bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in early onset colorectal cancer–related mortality among adults in the United States from 1999-2020.
Authors: Zafar Yousaf , Zafar Adnan , Iqbal Arsalan Zafar , Rizwan Marryum , Manzoor Laila
Published: January 2025

42

Background:
Colorectal cancer (CRC) has witnessed a decrease in incidence and mortality in the United States (US) for the past few decades likely due to increased screening and improvements in treatment . Despite the overall burden of CRC has declined and survival has been made for older adults, there is a simultaneous and alarming increase in CRCs diagnosed in individuals younger than 50 years of age. These Early Onset CRC (EOCRC) which now account for roughly 10% of new CRC cases in the US. The purpose of this study was to assess the trends and regional differences in EOCRC-related mortality among adults in the United States.
Methods:
Death certificates from the CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research) database were examined from 1999 to 2020 for -related mortality in adults <45 years of age. Age-adjusted mortality rates (AAMRs) per 10,000 persons and annual percent change (APC) were calculated and stratified by year, sex, race/ethnicity, and geographic region.
Results:
Between 1999 and 2020, 32,850 EOCRC-related deaths occurred among adults 25-44 years. The AAMR increased from 2.1 in 1999 to 2.6 in 2020. Men had consistently higher AAMR than women from 1999 (AAMR men: 2.0 vs women: 1.6) to 2020 (AAMR men: 2.6 vs women: 2.0). Non Hispanic (NH) African Americans had the highest overall AAMR (3.1), followed NH White (2.2), NH Asians (1.6) and Hispanics (AAMR 1.5) Caucasians have had a significant increase in mortality over the past 2 decades ( APC 1.4 (95%Cl 1.1-.7)) whereas the Hispanics have shown an APC of 4 (95% Cl 2.3-5.8 from 2012-2020). AAMR also varied substantially by region (overall AAMR: Midwest 2.1; South: 2.4; West: 1.9; Northeast: 2.0). States in the top 90th percentile of EOCRC-related AAMR were Mississippi, Arkansas, Oklahoma, South Carolina, Alabama West Virginia, Louisiana ,Kentucky and Tennessee which had approximately double the AAMRs compared with states that fell into the lower 10th percentile.
Conclusions:
EOCRC-related mortality in U.S. adults has been steadily increasing over the past two decades . The highest AAMRs were observed among African American adults and men, and among patients living in the Southern , Midwestern regions and those living in the nonmetropolitan United States. Targeted strategies are needed to prevent and treat EOCRC among older adults to curb increasing levels of EOCRC-related mortality.
FG-M108 plus capecitabine and oxaliplatin (CAPOX) for ﬁrst-line treatment of CLDN18.2+/HER2- advanced gastric/gastroesophageal junction adenocarcinoma (GC): Update results of a phase I/II trial to determine RP2D.
Authors: Gong Jifang , Liu Funan , Jin Zhaoyu , Zhang Miao , Zhang Shu , Zhang Yanqiao , Liang Xinjun , Li Yun , Yang Yaping , Zhu Lingyin , Shen Lin
Published: January 2025

431

Background:
There exists unmet need for previously untreated pts with CLDN18.2+/HER2- advanced GC. FG-M108, an mAb specifically targeting CLDN18.2 and exhibiting enhanced ADCC activity, has the potential to benefit these pts.
Methods:
This phase I/II trial evaluated safety, pharmacokinetics and preliminary antitumor activity of FG-M108 plus CAPOX in previously untreated pts with CLDN18.2+/HER2- advanced GC, where FG-M108 was administered intravenously at 300 mg/m
2
or 600 mg/m
2
Q3W. Here we compare results of FG-M108 at 300mg/m
2
(Cohort A) with 600mg/m
2
(Cohort B) to establish RP2D.
Results:
As of August 28, 2024, 63 pts with CLDN18.2+ (IHC 1/2/3+≥10%) GC were treated, 70% of whom had CLDN18.2 Medium-High expression (CMH, IHC 2/3+≥40%). Baseline characteristics were comparable between Cohorts A & B. Increasing the FG-M108 dosage did not result in a higher incidence or severity of treatment-related adverse events (TRAE) overall. However, nausea and vomiting, identified as CLDN18.2 on-target toxicities, were significantly more frequent and severe in Cohort B compared to Cohort A.When 300 or 600 mg/m² of FG-M108 was administered intravenously Q3W, serum trough concentration exceeded the target drug concentration predicted by in vitro ADCC activity. The 300 mg/m² dose is expected to provide sufficient drug exposure as the effective dose.Moreover, in Cohort A, pts with CMH expression had a conﬁrmed ORR of 78% (unconﬁrmed ORR=81%) and a median PFS of 11.0 months（95%CI 6.9-12.7）, signiﬁcantly better than those in Cohort B. Based on safety, PK and efficacy trends, the RP2D was determined to be FG-M108 at 300mg/m
2
plus CAPOX.
Conclusions:
FG-M108 plus CAPOX had a manageable safety profile and promising antitumor activity in GC, with RP2D at 300mg/m
2
. A phase III trial is ongoing to confirm the efficacy of FG-M108 at 300mg/m
2
plus CAPOX as first-line treatment (NCT06177041).
Clinical trial information: NCT04894825
.

Cohort A n=52
Cohort B n=11

CMH %
71
64

Primary lesion-Stomach %
92
100

Metastatic organs ≥3 %
27
9

ORR/DCR with CMH %
81/97
57/86

PFS/DOR with CMH months
11.0/9.9
5.5/4.2

≥G3 TRAE %
37
18

TRAE-Nausea % / ≥G3 Nausea %
38/2
64/9

TRAE-Vomiting % / ≥G3 Vomiting %
23/2
73/9
Neoadjuvant immunotherapy and nonoperative management of dMMR gastroesophageal adenocarcinoma (GEA): A retrospective case series.
Authors: Sahvan Oudai , Jamal Fares , Borad Mitesh J. , Bekaii-Saab Tanios S. , Wu Christina , Ahn Daniel H. , Sonbol Mohamad Bassam
Published: January 2025

