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Role of intraperitoneal paclitaxel in eosinophil activation and recruitment in the peritoneal cavity and anti-tumor effects against peritoneal metastasis from gastric cancer.
471 Background: Recent studies indicate that the efficacy of chemotherapy is significantly influenced by the tumor immune microenvironment. Peritoneal cavity contains many immune cells, however, the relationship between immune response within the peritoneal cavity and tumor response remains poorly understood. Methods: Single cell suspensions were obtained from ascites or peritoneal lavages from 41 patients with PM from GC. In 28 patients, cells were collected both before and after 1-3 courses of IP chemotherapy. These samples were immunestained with mAbs targeting to specific lymphoid or myeloid subsets, and their proportions in CD45(+) leukocytes were analyzed using flowcytometry. Eosinophils were purified by magnetic cell sorting for subsequent RNA-Seq analysis. Results: Among 41 patients with PM, tumor leukocyte ratio (TLR) calculated as CD326(+) tumor cells divided by CD45(+) leukocytes varied from 0.002% to 58.1%. TLR was not correlated with any ratios of immune cells, however, the ratios of CD8(+) T cells, NK cells and CD16(-) CD193(+) eosinophils tended to decrease with the increase in TLR. Conversely, the ratios of CD19(+) B cell, CD14(+) macrophages and CD16(+) neutrophils increased with elevated TLR. Mean survival time of these patients was 17.7 months. None of the leukocyte subsets showed significant association with patient outcome. In 28 patients, the ratios of lymphocytes mostly decreased with significant difference in CD4(+) T cells and CD19(+) B cells after IP treatment. In contrast, the ratio of CD11b(+) myeloid cells increased in peritoneal cavity after IP treatment. Among the myeloid cells, the ratio of CD16(-) CD193(+) eosinophils significantly increased. The change was particularly prominent in in post-treatment negative peritoneal lavage cytology (CY0) patients (M=0.47% vs M=10.0%, p<0.0001), while the difference was not significant in post-treatment positive peritoneal lavage cytology (CY1) patients (M=0.93% vs M=0.97%, p=0.84). Patients with eosinophil ratio of ≥2% after IP chemotherapy in peritoneal cavity had significantly longer overall survival compared to those with lower eosinophil ratios (17.3 mo vs 26.7 mo, p=0.034; HR =0.23[0.06-0.89]). The peritoneal eosinophils after IP treatment exhibited elevated levels of CD11b and CD63 expression compared to circulating eosinophils (p<0.01), while SSC-A levels tended to be lower. Gene ontology pathways revealed enrichment of cytokine-mediated signaling pathway, extracellular matrix organization and response to interferon-gamma in peritoneal eosinophils (p<0.0001). Conclusions: IP-PTX induces eosinophil activation and recruitment in the peritoneal cavity, while also affecting other types of immune cells. These effects may potentially contribute to the anti-tumor response against peritoneal metastases.
A phase II study of peri-operative NovoTTF-200T(P) in combination with gemcitabine and nab-paclitaxel for resectable pancreatic adenocarcinoma: Big Ten Cancer Research Consortium (BTCRC-GI21-500).
