bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of TU-100 on hepatocarcinogenesis and colorectal liver metastasis in MASH model.
Authors: Yamada Shinichiro , Morine Yuji , Ikemoto Tetsuya , Saito Yu , Teraoku Hiroki , Miyazaki Katsuki , Shimada Mitsuo
Published: January 2025

577

Background:
TU-100 is most commonly used herbal medicine in clinical setting. We have already reported that TU-100 suppressed dysbiosis (J Med Invest, 2013), bacterial translocation (Surg Today, 2017) and hepatic fibrosis (Surgery, 2016). This time we investigate the effect of TU-100 on hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) in MASH model.
Methods:
1: Effect on HCC: Seven-week-old Tsumura Suzuki obese diabetes mice, a model that shows the spontaneous onset of MASH and HCC, were used. They were divided into a TU-100 treated group and a control group. Mice were sacrificed at 24 and 48 weeks to evaluate hepatic steatosis, fibrosis, carcinogenesis, cytokine expression, and microbiome abundance. 2: Effect on CRLM: Six-week-old male C57BL/6J mice were used. They were divided into the western diet (WD) group and the WD+TU-100 group. MC38 colon cancer cells were injected into the spleen at 16 weeks, and mice were killed at 2 weeks after injection to evaluate hepatic steatosis, fibrosis and mRNA expression in the liver.
Results:
1: Effect on HCC: At 24 weeks, the TU-100 group showed significantly lower expression of IL6, IL1B, and ACTA2 mRNA in the liver (P<0.05). At 48 weeks, the TU-100 group showed a lower rate of MASH than the control group (28% vs 72%; P=0.1). Tumor diameter was significantly smaller in the TU-100 group compared with that in the control group (P<0.05). Regarding the intestinal microbiome, the genera Blautia and Ruminococcus were increased in the TU-100 group (P<0.05), whereas Dorea and Erysipelotrichaceae were decreased in the TU-100 group (P<0.05). 2: Effect on CRLM: Steatosis of the WD+TU-100 group was significantly suppressed compared with the WD group (p<0.05). The WD+TU-100 group showed significantly smaller tumor diameter than the WD group (p<0.05). In the WD+TU-100 group, expression of SAA1 and TIMP1 mRNA in the liver was significantly lower than in the WD group (p<0.05).
Conclusions:
TU-100 regulates the intestinal microbiome and may suppress hepatic steatosis and subsequent hepatocarcinogenesis in the MASH model. Furthermore, TU-100 may have effect on CRLM via suppression of SAA1/TIMP1.
Updated results from ALTER-H004 study: Anlotinib combined with TACE as adjuvant therapy in patients with hepatocellular carcinoma (HCC) at high risk of recurrence after surgery—A single arm, multi-center, phase II clinical trial.
Authors: Wu Zheng , Wang Zheng , Zhang Lei , Song Xiaojing
Published: January 2025

588

Background:
High recurrence rate after curative resection significantly compromised the long-term survival of patients with HCC patients (pts). TACE as adjuvant therapy was proved to improve clinical outcomes for pts with high recurrence risk factors after hepatectomy. However, the prognosis of TACE reminded unsatisfactory and controversial. Therefore, this study aimed to identify the efficacy and safety of anlotinib as maintenance adjuvant treatment following inductional TACE in pts with HCC. The preliminary results had been reported in 2024 ASCO GI (Poster 513) and the update results were reported here with longer follow-up duration.
Methods:
HCC pts with one of the following high risk factors after hepatectomy: ≥5 cm and <10 cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus resection (Cheng's classification I/II) were recruited. Eligible pts received cTACE treatment within 1-2 months after hepatectomy, on the 3-5th day after cTACE, oral anlotinib (12mg, qd, d1-d14, q3w) was given until disease recurrence or unacceptable toxicity. The predefined sample size was 30. The primary endpoint was disease free survival (DFS). Secondary endpoints included 1-year DFS rate, time to recurrence and safety.
Results:
The data cut-off date was April 2024, 29 pts were enrolled and 27 pts received at least once tumor assessment. The median follow-up was 34.1 (IQR, 32.0-40.9) months. Of 27 with assessable efficacy, mDFS was 40.9 (95% CI, 11.4-70.3) months, with 1-, 2-, and 3-year DFS rates of 72.1% (95% CI, 50.2%-85.6%), 63.0% (95% CI, 40.7%-78.9%), and 56.7% (95% CI, 33.6%-74.5%), respectively. 21 of 27 pts (77.8%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 5 pts (18.5%) included hypertension (7.4%), leukocytopenia (7.4%) and ascites (3.7%), and blood bilirubin increased (3.7%). No grade 4 or 5 TRAEs occurred.
Conclusions:
Anlotinib combined with TACE as adjuvant therapy in HCC pts at high recurrence risk exhibited encouraging efficacy and tolerable safety profile. And the conclusions needed to be confirmed in large scale clinical trials subsequently.
Clinical trial information: NCT04213118
.
Long-term outcomes and surgical conversion following immunotherapy in MSI-H biliary tract cancers.
Authors: Shah Priyanshi , Peersen Anina , Mahipal Amit , Ou Fang-Shu , Tran Nguyen H.
Published: January 2025

