bluuebunny/crossref_metadata_2025 huggingface dataset:
The mechanistic study of cancer-associated adipocytes promoting colorectal cancer peritoneal metastasis via FKBP5/UCP1-mediated lipid metabolism reprogramming.
Authors: Zhang Yue , Huang Chengzhi , Yao Xueqing
Published: January 2024

178

Background: Colorectal cancer (CRC) is a prevalent malignant tumor globally, with peritoneal metastasis as a significant late-stage dissemination pathway, severely impacting patient prognosis. Recent research increasingly suggests the critical role of lipid metabolism within the tumor microenvironment in tumor progression. Cancer associated adipocytes (CAAs), a vital component, contribute to tumor progression, yet the exact molecular mechanisms remain unclear. We aim to explore the role of CAAs in CRC peritoneal metastasis and their specific regulatory mechanisms. Methods: In this study, we analyzed clinical samples from 312 CRC patients to assess the expression levels of FKBP5 and UCP1 proteins in tumor-adjacent tissues. Purified exosomes from co-cultured adipocytes and tumor cells, along with exosomes from ordinary tumor cells, underwent miRNA profiling via sequencing to evaluate exosomal miR-200a-3p expression. We established FKBP5 stable knockdown (FKBP5-/-) transgenic mouse models, organotypic co-culture models, and patient-derived xenograft (PDX) models. Through experiments involving metabolomics, mass spectrometry, immunoprecipitation, western blotting, and qPCR, we investigated the role of the miR-200a-3p/FKBP5/PPARγ/UCP1 signaling pathway in CAAs in CRC peritoneal metastasis. Results: After co-culturing adipocytes and tumor cells, we observed brown adipocyte differentiation, resulting in significant downregulation of FKBP5 protein expression. FKBP5 exhibited a strong association with UCP1 expression. Tumor cells highly expressed miR-200a-3p, released via exosomes into the tumor microenvironment and internalized by adipocytes. Within adipocytes, miR-200a-3p orchestrated metabolic reprogramming via the FKBP5/PPARγ/UCP1 pathway, inducing brown adipocyte differentiation, generating CAAs. CAAs released FFAs, promoting tumor peritoneal metastasis by activating tumor cell surface G-protein coupled receptors (GPCRs). Conversely, miR-200a-3p inhibition in tumor cells yielded opposing effects. In a spontaneous mouse model of colorectal cancer using azoxymethane (AOM)/dextran sulfate sodium salt (DSS), FKBP5-/- mice exhibited increased brown adipocyte content in the tumor microenvironment, along with notably higher spontaneous colorectal tumor numbers and sizes compared to wild-type mice. Conclusions: This study elucidates the pivotal role of CAAs in the peritoneal metastasis of CRC, confirming the regulatory role of the FKBP5/UCP1 pathway-mediated lipid metabolism reprogramming in this process. These findings offer a fresh perspective for further exploration of the molecular mechanisms underlying CRC peritoneal metastasis, and provide a theoretical foundation for the identification of novel therapeutic targets.
High-resolution transcriptional signature to predict survival benefit in colorectal cancer (CRC) treated with EGFR inhibitors (EGFRi) independent of RAS/BRAF mutation status or tumor sidedness.
Authors: Thota Ramya , Yeatman Timothy , Gandhi Nishant , Yang Mingli , Schell Michael , Pflieger Lance , Loboda Andrey , Nebozhyn Michael , Elliott Andrew , Xiu Joanne , Sledge George W. , Khushman Moh'd M. , Lou Emil , Goel Sanjay , Pledger Warren Jack ,   Caris
Published: January 2024

203

Background: Cetuximab (CTX) and Panitumumab (PMB) therapies directed at EGFR have been restricted to left-sided CRC harboring wild-type KRAS ( KRASWT), limiting their utility. Approximately 50% of mCRC fail to respond to EGFRi, thus identification of predictive biomarkers is an unmet need. Here we evaluate a CTX sensitivity score (CTX-S) that we previously reported (Yang M. et al., 2019), in a large, real-world population of RAS/BRAF mutant vs wild-type and in right- vs left-sided tumors. Methods: CTX/PMB-treated CRC specimens (n=1124) with clinical outcomes, NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). 1097 specimens were MSS as determined by IHC of MMR proteins and/or NGS. Association of CTX-S with RAS/BRAF mutation and tumor sidedness was performed in MSS tumors. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RASMUT /BRAFMUT, or RASWT /BRAFWT if no mutation was detected for each gene. Samples were stratified based on CTX-S quintiles. Survival on EGFRi was calculated from the initiation of EGFRi to last contact using Kaplan-Meir method. Results: Higher CTX-S quintiles were significantly associated with longer survival on EGFRi in RAS/BRAF wild-type as well as -mutant subpopulations. Similar results were seen in left- vs. right-sided tumors (Table). Higher CTX-S quintiles were associated with a survival benefit in all CMS classes but CMS2; however, the vast majority of CMS2 tumors (460/467) were among the top 3 CTX-S quintiles. As the median survival among the top 3 quintiles was ~2-fold higher than the bottom 2 quintiles, we used stratification by the 40th percentile for the genomic analysis. CTX-S >40th percentile was associated with an increased prevalence in APC (91 vs 47%) and TP53 (93 vs 76%) mutations and decreased prevalence in BRAF (6 vs 32%), SMAD4 (8 vs 19%), RNF43 (1 vs 12%) and ATM (2 vs 5%) mutations (all q<0.05). Conclusions: Our data suggest that CTX-S may predict longer survival on EGFRi, surprisingly independent of RAS/BRAF mutation status as well as tumor sidedness. Patients with high CTX-S had increased prevalence of CMS2 and harbored more APC and TP53 mutations. A strong EGFRi biomarker would likely expand the utility of EGFRi to right-sided tumors and possibly to RASMUT tumors. Further validation of these biomarkers in a prospective clinical trial is warranted and could change our current standard of care for CRC.[Table: see text]
A quality-adjusted time without symptoms and toxicity (Q-TWiST) analysis comparing nivolumab plus ipilimumab (N+I) or nivolumab plus chemotherapy (N+CT) versus CT in patients (pts) with advanced esophageal squamous cell carcinoma (ESCC): CheckMate 648.
Authors: Chau Ian , Bridgewater John A , Wyrwicz Lucjan , Greenwood Mike , Blum Steven I. , Moreno-Koehler Alejandro , Worthy Gill , Taylor Fiona , Davis Catherine , Chen Clara
Published: January 2024