TPS795 Background: The recurrence rates and outcomes in resectable pancreatic ductal adenocarcinoma (R-PDA) is concerningly high. The benefit of neoadjuvant chemotherapy over traditional upfront surgery followed by adjuvant therapy is not clear. Electromagnetic fields generate bi-directional forces on highly polar intracellular components, causing abnormal microtubule polymerization during spindle formation and irregular cleavage furrow formation. We will leverage these anti-proliferative effects in managing R-PDA by tumor treating fields (TTF) with chemotherapy backed by strong in vitro and in vivo evidence. The PANOVA phase II trial (n=40) gave us safety and efficacy data of this combination in advanced PDA. No systemic effects were associated with TTF. The only notable safety issue was a small incidence of grade 3 device-related dermatitis. Methods: Our phase II single arm study will investigate perioperative use of TTF with gemcitabine and nab-paclitaxel (G-NP) combination. Eligible patients R-PDA (visible pancreatic mass, measurable disease, absence of arterial interface, venous interface ≤ 180°, patent portal splenic confluence, and no metastatic disease, including lymphadenopathy outside the surgical area) will wear TTF and receive three cycles of G-NP before restaging. Patients are expected to wear TTF for > 80% of the time during this period. If they proceed with resection, additional 3 cycles of Gem-NP with TTF will be given to the patient. This study employs a Bayesian Optimal Phase 2 (BOP2) design with primary endpoints of overall survival (OS) at 2 years and resection rate. The null hypothesis posits a 40% OS rate compared to a target of 60%, and a resection rate null hypothesis of 60% versus a target of 75%. The trial aims to enroll 30 patients, with an interim futility analysis planned after 15 participants. Enrollment will be terminated early if 8 or fewer patients undergo resection in the initial stage, providing 83% power and a type I error rate of 10%. Secondary endpoints include adverse events, overall response rate, TTFields compliance rate, relative dose intensity, and overall survival. The trial started actively recruiting patients in April 2024. The accrual goal is 38 patients. At the time of submission, one patient was enrolled. Clinical trial information: NCT05624918 .
Investigation of the association of <i>CTRB2</i> exon 6 deletion with time to progression and overall survival in pancreatic ductal adenocarcinoma.
770 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis and limited treatment options. A 584 bp deletion in CTRB2 , which impairs chymotrypsin B2 function, has been linked to increased PDAC risk. This study investigates the impact of this deletion on progression and survival outcomes in patients with PDAC. Methods: There were 633 patients in whom CTRB2ex6 deletion was genotyped; 263 patients received chemotherapy and had time to progression (TTP) information. TTP was calculated from diagnosis date until earliest of 1) progression date (event), 2) surgery, death, or next chemotherapy date (competing risk), or 3) date last known to be alive (censor). Overall survival (OS) was calculated for the cohort from diagnosis until date of death (event) or date last known to be alive (censor). TTP was analyzed using cumulative incidence methods accounting for competing risks; OS was analyzed using Kaplan-Meier methods. Cox proportional hazard models adjusted for age and sex were used to test associations and compute hazard ratios (HR) and 95% confidence intervals (CI). Results: Median TTP in those with CTRB2ex6 deletion negative carrier status (n=209) was 1.3 years vs 5.9 years for those with positive carrier status (n=54). Estimated 3-year progression rates were 54.2% for patients with no CTRB2ex6 deletions, 43.7% for patients with one deletion (n=48), and 33.3% for patients with two CTRB2ex6 deletions (n=6). TTP was not associated with CTRB2 deletion carrier status (HR: 0.8, 95% CI: 0.6-1.3). Median OS for CTRB2ex6 deletion negative carriers (n=514) was 1.0 year vs 0.9 years for positive carriers (n=119); within deletion carriers, heterozygous carriers (n=110) had a median OS of 0.9 years, and homozygous carriers (n=9) had a median OS of 2.6 years. OS was not associated with CTRB2 deletion carrier status (HR: 1.0, 95% CI: 0.9-1.3). Conclusions: Although we did not detect statistically significant differences in TTP and OS by CTRB2ex6 deletion carrier status, there was an interesting trend toward longer TTP and OS in the small number of patients who carried homozygous CTRB2ex6 deletions. Larger studies are warranted to validate these findings.
Current status and treatment outcomes of intraductal papillary mucinous carcinoma in Korea: A multi-center cohort study.
