimed to evaluate the mortality and healthcare utilization of AC with and without CC in the United States. Methods: A retrospective cohort study of adult patients hospitalized in 2020 for AC in acute care hospitals across the USA. Patients were selected from the Nationwide Inpatient Sample (NIS) database. Our study population included all patients with a discharge diagnosis of AC with or without CC using the International Classification of Diseases (ICD-10). The primary outcome was in-hospital mortality, and secondary outcomes were the proportions of Endoscopic Retrograde Cholangiopancreatography (ERCP), early ERCP (within 24 hours), length of hospital stay (LOS), and total hospitalization charges. Analysis was performed using STATA version 18.0. Univariable logistic regression analysis was used to calculate the unadjusted odds ratio (ORs) for the primary and secondary outcomes. Multivariable logistic regression analysis was used to adjust for potential confounders. Results: Out of 32 million discharges included in the NIS database for 2020, our study included 38465 with AC including 2692 with CC and 35772 without CC. Comparing both cohorts, patients with AC, and CC were less likely to be female or white and had a higher Charlson comorbidity index. Furthermore, patients with AC and CC had lower adjusted in-hospital mortality (OR 0.66, 95% CI: 0.45-0.96), lower LOS(mean difference 1.102, CI: 0.31-1.88), lower total hospitalization charges $ (mean difference 22463, CI: 12115-32810). Patients with AC and CC had higher adjusted rate of in-hospital ERCP (OR 1.29, 95% CI: 1.07—1.56), and early ERCP within 24 hours (OR 1.29, 95% CI: 1.03-1.62). Total mortality in AC was found to be 6.8% (n = 2630, CI: 2374-2885), whereas mortality in CC from AC was 5.7%. Conclusions: Cholangiocarcinoma was observed to have an impact on the in-hospital mortality outcome of Acute cholangitis with increased utilization of resources, including ERCP. However, lower mortality from AC in CC is potentially contributed by early ERCP within 24 hours and a lower Charlson comorbidity index than AC without CC. [Table: see text] [Table: see text]
Survival of primary gallbladder cancer in the United States: SEER database analysis from 2000-2020.
Authors: Guragain Ashish , Inban Pugazhendi , Vaz Clint , Cheriyath Pramil , Nookala Vinod , Poudel Urusha , Kansakar Sajog , Shikhrakar Shreeja , Maroules Michael
Published: July 2024

e16210

Background: Primary gallbladder cancer is a rare but aggressive cancer with poor outcomes. Our study aims to understand the survival trends of patients with Primary gallbladder cancer (PGC) and analyze the prognosis factors based on cases registered in the SEER database from 2000 to 2020. Methods: We usedSEER*Stat Version 8.4.3 software to extract primary gallbladder carcinoma cases from SEER 17 registries (2000-2020). 20,143 patients were included in the study. Those with unconfirmed histology were excluded. We analyzed overall mortality and primary gallbladder cancer-specific mortality (CSM) using a Cox proportional hazards model. The survival analysis was carried out using the Kaplan–Meier method and the log-rank test was used to compare survival curves. Results: There was an overall increase in gallbladder cancer cases by 23% in 2010-2020 compared to 2000-2010. There was no significant cancer-specific mortality difference identified between males and females (HR = 1.009; CI: 0.972-1.046). Non-Hispanic blacks had higher overall mortality (HR = 1.134; CI: 1.010-1.273) amongst different ethnicities. Crude analysis revealed overall mortality was higher among patients aged above 80 years (HR = 9.857; CI: 6.257-15.528). Crude analysis also revealed significantly higher cancer-specific mortality for cholangiocarcinoma (HR = 1.622; CI:1.509-1.744) amongst histological subtypes. Gallbladder cancer-specific mortality was high with regional disease (HR = 3.115; CI: 2.839-3.419) and increased significantly with distant metastases (HR = 7.169; CI 6.512-7.891). Treatment with surgery, chemotherapy, or radiation alone or in combination improved survival among patients. Conclusions: There is a significant increase in gallbladder carcinoma mortality even among patients with regional disease, and it was worse with metastatic disease. With limited early-stage diagnoses and poor overall survival rates, we recommend further research to develop effective screening methods, understand risk factors, and explore effective preventive and therapeutic strategies for primary gallbladder cancer.