bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of baseline liver function on survival outcomes in patients with unresectable hepatocellular carcinoma (uHCC) treated with camrelizumab + rivoceranib vs sorafenib: A post hoc analysis of study CARES-310.
Authors: Vogel Arndt , Cheng Ann-Lii , Shi Wei , Jang Seong , Alexander Laura , Meng Xianzhang , Raphael Natalia , Chan Stephen Lam 
Published: January 2024

509 Background: CARES-310 study (NCT03764293) evaluated the combination of camrelizumab, an anti-PD-1 inhibitor, and rivoceranib, a highly selective VEGFR-2 tyrosine kinase inhibitor, (cam + rivo) vs sorafenib (sora) for the treatment of uHCC. Cam + rivo significantly improved median overall survival ([mOS] 22.1 months [mo] vs 15.1 mo) and median progression-free survival ([mPFS] 5.6 mo vs 3.7 mo) compared to sora. This post-hoc analysis evaluated the impact of baseline albumin-bilirubin (ALBI) grade and Child-Pugh (CP) class on survival outcomes. Methods: In this randomized, open-label, international, multicenter, phase 3 study, patients were randomized 1:1 to receive cam 200 mg IV Q2W + rivo 250 mg PO QD (n=272) or sora 400 mg PO BID (n=271). Median overall survival (mOS), median progression free survival (mPFS), objective response rate (ORR), disease control rate (DCR), and safety were assessed by baseline ALBI grade and CP class. Results: mOS, mPFS, DCR, and ORR improved with cam + rivo vs sora regardless of baseline liver function (Table). Although treatment-related grade 3/4 AEs occurred at a greater rate in the cam + rivo arm vs the sora arm, the rate of these events was similar for patients with baseline ALBI grade 1 and grade 2 (cam + rivo, 82.1% and 81.7% vs sora, 53.9% and 54.0%, respectively). Median time-to-deterioration (mTTD) to CP class B was similar between treatment arms for ALBI grade 1 (not evaluable [NE], NE) and grade 2 (cam + rivo, 10.1 mo; sora, 10.6 mo; HR, 0.99). Conclusions: In this post-hoc analysis of Study CARES-310, the efficacy of cam + rivo was superior to sora regardless of baseline liver function as measured by both ALBI grade and CP class. Despite a higher rate of grade 3/4 AEs, there was no detrimental effect of cam +rivo on liver function in patients with both well- and moderately- preserved liver function compared to sora. These results support cam + rivo as a potential new first-line treatment option for patients with uHCC regardless of baseline liver function. Clinical trial information: NCT03764293 . [Table: see text]
Novel GPC3-targeting radiopharmaceutical therapy for hepatocellular carcinoma.
Authors: Lin Fanching , Clift Renee , Ehara Takeru , Yanagida Hayato , Horton Steven , Salvador Katrina , Richardson Samantha , Guest Matt , Noncovich Alain , Bhat Abhijit , Han Guangzhou , Song Ken , Rearden Jessica , Li Gary 
Published: January 2024

525 Background: Glypican-3 (GPC3) is a membrane-anchored oncofetal protein whose expression is largely absent in normal tissues. Significant upregulation of GPC3 protein has been observed in approximately 75% of hepatocellular carcinomas (HCC), and is associated with poor prognosis. The differential expression of GPC3 between tumor and normal tissues provides an opportunity for targeted radiopharmaceutical therapy (RPT) to treat HCC, a leading cause for cancer-related deaths worldwide. Methods: RAYZ-8009 comprises a novel macrocyclic peptide binder to GPC3, a linker, and a chelator that can be complexed with different radioisotopes. The affinity of peptide binders to GPC3 was determined by surface plasma resonance (SPR) and radioligand binding assays. Target-mediated cellular internalization was radiometrically measured at multiple time points. In vivo biodistribution, monotherapy and combination treatments with 177Lu or 225Ac were performed in HCC xenografts. Results: RAYZ-8009 showed high binding affinity (KD=0.7 nM) to human GPC3, with comparable affinity to GPC3 of human, mouse, canine and monkey origins, and no binding to other GPC family members. Potent cellular binding was confirmed in GPC3+ HepG2 cells, and was not affected by isotope switching. RAYZ-8009 achieved efficient internalization upon binding, with 42% internalized by 20 minutes in HepG2 cells. Biodistribution study of 177Lu-RAYZ-8009 showed sustained tumor uptake and fast renal clearance, with minimal or no uptake in other normal tissues. Exquisite tumor-specific uptake was also demonstrated in orthotopic HCC tumors with no uptake in surrounding normal liver tissue. Therapeutically, significant and durable anti-tumor effect and survival benefit were achieved with 177Lu- and 225Ac-labeled RAYZ-8009, as monotherapy or in combination with lenvatinib, in GPC3+ HCC xenografts. Conclusions: Preclinical in vitro and in vivo data demonstrate the potential of RAYZ-8009 as a theranostic agent for the treatment of patients with GPC3+ HCC.