812 Background: The spectrum of intraductal papillary mucinous neoplasm (IPMN) varies from benign cysts to intraductal papillary mucinous carcinoma (IPMC). There is a lack of large-scaled data on IPMC and high-grade dysplasia. We aimed to study the real-world status and treatment outcomes of IPMC in South Korea. Methods: This is a retrospective, multicenter study conducted in South Korea. We reviewed the electronic medical records of patients who were histologically diagnosed with IPMC or high-grade (HG) dysplasia between 2011 and 2020, and analyzed the baseline characteristics, treatment patterns, and survival. Results: A total of 388 patients were eligible from six institutes (145 female [37%]; median age 67.8; 259 IPMC [67%] vs 129 HG dysplasia [33%]). The median overall survival for IPMC patients was 75 months, compared to 133 months for HG dysplasia. In IPMC group, 217 (84%) were underwent surgical resection and 42 (16%) did not underwent surgery due to general condition or advanced stage whose median overall survival was 83 months and 49 months respectively. In resected IPMC, 104 (48%) received adjuvant chemotherapy (gemcitabine single 48%, 5FU+leucovorin 33%, others 19%) and 66 (30%) experienced recurrence and median recurrence-free survival (RFS) was 20 months. Among IPMC group, 11 (4.2%) was in advanced stage and eight of those received palliative chemotherapy (FOLFIRINOX 62.5%; gemcitabine single 25%; gemcitabine with erlotinib 12.5%). In HG dysplasia, 108 (84%) patients underwent surgery, and 21 (16%) patients did not undergo surgery whose OS were 171 and 133 months, retrospectively. In patients with resected HG dysplasia, 29 (27%) experienced recurrence and median RFS was 21 months. Conclusions: IPMC generally showed longer survival and a lower recurrence rate than those of historical data in PDAC, with HG dysplasia demonstrating even better outcomes. In real world, similar chemotherapy regimens used for PDAC were applied to IPMN patients. Treatment status of intraductal papillary mucinous carcinoma and high-grade dysplasia. IPMC(259) IPMN-HG(129) Total(388) Median overall survival (month) 75 133 85 Treatment OP 217(84%) 108(84%) 325(84%) Adjuvant chemotherapy 104(48%) 19(18%) 123(38%) Recurrence rate 66(30%) 29(27%) 95(29%) Median recurrence-free survival (month) 20 19 21 Palliative chemotherapy 8(3%) NA Progression rate 5(63%) NA Progression-free survival (month) 13 NA
Potential effect of the gut microbiome on tumour response to anti-cancer treatment in patients diagnosed with pancreatic ductal adenocarcinoma.
757 Background: Chemotherapy is the standard of care for pancreatic ductal adenocarcinoma (PDAC), however, recent research has identified bacteria in the human gut microbiome that may influence patient response to chemotherapy. These bacteria are also present in faeces, and are thought to be representative of the bacteria in the pancreatic ductal system. Preliminary studies have suggested that patients with more advanced PDAC demonstrate lower levels of Firmicutes, and higher levels of Proteobacteria. Additionally, research has shown bacteria in the Firmicutes phylum possess several anti-cancer properties, which may improve patient treatment response, meanwhile, Gammaproteobacteria (Proteobacteria phylum), have been shown to attenuate gemcitabine efficacy and worsen treatment response. Methods: This prospective study involved 14 participants with locally advanced PDAC. Participants received combinations of Gemcitabine, Nab-Paclitaxel, and durvalumab (immunotherapy). Participant tumours were assessed every 8 weeks using radiological imaging according to RECIST v1.1, and serum CA19-9 levels were analysed monthly. Gut microbial profiling was completed on stool samples taken pre-treatment using PacBio HiFi full-length 16S rRNA sequencing. Results: 16S rRNA sequencing identified that of the 4 patients that died due to disease progression, 3 patients had a low Firmicutes abundance, and a high Proteobacteria abundance. The rother patient demonstrated low levels of Actinobacteriota and Bacteroidota, and a low bacterial diversity. One participant showed a significant increase in CA19-9 (1066.7%), and exhibited a low abundance of Actinobacteriota and Bacteroidota, a high abundance of Proteobacteria, and a low diversity. 5 participants demonstrated a significant treatment response (according to CA19-9 and RECIST analysis), with 4 patients showing a high Firmicutes abundance, high levels of Actinobacteriota or Bacteroidota, and low levels of Proteobacteria. The remaining patient demonstrated a low abundance of Firmicutes and Proteobacteria, yet, displayed the highest abundance of Actinobacteriota and Bacteroidota. Conclusions: This exploratory study suggests an association between microbial composition and treatment response, with Firmicutes potentially being associated with an improved treatment response, and Proteobacteria with a worsened response. We believe this study to be one of the first to explore correlation of microbiome with clinical treatment response in PDAC.