451

Background:
Perioperative chemotherapy with surgery is the standard of care for patients (pts) with resectable gastric or gastroesophageal junction adenocarcinoma (GEA). However, recent studies have shown more favorable responses after neoadjuvant immunotherapy (NIO) in patients with mismatch repair deficient (dMMR) cancers. Herein, we present the outcomes of 10 cases with dMMR GEA.
Methods:
We retrospectively reviewed patients with GEA at Mayo Clinic Arizona who met the following criteria: have dMMR disease by IHC, nonmetastatic operable disease, and received NIO +/- chemotherapy. Patient demographics, disease characteristics, and clinical outcomes were extracted. The primary endpoint was clinical complete response (cCR) in patients treated with non-operative management (NOM) defined as complete radiological response and no residual disease on endoscopic ultrasound (EUS) and biopsy.
Results:
10 pts with dMMR GEA with a median age of 70 (43-85) were identified. 6 pts had T2N0, 1 had T4N0, 3 had N+ disease. 8 pts received NIO monotherapy upfront, 1 received NIO after progressing on chemotherapy, and 1 concurrently with chemotherapy. No grade 3/4 toxicities were reported, however, 2 pts discontinued therapy due to arthralgia and colitis. After NIO, 9/10 pts had significant or complete resolution of FGD avidity on PET/CT, while 1/10 had stable disease. 3/10 pts underwent surgical resection, with 2 achieving pathological complete response (pCR) and the third showing T1N0 disease with no recurrence 1 year after surgery. Notably, one of the pts with pCR passed away due to surgical complications. 7/10 patients had NOM, of whom, 4 had cCR and 3 had radiological response only, as no EUS data was available. 4/7 NOM pts had follow up data at 6 months with no evidence of progression, of whom one pt remained progression-free at 33 months. ctDNA testing was performed in 6/10 pts: 2 had undetectable ctDNA at baseline, while 3 became MRD-negative after NIO, consistent with radiological and/or pathological response, and 1 had persistent ctDNA both before and after NIO, despite cCR.
Conclusions:
This study demonstrates exceptional and prolonged response, along with good tolerability to NIO in pts with dMMR GEA, supporting the feasibility of non-operative management in such patients.
Non-metastatic gastric cancer (GC) in patients aged 80 years or older: Immediate and long-term outcomes of combined treatment.
Authors: Semenov Nikolay , Izrailov Roman , Khodos Nikita , Grechukhina Katerina , Zhukova Lyudmila
Published: January 2025

453

Background:
Comorbidities and increased risk of chemotherapy-induced toxicity in elderly patients presents significant challenges in management of GC. Here we presents a single-center experience in treatment patients aged 80 years or older with non-metastatic GS, reporting both immediate and long-term outcomes of surgical treatment (ST).
Methods:
This retrospective analysis includes 61 patients (pts) diagnosed with non-metastatic GC or cardio-esophageal junction (CEJ) cancer. The primary endpoint was relapse-free survival (RFS); secondary endpoints included overall survival (OS) and the incidence of surgical complications (SC).
Results:
Among the 61 pts (median age 82.7 years, range 80.0-89.2) 39.3% were men. ECOG PS was 0-1 in 49 pts (80.6%) and 2 – in 12 pts (19.4%). The primary tumor site was the stomach in 57 pts (93.4%) and the CEJ in 4 pts (6.6%). Tumor stage had been defined as cT
1-2
in 33.3% pts, cT
3-4
in 57.1%; cN
0
– in 36.1%, stage remained unknown in 6.3%. Radical surgery was performed in pts 78.7% (n=48), 29 pts (47.5%) of them underwent ST only without perioperative chemotherapy (CT). Neoadjuvant CT (NACT) received 23 pts (37.7%): platinum-based doublet regimen – 82.6% (n=19), while 17.4% (n=4) received capecitabine only. ST was performed in 47.8% (n=11) pts received NACT, other 12 pts didn’t undergo ST due to progression of disease (8.3%), comorbidities (33.3%), or patient preference (16.7%) in 1, 4 and 2 cases, respectively. Adjuvant CT was administered to 9 pts (14.3%). Surgical interventions included gastrectomy in 16.6% pts (n=9), proximal or distal resection – in 8.3% (n=4) and 74.1% (n=35), respectively. R0-resection was achieved in 42 pts (88.6%). SC has 20.8% (n=10) pts: classified as Clavien-Dindo grade (G) II – 4.4%, G IIIa – 8.9%, G IIIb - 8.9%; these included anastomotic leakage (6.7%), abscess formation (2.2%), cardiac events and thrombosis (4.4%), and eventration (2.2%). SC G IV or V not reported. The median duration of postoperative hospitalization was 8 days. In the overall cohort, the 3-y RFS was 53% (95%CI 28.9-53.9), 3-y OS – 67% (95%CI 27.9-75.2). Among the pts with stage IA (n=15), the 3-y RFS was 72% (95%CI 49.1-85.1), with a maximum follow-up period of 80 months and no cancer-related deaths. In patients with cT
2-4
N
any
3-y RFS was 70% in the overall cohort and 74% in the surgery-only group (HR 1.09; 95%CI 0.45-2.65, p=1).
Conclusions:
Our findings demonstrate that over 65% of patients aged 80 years or older survive for at least 3 years following surgery for GC, with 53% living without evidence of metastases. Additionally, the rate of SC in this elderly cohort is comparable to that observed in younger populations. The role of perioperative or neoadjuvant CT in this age group remains a topic of ongoing research and discussion. It is critical to manage such population at referral oncological centers with expertise in treating elderly cancer pts.
A liquid biopsy analysis of exosomal miRNA to detect lymph node metastasis in early gastric cancer.
Authors: Nishi Masaaki , Wada Yuma , Takasu Chie , Yoshimoto Toshiaki , Ishikawa Daichi , Kashihara Hideya , Tokunaga Takuya , Shimada Mitsuo
Published: January 2025