592

Background:
Deficient mismatch repair/microsatellite instability (MSI-H) in biliary tract cancers (BTC) is rare, estimated to be 1-5%. MSI-H across solid tumors has shown unprecedented durable response to immune checkpoint inhibitors (ICI) regardless of anatomic location. Here we describe the clinical outcomes of unresectable BTC patients with MSI-H treated with ICIs and their conversion to surgery.
Methods:
We conducted a multicenter, retrospective analysis of patients (pts) with advanced BTC who had been identified with MSI-H by molecular analysis performed between 2017 and 2024 at Mayo Clinic and University Hospitals Seidman Cancer Center. The outcomes of interest were overall survival (OS), defined as time from initiation of first-line systemic treatment to death; Time-to-treatment failure (TTF), defined as time from initiation of treatment to cessation due to any cause; and response. All analyses were done descriptively.
Results:
We identified 22 MSI-H pts with BTC, 19 with cholangiocarcinoma and 3 with gallbladder cancer. Median age at diagnosis was 61 (range 26-86), 20 (90.9%) were Caucasian, 9 (40.9%) were male gender, and 5 (22.7%) had etiology as Lynch syndrome. Twelve (54.5%) pts had metastatic disease at diagnosis. Twenty pts (90.9%) received first line systemic therapy, of whom 11 (55%) continued onto second line. Among the 20 pts that received first line therapy, median TTF was 7.6 months (95% CI: 4.8-14.3), objective response was observed in 7 (35%) pts, and disease control was observed in 15 pts (75%). Among the 11 pts that continued onto second line systemic treatment, objective response was observed in 4 pts (36%) and disease control was observed in 6 pts (55%). Among the 20 pts that received first line therapy, 19 (95%) ever received ICI +/- chemotherapy as a part of their treatment plan. Two-year OS for pts who ever received ICI was 63% (95% CI: 41%-96%). In total, 4 pts (20%) were restaged to resectable following treatment with an ICI, underwent resection, and currently have no evidence of disease.
Conclusions:
Administration of ICI during treatment plan in pts with MSI-H confirmed durable response and even downstage pts to resectable stage for curative intent. Testing for MSI-H should be performed upfront to guide treatment decision.
Phase I/Ib study of afatinib with capecitabine in patients with refractory solid tumors and pancreaticobiliary cancers.
Authors: King Gentry Teng , Baker Kelsey K. , Coveler Andrew L. , Safyan Rachael A. , Wong Kit , Shankaran Veena , Zhen David Bing , Lee Hannah H , Hensel Jeniece , Hibbert Reina , Durm Greg Andrew , Redman Mary Weber , Pritchard Colin C. , Shahda Safi , Chiorean E. Gabriela
Published: January 2025

594

Background:
The epidermal growth factor receptor (EGFR) and ErbB2/HER2 signaling is overactive in many solid tumors. Afatinib, an irreversible inhibitor of ErbB signaling, downregulates thymidine synthase and synergizes with capecitabine in preclinical models. This phase I trial evaluated the safety, maximum tolerated dose (MTD) and preliminary efficacy of afatinib plus capecitabine in patients (pts) with refractory solid tumors and pancreatic ductal adenocarcinoma (PDA) and biliary tract cancers (BTC).
Methods:
The phase I study had a 3+3 design with capecitabine 1000 mg/m
2
twice daily (BID) on days 1-14 and afatinib 20 mg, 30 mg or 40 mg daily (QD) in 21-day cycles. In phase Ib, 15 pts each with PDA and BTC were treated at MTD.
Results:
41 pts enrolled from November 2016 to October 2021, who received a median of 2 (range 1-5) prior therapies. No dose-limiting toxicities were observed. The MTD was 40 mg afatinib QD plus 1000 mg/m
2
capecitabine BID. Grade 3 treatment related adverse events were diarrhea (12.2%) and nausea (4.9%). Among 36 response evaluable pts, best response was 1 partial response (PR, 3%) in a pt with
KRAS
wild type (WT)/EGFR amplified BTC, and 8 stable diseases (SD, 22%), with disease control rate (DCR) of 25%. PDA pts (n=20) had DCR of 24%, median progression-free (PFS) and overall survival (OS) of 1.9 months (95% CI 1.05, 2.03) and 3.2 months (95% CI 2.01, 5.82) respectively. BTC pts (n=18) had DCR of 31%, median PFS and OS of 1.9 months (95% CI 1.55, 3.39) and 4.6 months (95% CI 1.88, 6.09), respectively. Eight pts with cancers with EGFR/HER2/HER3 pathway alterations, most

KRAS
WT

(n=6), had DCR of 29%, and median PFS and OS of 2.1 months (95% CI 1.05, 4.14) and 3.5 months (95% CI 1.64, 6.09), respectively.
Conclusions:
Afatinib plus capecitabine is tolerable but does not have significant efficacy in pts with refractory PDA/BTC, including in

KRAS
WT

cancers with EGFR/HER2/HER3 alterations.
Clinical trial information: NCT02451553
.
Clinical outcome of radiofrequency ablation in elderly hepatocellular carcinoma patients over 80 years old.
Authors: Takaura Kenta , Tsuchiya Kaoru , Tamaki Nobuharu , Yasui Yutaka , Nakanishi Hiroyuki , Izumi Namiki , Kurosaki Masayuki
Published: January 2025

603

Background:
The SURF trial showed the efficacy and safety of radiofrequency ablation(RFA). However, patients over 80 years old were excluded from the study. Aims: To evaluate clinical outcomes of RFA for largest hepatocellular carcinoma (HCC) diameter ≤3 cm, and ≤3 HCC nodules in patients over 80 years.
Methods:
Patients who underwent RFA at our institution for initial treatment of largest HCC diameter ≤3 cm, and ≤3 HCC nodules from January 2011 to December 2023. Treatment outcome and prognosis were examined in the elderly group for cases 80 years or older and in the non-elderly group for cases under 80 years. The Cox proportional hazards model was used to analyze the factors associated with treatment outcome and prognosis.
Results:
Of the 518 eligible patients, 136 patients were 80 years or older. Median overall Survival (OS) was 80 (95%CI 60-96) vs. 123 (95%CI 101-NA) months (p=0.021) in the elderly vs. nonelderly group. The median recurrence-free survival was 16 (95%CI 14-22) vs. 26 (95%CI 19-30) months (p=0.023), better in the non-elderly group, Interestingly, for liver disease-related deaths, median OS was 97 (95% CI 80-NA) vs. NR (95% CI NA-NA) months (p=0.62) in the elderly vs. non-elderly group. In the multivariate analysis, factors associated with OS were ALBI grade 2 or 3 (HR 1.67, 95%CI 1.07-2.60), DCP ≥ 40mAU/ml (HR 2.08, 95%CI 1.42-3.05), persistent HCV infection (HCV non-SVR) (HR 5.45, 95%CI 3.07-9.67), nonviral liver disease (HR 4.18, 95%CI 2.31-7.55). HCC recurrence was significantly associated with male (HR 1.51, 95%CI 1.18-1.94), elderly group (HR 1.46,95%CI 1.10-1.95), PT ≥80% (HR 0.69, 95%CI 0.53-0.91), DCP ≥40mAU/ml (HR 1.37, 95%CI 1.07-1.76), and HCV non-SVR (HR 1.73, 95%CI 1.35-2.21). The factors associated with liver disease-related death were ALBI grade 2 or 3 (HR 2.16, 95% CI 1.25-3.73), DCP ≥ 40mAU/ml (HR 2.34, 95% CI 1.48-3.70) and HCV non-SVR (HR 2.22, 95% CI 1.39-3.56).
Conclusions:
In RFA for diameter ≤3 cm, and ≤3 HCC nodules, over 80 years was not a significant factor associated with OS or liver disease-related death. The results support that RFA would be a promising treatment option for HCC patients over 80 years.
First-in-human phase 1/2 study (MYCHELANGELO I) of first-in-class epigenomic controller OTX-2002 targeting MYC oncogene in patients with hepatocellular carcinoma (HCC) and other solid tumors.
Authors: Mizrahi Jonathan , Senapedis William , O'Donnell Charles , Hodgson J. Graeme , Newman Joseph V. , Siecinski Stephen , Lin Chia-Chi
Published: January 2025