Exploratory study of TAS-102 combined with intermittent administration of fruquintinib in the treatment of third-line metastatic colorectal cancer.
174 Background: Fruquintinib and TAS-102 are two globally recognized standard therapies for mCRC patients who have previously undergone standard chemotherapy. A phase II exploratory study suggested that the combination of TAS-102 and fruquintinib could prolong progression-free survival (PFS) and overall survival (OS) in these patients. However, the benefits are sometimes limited due to tolerability issues associated with continuous dosing. This study aimed to investigate the efficacy and safety of intermittent administration of TAS-102 combined with fruquintinib as a third-line treatment for mCRC patients. Methods: This open-label, single-arm, single-center, exploratory clinical trial enrolled mCRC patients who had failed at least two standard treatment regimens. Eligible patients received oral fruquintinib (3 mg, once daily, on days 1-5 and 8-12) and TAS-102 (35 mg/m², twice daily, on days 1-5) every two weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was objective response rate (ORR). Secondary endpoints included OS, PFS , DCR, and safety. Results: From August 2023 to September 2024, 26 eligible patients were enrolled. The median age of the patients was 58 years (range: 19-77), with 61.5% being female. RAS mutations were present in 57.7% of patients, 57.7% had left-sided colon or rectal cancer, 57.7% had liver metastases, and 76.9% had multiple metastases. As of September 10, 2024, 22 patients had undergone at least one tumor assessment, and 12 patients were still on treatment. Among them, 18.2% (4/22) achieved partial response , and 50% (11/22) had stable disease as the best response. Median PFS (mPFS) was 135 days (95% CI: 60.52-209.48). mPFS in RAS-mutant and RAS wild-type patients was 161 days (95% CI: 63.37-258.63) and 135 days (95% CI: 60.20-209.80), respectively, with ORRs of 25% and 12.5%. mPFS in patients with liver metastases (LM) and non-LM was 135 days (95% CI: 45.42-224.58) and 161 days (95% CI: 87.84-234.16), respectively, with ORRs of 14.3% and 25%. mPFS in patients with multiple metastases was 135 days (95% CI: 71.86-198.14), with an ORR of 17.6%. Median OS was not yet mature. Treatment-related adverse events (TRAEs) were generally manageable and tolerable. The most common hematological TRAEs (any grade, grades 3-4) included leukopenia (76.9%, 11.5%), neutropenia (73.1%, 11.5%), and anemia (53.8%, 7.7%). Non-hematological TRAEs were mostly grades 1-2, including anorexia (46.2%) and fatigue (19.2%). One case of grade 3 hypertension was reported. No treatment-related deaths were observed. Conclusion s: These preliminary results suggest that intermittent administration of TAS-102 in combination with fruquinitinib as a third-line treatment for patients with mCRC reduces hematological toxicity and is well tolerated, with encouraging clinical results. Clinical studies are ongoing. Clinical trial information: ChiCTR2300078241 .
Risk of peritoneal recurrence following laparoscopic versus open surgery for stage II or III colorectal cancer (JCOG2310A): An integrated analysis of three phase III randomized controlled trials.