251

Background: In CheckMate 648, pts with advanced ESCC treated with first-line N+I or N+CT had significantly longer overall survival (OS) vs CT and maintained quality of life (QoL) with no new safety signals. Here we compare between-treatment differences in quality-adjusted survival using a Q-TWiST analysis in all randomized pts (29-month minimum follow-up). Methods: Survival time was partitioned into 3 health states: toxicity (TOX), time without symptoms of disease progression or toxicity (TWiST), and relapse (REL). TOX was defined as time spent with all-cause grade 3/4 adverse events after randomization, prior to disease progression. TWiST was defined as time prior to REL where pts did not experience TOX. REL was defined as time between disease progression and death, or the last known date alive. Mean duration of time in each state was calculated for each treatment group using descriptive statistics and Kaplan-Meier analysis. Utility values from the 3-level EQ-5D (EQ-5D-3L) questionnaire were used to adjust the time spent within each health state for QoL and to calculate Q-TWiST as the utility-weighted sum of the mean health state durations. Bootstrapping (500 samples) was used to estimate time in each health state and to compare mean Q-TWiST estimates between treatments. A between-group difference in Q-TWiST of 5 weeks was prespecified as being clinically important (defined as 10% of OS; based on a median OS in CT group of 10.7 months). Sensitivity analyses were conducted using different combinations of prespecified utility weights for each health state. Results: 970 pts were randomized 1:1:1 to N+I (n = 325), N+CT (n = 321), or CT (n = 324) and included in the Q-TWiST analysis. Median duration of follow-up for survivors was 155 weeks. Mean time in each health state was significantly longer for pts treated with N+I or N+CT compared to CT (Table). Between-group differences in Q-TWiST score were considered clinically important: 5.7 weeks (95% CI 5.5–6.0) favoring N+I vs CT and 7.6 weeks (95% CI 7.4–7.9) favoring N+CT vs CT. Sensitivity analyses supported these findings. Conclusions: In CheckMate 648, pts with unresectable advanced ESCC treated with N+I or N+CT had significantly longer OS compared with those treated with CT. Quality-adjusted survival using Q-TWiST also significantly favored N+I and N+CT compared to CT alone. Pts treated with N+I and N+CT not only experienced increased survival time, but also better QoL during their survival time. Clinical trial information: NCT03143153 . [Table: see text]
Real-world treatment patterns, testing patterns, and clinical outcomes of first-line (1L) therapy for metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma (mGC/GEJC/EAC).
Authors: Kakehi Sumie , Betts Keith A. , Nie Xiaoyu , Kitchen Sophie A. , Ray Saurabh
Published: January 2024

275

Background: GC/GEJC/EAC are among the leading causes of cancer-related morbidity and mortality worldwide. Nivolumab + fluoropyrimidine- + platinum-containing chemotherapy (NIVO+chemo) has demonstrated superior efficacy in patients with advanced non-HER2-positive (HER2-) GC/GEJC/EAC versus chemo alone in the CheckMate 649 trial. The objective of this study was to characterize real-world treatment and PD-L1 testing patterns in the 1L setting for mGC/GEJC/EAC since the FDA approval of NIVO+chemo on April 16, 2021. Methods: This retrospective observational study used the electronic medical record data from the ConcertAI Patient360 database. Adult patients with HER2- mGC/GEJC/EAC and 1L initiation date (index date) between April 16, 2021 and October 31, 2022 were included. PD-L1 testing patterns and 1L regimens were described overall and stratified by PD-L1 testing. The analyses of clinical outcomes are currently ongoing. Results: A total of 161 patients with mGC/GEJC/EAC met the inclusion criteria. The median age at index was 67.0 years, 76.4% were male, and the median follow-up time from index date was 6.7 months. 81 (50.3%) patients had evidence of receiving at least one PD-L1 test (median [interquartile range] time from first test to 1L initiation: 0.4 [-0.1, 1.0] months) among whom 28 (34.6%) had the first test documented after 1L initiation. Overall, 1L immunotherapy-based regimens were received by 63 (39.1%) patients, with NIVO+chemo being the most common (n = 47; 29.2%). 1L fluoropyrimidine- + platinum-containing chemotherapy and other chemotherapies were received by 51 (31.7%) and 42 (26.1%) patients, respectively. Among patients with evidence of PD-L1 testing, 31 (38.3%) received NIVO+chemo, and 37 (45.7%) received chemotherapy alone. Among those without evidence of PD-L1 testing, 56 (70.0%) received chemotherapy alone, and 16 (20.0%) received NIVO+chemo. Conclusions: These preliminary findings show an early uptake of NIVO+chemo in the advanced or metastatic GC/GEJC/EAC patient population. With a majority of PD-L1 untested patients receiving chemotherapy only as 1L therapy, there is an opportunity for these patients to potentially benefit from immuno-oncology containing regimens. Further analyses are needed to characterize the chemotherapy only treated patient population.
Changes in circulating immune biomarkers following nivolumab with or without ipilimumab for metastatic anal cancer (NCI9673).
Authors: Morris Van K. , Ochieng Joshua , Ciombor Kristen Keon , Polite Blase N. , Mukherjee Sarbajit , Krauss John C. , Shields Anthony F. , Aranha Olivia , Hays John L. , Kazmi Syed Mohammad Ali , Weinberg Benjamin Adam , Benson Al B. , Lieu Christopher Hanyoung , Iqbal Syma , Hochster Howard S. , Xiao Lianchun , Haymaker Cara L. , Eng Cathy
Published: January 2024