606

Background:
The c-MYC (MYC) oncogene is a master transcription factor of tumor cell and microenvironment regulation; it is often dysregulated in cancer, including HCC. OTX-2002 is a MYC-targeted Epigenomic Controller (MYC-EC), an mRNA drug substance encapsulated in a clinical lipid nanoparticle (LNP), designed to downregulate MYC expression pre-transcriptionally with high specificity and durability, inhibiting tumor cell viability while sparing normal cells.
Methods:
A first-in-human dose-escalation study (NCT05497453) investigates OTX-2002 monotherapy in HCC and other solid tumors. Key outcomes include safety, tolerability, pharmacokinetics (PK) and the recommended dose for expansion. In addition to standard safety measures, LNP-associated safety measures including cytokine profiling and an assessment of the presence of anti-PEG antibodies (ADA) were included. Initial pharmacodynamic activity (PD) was assessed via measurement of DNA methylation at the MYC locus in cell-free DNA [cfDNA] from whole blood.
Results:
As of August 23, 2024, 24 patients were treated at 6 doses (19 HCC, 1 colorectal, 1 cervical, 1 pancreatic, 2 sarcoma). OTX-2002 was generally well-tolerated; most adverse events (89%) were low grade, with infusion-related reactions being the most common (30%). Consistent with known LNP profiles, OTX-2002 adverse events were transient and manageable, including cytokine and ADA expression levels. Plasma PK exposures of OTX-2002 were linear across the first five doses analyzed. Significant, on-target dose-dependent changes in MYC gene methylation were seen in cfDNA for all patients post-dose and were durable for at least 15 days, consistent with the designed durability of the MYC-EC. Updated data will be presented.
Conclusions:
OTX-2002 is well-tolerated and induces rapid and durable epigenomic changes to the MYC locus. These results provide clinical proof of mechanism of the epigenomic controller platform and support continued development of OTX-2002.
Clinical trial information: NCT05497453
.
Safety and efficacy of combining PD-L1 and CTLA-4 blockade with transarterial chemoembolization in intermediate-stage hepatocellular carcinoma: A phase II study.
Authors: Kim Amy K. , Yarchoan Mark , Baretti Marina , Griffith Paige , Ho Won Jin , Parkinson Rose , Kulikowicz Ewa , Cetasaan Yvette , Wilt Brad , Luu Harry , Wang Hao , Song Hyunsoo , Liddell Robert , Georgiades Christos , Hong Kelvin , De Jesus Acosta Ana
Published: January 2025

609

Background:
Transarterial chemoembolization (TACE) is the standard treatment for intermediate-stage hepatocellular carcinoma (HCC) defined as Barcelona Clinic Liver Cancer (BCLC) B, but the benefit of adding systemic therapy remains unclear. While durvalumab and tremelimumab are approved for advanced HCC, the safety and efficacy in combination with TACE for intermediate-stage disease is undefined. Combining these PDL1 and CTLA4 inhibitors with TACE may enhance anti-tumor activity by leveraging TACE’s proinflammatory effects while blocking immune evasion and reducing immune suppression. This phase IIb study evaluates the safety and efficacy of this combination in BCLC-B HCC.
Methods:
We enrolled patients with intermediate-stage HCC that are also unresectable and ineligible for transplant. All patients received drug-eluting bead TACE (DEB-TACE) followed by durvalumab (1500 mg Q4W) and tremelimumab (300 mg once). Durvalumab monotherapy was continued until disease progression or unacceptable toxicity, for a maximum of 13 cycles. Primary endpoints include objective response rate (ORR) based on mRECIST. Secondary endpoints were overall survival (OS), and safety/adverse events (AEs). The trial is designed to rule out ORR of 30%. We obtained 3 serial biopsies and plasma for participating patients prior and one week after TACE and after the administration of immunotherapy for correlative studies.
Results:
21 patients were enrolled. Of these, 20 patients were considered evaluable after receiving at least one dose of TACE and immunotherapy. ORR was 55% (95% CI: 32%-77%, CR 10% (n=2), PR 45% (n=9), meeting the primary endpoint. Five patients had PD (25%) per mRECIST, of which two were unconfirmed on repeat imaging and continued treatment beyond progression. Three patients received curative intent treatment as the result of treatment: surgical resection (n=1) and transplant (n=2). At a median follow-up of 18.4 months, median OS was 28.8 mo (95% CI: 15.1, NA) and mPFS was 6.1mo (95% CI: 3.3, NA). Grade 3 or higher immune related adverse events were rash (n=2), diarrhea, myalgia, nausea, elevated AST/ALT. One patient developed multiple irAEs after first dose (myocarditis, myositis, pericarditis) and was taken off study.
Conclusions:
The combination of DEB-TACE with PD-L1/CTLA-4 blockade is safe and shows promising activity in patients with BCLC-B HCC. The ongoing immune analysis and biomarker studies on serial blood and tissue biopsies will provide further insights into the mechanistic effects of this combination approach and inform future therapeutic strategies.
Clinical trial information: NCT03638141
.
Investigating the real-world outcomes of single- versus multi-agent preoperative chemoradiotherapy for locally advanced rectal cancer: NCDB analysis from 2004-2020.
Authors: Sharma Gaurav , Boyd Justin , Bell Alana , Ray Gannon , Abdalla Ahmed
Published: January 2025