Progression pattern and post-progression survival following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.
Authors: Kobayashi Satoshi , Fukushima Taito , Ueno Makoto , Chuma Makoto , Numata Kazushi , Tsuruya Kota , Arase Yoshitaka , Hirose Shunji , Kagawa Tatehiro , Hattori Nobuhiro , Watanabe Tsunemasa , Matsunaga Kotaro , Uojima Haruki , Hidaka Hisashi , Kusano Chika , Morimoto Manabu , Maeda Shin 
Published: January 2024

539 Background: Although the combination of atezolizumab and bevacizumab (ATZ + BEV) is a standard treatment for advanced hepatocellular carcinoma (HCC), strategies for addressing treatment failure and prognostic factors of post-progression survival remain unestablished. Methods: We conducted a multicenter retrospective study to evaluate post-progression survival following ATZ + BEV treatment in patients with advanced HCC. We classified the patients into four groups: BCLC stage B with or without new intrahepatic lesions (BCLCp-B1 and BCLCp-B2, respectively) and BCLC stage C without or with new extrahepatic lesions (BCLCp-C1 and BCLCp-C2, respectively) at the time of progression. Results: Of the 204 patients who started ATZ + BEV treatment between October 2020 and September 2022, 110 showed disease progression, with 25, 8, 55, and 22 showing the BCLCp-B1, BCLCp-B2, BCLCp-C1, and BCLCp-C2 stages of the disease, respectively. Specifically, patients with the BCLCp-B1 stage of the disease showed better overall survival than those with the BCLCp-B2, BCLCp-C1, and BCLCp-C2 stages (hazard ratios: 2.19 (95% confidence interval [CI], 0.61–7.86), 2.16 (95% CI, 1.13–4.11), and 2.97 (95% CI, 1.42–6.23) for HCC stages BCLCp-B2, BCLCp-C1, and BCLCp-C2, respectively). Via multivariable analysis, we identified the BCLCp-C1 and BCLCp-C2 stages, as well as performance status, Child-Pugh class, and alpha-fetoprotein as poor prognostic factors for post-progression survival. Conclusions: BCLCp-B1 stage was identified as a better prognostic factor for post-progression survival following ATZ + BEV treatment compared with BCLCp-B2 stage as well as BCLCp-C1 and BCLCp-C2 stages. This may help in making decisions regarding subsequent treatment after ATZ + BEV.
Extrahepatic cholangiocarcinoma: Genomic variables associated with anatomical location and outcome.
Authors: Preston William A , Drill Esther N. , Boerner Thomas , Harding James J. , Cercek Andrea , O'Reilly Eileen Mary , Abou-Alfa Ghassan K. , Park Wungki , Balachandran Vinod P. , Drebin Jeffrey A. , Soares Kevin , Wei Alice Chia-Chi , Kingham T. Peter , D'Angelica Michael Ian , Jarnagin William R. 