3

Background: Approximately 25% of patients (pts) with squamous cell carcinoma of the anal canal (SCCA) develop metastatic disease. The ETCTN-led NCI9673 phase II trial evaluated PFS of the anti-PD-1 antibody nivolumab (N) with or without the anti-CTLA-4 antibody ipilimumab (I) in metastatic SCCA. We analyzed serial blood samples from NCI9673 for immune biomarker profiling following N or N+I. Methods: PBMCs from 47 pts (24 N, 23 N+I) were collected at pretreatment (N=47), week 9 (N=26), and at progression (N=15). Immune cell populations - effector CD4 T cells, CD8 T cells, natural killer (NK) cells, and regulatory T cells - were analyzed by flow cytometry for immune inhibitory (PD-1, CTLA-4, TIM-3, LAG-3, TIGIT) and immune stimulatory (OX40, ICOS) expression. Mean expression (as percentage of cells with any expression) for each biomarker at a matched time point was compared between the N and N+I arms by a corrected student’s t test, with an alpha= .10 for significance. Changes in mean expression for each biomarker were compared by one-way ANOVA. Results: Mean TIGIT expression at baseline was highest on CD4 and CD8 T-cells relative to other immune checkpoint biomarkers (p< .0001 for all subsets; see Table). N+I was associated with higher TIGIT expression on CD4 cells at progression than for N alone (21.3% vs. 10.9%, p=.08). Among NK cells, TIGIT expression decreased at progression relative to baseline for N (14.1% vs. 5.9%, p=.06). Relative to non-responders, responders to N had OX40 expression that increased on CD4 T cells but decreased on NK cells at week 9 relative to baseline. Conclusions: In previously metastatic SCCA pts, TIGIT expression was greater on CD4 and CD8 T cells and was modulated on differing immune cell populations according to treatment arm. These data not only implicate T and NK cells in mediating treatment effect following single agent and/or combination immunotherapy, but also support the exploration of TIGIT as a potential novel target for treatment of metastatic SCCA.[Table: see text]
The overall safety and short-term efficacy of nivolumab plus ipilimumab for advanced esophageal squamous cell carcinoma.
Authors: Shiraishi Kazuhiro , Yamamoto Shun , Yoshinami Yuri , Ohara Akihiro , Itoyama Mai , Yokoyama Kazuki , Honma Yoshitaka , Kashiraha Tairo , Kurita Daisuke , Ishiyama Koshiro , Oguma Junya , Igaki Hiroshi , Daiko Hiroyuki , Kato Ken
Published: January 2024

329

Background: Although nivolumab plus ipilimumab (Nivo+Ipi) is strongly recommended as 1st-line treatment for patients with advanced esophageal squamous cell carcinoma (ESCC), tumor proportion score (TPS) should be considered. Despite the efficacy, patients who received Nivo+Ipi often experienced serious immune related adverse events (irAEs). However, there are few data on safety and short-term efficacy of Nivo+Ipi in real world. Methods: We retrospectively collected data of pts who received Nivo+Ipi for advanced ESCC between May 2022 to July 2023 in the National Cancer Center Hospital. We evaluated adverse events by CTCAE v5.0 and multivariate analysis using a logistic regression model. estimated overall response rate (ORR) by RECIST v1.1 and progression-free survival (PFS). Results: Thirty pts were subjects in this study. The characteristics were as follows: median age (range): 63.5 (36-80) years, male/female: 24/6, metastatic/recurrent: 3/27, ECOG PS 0/1≤: 16/14, PD-L1 TPS 1%≤: 17, number of organs with metastases 1/2≤: 13/17, treatment-line 1st/2nd≤ 6/24 Median follow-up time was 5.0 months (mo) (reverse Kaplan-Meier, 95%CI; 3.0-8.3 mo). Any grade and grade 3≤ irAEs were observed in 12 (40.0%) and in 5 pts (17.9%), respectively. In grade 3≤ irAEs, AST/ALT elevation (n=2, 7.1%), adrenal insufficiency (n=1, 3.6%), pneumonitis (n=1, 3.6%), myositis (n=1, 3.6%), encephalopathy (n=1, 3.6%), stevens-Johnson syndrome (n=1, 3.6%) were reported. The pts who received systemic steroid therapy was 8 pts (28.6%). Two pts received high-dose steroid with methyl-prednisolone, 1 g/body for 3 days, four pts needed steroid therapy with prednisolone, 1-2 mg/kg and two pts added mycophenolate mofetil. No treatment-related deaths were reported. For the pts who received Nivo+Ipi as a first-line treatment (n=6), 3 pts (50%) achieved partial response and 2 pts (33.3%) had stable disease. 6-mo PFS rate of the 1st line pts was 63%. For the pts who received Nivo+Ipi in later-line, the ORR and the median PFS were 33.3% and 2.6 mo (95%CI; 1.4-3.9 mo), respectively. Fifteen pts received subsequent systemic therapy, which consisted of taxane (12 pts), fluoropyrimidine plus platinum (2 pts) and 1 pt continued Nivo+Ipi beyond progression. Conclusions: Our study may demonstrate a consistent incident of irAEs in pts who received Nivo+Ipi in the real world, compared to the results of the CheckMate 648. Despite of the short time of follow-up period, 1st-line treatment with Nivo+Ipi appeared to be more efficacious than Nivo+Ipi used as a later-line treatment.
Clinical significance of time interval between surgery and adjuvant chemotherapy in patients with gastric cancer after gastrectomy: A population-based cohort study using a nationwide claims database.
Authors: Maeng Chi Hoon , Kim Hoseob , Kim Mina
Published: January 2024