61

Background:
Fluorouracil-based chemoradiotherapy is the standard initial treatment for locally advanced rectal cancer, demonstrating improved pathological response and reduced local recurrences compared to radiation alone. Fluorouracil-based chemo-radiation therapy has no impact on distant recurrences. Oxaliplatin was tested in addition to fluorouracil-based chemo-radiotherapy in clinical trials to improve pathological complete response (pCR), distant recurrence-free survival, and overall survival. The trial results are conflicting. In this study, we aim to compare single-agent (SA) versus multi-agent (MA) chemotherapy using real-world data from the National Cancer Database (NCDB).
Methods:
The NCDB was used to identify 39,667 patients with rectal cancer who received concurrent chemoradiotherapy between 2004 and 2020. We compared patients who received SA chemotherapy with those who received MA concurrent chemotherapy. The primary outcomes of interest were overall survival and pCR. The groups were compared using univariate analysis and Cox proportional hazard models to adjust for potential confounding factors.
Results:
Of 39,667 patients with rectal cancer, 24,452 received single-agent (SA) chemotherapy and 14,215 received multi-agent (MA) chemotherapy. Patients in the SA group were of advanced age, had a greater number of comorbidities (as calculated by the Charleson-Dayo score), were treated within community facilities, had a higher income status, were covered by government insurance, were situated on the east coast, and had lower educational attainment compared to those in the MA group (p<0.05). SA group had higher T4 and N1 disease, however MA group had more N2 disease. Upon survival analysis, patient in MA group had higher survival (41.2 vs 38.9 months, p=0.005), however pCR was significantly higher in SA group (10.4% vs 6.4%, p<0.001).
Conclusions:
MA chemoradiotherapy for rectal cancer improves survival, with the SA regimen showing enhanced complete pathological response. Differences in baseline characteristics may explain the outcomes. While MA chemotherapy offers modest overall survival benefits, potential toxicity needs to be considered and confirmed in future studies.

Comparison between single agent vs multi-agent chemo-radiotherapy group.

Outcome
Single-agent chemotherapy
Multiagent chemotherapy
Chi Squared p-value

No readmission within 30 days of surgical discharge
22,727 (89.3 %)
12,921 (90.9 %)
<0.001

30-day mortality after surgery
360 (1.5 %)
59 (0.5 %)
<0.001

90-day mortality after surgery
716 (3.0 %)
158 (1.3%)
<0.001

Median duration of surgical admission
6.0
5.0
<0.001

Median survival-vital = deceased (months)
38.9
41.2
0.005

Median survival-vital = alive (months)
66.9
52.0
<0.001

Pathological complete response (pCR)
2,644 (10.4%)
904 (6.4%)
<0.001
Rates and risk factors for recurrence of hepatocellular carcinoma after initial complete remission in response to transcatheter arterial chemoembolization: A systematic review and meta-analysis.
Authors: Thakurdesai Aishwarya , Ingawale Sushrut , Liu David , Gandhi Tanmay , Mody Shefali , Stuart Ansley , Mohan Babu , Barve Ashutosh
Published: January 2025

612

Background:
Transcatheter arterial chemoembolization (TACE) is used for palliative treatment of patients with inoperable hepatocellular carcinoma (HCC). Despite remarkable initial remission rates, frequent recurrences of HCC after TACE have resulted in questionable survival benefit. Our investigation aimed to study the rates and risk factors for HCC recurrence following remission after TACE.
Methods:
Comprehensive search of 5 databases (EMBASE, Web of Science, PubMed, CINAHL, ClinicalTrials.gov) was conducted to yield 4263 studies, which were screened based on prespecified inclusion and exclusion criteria. Outcomes assessed were total recurrence rate; 6-month, 1, 2, and 3-year cumulative recurrence rates; and 1 and 3-year survival rates for patients with and without recurrence. Meta-analysis was conducted by the random-effects model and heterogeneity was assessed by the I
2
statistic and 95% prediction interval. Systematic review of risk factors for recurrence was performed.
Results:
Twelve studies and 1,152 patients who underwent complete remission in response to TACE were included. The pooled rate of total recurrence was 60% (95% CI 53-67%). The pooled 6-month, 1-year, 2-year, and 3-year cumulative recurrence rates were 26% (95% CI 18-33%), 33% (95% CI 22-43%), 49% (95% CI 34-64%), and 62% (95% CI 53-71%), respectively. The pooled 1-year survival rates for patients with and without recurrence were 94% (95% CI 89-99%) and 99% (95% CI 99-100%), respectively. The pooled 3-year survival rates for patients with and without recurrence were 61% (95% CI 31-90%) and 91% (95% CI 81-100%). Heterogeneity was considerable based on the 95% prediction interval. Predominant risk factors for recurrence were larger tumor size, multinodularity, portal vein thrombosis, and higher AFP levels.
Conclusions:
HCC frequently recurs after initial remission achieved through TACE, with differences in survival rates between patients with and without recurrence. Identifying high-risk patients based on tumor size, multinodularity, portal vein thrombosis, and AFP levels could improve long-term outcomes.
Evaluating immune cell abundance across hepatocellular carcinoma disease stages I-III: Findings from TCGA analysis.
Authors: Jaradat Jaber H. , Ilerhunmwuwa Nosakhare Paul , Singh Meghana , Sahin Ibrahim Halil , Saeed Anwaar
Published: January 2025