161 Background: Peritoneal recurrence in colorectal cancer (CRC) has long been a concern. Although studies have examined the higher risk of peritoneal recurrence following laparoscopic (LAP) compared with open (OP) surgery, the issue remains unresolved, largely due to the heterogeneity of existing data and the limited number of observed peritoneal recurrence events, preventing any definitive conclusions. This study aimed to evaluate whether LAP for pStage II/III CRC presents a potential risk factor for peritoneal recurrence compared with OP. Methods: Data from three phase III trials (JCOG0404, JCOG0910, JCOG1006) were extracted from an ancillary research database (JCOG2310A). From this cohort, patients with pStage II or III CRC who underwent curative surgery were included, and the incidence of peritoneal recurrence was compared between LAP and OP. A multivariate analysis was conducted to adjust covariates between the two groups. The primary outcome was the cumulative incidence of peritoneal recurrence, and the secondary outcome was recurrence in specific high-risk subgroups identified through a univariate analysis. Results: From 3061 patients (OP: 1734; LAP: 1327), pT4 (25% vs. 17%), pStage III (65% vs. 83%), and right-sided tumor (63% vs. 70%) were different between OP and LAP, respectively. With a median follow-up for peritoneal recurrence of 6.2 years, the 5-year cumulative incidence of peritoneal recurrence was 2.8% in the OP group and 2.9% in the LAP group (hazard ratio (HR): 0.940, 95% confidence interval (CI): 0.621-1.425 in the univariate analysis, and HR: 1.086, 95% CI: 0.683-1.727 in the multivariate analysis. The univariate analysis identified pT4, pN2, pStage III, right-sided tumor, poorly differentiated (por/sig/muc), and ECOG-PS 1 as risk factors for peritoneal recurrence. No significant difference was observed in the subgroups (see table). An exploratory propensity score matching analysis with 1066 patients in each group also showed no difference between the groups (the 5-year cumulative incidence of peritoneal recurrence was 2.8% in the OP group and 3.0% in the LAP group [HR: 1.002, 95% CI: 0.625-1.607]). Conclusions: This study revealed that LAP was not a risk factor regarding peritoneal recurrence following curative surgery for Stage II/III CRC. Subgroup analysis of cumulative incidence of peritoneal recurrence. OutcomeMeasures Subgroups pT4 pN2 pStage III Right-sided Poorly differentiated ECOG PS 1 N(OP vs. LAP) 428 vs. 229 274 vs. 184 1133 vs. 1105 635 vs. 403 122 vs. 66 56 vs. 25 Event(OP vs. LAP) 31 vs. 23 13 vs. 10 45 vs. 32 28 vs. 18 10 vs. 2 7 vs. 2 5-year peritoneal recurrence rate (OP vs. LAP)(%) 6.8 vs. 10.1 4.8 vs. 5.4 3.6 vs. 2.9 4.1 vs. 4.5 7.5 vs. 3.0 9.1 vs. 8.0 HR (95% CI) 1.403(0.819-2.402) 1.144(0.503-2.603) 0.725(0.461-1.139) 1.014(0.562-1.829) 0.372(0.081-1.699) 0.609(0.130-2.862)
Highly accurate detection of early-stage colorectal cancer using tumor and immune extracellular vesicles biomarkers.
262 Background: Colorectal cancer (CRC) is one of the most common cancers worldwide, and early detection is critical for successful treatment and improved survival rates. However, precancerous and early-stage CRC present significant diagnostic challenges due to the small size of lesions and the very low expression of tumor-specific biomarkers in the bloodstream. Current genomics-based diagnostic methods struggle to detect these early-stage and precancerous lesions, making it imperative to develop more sensitive and specific approaches. Circulating extracellular vesicles (EVs) are emerging as a promising solution for early-stage CRC detection. Since EVs are produced by tumor cells as well as tumor microenvironment and host immune response cells, EVs offer the means to detect and monitor small early-stage tumors through both direct detection of tumor-associated biomarkers as well as tumor specific host response and tumor microenvironment biomarkers. Methods: To identify novel early-stage CRC specific biomarkers, we performed proteomics analysis on EVs purified from patient plasma using size exclusion chromatography and a proprietary buffer system that enhances EV and corona protein recovery. TrueDiscovery Data-independent acquisition (DIA) mass spectrometry (MS) analysis was conducted on 24 pre-cancer/stage 0 and 25 stage 1 CRC patients and 75 normal patient plasma samples. An in-house developed machine learning pipeline was used to identify differentially expressed proteins and model candidate multiplexes to identify those with extremely high diagnostic accuracy (> 0.99). Results: An average of ~2,500 proteins were identified per sample and included in bioinformatics analysis. Comparative analysis between control patient EVs and either pre-cancerous/Stage 0, or Stage 1 colon cancer EVs using an in-house Machine Learning pipeline identified 336 and 493 differentially expressed proteins for each group (FDR adjusted p-value < 0.001). Of these, the best 17 pre/stage 0 proteins and 53 stage 1 proteins were trained and tested using Support Vector Machine to assess all potential 3-plexes in order to identify those with mean diagnostic accuracy > 99%. This yielded 5 3-plexes in precancer/stage 0 and 34 3-plexes in stage 1 with near perfect diagnostic accuracy. These plexes are currently being assessed in single analyte and multiplex immunoassays with the goal of translating candidate 3-plexes to the clinical. Conclusions: Key biomarkers from CRC patient EVs indicate the potential to detect and diagnose early-stage and low tumor burden cancers using our methods. Interestingly, the most accurate 3-plexes consist of proteins from immune, inflammatory and metabolic processes, suggesting that for the detection of early stage cancer it may be critical to include both tumor and host specific biomarkers.