333

Background: Adjuvant chemotherapy can reduce recurrence rates by eradicating microscopic metastases which may persist after curative resection. However, the optimal time interval (TI) between the surgery and chemotherapy remains controversial. Methods: The data were obtained from the NHIS of Korea. We included patients who underwent gastrectomy for gastric cancer between 2013 and 2018. To determine the optimal cut-off point of TI, a restricted cubic spline cox regression model was established, and categorized the population into three groups based on TI: the early group (≤ 20 days), the reference group (21-34 days), and the late group (≥ 35 days) with the reference interval group having the lowest mortality and recurrence. Propensity score matching was performed for each group. The primary outcomes were disease-free survival (DFS) and overall survival (OS). Results: During the study period, 98,556 patients underwent surgery for gastric cancer. After excluding ineligible participants, 6,602 patients were included in the analysis. The median DFS and OS did not differ significantly between the early and reference groups ( p=0.7258 and p=0.6056, respectively). In comparison between the late and reference groups, the median DFS was significantly lower in the late group ( p=0.0079). 5-year DFS were 77.6% and 81.3% in the late and reference groups, respectively. Furthermore, the late group showed worse OS than the reference group ( p=0.0336). OS at 5-year were 82.1% and 85.0% in the late and reference groups, respectively. In the multivariable analysis, DFS in the late group retained inferiority (aHR 1.138, 95% CI: 1.003-1.292, p=0.045). OS showed a worse trend without significance compared to the reference group (aHR 1.138, 95% CI: 0.984-1.317, p=0.0805). Conclusions: Adjuvant chemotherapy after gastrectomy in patients with gastric cancer should be initiated within five weeks of surgery. A delay of more than five weeks may have a detrimental effect on the subsequent disease course.
Subgroup analyses of the effect of ramucirumab in pretreatment with immune checkpoint inhibitor in RINDBeRG: A randomized clinical trial in third- or further-line treatment of gastric cancer.
Authors: Kawabata Ryohei , Sakai Daisuke , Kadowaki Shigenori , Tsuduki Takao , Suzuki Takahisa , Masuzawa Toru , Shimozaki Keitaro , Tsuda Masahiro , Yamada Takeshi , Yamaguchi Toshifumi , Ueda Shugo , Kito Yosuke , Hirose Toshiharu , Kawase Tomono , Nomura Takashi , Nishikawa Kazuhiro , Kawakami Hisato , Shimokawa Toshio , Boku Narikazu , Satoh Taroh
Published: January 2024

339

Background: To confirm synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment, we evaluated the effect of pretreatment with immune checkpoint inhibitors to ramucirumab plus irinotecan versus irinotecan in the third or later line treatment beyond progression after ramucirumab for advanced gastric cancer from the RINDBeRG trial. Methods: Patients received ramucirumab at 8 mg/kg plus irinotecan at 150 mg/m2 or irinotecan alone. End points were compared between treatment arms and pretreatments with nivolumab (NIVO+, n = 226) or without nivolumab (NIVO-, n = 169). Results: The overall survival hazard ratio was 0.84 (95 % confidence interval, 0.64-1.12) in the NIVO+ population and 1.05 (95 % confidence interval, 0.76-1.44) in the NIVO- population. The progression-free survival hazard ratio was 0.67 (95 % confidence interval, 0.51-0.87) in the NIVO+ population and 0.83 (95 % confidence interval,0.61-1.12) in the NIVO- population. The objective response rate was higher for ramucirumab plus irinotecan in both populations (NIVO+ population, 17.5 % vs 28.8 %; NIVO- population, 10.9 % vs 14.5 %). Safety profiles of the ramucirumab plus irinotecan arm were similar between populations. Conclusions: Progression-free survival and objective response rate improvements were observed for ramucirumab plus irinotecan in both populations and these benefits were enhanced with prior nivolumab therapy. Clinical trial information: jRCTs051180187 .
Phase II study of GEN-001 in combination with avelumab in patients with PD-L1–positive locally advanced, or metastatic gastric cancer (GC) or gastroesophageal junction cancer (GEJC) who have progressed after second-line (2L) and beyond (GEN001-201 study).
Authors: Lee Jeeyun , Jung Minkyu , Lee Keun-Wook , Ryu Min-Hee , Kwon Minsuk , Park Kyung Mi , Yoon Young-Kwang , Kim Mincheol , Park Hansoo
Published: January 2024

368

Background: The relationship between gut microbiota and the response to immune checkpoint inhibitors is likely due to cross-reactivity between microbial and tumor antigens, enhancing dendritic cell (DC) activation, antigen presentation, and inflammatory cytokine production. GEN-001 is a live biotherapeutic product (LBP) consisting of a lyophilized formulation of a strain of Lactococcus lactis. This study is designed to investigate the safety and efficacy of GEN-001 in combination with avelumab (the PD-L1 inhibitor) for patients with PD-L1 positive advanced GC/GEJC. Methods: This is an open-label, single arm, phase II clinical trial for PD-L1 positive (CPS ≥1) patients with unresectable, locally advanced, or metastatic GC/GEJC who have progressed after second-line and beyond. All patients were treated with GEN-001 (9x1011 CFU, administered as oral once daily) in combination with avelumab (800 mg, administered as an intravenous infusion every two weeks) until progressive disease, unacceptable toxicity, death, or withdrawal. Tumor response was assessed every 8 weeks for 6 months and every 12 weeks thereafter. The primary endpoint was objective response (OR); secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Results: As of August 31, 2023, a total of 42 patients were enrolled. 37 patients have been assessed for response. The confirmed partial response (PR) and unconfirmed PR were achieved by 5 patients and 1 patient respectively, 8 patients have experienced as stable disease (SD). Median PFS and median OS were 1.73 months (95% confidence interval [CI]: 1.67-2.37 months) and 7.9 months (95% [CI]: 6.07-NE months). Treatment-related adverse events (TRAEs) of any grade occurred in 12 patients (28.6%) and Grade ≥3 TRAEs occurred in 2 patients (4.8%) out of 42 patients. Conclusions: Treatment of patients with GC/GEJC with GEN-001 in combination with avelumab in the ≥ 3L setting showed promising antitumor activities with an overall manageable safety profile. The results from this trial will be updated about its effects on clinical outcome, including survival, safety, and biomarker findings. Clinical trial information: NCT05419362 .
Detection of early-stage gastrointestinal cancers by micronuclei DNA from erythrocytes.
Authors: Sun Haobo , Yao Xingyun , Han Yuehua , Jiao Yurong , Kong Xiangxing , Liu Chengcheng , Guo Qingqu , Meng Fei , Liang Honghao , Fan Xiuqin , Li Jun , Gao Xiaofei
Published: January 2024