Published: January 2024

554 Background: Genomic determinants of outcome in intrahepatic cholangiocarcinoma have become clear but remain ill-defined in extrahepatic cholangiocarcinoma (ECA). We aimed to clarify the genomic alterations that define ECA, analyze differences between perihilar (PCA) and distal (DCA) disease, and determine clinicopathologic and genomic factors associated with survival. Methods: Patients with EHC with tissue available for targeted next-generation sequencing at Memorial Sloan Kettering Cancer Center were identified. Differences between PCA and DCA were compared, stratified by disease extent and treatment. Associations between genomic alterations and clinicopathologic features and outcomes were analyzed. Univariable and then multivariable cox proportional hazards regression were used to compare survival, which was reported from operation in resected patients and from diagnosis in non-resected patients. Results: Two-hundred-twenty-four patients (n=127 PCA, n=97 DCA, 2006-2022) met inclusion criteria. Median survival was 29 months (IQR [25, 35]; 43 months [35, 48] resection, 17 months [13, 19] without). Compared to PCA, DCA was enriched in TP53mut (67 [69%] vs. 42 [33%]), Q<0.01) and epigenetic pathway alterations (44 [45%] vs. 37 [29%], Q=0.041) and had more altered pathways (3 vs. 2, Q<0.01). KRASmut was similar between PCA (46 [36%]) and DCA (36 [37%]); however, PCA was enriched in KRAS G12V (16 [13%] vs. 4 [4%]) and Q61H (11 [9%] vs. 3 [3%], P=0.002). No other clinicopathologic or genomic variables distinguished PCA from DCA (Table). MDM2mut occurred in 19/141 (13%) patients with nodal/metastatic disease compared to 1/83 (1%) patients with local disease ( Q=0.03), but conferred no survival disadvantage. In resected patients, survival was similar between PCA and DCA and no genomic alterations were associated with outcome. By contrast, in patients without surgery, CDKN2Adel (HR 2.59, 95% CI [1.48, 4.52]) and APCmut (HR 5.11, 95% CI [1.96, 13.3]) were associated with survival disadvantages. Lack of resection (HR 3.13, 95% CI [2.25, 4.36]), CDKN2Amut (HR 1.80 [95% CI 1.80, 2.68), and APCmut (HR 2.00 [95% CI 1.04, 3.87]) were associated with poor survival in the entire cohort. Conclusions: In this study, aside from a higher incidence of TP53mut in DCA and some differences in KRAS subtype alteration patterns, genomic alterations were comparable between PCA and DCA. CDKN2Amut and APCmut were associated with poor survival in all patients but no biomarkers provided significant prognostic information when tumors were resected. [Table: see text]
Surrogate endpoints for overall survival in advanced hepatocellular carcinoma: A meta-analysis.