621

Background:
Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the sixth most prevalent cancer globally and a leading cause of cancer-related mortality. The tumor microenvironment (TME) in HCC, characterized by complex interactions between immune and tumor cells, significantly influences tumor progression and immune suppression. Understanding the immune landscape across the different stages of HCC can inform prognosis and therapeutic strategies.
Methods:
We analyzed RNA seq data from 333 HCC patients (disease stages I-III), from The Cancer Genome Atlas (TCGA), using the immune deconvolution algorithms CIBERSORT and xCell. Differential gene expression analysis was performed using the DESeq2 package in R. Immune cell abundance across various HCC stages was imputed, and survival analyses was conducted using Kaplan-Meier curves and log-rank tests.
Results:
Of the 19,514 genes analyzed, 2,774 were up-regulated and 947 were down-regulated in stage II and III in comparison to stage I. CIBERSORT and xCell analyses revealed significant variability in the immune cell composition between HCC stages. Notable differences were observed in the T cells (CD4 and CD8 subsets), B cells, plasma cells, and stromal components. ANOVA and post hoc tests identified significant stage-specific differences in several immune cell types. For the survival analysis, we categorized patients into low and high groups based on median cell abundances. Overall survival showed no statistically significant differences among the various groups for common myeloid and lymphoid progenitor cells. In contrast, disease-free survival demonstrated statistically significant differences across the groups for both cell types.
Conclusions:
This study emphasizes the tumor microenvironment's pivotal role in HCC, revealing that immune cell composition significantly influences disease-free survival, despite limited effects on overall survival. These findings advocate for further exploration into targeted immunotherapies and the development of predictive models that integrate immune landscape characteristics, ultimately aiming to enhance patient outcomes in HCC.

Cell type
xCell
Cibersort

Mean

SD

Mean

SD

T cell CD4 naive
0.00466
0.01994
1.31e-5
1.69e-4

T cell CD8
0.01368
0.03253
0.03161
0.04947

Eosinophil
3.96e-5
3.41e-4
1.67e-4
8.69e-4

Macrophage
0.02323
0.02441
0.02924
0.04345

Macrophage.M1
0.00914
0.01526
0.01806
0.02054

Macrophage.M2
0.02303
0.01697
0.05439
0.04815

B cell memory
0.00196
0.01418
0.00107
0.00733

B cell naive
0.00163
0.01034
0.01319
0.02148

Neutrophil
2.14e-4
0.00137
0.00112
0.00539

Immune score
0.04621
0.06817

-

-

Table presents various cell type abundances for each algorithm used.
Effects of the delay of surgery in localized rectal cancer.
Authors: Miranda Thiago do Amaral , Braga dos Santos Azevedo Clara , Batalha Filho Eronides Salustiano , Gadia Rafael , Gheller Alexandre , Alves Fabiola , Girardi Daniel da Motta , Pereira Allan Andresson Lima
Published: January 2025

63

Background:
The treatment landscape for localized rectal cancer has evolved significantly in recent years, with long-course neoadjuvant chemoradiation (CRT) and total neoadjuvant therapy (TNT) emerging as the primary options. However, the optimal timing of surgery remains an important clinical question, particularly in resource-limited settings where surgical delays can occur. Data from previous studies have shown conflicting results. This retrospective study aimed to assess the impact of delaying surgery beyond the longer interval used in previous studies, focusing on its effects on Pathologic Complete Response (pCR), DFS, and OS.
Methods:
We conducted a retrospective cohort study using electronic medical records from three centers in Brazil between the years 2013-2024. The study included 236 patients with localized rectal cancer treated with neoadjuvant CRT and/or chemotherapy. Patients were divided into two pre-specified groups based on the interval between the end of neoadjuvant therapy and surgery: ≤11 weeks and >11 weeks. The primary endpoint was DFS. Secondary endpoints were pCR rates, and OS. Descriptive statistics were used for population analysis, while the Kaplan-Meier method estimated DFS and OS, with comparisons made using the log-rank test. A Cox proportional-hazards model was used to estimate hazard ratios and 95% confidence intervals.
Results:
The median age of the study population was 62 years, with males comprising 56.4% of the sample. The majority of the sample consisted of stage III patients, making up 72.2%, followed by stage II patients at 25.8%, and stage I patients at 1.9%. Most patients (77.8%) had surgery more than 11 weeks after completing neoadjuvant therapy, with a median time to surgery of 16 weeks. The pCR rates did not significantly differ between the two groups (29% for ≤11 weeks vs. 21.5% for >11 weeks; p = 0.271). After a median follow-up of 30 months, the median DFS was not reached, and there was no significant difference between the groups (HR: 0.86; 95% CI: 0.48-1.5; p = 0.63). Similarly, the median OS was not reached, and no difference was observed between the groups (HR: 0.85; 95% CI: 0.47-1.54; p = 0.88).
Conclusions:
Delaying surgery beyond 11 weeks did not result in greater tumor downstaging in patients with localized rectal cancer. Furthermore, DFS and OS were not significantly impacted by extended intervals between neoadjuvant therapy and surgery.
Exploring Nectin-4 expression in hepatocellular carcinoma.
Authors: Chuang Chien Huai , Yuan Chang-Tsu , Chang Ching-Cheng , Liu Tsung-Hao , Shen Ying-Chun , Lu Li-Chun , Ou Da-Liang , Hsu Chih-Hung , Cheng Ann-Lii
Published: January 2025