Transition of Perovskite Solar Technologies to Being Flexible
Abstract Perovskite technologies has taken giant steps on its advances in only a decade time, from fundamental science to device engineering. The possibility to exploit this technology on a thin flexible substrate gives an unbeatable power to weight ratio compares to similar photovoltaic systems, opening new possibilities and new integration concepts, going from building integrated and applied photovoltaics (BIPV, BAPV) to internet of things (IoT). In this perspective, the recent progress of perovskite solar technologies on flexible substrates are summarized, focusing on the challenges that researchers face upon using flexible substrates. A dig into material science is necessary to understand what kind of mechanisms are limiting its efficiency compare to rigid substrates, and which physical mechanism limits the upscaling on flexible substrate. Furthermore, an overview of stability test on flexible modules will be described, suggesting common standard procedure and guidelines to follow, showing additional issues that flexible modules face upon bending, and how to prevent device degradation providing an ad‐hoc encapsulation. Finally, the recent advances of flexible devices in the perovskite market will be shown, giving an outline of how this technology is exploited on flexible substrates, and what are still missing that need stakeholders’ attention.
Genetic differences in colorectal cancer across race and ethnicity.
28 Background: Colorectal cancer (CRC) is the fourth most common cause of cancer death and cancer-related mortality is expected to increase exponentially. Ethnic minorities, in particular African Americans, have increased mortality from CRC. Although multifactorial, differences in somatic gene mutations could contribute to these racial discrepancies. Mutations in the critical oncogene KRAS are associated with worse prognosis in CRC. Recent literature suggests that in CRC patients, KRAS mutations are more frequently found in African Americans compared to Caucasians. This finding led to our hypothesis that molecular alterations across multiple races/ethnicities could explain differences in patient outcomes. This project will also inform a larger analysis using artificial intelligence learning models to predict race from tumor-specific genetic variants, as a tool to identify genetic drivers of race-specific patient outcome. Methods: We examined the molecular alterations in 304 patients diagnosed with CRC who had genetic testing between June 2021 and April 2023 at NYP Queens, NYP Brooklyn, and NYP Cornell. Race and ethnicity, genetic mutations, mortality, tumor location, and age, stage, and the presence of metastasis at diagnosis was collected. Patients self-identified as Non-Hispanic Black (NHB), White (NHW), Asian (NHA), American Indian (NHAI), or Hispanic, Other, or Declined. Median and interquartile range were used to summarize continuous variables, and frequency and proportion were used to summarize categorical variables. The significance of difference across ethnicity groups was tested using Kruskal-Wallis rank sum test for continuous variables and Fisher’s exact test for categorical variables. Mutational correlates of race using a multiple-instance learning artificial intelligence approach (i.e. Anaya et al., Nature Biomedical Engineering, 2023), will be presented. This method will predict race from patients' tumor-specific genetic variants, allowing us to identify specific variants and patterns predictive of race, and potential drivers of patient outcome. Results: Amongst the 304 CRC patients, we identified 116 NHW, 51 NHA, 40 NHB, 35 Hispanic and 1 NHAI, for a total population of 243. BRAF mutations were almost absent in NHB (2.5%) and NHA (3.9%), compared to NHW (13.8%; p=0.02). KRAS mutations were also more prevalent in underserved populations; 65.7% Hispanic, 57.5% NHB, compared with 44.8% NHW (p=0.14). We further identified substantial differences in KRAS mutations when dividing the Asian population into East Asian (62.9%) and South Asian (37.5%). Conclusions: We identified significant differences in key molecular drivers between ethnicities. Our findings suggest that genomic and tumor specific differences across ethnicities could in part explain differences in patient survival across these groups. Mutational correlates of race and survival using natural language processing will be presented.