382

Background: Gastrointestinal (GI) cancers account for over a third of cancer deaths. However, their early detection remains a challenge. Micronuclei (MN) are extranuclear bodies containing damaged chromosome segments indicative of genomic instability. Increased MN frequency in hematopoietic cells is observed in patients with solid tumors. We have developed a method (WO2021/228246 A1) for purifying and characterizing micronuclei DNA (mnDNA) in erythrocytes from peripheral blood. Here, we evaluated the potential of mnDNA for early-stage GI cancer detection, including colorectal (CC) and gastric (GC) cancers. Methods: Peripheral blood (1 ml) was collected from healthy donors (HD) and cancer patients mnDNA isolation and purification from erythrocytes. Participants were randomly divided into training, validation and independent test cohorts in a 7:2:1 ratio, maintaining similar cancer types, CC/GC/HD ratio, gender and age distribution. Distinct mnDNA features between cancer patients and HDs were identified using sequencing data. Logistic regression algorithms were applied using these features for cancer detection. Results: The study enrolled 1046 participants, including 419 HDs, 366 CC and 261 GC cases. Of these, over half were diagnosed with early-stage diseases; TNM stage I accounted for 38.7%, stage II for 22.8%, stage III for 30.5% and stage IV for 8.0%. The cancer detection model with mnDNA features yielded an overall accuracy of 84.8%, with a sensitivity of 84.1% and specificity of 85.7%. For individual caner types, sensitivity was 89.2% for CC and 76.9% for GC. For early-stage (stage I-II) CC and GC, the model demonstrated sensitivities of 88.9% and 76.5%, respectively, at 85.7% specificity. Conclusions: Unlike cell-free DNA, mnDNA are chromosomal fragments in the cytoplasm. The abundance of erythrocytes in peripheral blood provides an easily accessible source for mnDNA enrichment. This pilot study illustrates the potential of mnDNA as a tool for early GI cancer detection, contributing to large-scale efforts towards developing an effective GI cancer screening test.
Survival trends in gastric cancer in Brazil: Real-life data from a large cancer center.
Authors: Brito Angelo Borsarelli Carvalho , Mendonca e Silva Diego Rodrigues , Curado Maria Paula , Durant Lais Corsino , Taboada Rodrigo Gomes , Pelosof Adriane Graicer , Diniz Alessandro Landskron , Coimbra Felipe José Fernández , Felismino Tiago Cordeiro
Published: January 2024

413

Background: Gastric cancer (GC) is the fourth leading cause of cancer deaths globally. There is a paucity of real-life data on GC in Brazil. Our study aimed to evaluate survival trends in gastric adenocarcinoma (GA) in a large cancer center in Brazil during 2000-2017. Methods: Based on our Hospital Cancer Registry Database, all individuals diagnosed with GA between 2000 and 2017, and treated at A.C. Camargo Cancer Center, were retrospectively included. The primary objectives were to describe the patient demographics, clinicopathological characteristics, treatment modalities, and survival trends during four separate periods of diagnosis (2000-2004; 2005-2009; 2010-2014; and 2015-2017). χ2 test was performed between two specified periods (2000-2004 and 2015-2017) to compare categorical variables. Overall survival (OS) curves were stratified by four separate periods and compared with log-rank tests. Results: The current analysis comprises a retrospective cohort of 1406 patients (552 female and 854 male individuals). Across all periods, most patients were men aged 50 to 69 and presented with Lauren’s intestinal subtype. There were significant differences between staging groups during the study. Specifically, between 2000-2004, stage IV varied from 43.6% to 32.8% in 2015-2017 (P<0.001). The most substantial variation in nonmetastatic cases occurred in stage II, comprising 9.4% of cases from 2000-2004 and rising to 24.8% in 2015-2017 (P<0.001). Concerning treatment modalities, we observed an increased utilization of a combined approach involving chemotherapy and surgery throughout the investigation. Specifically, from 2000-2004, only 12% of patients received a multimodal treatment regimen consisting of chemotherapy and surgery, whereas, between 2015-2017, this proportion increased to 36.3% (P<0.001). Also, patients receiving surgery + radiotherapy + chemotherapy varied from 12.4% of patients in 2000-2004 to 4.5% in 2015-2017 (P<0.001). When the entire cohort was analyzed, the predicted 5-year OS of patients with GA between 2000-2004 was 27.8%, which increased to 53.9% in the period from 2015-2017 (P<0.001). Among females, 5-year OS increased from 31.3% between 2000-2004 to 58.5% between 2015-2017 (P=0.001). Among males, 5-year OS increased from 25.2% to 51.0% in the same comparison (P<0.001). Conclusions: Our hospital-based data shows an upward trend in survival rates across patients with GA. We observed that 5-year OS almost doubled among men and women during the analyzed period. Recent improvements in staging methods and treatment have increased cure rates. Nevertheless, further investigation is essential to determine significant differences in OS between males and females.
Analysis of patients (pts) with unresectable hepatocellular carcinoma (uHCC) and Child–Pugh (CP)-B liver function treated with regorafenib in routine clinical practice in the observational REFINE study.
Authors: Kim Yoon Jun , Merle Philippe , Finn Richard S. , Kudo Masatoshi , Klümpen Heinz-Josef , Lim Ho Yeong , Pinter Matthias , Babajanyan Svetlana , Khan Javeed , Awan Maria , Özgürdal Kirhan , Qin Shukui
Published: January 2024