632

Background:
Nectin cell adhesion protein 4 (Nectin-4) is overexpressed in various malignancies, contributing to cancer progression and poor prognosis. We aimed to assess Nectin-4 expression in hepatocellular carcinoma (HCC).
Methods:
Patients who underwent primary liver tumor resection for HCC upon initial diagnosis at National Taiwan University Hospital in 2019 were included. Exclusion criteria consisted of prior systemic or loco-regional therapy, or death within three months post-surgery. Immunohistochemical (IHC) staining for Nectin-4 (EPR15613-68, Abcam) was conducted and independently reviewed by two pathologists. Nectin-4 expression patterns (membranous, cytoplasmic, and nuclear) and intensity were scored on a 0–3 scale, with normal eccrine glands (2+) serving as a positive control. Nectin-4 expression was further assessed in primary and paired progressive or metastatic tissue samples from patients with available paired samples.
Results:
Of the 193 patients, 175 had specimens available for IHC analysis. Nectin-4 expression was detected in 22.9% of these patients, with intensity scores of 0 in 77.1%, 1 in 22.3%, and 2 in 0.6%. The majority of staining pattern was cytoplasmic (94.3%), with membranous staining observed in 5.1% of cases. Nectin-4 expression was significantly associated with higher pathological grades (
p
= 0.005) but showed no correlation with recurrence-free survival (
p
= 0.771) or overall survival (
p
= 0.396) after surgery. Importantly, Nectin-4 expression intensity significantly increased in paired progressive or metastatic samples compared to initial HCC specimens (
p
= 0.046; n = 27).
Conclusions:
Nectin-4 expression is associated with higher pathological grades but not related to clinical outcomes in HCC. Increased Nectin-4 expression in progressive or metastatic disease highlights its potential as a therapeutic target.
Radiomics-based prediction of HCC response to atezolizumab/bevacizumab.
Authors: Rodriguez Isaac , Vellala Abhinay , Itzel Timo , Vácha Michael , Chang De-Hua , Dill Michael , Seidensticker Max , Mayerle Julia , Munker Stefan , Schönberg Stefan O. , Mueller Lukas , Galle Peter Robert , Weinmann Arndt , Tamandl Dietmar , Pinter Matthias , Scheiner Bernhard , Teufel Andreas , Froelich Matthias , Ebert Matthias Philip , Venerito Marino
Published: January 2025

636

Background:
Advanced hepatocellular carcinoma (HCC) treatment has evolved with the introduction of atezolizumab/bevacizumab, showing improved outcomes over sorafenib. However, the response varies among patients, particularly between viral and non-viral etiologies. This study aimed to develop and evaluate multimodal prediction models combining quantitative imaging and clinical markers to predict treatment response in HCC patients.
Methods:
From March 2020 to May 2023, patients with advanced HCC treated with atezolizumab/bevacizumab were retrospectively identified from six centers in Germany and Austria. Patients underwent baseline contrast-enhanced liver MRI and follow-up imaging to assess therapy response. Machine learning models, including RandomForestClassifier, were developed for radiomics, clinical, and combined datasets. Hyperparameter tuning was performed using RandomizedSearchCV, followed by cross-validation to evaluate model performance.
Results:
The study included 103 patients, with 70 achieving disease control (DC) and 33 experiencing disease progression (PD). Key findings included significant differences in treatment response and progression-free survival between DC and PD groups. The radiomics model, using 14 selected features, achieved 73.1% accuracy and a ROC AUC of 0.635 on the test set. The clinical model, with 4 selected features, achieved 73% accuracy and a ROC AUC of 0.649 on the test set. The combined model showed improved performance with 69% accuracy and a ROC AUC of 0.753 on the test set. Hyperparameter tuning further enhanced the combined model's accuracy to 80.1% and ROC AUC to 0.771 on the test set.
Conclusions:
The hybrid model combining clinical and radiological data outperformed individual models, providing better predictions of response to atezolizumab/bevacizumab in HCC patients.
Alteration of gut microbiota in patients with advanced hepatocellular carcinoma.
Authors: Charoenthanadhol Thanakorn , Wirasorn Kosin , Sookprasert Aumkhae , Chindaprasert Jarin , Sanlung Thanachai , Watcharenwong Piyakarn , Putraveephong Siraphong , Phetcharaburanin Jutarop
Published: January 2025

641

Background:
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer-related death worldwide. Despite advancements in treatment, such as novel combinations of immunotherapy and targeted therapy or dual immunotherapy, the prognosis remains poor due to a lack of predictive biomarkers for treatment response. Gut microbiota alterations have been proposed as both potential diagnostic biomarker and predictive biomarker. However, data in this field are not well-established and are mostly derived from studies conducted in China and Western countries, which may not fully reflect the situation in Thailand.
Methods:
Fecal samples were collected from pre-treated advanced HCC patients who visited medical oncology outpatient clinic at Srinagarind hospital, Khon Kaen University (HCC group = 27) and analyzed using 16S rRNA sequencing of gut microbiota. Additional sequenced data from a healthy population (Control group = 31) who had no underlying disease and had normal liver ultrasonography were retrieved from a previous study conducted by Khon Kaen University (Cholangiocarcinoma Screening and Care Program, CASCAP). The datasets were compared using the Wilcoxon rank-sum test to analyze the alteration of gut microbiota between HCC group and control group.
Results:
The HCC group exhibited significantly lower biodiversity index (p< 0.001) than control group in terms of richness, Shannon diversity index and Simpson’s index. The HCC group had significantly higher relative abundance of the phylum Proteobacteria (p< 0.001), Firmicutes (p< 0.001) and a lower abundance of the phylum Actinobacteria (p< 0.001) compared to the control group. Additionally, the HCC group had significantly higher relative abundance of Stenotrophomonas, Granulicatella, Ruminococcus, Blautia, Phascolarctobacterium, Butyricoccus, Streptococcus, Escherichia-Shigella, Flavonifractor, Haemophilus and Lachnospira at the genus level. Further analysis of relative abundance of gut microbiota at the genus level and clinical prognostic parameters showed positive correlation between Streptococcus and 6-month survival status.
Conclusions:
Gut microbiota profile in patients with advanced HCC was significantly altered from healthy control group. This could be the evidence of microbial dysbiosis and may potentially be biomarker for prognosis.
Total cost of care of immune-oncology treatments for unresectable hepatocellular carcinoma: A Singapore healthcare perspective analysis.
Authors: Fullarton John , Yap Serene , Krivasi Tania , Rodgers-Gray Barry , Tay Doreen
Published: January 2025