Authors: Saleh Yacob , Baskurt Zeynep , Farooq Abdul Rehman , Goodwin Rachel Anne , Knox Jennifer J. , Chen Eric X 
Published: January 2024

563 Background: Recent advances in systemic therapies have resulted in improved overall survivals (OS) for patients with advanced hepatocellular carcinoma (aHCC). The most commonly utilized primary endpoint for phase III trials in aHCC is OS. A robust surrogate endpoint (SEP) can reduce time and financial costs of future trials and accelerate regulatory approvals of new therapies. We conducted a literature-based meta-analysis to evaluate SEPs for OS in aHCC. Methods: Randomized controlled trials evaluating systemic therapies in aHCC published 2007 - 2023 were identified through a systemic literature search of Cochrane and Medline databases as well as of abstracts presented at ASCO and ESMO meetings. Hazard ratios (HR) for OS and progression-free survival (PFS) and time to progression (TTP) were extracted. ΔORR was calculated as the difference in overall response rates (ORR) between control and experimental arms. Pearson correlation and mixed-effects meta-regression analyses were performed. Surrogate threshold effect (STE) was determined for each comparison when possible. A p < 0.05 was considered to be statistically significant. Results: 26 trials were identified in the first-line setting with 14,827 patients and 11 trials in the subsequent-line setting with 5,316 patients. In first-line trials, immunotherapy (IO) is associated with higher ORR than other agents (p=0.003). There are statistically significant correlations between HRs of PFS/TTP/ΔORR and OS (Table). The relationship between HR-PFS and HR-OS persists in trials with or without IO, but only in trials enrolling < 30% patients of non-viral aetiologies. In subsequent-line trials, there are statistically significant correlations between HRs of PFS/TTP and OS (Table). STE for HR PFS is 0.68 and 0.87 respectively for 1st and subsequent line trials. Conclusions: There are moderate to strong correlations between PFS and OS in aHCC in first-line and subsequent line trials. STE for HR-PFS of 0.68 in first-line and 0.87 in subsequent-line settings can guide sample size calculation in future clinical trials. [Table: see text]
Preoperative weight loss program for hepatocellular carcinoma patients with high body mass index in hepatectomy.
Authors: Saito Yu , Morine Yuji , Yamada Shinichiro , Teraoku Hiroki , Ikemoto Tetsuya , Shimada Mitsuo 
Published: January 2024

565 Background: This study aimed to investigate the usefulness of a weight-loss program (WLP) in patients with a high body mass index (BMI) prior to liver resection (Hx) for hepatocellular carcinoma (HCC). Methods: Among 445 patients with HCC who underwent initial Hx between 2000 and 2020, 19 with a high BMI (≥25.0) were enrolled in our WLP since 2014. For calorie restriction, the amount of energy consumed was calculated as the standard body weight (SBW) kg × 20–25 kcal/day. Protein mass was calculated as SBW kg × 1.0–1.2 g/day to maintain skeletal muscle mass. Patients also performed both aerobic and resistance exercises. The before-and-after changes were compared, and the effect of WLP on the short- and long-term results was investigated. Results: The average length of WLP was 21 days, and weight loss was successfully achieved in all patients. Body fat mass was reduced during the program, while skeletal muscle mass was maintained. WLP led to improvements in liver function and fibrotic markers, without tumor progression. There were no postoperative complications (≥Clavien–Dindo [CD] III). A retrospective comparison of postoperative outcomes revealed that those in the WLP group showed a significantly shorter operation time and improved postoperative morbidity rate (≥CD III) with decreased postoperative hospital stay. There were no significant differences in long-term prognosis based on participation in the WLP. Conclusions: WLP with multidisciplinary intervention improved short-term outcomes after Hx in patients with HCC and a high BMI.
Correlation of cancer testis antigen expression with high type-I interferon signal and prognosis in small bowel neuroendocrine tumors.