452

Background: Pts with HCC and compromised liver function are typically excluded from clinical trials. The REFINE real-world study (NCT03289273) assessed a more varied pt population treated with regorafenib than the phase 3 RESORCE trial.1 Median overall survival (OS) in REFINE was 13.2 months and treatment-emergent adverse events (TEAEs) were consistent with RESORCE. We present a subgroup analysis of outcomes in pts from REFINE with CP-B liver function. Methods: REFINE is an international, prospective observational study of pts with uHCC for whom the decision to treat with regorafenib according to the local health authority approved label was made by their physician before enrollment. The primary endpoints were safety (Medical Dictionary for Regulatory Activities v25) and dose modifications due to drug-related TEAEs. Secondary endpoints included OS and duration of treatment (DoT). Results: Of 1005 evaluable pts, 123 (12%) were classified as CP-B at study entry, with most being CP-B7 (Table). Of the CP-B pts, 40/123 (9%), 9/123 (18%), and 58/123 (15%) initiated regorafenib at 160 mg, 120 mg, and 80 mg, per day, respectively. Median DoT with regorafenib was 2.3 months in CP-B pts and 3.7 months in the overall cohort. Incidence rates of TEAEs in CP-B pts and the overall cohort were similar (93% and 92%) and TEAEs were drug-related in 70% and 74% of pts, respectively. Grade 3–4 TEAEs occurred in 41% of CP-B pts and 39% of the overall cohort and were drug-related in 27% and 26% of pts, respectively. Serious TEAEs were observed in 48% of CP-B pts and 37% of the overall cohort, and were drug-related in 11% and 9% of pts, respectively. Drug-related TEAEs led to less frequent dose modifications in CP-B pts than in the overall cohort (28% vs 37%), but more frequent permanent discontinuations (28% vs 16%). Median OS in CP-B pts was 6.3 (95% confidence interval [CI] 4.9, 7.8) months and in CP-B7 pts was 6.7 (95% CI 5.1, 8.7) months. Conclusions: In REFINE, pts with uHCC and CP-B liver function had similar rates of grade 3–4 TEAEs, but a higher occurrence of serious TEAEs due to underlying cirrhosis led to more frequent permanent discontinuations in CP-B pts. Median OS in CP-B7 pts was comparable with OS in CP-B pts overall. The evaluation of prognostic models to identify CP-B pt subgroups who may benefit from regorafenib treatment is a subject for further research. 1. Kim YJ, ILCA 2022. [Table: see text]
Real-world (RW) study in patients (pts) with metastatic colorectal cancer (mCRC) with long-term responses to regorafenib in the USA.
Authors: Kim Richard D. , Pan Xiaoyun , Ostojic Helene , Zhang Yiqiao , Lunacsek Orsolya , Pisa Federica , Peeters Marc
Published: January 2024

48

Background: Anecdotal evidence suggests that some pts with mCRC experience significantly longer responses to REG in clinical care settings, including a case exceeding 9 years. However, comprehensive studies on long-term responders to REG are lacking. We evaluated demographic/clinical characteristics of pts with long-term response (LTR) to REG using duration of treatment (DOT) as a surrogate for treatment response. Methods: This was a retrospective cohort study using the US nationwide de-identified Flatiron Health Electronic Health Record-derived database. The study period was January 1, 2013 to May 31, 2023, and adult pts with mCRC who initiated REG monotherapy (index date) from July 1, 2013 to December 31, 2022 were included. DOT for pts with LTR of ≥5 months (LTR5 [primary objective]; mos) or ≥4 mos (LTR4 [secondary objective]) were determined. Results: A total of2,326 eligible pts (median age 64 yrs; 56% male) had initiated REG during the study period. Overall, 346 pts (15%; median age 65 yrs) had LTR5 and 503 pts (22%; median age 65 yrs) had LTR4. Among pts with LTR5, 46% had stage IV disease at initial diagnosis, 68% had ECOG performance status (ECOG PS) 0‒1 at index, 64% received prior bevacizumab (BEV), and of pts tested at index with results, the median carcinoembryonic antigen (CEA) level was 35 ng/mL, and 51% and 5% had a KRAS and BRAF mutation at index, respectively; pts with LTR4 had similar characteristics (Table). Median time from initial CRC diagnosis to index date was 39.2 mos for pts with LTR5 and 38.6 mos for pts with LTR4. Of pts who initiated REG before 2019 (n = 1,070), 14% had LTR5 and 21% had LTR4; of pts who initiated REG from 2019 onwards (n = 1,256), 16% had LTR5 and 22% had LTR4. Among pts with LTR5, 33% and 23% had received REG as third-line (3L) or fourth-line (4L) treatment, respectively; among pts with LTR4, 34% and 23% had received REG as 3L or 4L treatment, respectively. Median time to discontinuation of REG was 7.3 (95% CI 6.9, 7.8) mos in pts with LTR5 and 6.0 (95% CI 5.7, 6.2) mos in pts with LTR4. Median follow-up time (from index date) was 13.3 mos and 11.1 mos in pts with LTR5 and LTR4, respectively. Conclusions: This is the first large-scale RW evidence study to describe demographic/clinical characteristics of pts with LTR to REG. Pts demonstrating LTR typically had favorable ECOG PS at REG initiation, less advanced disease at initial diagnosis, and the majority had received prior BEV. [Table: see text]
Evaluating the safety and efficacy of the addition of liver radiation (RT) to atezolizumab and bevacizumab (A/B) in advanced hepatocellular carcinoma (HCC): A retrospective cohort analysis.
Authors: Brown Timothy J. , Amit Uri , Ben-Josef Edgar , Karasic Thomas Benjamin
Published: January 2024