642

Background:
Tremelimumab + durvalumab (STRIDE) and atezolizumab + bevacizumab are recommended first-line immune-oncology treatment options for unresectable hepatocellular carcinoma (uHCC). This study aimed to quantify the total economic burden to the Singapore healthcare system of treating patients with uHCC using STRIDE
versus
atezolizumab + bevacizumab.
Methods:
A model was developed to estimate the total cost of care of using STRIDE or atezolizumab + bevacizumab, which followed patients with uHCC eligible for first-line systemic therapy, considering direct medical costs. Costs considered in the model included treatment acquisition and administration, endoscopy, healthcare resource use, and cost for treating grade ≥3 treatment-emergent adverse events (TEAEs). Data on treatment regimens and TEAEs were taken from the HIMALAYA (STRIDE) and IMbrave150 (atezolizumab + bevacizumab) trials. Resource use rates were based on an average of 168 days treatment for both regimens. All costs were obtained from Singaporean sources.
Results:
The total cost of care for STRIDE and atezolizumab + bevacizumab was estimated at SGD$40,277 (USD$30,932) and SGD$43,605 (USD$33,487)
per
patient, respectively. This translates into an average cost savings of SGD$3,328 (USD$2,555])
per
patient when treated with STRIDE compared to atezolizumab + bevacizumab. The main driver of cost savings was treatment acquisition and administration (-SGD$1,917 [-USD$1,472], -6%) though lower costs were also associated with resource use (-SGD$927 [-USD$712], -8%), endoscopy (-SGD$342 [-USD$263], -77%) and TEAE management (-SGD$141 [-USD$108], -74%). Assuming an incident population of 260 patients eligible for treatment, the total burden was estimated at SGD$10,489,604 (USD$8,055,696) when all patients were treated with STRIDE, and SGD$11,356,273 (USD$8,721,271) when treated with atezolizumab + bevacizumab (Table). The incremental cost offset to the health plan was SGD$866,669 (USD$665,575) when treated with STRIDE.
Conclusions:
This study suggests that STRIDE offers cost savings over atezolizumab + bevacizumab for uHCC treatment in the Singapore healthcare system. Additional real-world evidence studies are warranted to capture the long-term survival benefits and associated treatment costs.

Annual cost of care based on 260 patients receiving first-line immune-oncology treatment.

Category
STRIDE
Atezolizumab + Bevacizumab
Incremental difference

Endoscopy costs
$26,358
$115,555
-$89,197

Resource Use costs*
$2,607,000
$2,848,307
-$241,307

Adverse events costs
$12,899
$49,716
-$36,817

Treatment acquisition and administration
$7,843,347
$8,342,696
-$499,349

TOTAL

$10,489,604

$11,356,273

-$866,669

All costs in SGD$. *Includes: physician visits; laboratory and radiological tests; and hospitalisation.
Clinicopathological factors related to survival in gastroenteropancreatic neuroendocrine tumors (GEP-NET): 20 years experience in the American British Cowdray Medical Center.
Authors: Wuotto Alvarado Susy , Gerson-Cwilich Raquel , Huitzil Melendez Fidel David David , Olivares Guillermo , Salcedo Ivonne , Villalobos Alberto , Serrano Juan Alberto , Aguayo Alvaro , Meneses-Medina Monica Isabel , Camacho Limas Christian Patricio , Shveid Gerson Daniela , Rosas Camargo Vanessa , Camberos-Mercado Carlos Arturo , Martínez-Herrera José Fabián , Noguez-Ramos Alejandro ,   The American British Cowdray Medical Center, México City
Published: January 2025

656

Background:
Neuroendocrine neoplasms (NEN) are a diverse group of tumors originating from neuroendocrine cells found throughout the body. Their “rarity”, heterogeneity, and non-specific presentation contribute to limited reliable epidemiological data, especially in developing countries such as Mexico. This study aims to analyze the clinical and pathological features of gastroenteropancreatic neuroendocrine tumors (GEP-NET) and their association with survival in a third-level center in Mexico.
Methods:
A retrospective cohort study at the American British Cowdray Medical Center, in Mexico City, was conducted. We included all histopathological confirmed GEP-NET from 2004 to 2024. Clinical, biochemical, and radiological features at diagnosis were analyzed. Survival was estimated using Kaplan-Meier and Log-Rank test.
Results:
We identified 110 NENs, of which 89% were GEP-NET, 56.1% were female, and the median age was 57.7 (SD 13.8) years. The clinical stage was metastatic (50%), localized (37.7%), and locally advanced (6.1%). The primary sites were the pancreas (49%), small bowel (23.5%), gastric (10.2%), colon (7.1%), rectum (5.1%), appendix (3.1%), and unknown (2%). ECOG performance status were 0-1 in 96.9%. In the metastatic setting, liver involvement was 96.2%, mainly high hepatic burden (59.6%). Symptoms were abdominal pain (34.6%), diarrhea (16.3%), and bowel obstruction (6.1%). Functioning tumors were 26.8%, and carcinoid syndrome was found in 9.2%. Grades 1, 2, and 3 were 62.9%, 34%, and 3.1% respectively. The median of Ki-67 was 6.4%. At diagnosis, Ga-68 PET/CT scan, serum CgA, and urinary 5-HIIA were performed in 98.2%, 39.7%, and 16.3% of patients. Among metastatic patients, 87.1% received at least one line of systemic treatment, primarily with somatostatin analogs (62.9%). In all population, the median follow-up was 42.5 months and the median overall survival (OS) was 164.9 (SD 12.2) months. Univariate analyses showed that primary site (p=0.02), Ki-67 <5% (p=0.02), CgA <700 ng/ml (p=0.03), and low hepatic burden (p=0.01) were statistically significantly associated with OS.
Conclusions:
This study provides critical insights into GEP-NET characteristics in a Mexican population, highlighting clinical, biochemical, and radiological factors associated with better survival.
Efficacy of immune checkpoint inhibitors in patients with advanced pancreatic NETs displaying high TMB and MMR alterations following treatment with alkylating agents.
Authors: Strosberg Jonathan R. , Koumarianou Anna , Riechelmann Rachel , Hernando Jorge , Cingarlini Sara , Crona Joakim , Al-Toubah Taymeyah E. , Apostolidis Leonidas , Bergsland Emily K. , Halfdanarson Thorvardur Ragnar , Cros Jerome , De Mestier DU Bourg Louis
Published: January 2025