Authors: Ayabe Reed I. , Seo Yongwoo David , Melendez Brenda , Lazcano Segura Rossana , Fields Brittany C. , Wani Khalida M. , Johnson Sarah , Witt Russell , Chelvanambi Manoj , Hudgens Courtney , Hernandez Sharia D. , Ajami Nadim J. , Wargo Jennifer Ann , Lazar Alexander J. , Halperin Daniel M. , Estrella Jeannelyn , Maxwell Jess 
Published: January 2024

596 Background: Patients with small bowel neuroendocrine tumors (SBNET) frequently present with metastatic disease, and efficacy of available therapies, including immune checkpoint inhibitors (ICI), is limited. Toward developing novel immunomodulatory strategies, we evaluated the tumor immune microenvironment of SBNETs using bulk transcriptional and digital spatial profiling (DSP). Methods: Patients with SBNET who underwent surgical resection at MD Anderson Cancer Center from 2003-2016 were retrospectively analyzed. Overall survival (OS) was assessed using the Kaplan-Meier method and Cox proportional hazards model was used for multivariate analysis (MVA). Bulk transcriptional profiling was performed using the Nanostring PanCancer-Immune Panel. DSP was performed with whole human transcriptome using PanCK to segment tumor and adjacent stroma; 88 distinct regions were analyzed using differential gene expression and Reactome pathway enrichment pipelines. Results: Resected SBNETs from 42 patients were selected for transcriptional analysis. Unsupervised clustering of gene expression demonstrated dichotomization into high and low cancer testis antigen (CTA) expression. CTA-high patients (n=12) demonstrated elevated expression of type-I interferons (IFN) and CTAs such as PRAME, GAGE1, and MAGEA3 and had significantly longer OS compared to CTA-low patients (n=30; median OS not reached vs 1975 days, p=0.008). MVA controlling for age, sex, metastatic disease, and Ki-67% confirmed CTA-high status as an independent predictor of longer OS (hazard ratio [HR] 0.2, 95% confidence interval [CI] 0.05-0.83). A pilot DSP experiment with 4 CTA-high and 4 CTA-low tumors revealed higher expression of epigenetic modification genes (e.g., H3C1, H2BC8, p<0.001) in CTA-high tumors with significant enrichment in epigenetic pathways (e.g., histone acetylation, DNA methylation). CTA-high tumors exhibited increased M2 macrophage presence (p=0.025) and increased stromal compartment NK cell activation (p=0.001). Conclusions: High expression of CTA and type-I IFN in resected SBNET is associated with longer survival, agnostic of stage or grade. While CTA expression has been implicated in tumor immunogenicity, this is the first work to identify a clinical signal in SBNET. Increased IFN in CTA-high tumors, corroborated by increased stromal NK cell activation, suggests an immune-mediated component of improved survival. Spatial transcriptomic analysis reveals epigenetic differences in CTA-high tumors and highlights the potential for combination epigenetic modifiers and immunotherapy in future trials.
Second-line chemotherapy in elderly patients with advanced pancreatic cancer: A mono-institutional retrospective experience.
Authors: Trovato Giovanni , Bensi Maria , Beccia Viria , Spring Alexia , Barone Diletta , Ceccarelli Anna , Perazzo Serena , Messina Gloria , Chiofalo Laura , Bagalà Cinzia , Quero Giuseppe , Alfieri Sergio , Tortora Giampaolo , Salvatore Lisa 
Published: January 2024

606 Background: Only few randomized clinical trials have been conducted for second line therapy in advanced pancreatic cancer (APC). In these studies, elderly patients are poorly represented, even if the median age at diagnosis of APC is increasing; therefore, limited efficacy and safety data are available. Here, we present a retrospective monocentric analysis of second line chemotherapy in elderly patients treated at our Hospital. Methods: This study included patients with APC and aged>70 years old receiving a second-line chemotherapy for APC at our institution from March 2015 to August 2020. The primary endpoints were progression-free survival to second line (PFS2) and overall survival (OS); the secondary endpoint was safety. The Kaplan–Meier method was used to estimate efficacy outcome; log-rank test and Cox-regression model were used to compare the differences, considering a statistically significant p value < 0.05. Results: 169 pts affected with APC received first-line chemotherapy and 61 of them (36%) received second-line therapy. The median age at diagnosis was 74 Years (70-83), 31 (50%) were female; ECOG PS was 0-1 in 44 pts (59%), 41% had at least 2 comorbidities. The regimens of chemotherapy used were: mFOLFOX (28; 46%), Gemcitabine (11; 18%), Capecitabine (15; 24.6%), FOLFIRI (6; 9.8%), mFOLFIRINOX (1; 1.6%). 4 pts (6.6%) had a partial response and 22 (36.1%) had a stable disease, with a disease control rate of 42.7%. The median follow-up was 22.8 months; median PFS2 was 4.5 months (IC 95%: 2.5-6.5) and median OS was 15.4 months (IC 95%: 7.2-23.6). At the univariable analysis, there was a statistically significant difference in mPFS2 according to ECOG PS (0-1 vs 2: 5.3 [IC 95%: 3.5-7.0] vs 2.2 [IC 95%: 1.2-5.4] months; p 0.02) and number of metastatic sites at the beginning of second line therapy (1 vs 2 or more: 5.8 [IC 95%: 4.8-6.7] vs 3.4 [IC 95%: 3.1-3.8] months; p 0.006). At the multivariable analysis, both number of metastatic sites and ECOG PS were confirmed associated with mPFS2. Number of metastatic sites and ECOG PS were both also associated with mOS. No unexpected adverse events were reported, and no patients had to interrupt treatment due to toxicity. Conclusions: In our experience, only about a third of elderly pts with APC received second-line therapy; in these patients, ECOG PS, disease’s burden and the response to therapy are all positive prognostic factors. With regard to the safety profile, older age does not seem to negatively increase serious toxicities. In conclusion, elderly pts should not be precluded from an active treatment (also in later lines setting) and careful patients selection should guide treatment indication.