481

Background: Recently, the addition of stereotactic body RT to sorafenib in patients (pts) with advanced HCC demonstrated improved overall survival. However, A/B is the current standard of care for pts with advanced HCC based on IMBrave150. For these pts, RT may potentiate the antitumor immune response of A/B but carries the risk of bowel toxicity and impaired liver function. To date, there are limited data regarding safety and outcomes with the addition of liver RT to A/B in pts with advanced HCC. Here, we describe our single-center experience of adding RT to A/B for pts with advanced HCC. Methods: This single-center retrospective cohort study was conducted at the University of Pennsylvania. We identified all pts with HCC naïve to systemic therapy who received infusions of A/B and those who received RT to the liver within 30 days of starting A/B until discontinuation from 1/1/2020 until 2/2/2023. We assessed the real-world response rate (rwRR) determined from clinician impression after initiating A/B, safety outcomes, overall survival (OS), and time-to-progression (TTP) from initiation of A/B. Time-to-event outcomes were analyzed by the Kaplan-Meier method with log-rank test and Cox proportional hazards modeling. Results: We identified 49 pts (n=34 control, n=15 RT) with advanced HCC receiving first-line A/B. Those who received RT were more likely to have alcoholic liver disease (p=0.013) and were less likely to have ascites (p=0.04) but were otherwise balanced regarding demographics, prior locoregional therapies, presence of macrovascular invasion and extrahepatic spread, and baseline laboratories. The median RT dose was 63 Gy. The rwRR in the RT group was 73.3% (11/15) compared to 17.6% (6/34) in the control group (Risk Ratio (RR) 3.9, 95% CI 1.7-8.6, p<0.001). Two pts in the control group (5.8%) and one patient in the RT group (6.7%) experienced clinically significant bleeding (RR=1.1 95% CI 0.1-11.6). In the RT group, three pts (20%) developed worsening liver dysfunction after completing RT, concerning for possible radiation-induced liver disease. Six pts in the control group and one patient in the RT group developed immune-related adverse events leading to discontinuation of A/B. The median OS in the RT group was 14.4 mos and 10.8 mos in the control group (Hazard Ratio (HR) death 0.49 (95% CI 0.20-1.22, p=0.12)). Median TTP was 6.4 months (mos) with RT compared to 5.8 mos in the control group (HR progression 0.72 (95%CI 0.35-1.46, p=0.36. Conclusions: In our retrospective cohort, the addition of liver RT to standard A/B resulted in increased responses and a non-significant improvement in outcomes without an increased risk of bleeding. An assessment of changes in liver dysfunction by Child-Pugh and ALBI score is ongoing. Overall, these data support prospective trials to evaluate the addition of RT to A/B.
Therapeutic effectiveness of high-intensity focused ultrasound (HIFU) ablation in patients with unresectable hepatocellular carcinoma.
Authors: Kim Jin Il
Published: January 2024

490

Background: High-intensity focused ultrasound (HIFU) ablation is a new therapeutic method for treatment of solid tumor. To determine the efficacy and safety of HIFU, we report our experience for local therapy of primary or metastatic hepatocellular carcinoma (HCC). Methods: From January 2015 to December 2022, forty- eight patients with unresectable HCC underwent single or two therapeutic sessions of HIFU under general anesthesia. Ten patients with liver metastasis from colon cancer and three patients with liver metastasis from stomach cancer were included. We used HIFU, ultrasound-guided extracorporeal system (HIFU Technology Company, Chongqing, China). Thirty-three patients received transarterial embolization before HIFU. Thirteen patients were treated with chemotherapy before HIFU. Technical effectiveness per patient and per masses was assessed according to clinical findings and MR imaging at follow-up. Complications were also recorded. Results: We treated total 78 tumors in 48 patients. The tumor size ranged from 1.3 cm to 12 cm in diameter. Small (< 3 cm), intermediate (3-5 cm) and large tumors (>5 cm) are 44, 24 and 10 patients, respectively. Average procedure time was 4 hours 10 minutes with 68 minutes treatment time. We made the artificial pleural effusion to get treatment field in 25 patients. Mean follow-up period was 52 weeks. For the technical effectiveness per patient as follows: complete ablation with no evidence of recurrence on follow up in 18%, apparent complete ablation of target mass with progression of new lesions on follow up in 29%, recurrence after apparent complete ablation in 26%, and incomplete ablation at 2 week follow up in 27%. Average post-procedure hospital day was 5.4 days. No severe complication except mild right upper quadrant pain was observed after treatment. Conclusions: HIFU is an effective and safe treatment option for local image-guided tumor ablation in patients with unresectable HCC. Although further study is necessary, these results show that HIFU may be helpful in treating unresectable HCC.
Adjuvant TACE plus lenvatinib as compared with TACE alone in patients with hepatocellular carcinoma at high risk of recurrence after surgery: A prospective controlled study.
Authors: Zhang Bin , Jin Renan , Xu Junjie , Chen Ming yu , Chen Jiang , Zhu Hepan , Cao Jiasheng , Song Chao , Yang Zaibo , Zhang Yewei , Liang Xiao
Published: January 2024