469

Background:
Additional surgical resection is required to achieve a complete cure in patients with early gastric cancer (EGC) due to the potential risk for lymph node metastasis (LNM) after pathological analysis. However, LNM is estimated to occur in approximately 10% of patients with high-risk EGC. In this study, we investigated a blood-based liquid biopsy assay of exosomal miRNA for the noninvasive detection of LNM in patients with high-risk EGC.
Methods:
Two genome-wide miRNA expression profiling datasets (GSE164174 and TCGA) were analyzed to prioritize biomarkers in pretreatment plasma samples from clinical training and validation cohorts of GC patients. An integrated exosomal miRNA panel was developed and a risk stratification model combining the miRNA panel with clinical risk factors was established.
Results:
Using comprehensive expression profiling of public datasets, we identified a transcriptomic panel of four miRNAs (miR-34b, miR-130a, miR-375, and miR-627) that robustly identified patients with LNM [area under the curve (AUC) = 0.86, 95% confidence interval (CI) = 0.77-0.92]. We assessed panel performance in a training cohort (AUC=0.86, 95% CI=0.67-0.96) and validated it in an independent validation cohort (AUC=0.84, 95% CI=0.64-0.95). Our risk stratification model was more accurate than the panel and was an independent predictor of LNM identification (AUC=0.97).
Conclusions:
A novel noninvasive, liquid biopsy-based method for patients with EGC may predict those traditionally classified as high-risk patients with LNM who are unlikely to benefit from surgical resection.
Concordance between PD-L1 assays 28-8 and SP263 and their respective scoring algorithms in procured upper gastrointestinal adenocarcinoma samples.
Authors: Pham Thinh , Liu Yihua , Sharpnack Michael , Lum Jenifer , Koralek Daniel O. , Das Thakur Meghna
Published: January 2025

479

Background:
PD-L1 is being studied as a predictive immunohistochemical (IHC) biomarker for gastroesophageal junction (GEJ), gastric (GC), and esophageal (EAC) adenocarcinomas, and anti-PD-(L)1 therapies are used to treat them. Here, we compare the VENTANA PD-L1 (SP263) IHC assay and its tumor area positivity (TAP) algorithm with the clinically validated Agilent PD-L1 IHC 28-8 pharmDX combined positive score (CPS) algorithm in GEJ, GC, and EAC samples. The degree of concordance between SP263 TAP ≥ 5% and 28-8 CPS ≥ 5 is important for interpreting real-world settings and emerging clinical trial data.
Methods:
GEJ, GC, and EAC tumor samples procured from company-sponsored clinical trials (NCT02545504, NCT02862535, NCT02864381) and external vendors with informed consent were analyzed 4 ways: SP263 TAP, SP263 CPS, 28-8 TAP, and 28-8 CPS. Readouts were evaluated by a single pathologist and were analyzed with Pearson correlation coefficients.
Results:
286 patient samples were analyzed (GEJ, n = 106; GC, n = 88; EAC, n = 92). The agreement among the SP263 TAP ≥ 5% and 28-8 CPS ≥ 5 prevalence is shown in the Table. The overall correlation coefficient between 28-8 CPS and SP263 TAP was high (
R
= 0.95;
P
< 2.2 × 10
−16
). In addition, when applying the same scoring algorithm to both assays (SP263 TAP vs 28-8 TAP or SP263 CPS vs 28-8 CPS), the correlation coefficients remained high (
R
= 0.97;
P
< 2.2 × 10
−16
). When both algorithms were applied to the same IHC assay (SP263 TAP vs SP263 CPS or 28-8 TAP vs 28-8 CPS), the correlation coefficients were also high (
R
= 0.98;
P
< 2.2 × 10
−16
).
Conclusions:
In this controlled experiment the PD-L1 assays 28-8 and SP263 concordance was high. The scoring algorithms for GEJ, GC, and EAC samples were observed as highly correlated; minor differences were likely driven by the distinct PD-L1 monoclonal antibody clones utilized in the IHC assays. These data suggest that the 2 assays are comparable for evaluating PD-L1 expression at the TAP ≥ 5% and CPS ≥ 5 cutoffs.

Clinical trial information:
NCT02545504

,

NCT02862535

,

NCT02864381

.

Concordance of SP263 TAP ≥ 5% with 28-8 CPS ≥ 5.

Positive percentage agreement: 0.96Negative percentage agreement: 0.95Overall percentage agreement: 0.95
28-8 CPS ≥ 5: Positive
28-8 CPS ≥ 5: Negative

SP263 TAP ≥ 5%: Positive
116
9

SP263 TAP ≥ 5%: Negative
5
156
Genomic landscape study of esophago-gastric adenocarcinoma (EGAC) in young patients under the age of 30 years.
Authors: Nam Myungwoo , Ross Jeffrey S. , Pavlick Dean , Jamaspishvili Tamara , Basnet Alina
Published: January 2025

480

Background:
Despite recent advances in treatment of EGAC, prognosis continues to be poor with reported 5-year survival of less than 30%. EGAC is more frequently diagnosed at an old age with the median age at diagnosis around 65 years. However, approximately 10% of EGAC are diagnosed at a younger age of less than 50 years and those patients present with more advanced stages resulting in worse prognosis. Our study investigated the genomic landscape of EGAC diagnosed under the age of 30 years to better understand the characteristics of EGAC occurring in very young population.
Methods:
8,001 cases of clinically advanced EGAC who underwent comprehensive genomic profiling (CGP) from 2012 to 2024 were included in the study. Patients aged less than 30 years were classified as ‘EGAC-young’ and patients aged 50 and older were classified as ‘EGAC-old’. All classes of genomic alterations (GA), microsatellite instability high (MSI-high) status, tumor mutation burden (TMB), genomic ancestry, genomic signature, and homologous recombination defect signature (HRDSig) were determined from the sequencing data. PD-L1 was measured by IHC using the Dako 22C3 tumor proportional score (TPS) system. Comparisons utilized the Fisher Exact method with the Benjamini-Hochberg adjustment to reduce the false discovery rate.
Results:
Out of 8,001 cases, 7389 (92.4%) were classified as ‘EGAC-old’ and 26 (0.3%) as ‘EGAC-young’. Both groups had a higher frequency of male patients but there was no significant difference between the two groups (86.4% vs 76.9%; NS). Median GA per tumor was 6 in both groups. The ‘EGAC-old’ featured a significantly higher frequency of EUR ancestry (92.0% vs 73.1%; P=0.026). There were no significant differences in clinically important GA between both groups, including similar ERBB2 GA (21.2% vs 30.8%; NS) and FGFR3 GA (1.2% vs 7.7%; NS). There was a trend of more frequent GA of AKT2, CCNE1, and KEAP1 noted in ‘EGAC-young’ (0.9% vs 11.5%, 8.5% vs 26.9%, 1.3% vs 11.5%, respectively; P=0.071). MSI-high status was 3.1% in the ‘EGAC-old’ but not detected in the ‘EGAC-young’ (NS). The median TMB was higher in the ‘EGAC-old’ vs ‘EGAC young’ (3.8 mutations/Mb vs 1.9 mutations/Mb; P=.003). The frequencies of a positive HRDSig were similar in both groups (5.6% vs 8.0%; NS). There were no significant differences in COSMIC trinucleotide signatures. PD-L1 expression was identified in greater than 20% of the ‘EGAC-old’ but was not measured in the ‘EGAC-young’.
Conclusions:
Clinically advanced EGAC in young patients under the age of 30 years features a genomic landscape that differs from EGAC identified in older patients, including lower TMB and a trend of increased GA frequency of genes related to poor prognosis in other types of cancer. Further studies are warranted to utilize CGP findings in identifying potential implications for treatment and prognostication in these rare cases of EGAC occurring in very young patients.
The expand indication of HER2 targeted therapies by monitoring of circulating tumor cells.
Authors: Suzuki Koichi
Published: January 2025