662

Background:
Alkylating-based chemotherapy (ALK) is one of the main treatments used in patients with advanced pancreatic neuroendocrine tumors (PanNETs). Its use has been associated with an increased risk of grade progression and acquisition of a hypermutator phenotype, associated with frequent alterations of the mismatch repair (MMR) genes. This suggests a potential benefit of immune checkpoint inhibitors (ICI) that are otherwise ineffective in ALK-naïve PanNETs, which are mostly hypomutated. We aimed to describe the efficacy of ICI in patients with advanced PanNET pretreated with ALK.
Methods:
We assembled an international retrospective cohort of patients with advanced PanNET who received at least one cycle of ICI, and who had previously received at least 3 months of ALK. Patients with poorly-differentiated neuroendocrine carcinoma were excluded. The primary endpoint was progression-free survival (PFS) and the secondary endpoint was the objective response rate (ORR). The impact of tumor mutational burden (TMB, high being defined by >10 mut/Mb) and MMR alterations (mutations or IHC) was explored.
Results:
We included 39 patients (median age 58.7, male sex 62%). All PanNETs were progressive at baseline and presented a median of 3 (IQR, 2-4) metastatic sites. Tumors were predominantly classified as G2 (47%) or G3 (42%), with a median Ki-67 of 18.5% (IQR, 12-35). 23/27 patients with tumor tissue or ctDNA NGS testing had high TMB (median, 35 mut/Mb; IQR, 24-106) and 12/22 had MMR alterations. Patients had previously received an average of 14 cycles (IQR, 7-25) of ALK (temozolomide 78%, streptozotocin 18%, dacarbazine 4%), which had yielded objective response in 72% of cases. In addition, patients had received a median of 4 (IQR, 3-5) other treatments (including platinum drugs in 80% and PRRT in 51%). ICI mainly consisted in an anti-PDL1/PD1 + anti-CTLA4 combination (85%) or a monotherapy (15%), with a median of 3 (IQR, 2-8) cycles. The ORR was 18% and the disease control rate was 46%. Median PFS was 2.8 months (95% CI, 0.62-4.96) and 6-month PFS rate was 31%. 19% of patients had grade 3-4 toxicity. Patients with high TMB had higher ORR (30% vs. 0%, p=0.03) and longer median PFS (4.9 vs. 2.1 months, p=0.004) compared with patients with low/unknown TMB. Patients with altered MMR had higher ORR (42% vs. 7%, p=0.02) and longer median PFS (8.9 vs. 2.5 months, p=0.014) compared with patients with no/unknown MMR alterations.
Conclusions:
While ICI shows limited efficacy in unselected patients with advanced PanNETs pretreated with ALK, it may be an effective treatment option in case of high TMB and MMR alterations.
Racial disparities in receipt of guideline concordant pancreatic cancer care among older adults in the US.
Authors: Herb Joshua , Liao Kai-Ping Eric , Lewis Kever , Katz Matthew H. G. , Lin John Kent , Snyder Rebecca A
Published: January 2025

679

Background:
Patients racialized as Black experience higher incidence and mortality from pancreatic cancer (PC). The aim of this study was to examine differences in receipt of guideline concordant care (GCC) among older adults with PC racialized as Black, White, or Hispanic ethnicity.
Methods:
Patients 65 years and older with incident PC racialized as White, Black, or Hispanic ethnicity were identified in the SEER-Medicare database from 2004-2019. The primary outcome was receipt of GCC (stage I/II: surgery+chemotherapy+/-radiation; stage III: chemotherapy+/-surgery+/-radiation; stage IV: chemotherapy+/-radiation). Multivariable logistic regression was used to identify factors associated with GCC. Oaxaca-Blinder decomposition was used to examine the contribution of measured and unmeasured variables to racial disparities in receipt of GCC.
Results:
Of 12,772 patients included, 85.5% of patients racialized as White (n=10,915), 7.8% Black (n=992), and 6.8% Hispanic ethnicity (n=865). Patients racialized as Hispanic ethnicity and Black were more often dual-eligible for Medicare/Medicaid than patients racialized as White (38.6%, 26.9%, and 7.5%, respectively). In total, 56.3% received GCC. On adjusted analysis, patients racialized as Black were less likely to receive GCC for early stage (stage I/II) disease compared to patients racialized as White (OR 0.66; 95% CI 0.53-0.83), but not for stage III (OR 0.65; 95% CI 0.41-1.01) or stage IV (OR 0.87; 95% CI 0.66-1.14) disease. No difference in GCC was observed among patients of Hispanic ethnicity when compared to patients racialized as White. Increased age and dual-eligibility were associated with decreased likelihood of GCC across stages. Differences in receipt of GCC among patients racialized as Black and White remain largely unexplained. Of the measured factors, comorbidities, dual-eligibility, and area level poverty contributed most to the disparity in GCC (Table).
Conclusions:
Just over half of an insured population with PC receive GCC. Despite an increased focus on equity in cancer care, Black-White racial disparities in receipt of GCC are prevalent, particularly among patients with early-stage disease. Further studies are critical to identify and address the unmeasured factors driving treatment disparities.

Contributing factors to racial disparities in guideline concordant care for patients with pancreatic cancer.

Stage I/II
Stage III
Stage IV

Difference (White-Black)
11.6%
9.4%
4.1%

Explained

Age
-3.0%
-2.0%
-1.0%

Sex
0.1%
0.8%
0.1%

Dual-Eligibility
2.0%
3.1%
0.8%

Charlson Comorbidity Index
1.3%
0.2%
0.7%

Area Level Poverty
2.2%
-0.8%
0.7%

Hospital/Practice Volume
1.2%
-0.3%
-0.03%

Region
0.4%
0.9%
-0.2%

Year of Diagnosis
-0.1%
0.5%
0.1%

Unexplained
7.5%
7.0%
3.0%

Positive values indicate these factors increased the measured disparity, while negative values indicate these decreased the measured disparity.