Pancreatic biopsy evaluation with nsCanary: A “smart ROSE” device for feedback on sample adequacy and cancer presence in endoscopic biopsies—Initial human clinical trial results.
Authors: Bogdanowicz Les , Fidaner Onur , Guidetti Martina , Dibennardo Federica , Gehrke Daniel , Ceres Donato , John Margaret , Bovalis Constantine , Raijman Isaac 
Published: January 2024

618 Background: Pancreatic cancer (PC) accounts for 0.5 million new cases and 4.7% of the world's cancer-related deaths in 2020. Endoscopic ultrasound (EUS) guided fine needle biopsies (FNB) are the current standard of care for confirming suspicious lesions, however the diagnostic accuracy is reported below 70%. Rapid on-site evaluation (ROSE) improves the diagnostic performances of biopsies to reduce the number of needle passes, complication rates, and the need for additional procedures. However, availability of an on-site pathologist is often not feasible. NovaScan has pioneered the use of an impedance spectroscopy biomarker for cancer detection in different tissues based on the Cole Relaxation Frequency (CRF). NovaScan has developed the nsCanary, a ”smart ROSE” device that assesses PC presence in FNBs obtained during endoscopic procedures ex vivo, in real-time and on-site, without altering the tissue sample or affecting the workflow. Methods: Data were collected in a double-blind, IRB approved study from a cohort of 53 patients (28 males, 25 females) undergoing EUS procedures for suspected pancreatic lesions at the Texas International Endoscopy Center. FNBs were performed with a 22 gauge biopsy from a transduodenal approach. Each biopsy sample was transferred onto a disposable strainer allowing for any excess fluid to drain. An electrode for scanning was placed onto the core samples for data collection with the nsCanary a low cost, portable device used in the operating room. CRF is measured in the 1 kHz - 10 MHz frequency range via custom-designed hardware and assessment of the sample is completed in a few seconds. Subsequently, the sample is flushed into a pathology jar to undergo the standard workflow for cytology. The algorithm for extracting the CRF from the measurement was developed based on our previous preclinical study with transgenic KPC mice Samples with a CRF below 1 MHz were considered noncancerous, while CRF values above 1MHz or the absence of a CRF reading were considered cancerous. Results: PC assessment provided by nsCanary was validated against pathology outcomes for each biopsy sample. Findings showing a sensitivity of 86.7% and a specificity of 84.2% are reported in the table. Conclusions: We believe the nsCanary device will provide immediate feedback to the endoscopist on cancer presence and on the adequacy of the sample. This device is intended to support the decision-making process, by enabling clinicians to overcome the challenge of proving cancer presence during the first biopsy procedure, ultimately avoiding revisits and unnecessary trauma.[Table: see text]