482

Background:
Despite success in the HER2 targeted therapies for metastatic gastric cancer patients, the conventional assessment of HER2 status in tumor tissue specimens is still under debate.
Methods:
On-chip sorting system was used for the isolation of circulating tumor cells (CTCs). The fluorescence signal intensity > 50 is set to be a threshold value for distinguishing between positive and negative HER2 on CTCs. Epithelial mesenchymal transition (EMT) was assessed by the vimentin and cytokeratin. DNA was extracted from CTCs and applied to the cancer gene panel.
Results:
In 27 patients with metastatic gastric cancer, 13 patients showed HER2 positive in tumor tissues (Group A) who were treated with cytotoxic agents and HER2-targeted therapy while 14 patients exhibited negative and treated with cytotoxic agents. In these 14 patients, 8 patients showed HER2 positive (Group B) and 6 patients displayed HER2 negative (Group C) on CTCs. HER2 expression on CTCs was associated with EMT (p<0.001). Increased expression of EMT was seen in Group A and B, indicating they are likely to have metastasis. Group B exhibited worse PFS than others (13.8 M in A, 7.0 M in B and not reached in C, p=0.012). In addition, genomic analysis identified cancer gene mutations, some of which were involved in mechanisms underlying EMT and were shared between Group A and B. Considering HER2 expression on CTCs in Group B, an additional HER2-targeted therapy may be beneficial.
Conclusions:
Our study suggests that monitoring of circulating tumor cells leads to the expand indication of the HER2 targeted therapies in patients with metastatic gastric cancer.
A study of the homologous recombination deficiency signature (HRDSig) status of advanced esophageal squamous cell carcinoma (AESCC) by utilizing comprehensive genomic profiling (CGP).
Authors: Mohamed Jiffry Zakee , Pavlick Dean , Sokol Ethan , Graf Ryon P , Schrock Alexa Betzig , Li Gerald , Quintanilha Julia , Mitchell Jerry W. , Jamaspishvili Tamara , Ross Jeffrey S. , Basnet Alina
Published: January 2025

485

Background:
The role of poly-ADP-ribose polymerase (PARP) inhibitors is currently under investigation as a potential therapeutic option for AESCC. Homologous recombination deficiency signature status (HRDSig) positivity has been shown to predict biallelic loss of BRCA1/2 which may simultaneously portend a worse prognosis and a sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors. In this study, we attempt to characterize the genomic alterations present in AESCC based on HRDSig status utilizing comprehensive genomic profiling (CGP) techniques.
Methods:
2,029 cases of AESCC underwent comprehensive genomic profiling with an examination of all genomic alterations (GA). MSI high status, tumor mutation burden (TMB) levels, genomic ancestry and genomic trinucleotide signatures were determined from the sequencing data. HRDSig status was calculated using a broad set of genome-wide copy number features (PMID 37769224). Results were compared using the Fisher exact system with the Benjamini-Hochberg adjustment to correct for false discovery.
Results:
154 (7.6%) of the 2029 AESCC cases featured a positive HRDSig status (HRDSig+). The age (66-67) and gender (58%-63% male) distribution were similar in the HRDSig+ and HRDSig- AECSS cases as was the frequency of GA/tumor (9 for both). The median TMB was higher in the HRDSig+ (6.3 vs 3.8; P<.0001) as was frequency of TMB > 10 mutations/Mb (19.5% vs 10.0%; P=.004). An APOBEC trinucleotide signature was also more frequent in the HRDSig+ AESCC (11.0% vs 5.4%; P=.05). As anticipated, GA in genes associated with HRD including
BRCA1
(10.4% vs 1.4%; P<.0001) and
BRCA2
(14.3% vs 2.0%; P<.0001) was present. MTOR pathway activating mutations were also more frequent in the HRDSig+ AESCC group including
PTEN
(13.0% vs 7.3%; P=.06).
Conclusions:
With a 7.6% frequency, HRDSig+ status is a relatively rare event in AESCC. CGP with determination of HRDSig status in AESCC may prove useful in tailoring PARP inhibitor-based treatment regimens and may potentially uncover other genomic alterations that can aid in designing targeted therapy combinations in future.

Characteristics of comprehensive genomic profiling of clinically advanced esophageal squamous cell carcinoma by HRDSig status.