505

Background: Hepatocellular carcinoma (HCC) remains the fourth leading cause of cancer related deaths globally. Radical resection is still the main curative approach for patients with resectable HCC in China. However, the high 5-year postoperative recurrence rate of about 40% to 70% had become the main negative factor affecting the long-term survival benefit. Although transarterial chemoembolisation (TACE) can effectively reduce the recurrence rate and improve disease-free survival (DFS) and overall survival (OS), the outcomes of patients at high risk of recurrence are still not satisfactory. Thus, there is an urgent need for new adjuvant treatment regimen to further improve the survival outcomes. In this study, we compared the efficacy and safety of the lenvatinib plus TACE with TACE alone for postoperative patients with HCC who were at high risk of recurrence. Methods: The factors associated with high risk of recurrence were defined as pathological suggested vascular invasion (including vascular embolus, cholangiocarcinoma embolus and microvascular invasion), suspicious positive surgical margin or surgical margin < 1cm, satellite lesion with cancer, positive lymph nodes, low differentiation and incomplete envelope. Eligible patients were those who had received radical resection for HCC and had risk factors above. Patients were assigned in a 1:1 ratio to receive the combination of lenvatinib and TACE or TACE alone. Results: From September 2019 to May 2023, 119 patients were enrolled in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. Sixty received TACE + lenvatinib and 59 received TACE only. The baseline characteristics were similar between two groups. The median duration of follow-up was 22.5 months (rang: 3 to 47) in TACE + lenvatinib group and 23 months (rang: 5 to 48) in TACE group. The 1-year DFS rate was 81.2% (95% CI: 70.8%-93.1%) in lenvatinib + TACE group, which was significantly higher than that of TACE group (58.3% [95% CI: 46.8%-72.7%], p = 0.0087; HR = 0.44 [95% CI: 0.23-0.83]). The median DFS was not reached (95% CI: 28-NR) in lenvatinib + TACE group, and was 20.0 months (95% CI: 12.0-NR) in TACE group. Patients' liver function after treatment with TACE + lenvatinib was comparable to that in the baseline. Conclusions: The preliminary results of this study suggested that adjuvant lenvatinib in combination with TACE can significantly improve DFS compared with TACE alone in patients with HCC at high risk of recurrence after surgery. The toxicity of combined treatment was tolerable and manageable. The follow up is still ongoing to observe the long-term benefit of this treatment regimen.
Liver toxicity following reirradiation and multiple-target SBRT for primary hepatocellular carcinoma.
Authors: Hall Jacob , Moon Andrew M , Young Michael , Tan Xianming , Darawsheh Rami , Danquah Flora , Tepper Joel E. , Yanagihara Ted K.
Published: January 2024

514

Background: Stereotactic body radiation therapy (SBRT) is increasingly used to treat hepatocellular carcinoma (HCC), but its safety in the treatment of multiple synchronous or recurrent lesions is underreported. We aim to better characterize SBRT-related hepatic toxicity in this population. Methods: We conducted a retrospective analysis of patients with primary HCC who underwent SBRT for 2 or more synchronous or recurrent liver lesions. We collected patient characteristics and dosimetric data (mean liver dose, cumulative effective volume [Veff], cumulative volume of liver receiving 15Gy [V15Gy], and cumulative planning target volume [PTV]) along with liver-related toxicity (measured by albumin-bilirubin [ALBI] and Child-Pugh [CP] scores). We employed a linear mixed-effects model to assess the effect of multi-target SBRT on changes in ALBI. Results: There were 25 patients and 56 lesions with median follow-up of 29 months. Eleven patients had synchronous lesions and 14 had recurrent lesions treated with separate SBRT courses. Eight local failures occurred at a median of 8 months (range: 4 – 25 months) after SBRT. Among those receiving multiple SBRT courses, there were 7 lesions with overlap of V15Gy (median V15Gy overlap: 35mL, range: 0.5 – 388mL). There was no association between cumulative Veff, V15Gy, or PTV and change in ALBI. Four of 25 patients an increase of Child-Pugh (CP) score by ≥ 2 points, within 3 to 6 months after SBRT. Neither increase in CP nor ALBI were associated with cumulative Veff, V15Gy, and PTV. Comparing the groups that received SBRT in a single course versus multiple courses revealed no statistically significant differences in liver toxicity. Conclusions: LiverSBRT for multiple lesions in a single or in separate courses results in worsening of CP scores or ALBI in a small percentage of patients, suggesting a low risk of RILD. Prospective studies with a larger cohort are needed to better characterize safety in this population.
Des-gamma-carboxy prothrombin (DCP) as a biomarker for treatment response in hepatocellular carcinoma.
Authors: Conner Elizabeth , Chang Jeremy , Burgoyne Adam
Published: January 2024

547

Background: Causes of variable disease response to first-line treatment with atezolizumab/bevacizumab (atezo/bev) in hepatocellular carcinoma (HCC) patients remain unclear. Identifying tumor markers that predict treatment efficacy may help raise clinical suspicion for early disease progression. The role of des-gamma-carboxy prothrombin (DCP) is not well established in Hepatitis B Virus (HBV) non-endemic areas. This study aimed to investigate DCP as a predictive biomarker of atezo/bev treatment response in HCC patients. Methods: This single-center retrospective analysis evaluated DCP and radiographic response in HCC patients who received atezo/bev in the first-line setting. DCP was measured at the time of best response evaluation and compared to day one of atezo/bev initiation. Elevated DCP was defined by >=7.5 ng/mL. DCP response was defined as a decrease of >=50% at response assessment compared with baseline. Treatment response was evaluated based on imaging modalities including computed tomography and/or magnetic resonance imaging. Objective response rate (ORR) was defined as the percentage of patients with complete response (CR) and partial response (PR). Disease control rate (DCR) was defined as the percentage of patients with CR, PR, and stable disease (SD). No Response (NR) was defined as the percentage of patients with SD and PD. Comparisons of treatment effects were performed using two-tailed Fisher Exact Probability Test. Results: A total of 53 HCC patients treated with atezo/bev as first-line therapy were included. The best treatment responses according to radiographic evaluation were as follows: CR 3.8%, PR 22.6%, SD 52.8%, and PD 20.8%, respectively. Patients with DCP response had ORR of 69% (odds ratio, 15.75; 95% CI, 3.50-70.9; P=.0002) and DCR of 100% ( P=.047). Patients with >=50% increase in DCP at response evaluation compared to day one of treatment had ORR of 4.5% and NR of 95% ( P=.0035). On day one of treatment, 70% of patients had an elevated DCP. There was no difference between elevated DCP vs non-elevated DCP on day one of treatment and ORR. Conclusions: This study found that DCP has utility in predicting response to atezo/bev for HCC patients in HBV non-endemic areas. Further studies are needed to confirm findings and evaluate the prognostic implications of DCP in HBV non-endemic areas.