AESCC HRDSig- (n=1875)
AESCC HRDSig+ (n=154)
P-value

Pathogenic genomic alterations

BRCA1
1.4% (26)
10.4% (16)
0.00

BRCA2
2.0% (36)
14.3% (22)
0.00

PTEN
7.3% (137)
13.0% (20)
0.06

 COSMIC trinucleotide signature

APOBEC
5.4% (101)
11.0% (17)
0.05

Tumor mutational burden (TMB)

Median TMB (range) (IQR)
3.8 (0-85) (2.5-6.3)
6.3 (0-61) (3.8-8.8)
0.00

TMB≥10 mut/Mb
10.0% (188)
19.5% (30)
0.00
Transcriptomic features of Epstein-Barr virus-associated gastric cancer based on PD-L1 status.
Authors: Rha Sun Young , Kwon Woo Sun , Lee Choong-kun , Park Sejung , Poh Zhong Wee , Teo Eunice , Chew Jingming
Published: January 2025

489

Background:
Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) accounts for 5-10% of all gastric cancers and has a relatively favorable prognosis compared to other subtypes. While the genomic profile of EBVaGC has been previously reported to exhibit extensive CpG island methylation, elevated levels of PD-L1/2, and an absence of TP53 mutations, transcriptomic features remain less explored. The response to immunotherapy of EBVaGC has been various. This study comprehensively investigates the transcriptomic characteristics of EBVaGC in relation to PD-L1 status.
Methods:
RNA sequencing was conducted on formalin-fixed, paraffin-embedded samples from 27 EBV-positive and 12 EBV-negative patients with HER2-negative gastric cancer. Gene expression was quantified using the RSEM package. Predict-IO, a machine learning-based predictive algorithm developed at Auristone Pte Ltd based on initial work done at the Genome Institute of Singapore (GIS), assessed the likelihood of a patient responding to immunotherapy based on transcriptome expression data. PD-L1 immunohistochemistry was performed using the 22C3 pharmDx assay, and status was classified by CPS.
Results:
A total of 200 differentially expressed genes (DEGs; log2FC > 2, FDR < 0.05) were identified in EBV-positive versus negative samples, with 157 genes down-regulated and 43 genes up-regulated. Upregulated genes included immune response related genes such as DMBT1, IDO1, PLA2G2A, and IL13RA2, while downregulated genes were primarily associated with cell adhesion, including LAMA1 and CCN6. In the EBV positive group, immune response pathways were enriched; however, within the PD-L1-Low group (CPS < 1), activated signaling pathways such as MYC, E2F, and MTORC1 were observed. Conversely, the PD-L1-High group (CPS ≥ 5) exhibited upregulated snoRNAs. In the EBV negative group, the PD-L1-Low cohort displayed suppressed immune response and ECM remodeling factors, whereas the PD-L1-High cohort showed enrichment of ECM remodeling factors. The Predict-IO Score, which predicts immunotherapy response, was significantly higher in EBV-positive compared to EBV-negative samples (
p
= 0.003), and scores were elevated in the PD-L1-High group compared to the PD-L1-Low group.
Conclusions:
In summary, EBVaGC includes subsets of different PD-L1 expression patterns with distinct activated signaling pathways, differences in ECM remodeling factors, and varying Predict-IO Scores. With these information, we could properly select the responsive patients to immunotherapy among EBVaGC.
Exploration of novel biomarkers and novel therapies for immune checkpoint inhibitors (ICIs) in genetic variants of esophageal squamous cell carcinoma (ESCC): A study of 1,059 Japanese cases.
Authors: Morita Ryuichi , Ishikawa Takeshi , Doi Toshifumi , Itani Junichiro , Sone Daiki , Iwai Naoto , Iwasaku Masahiro , Inoue Ken , Dohi Osamu , Yoshida Naohisa , Uchiyama Kazuhiko , Takagi Tomohisa , Konishi Hideyuki , Takayama Koichi , Itoh Yoshito
Published: January 2025

495

Background:
In Japan, cancer genome profiling (CGP) tests will be covered by insurance in 2019, and more than 1,000 ESCC cases have been accumulated in the national database. ICIs are currently the key drugs for esophageal cancer, and MSI and TMB status can work as biomarkers for ICIs in solid tumors. Therefore, to improve the prognosis of esophageal squamous cell carcinoma (ESCC), we aim to search for gene variants that may predict the efficacy of ICIs and explore the possibility of new treatment from genetic data accumulated in the Japanese nation-wide C-CAT database.
Methods:
We retrospectively analyzed 1,059 ESCC cases from C-CAT data accumulated from June 2019 to February 2024. We used the registered clinical and genetic information to examine gene variants and carcinogenic pathways that could serve as biomarkers for ICIs.
Results:
Of the 1059, 152 (14.4%) had TMB-H and 3 (0.3%) had MSI-H, with a median TMB of 5.0 Muts/Mb (range: 0-268).
XPO1
and
TP53
were found to be positively and negatively correlated as genes affecting TTF in nivolumab monotherapy (FDR P value < 0.01). TMB has the potential to be a biomarker for ICI, but TMB was significantly higher in the group with variants in the
ARID
family (
ARID2
,
ARID1A
plus
ARID5B
) (median TMB 5.0 vs 8.0 Muts/Mb, P<0.001). In addition, 709 patients (66.9%) had any variants in three pathways (TP53, RTK and cell cycle), which are thought to be involved in the carcinogenesis of ESCC. PIK/Akt/mTOR and epigenetic modulation pathways were also found to be abnormal in many cases, and abnormalities in the epigenetic modification pathway were found to contribute significantly to TMB-H (FDR P value<0.01, Logarithmic value=19.2).
Conclusions:
This is the first case-specific report on the relationship between mutations in the
ARID
family and TMB in ESCC and the signalling pathways leading to carcinogenesis. In the present study, the association between the
ARID
family and TMB, and between abnormalities in the epigenetic modification pathway and TMB, which has been previously reported in other cancer types but not in esophageal cancer, suggests that multiple pathological mutations including these may be new biomarkers for ICI in 1059 Japanese patients. Furthermore, multiple pathways are often involved in ESCC carcinogenesis at the same time, and a separate, combined approach that takes these into account may be necessary in the development of new drugs.
Development and validation of a prognostic model for advanced gastric and oesophageal carcinoma (AGOC) using individual patient data from two clinical trials.
Authors: Naher Sayeda Kamrun , Espinoza David , Grimison Peter S. , Shitara Kohei , Pavlakis Nick , Goldstein David , Stockler Martin R , Mercieca-Bebber Rebecca , Sjoquist Katrin
Published: January 2025

499

Background:
Estimating survival in advanced gastric and oesophageal carcinoma (AGOC) remains a significant challenge. We developed a prognostic model incorporating readily accessible patient and clinical data and specific patient-reported outcomes (PROs), utilizing individual participant data from two randomized trials.
Methods:
We used data from 2 trials comparing regorafenib to placebo; AGITG INTEGRATE IIa (n=251) for model development and AGITG INTEGRATE (n=152) for validation. Both trials enrolled metastatic or AGOC following failure of 1 or more prior lines of systemic therapy. Candidate variables were chosen from systematic literature review and expert consultation. Significant prognostic factors for inclusion in the multivariable model were identified using univariable Cox proportional hazards models with p-value threshold of 0.1. Multivariable models were developed via Lasso regression. An initial model was created using clinical variables alone, followed by the integration of PROs. C statistics were used to discriminate the model’s efficiency.
Results:
Univariable analysis identified 9 clinical variables and 4 PRO domains as significant, including body mass index (BMI)(p=0.08), ECOG PS (0.02), extent of cancer (p<0.001), liver involvement (p=0.04), treatment with regorafenib (p=0.005), neutrophil-lymphocyte ratio (NLR) (p<0.001), LDH (p<0.001), albumin (p<0.001), and CA 19-9 (p=0.007). Significant baseline PROs included appetite loss (p<0.001), constipation (p<0.001), fatigue (p<0.001), and pain (p<0.001). Gastrectomy violated the Cox model proportional hazards assumption necessitating that the analysis be stratification by gastrectomy. The primary model (M1) incorporated region (Asia vs non-Asia, p=0.25, was included because it was significant in previous analysis (INTEGRATE), ECOG PS status, cancer extent, treatment with regorafenib, NLR, BMI, LDH, CA 19-9, and albumin. The final model (M2), which included PROs, demonstrated superior discriminative ability with the highest c-statistic values in both the gastrectomy and non-gastrectomy strata. The c-statistic increased from 0.695 for M1 to 0.723 for M2, indicating the added prognostic value of including PROs.
Conclusions:
The prognostic model that integrated both clinical data and PROs, proved robust for predicting survival in AGOC. The addition of PROs significantly enhanced prognostic accuracy, highlighting their importance in survival models. Further validation and refinement of the model is ongoing.
Assessment of clinical value and barriers to use of new investigational targeted agents in the community setting: A study of claudin 18.2 and zolbetuximab.
Authors: Wright Griffin M , Stanvitch Gerald , Salehi Maryam , Manigault Isabella , Vissers Eugene
Published: January 2025

500

Background:
Rapid integration of novel agents in clinical practice can be lifesaving. However, community-based practices may experience extended adoption times, due to practical barriers. REFLECT was developed to assess new drug implementation in the community setting.
Methods:
REFLECT consists of a 20-minute prerecorded presentation, followed by a data-collection event for community oncologists. It was developed to evaluate and assess challenges of implementing novel targeted agents in the community practice setting. In this pilot study, awareness of zolbetuximab (zolbe), a potential first-in-class claudin 18.2 (CLDN18.2) monoclonal antibody and companion diagnostic, was assessed. Between April and August 2024, 53 data-collection events were held representing 26 states across the US. Data from 492 oncologists were recorded and analyzed.
Results:
Nearly half the community oncologists (47%) were not familiar with CLDN18.2 as a therapeutic target in gastric/gastroesophageal junction (G/GEJ) cancer. Awareness of zolbe data was low among community oncologists; 79% indicated they had not seen the results from the phase 3 studies. However, 96% of oncologists reported the data will at least moderately impact their treatment of CLDN18.2+ patients with metastatic (m)G/GEJ cancer. Only 40% of oncologists reported having access to CLDN18.2 testing. Uncertainty regarding availability of CLDN18.2 testing was high among oncologists in the Central US (52%), representing a significant awareness gap for CLDN18.2 testing. Opinions were divided regarding the treatment approach for CLDN18.2+, immunosensitive patients (Table). In a HER2–, CLDN18.2+ patient with mG/GEJ cancer and a combined positive score (CPS) of 10; 58.1% would recommend first-line chemotherapy (chemo) plus immunotherapy (IO) and 40.4% would recommend chemo plus zolbe.
Conclusions:
First-in-class targeted agents often encounter additional challenges and knowledge gaps regarding adoption in the community practice setting, particularly associated with molecular testing. Timely education on patient identification and correct utilization may accelerate adoption of new regimens, and potentially save lives. Data-sharing and -collection platforms including REFLECT can be instrumental in the identification of challenges associated with widespread and rapid implementation of novel agents in the community oncology setting.

What treatment approach would you recommend in a patient with the following characteristics, if all treatments were available? mGEJ adenocarcinoma, HER2– disease, CLDN18.2+ staining in >75% of tumor cells, CPS 10.

Treatment
Total: N = 492% (n)

Chemo

mFOLFOX6

1.0 (5)

CAPOX

0 (0)

Chemo + IO

mFOLFOX6 + IO

52.8 (260)

CAPOX + IO

5.3 (26)

Chemo + zolbe

mFOLFOX6 +
zolbe

33.9 (167)

CAPOX +
zolbe

6.5 (32)

Other

0.4 (2)
Adjuvant cytokine-induced killer cell immunotherapy in hepatocellular carcinoma: Extended follow-up of a randomized controlled trial and post-treatment immune cell profiling.
Authors: Lee Jeong-Hoon , Park Youngsu , Shin Hyunjae , Song Byeong Geun , Choi Won-Mook , Han Hyung Joon , Lee Youngwoo , Song Tae-Jin , Yeon Jong-Eun , Lim Young-Suk , Lee Joon Hyeok , Yoon Jae Woong , Ko Yunmi , Park Jeayeon , Hur Moon Haeng , Lee Yun Bin , Kim Yoon Jun , Lee Hyejeong , Park Joo-Young , Yoon Jung-Hwan
Published: January 2025

518

Background:
Notwithstanding the pressing need for adjuvant therapy for hepatocellular carcinoma (HCC), most adjuvant therapies, including atezolizumab/bevacizumab, have failed. Meanwhile, adjuvant immunotherapy utilizing autologous cytokine-induced killer (CIK) cells for HCC improved recurrence-free survival (RFS) in a previously reported randomized controlled trial (RCT) and real-world data. This study aimed to assess the longer-term outcomes of the RCT and elucidate the underlying mechanisms of sustained effects of CIK cell treatment.
Methods:
This study comprised two parts: a long-term follow-up of the preceding RCT and an analysis of immune cells in patients who received adjuvant CIK cell treatment. In the original RCT, 226 patients who underwent curative treatment for stage I or II HCC were randomly allocated to either the CIK (n=114, 16 injections of 6.4×10
9
CIK cells over an 11-month period) or control group (n=112). The follow-up period was extended to 9 years after the enrollment of the last patient. The primary endpoint was recurrence-free survival (RFS). The secondary endpoints included cancer-specific survival (CSS) and overall survival (OS). Parallelly, a prospective study was conducted to investigate post-treatment changes of immune cells in peripheral blood of 7 patients, who received repeated transfer of CIK cells after curative treatment for HCC, using flow cytometry.
Results:
In the extended follow-up of the RCT (median follow-up=115.7 months, interquartile range=74.2–130.5 months), the CIK group sustained a significantly prolonged RFS (median=43.5 vs 27.4 months; hazard ratio [HR]=0.74, 95% confidence interval [CI]=0.55–0.99,
P
=0.045) and CSS (median=unreached; HR=0.49, 95% CI=0.25–0.95, P=0.04) compared to the control group. Adjuvant CIK cell therapy reduced the risk of overall death by 30%, although it did not achieve statistical significance (median=unreached; HR=0.70, 95% CI=0.44–1.11, P=0.1). A preliminary analysis of peripheral blood immune cells revealed that the CIK cell treatment tended to increase the frequencies of CD8
+
and CD4
+
classical memory cells.
Conclusions:
Adjuvant CIK cell treatment demonstrated significantly enhanced RFS and CSS in the prolonged follow-up of the RCT extending to 9 years in patients who received curative treatment for HCC. The CIK group also demonstrated a consistent trend of improved OS. The increase in memory T cell populations might be linked to the sustained off-treatment anti-tumor efficacy of CIK cell treatment.
Gender and ethnic disparities in hepatocellular carcinoma: Trends in incidence rates across U.S. populations from 2000 to 2021.
Authors: Guerrero Negrón Lauren , Buckstein Michael , Grace Mhango
Published: January 2025

524

Background:
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver strongly associated with liver cirrhosis and the etiologies producing cirrhosis. As such, racial and ethnic factors might affect incidence rates of HCC resulting in disparities. While disparities have been reported, the effect of gender within certain populations, particularly Hispanic and non-Hispanic White ancestry, have not been fully explored. This study looks at the changing incidence rates of HCC in the US amongst different populations with a particular focus on the impact of gender on incidence.
Methods:
Incidence rates of HCC between 2000 and 2021 among different sexes within racial and ethnic groups in the United States were analyzed utilizing delay-adjusted data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Annual percent change (APC) was calculated by using Joinpoint Regression software.
Results:
Overall, HCC incidence rates since 2014 to 2021 show a slight decrease (APC, -0.06). While Hispanic men HCC incidence rates declined from 2012 to 2021 (APC, -0.44), Hispanic women incidence have had a steady increase since 2000 (APC, +2.52). Non-Hispanic Black men (APC, -3.07) rates vastly declined from 2015 to 2021 while non-Hispanic black women interestingly experienced a slight decrease in incidence from 2013 to 2021 (APC, -0.34). Non-Hispanic White men experienced stagnant rates of HCC since 2014 (APC, -0.05) while non-hispanic white women (APC, +3.59) showed increasing trends in HCC incidence since 2003. For comparison, non-Hispanic Asian/Pacific Islander men (APC, -2.19) and women (APC, -2.36), which both experienced a decline since 2007. This analysis was repeated without significant change. Further corroborations are necessary to validate these findings.
Conclusions:
These findings show that while the incidence rates of HCC overall have decreased, this benefit appears to be largely driven in male populations. In contrast, in women, and particularly Hispanic and Non-Hispanic White women, incidence rates have been increasing. This phenomenon likely reflects the changes in etiologies of cirrhosis and HCC. Surveillance strategies and screening might need to be optimized to reflect these trends.
Concurrent transarterial chemoembolization plus atezolizumab and bevacizumab in unresectable hepatocellular carcinoma: Interim analysis from a multicenter real-world study (CHANCE 023).
Authors: Yan Rong , Zhu Haidong , Lu Jian , Teng Gao-Jun
Published: January 2025

542

Background:
Combining transarterial chemoembolization (TACE) with systemic therapies such as atezolizumab and bevacizumab (T+A) has shown potential efficacy in patients with unresectable Hepatocellular carcinoma (HCC) This interim analysis aims to evaluate the efficacy and safety of this combination therapy when administered concurrently within a two-month period.
Methods:
This multicenter, real-world study included patients diagnosed with unresectable HCC who received TACE combined with T+A from January 2020 to June 2024, across 37 centers in mainland China. The primary endpoint was overall survival (OS). This trial is registered with ClinicalTrials.gov, NCT06024252.
Results:
Out of a cohort of 335 patients, 293 (259 males) met the inclusion criteria, and 37.5% (112/293) adopted this regimen as second-line therapy. The interim analysis showed a median OS of 29.97 months and a one-year survival rate of 76.50%. The median PFS was 19.23 months, and the objective response rate (ORR) was 41.6%, with 26 complete responses and 96 partial responses. The disease control rate (DCR) was 84.6%. Common adverse events included bone marrow suppression, decreased white blood cell or platelet counts, among others. Serious adverse events occurred in 9.2% of patients (27/293) and were manageable with standard interventions.
Conclusions:
This study is a real-world analysis to highlight the potential benefits of combining TACE with T+A in this patient population. However, longer follow-up is required to better assess both overall survival and the long-term safety profile of this treatment strategy.
Clinical trial information: NCT06024252
.
Real-world insights into immune-related adverse events (irAE) in gastrointestinal (GI) malignancies.
Authors: Manne Ashish , Paul Samuel , Min Eric , Malalur Pannaga
Published: January 2025

545

Background:
This retrospective review aimed to examine the incidence and baseline characteristics (BLC) that irAE risk in patients with gastrointestinal (GI) cancers undergoing immune checkpoint inhibitor (ICI) therapy at our institution.
Methods:
GI cancer patients who received at least one dose ICI-only between 1/1/2017 and 7/31/2021 at the Ohio State University were included in the study. The BLC including hematological and chemistry labs were extracted with immune-related adverse events (irAE) details. Statistical analyses included descriptive statistics, chi-square test, logistic regression, and matched pairs t-tests were performed.
Results:
Our analysis included 198 patients (14 anal (Al), 65 hepatobiliary (HPB), 46 lower (LGI) and 74 upper (UGI)) with irAEs reported in 37 patients (19%). Median age of irAE-group was 67 years (range: 26 to 88) with 54% males and 86% Caucasians. Most of them (n=36) in had single agent ICI. Pneumonitis was most frequently (n=7) noted followed by dermatitis (n=), colitis (n=5), hypophysitis (n=5), and hepatitis (n=4). Relatively rare ones were hypothyroidism (n=3), nephritis (n=2), encephalitis (n=2), diabetes mellitus (n=1), neutropenia (n=1), and myasthenia gravis (n=1). In irAE-group, 18 (49%) required hospitalization (≥ grade 3) and 5 (14%) had irAE-related deaths. Complete recovery from irAEs was reported in 20 patients (54%), with 13 patients (35%) restarting ICI therapy. The irAE incidence in HPB group was significantly higher than other GI malignancies (HPB vs. LGI vs. Al vs. UGI = 46% vs. 24% vs. 16% vs. 14%, p=0.004). History of asthma (41% vs. 16% (p=0.004) and female gender (26% vs. 15%, p=0.04) increased irAE-risk; presence of liver (9 % 22%, p=0.04) and > 3 lung (8 vs. 21%, p=0.04) metastasis reduced the risk. Compared to non-irAE group, the irAE-group had significantly lower baseline (mean) whole blood cell count (WBC: 6.3 vs. 7.6 K/uL, p=0.02), neutrophil count (NC: 4.2 vs. 6.8 K/uL, p=0.04), and neutrophil-lymphocyte-count (NLR: 5.1 vs. 9.3, p=0.03), and lower albumin (3.7 vs. 3.5 mg/dL, p=0.02). A significant rise in NC (2.1 K/uL, p=0.0008), NLR (by 2.5, p=0.004), WBC (by 2.1 K/uL, p=0.002) from baseline was noted at irAE-incidence. Heterogeneity in the primary tumors and treatments received is a notable limitation of this analysis.
Conclusions:
Overall, the risk of irAEs in patients with GI cancers is relatively low, and certain BLC can predict their incidence.
HCC in the Rio Grande Valley: Outcomes in a predominant Latino community.
Authors: Hernandez Llamas Sergio , Reyes-Uribe Laura , Lopez Pacheco Edgar , Membreno Fernando E. , Cruz José
Published: January 2025

550

Background:
Hepatocellular carcinoma (HCC) has slowly increased in the U.S. in recent years, with a higher incidence among racial and ethnic minorities, particularly Latinos. This retrospective study examines the different etiologies, presentation of diagnosis, management, and outcomes of patients presented in a multidisciplinary-liver tumor board in the Rio Grande Valley, home of 1.3 million Latinos.
Methods:
A retrospective chart review was conducted on patients with HCC diagnosis who were presented at the Liver Tumor Board of DHR Health Transplant Institute between 2017 and 2023. The data collected was extracted from the EHR, including medical history, laboratory results, and radiological studies required for staging, transplant eligibility assessments, clinical characteristics, and treatments.
Results:
A total of 250 cases were reviewed, and 70 patients with complete clinical data and a diagnosis of HCC were included in the study. Of those, 98.5% were identified as White/ Hispanic. The median age at diagnosis was 64.4 ± 9.2 years, with 72.9% male and 11.4% uninsured. The average BMI was 31.5 kg/m
2
, metabolic-associated liver disease (MALD) was present in 28.6% of patients, 25.7% were alcohol-related, and 38.6% presented multiple etiologies. A descriptive analysis of this population is found in the table. Ablative therapy was used in 68 (97.1%) of the patients. The number of patients sent for liver transplant evaluation was 31 (44%), and only 3 (4.2%) patients received a liver transplant. Barriers to transplant included lack of transportation, inadequate social support, underinsurance, and fear of the transplant itself.
Conclusions:
Our data by staging aligns with the national distribution of incidence cases from 2012-2022 per SEER program. The rate of transplantation at our institution is below the national average, highlighting the need to bridge this disparity and address race-specific barriers to transplant within the Latino community.

Sociodemographic data.

Parameter
Stage IAN=15 (21.4%)
Stage IBN=20 (28.6%)
Stage IIN=10 (14.3%)
Stage IIIAN=8 (11.4%)
Stage IIIBN=9 (12.9%)
Stage IVAN=5 (7.1%)
Stage IVBN=3 (4.3%)
All StagesN=70 (100%)

Child Pugh A
7 (46.7%)
8 (40.0%)
5 (50.0%)
4 (50.0%)
2 (22.2%)
2 (40.0%)
1 (33.3%)
29 (41.4%)

Child Pugh B
6 (40.0%)
6 (30.0%)
5 (50.0%)
2 (25.0%)
5 (55.6%)
2 (40.0%)
2 (66.7%)
28 (40.0%)

Child Pugh C
2 (13.3%)
6 (30.0%)
0 (0.0%)
2 (25.0%)
2 (22.2%)
1 (20.0%)
0 (0.0%)
13 (18.6%)

MELD-Na mean, (min-max)
12.8(7.0-21.0)
13.6(6.0-23.0)
12.8(6.0-20.0)
12.3(5.0-17.0)
13.6(8.0-26.0)
13.0(10.0-19.0)
11.3(7.0-14.0)
13.6(6.0-26.0)

Therapy*:Ablative (TACE, Y90, Radiation, other)
15
21
10
6
8
6
2

Surgery (including transplant)**
1
1
2
2
2
0
0

Systemic
2
6
5
4
6
3
1

Overall Survival (months)
29.5
26.8
34.7
17.5
24.1
17.3
14.9
25.3

*Several patients received one or more types of therapy.

**All transplant patients received ablation therapy.