Use of pathological response versus RECIST assessment in predicting relapse-free survival following neoadjuvant immunotherapy for hepatocellular carcinoma.
633 Background: Immune checkpoint inhibitors (ICI) administered prior to liver resection (LR) lead to pathological responses in patients with hepatocellular carcinoma (HCC). However, the relative value of pathological versus radiological response in predicting relapse-free survival (RFS) remains unclear. Methods: We pooled patient-level data from 111 patients (pts) with HCC receiving ICI prior to LR as part of 5 phase I/II trials and observational clinical studies conducted in 12 centres in the United States, United Kingdom and Asia, as part of an academic consortium (NeoHCC). Pathological response was measured as the percentage of non-viable tumour in the resected specimen, with major (pMR) and complete pathological response (pCR) corresponding to ≥70% and 100% tumour regression. Radiological overall response rate (ORR) was assessed by RECIST v1.1 and modified RECIST (mRECIST) criteria. We correlated pathological response and ORR with RFS using Cox regression. Results: Pts received preoperative ICI between Oct 5, 2017, and Nov 15, 2023, mostly ICI combinations (69%, n=76). Most pts were male (78%, n=87) with viral chronic liver disease (66%, n=73), BCLC stage A HCC (55%, n=61). ORR was 28% per RECIST v1.1 and 32% per mRECIST criteria (available for n=81). Out of the 104 pathologically evaluable pts, pMR and pCR rates were 32% (n=33) and 18% (n=19). Radiological response by RECIST v1.1 showed a significant correlation with pathological response (R 2 = 0.43, p<0.001). When using RECIST v1.1, 74% of pts with ORR achieved pMR vs 14% of those without ORR (n=23/31 vs 10/73, p<0.001). However, 30% of pMR were not predicted by ORR (n=10/33). The discrepancy between pMR and ORR decreased using mRECIST. ORR per mRECIST was 83% in pMR pts (n=19/23), whereas it was 10% in non-pMR (n=5/51). After a median follow-up of 27.2 mos (95%CI 22.3-32.1), median RFS for the whole cohort was 43.6 mos (95%CI 28.3-NE). Achievement of pMR, pCR and ORR was associated with improved RFS (Table). However, reduction in the risk of relapse and/or death was higher in pts achieving pMR or pCR than ORR, regardless of the use of RECIST v1.1 or mRECIST. Conversely, pts without pMR had a lower mRFS than pts without ORR (28.3 mos [95%CI 12.8-43.8] and 32.8 mos [95%CI 13.7-51.9], respectively). Conclusions: Whilst radiological responses to neoadjuvant ICI are associated with improved RFS in pts with HCC, achievement of pMR is more accurate than RECIST and mRECIST-based responses in predicting for RFS, with lack of pMR identifying pts at a higher risk of relapse or mortality. Cox regression for RFS HR (95% CI) p value pCR 0.19 (0.05-0.78) 0.02 pMR 0.25 (0.10-0.66) 0.005 RECIST 1.1 0.34 (0.13-0.86) 0.02 mRECIST 0.38 (0.13-1.11) 0.08 RFS, relapse-free survival; HR, hazard ratio; CI, confidence interval; pCR, complete pathological response; pMR, major pathological response; mRECIST, modified RECIST.
Short-course radiotherapy-based total neoadjuvant therapy combined with tislelizumab in the treatment of locally advanced rectal cancer (Neo-STAR): Early outcomes of a prospective, randomized phase II trial.
150 Background: It has been found that radiotherapy possess synergistic anticancer effect with immune checkpoint inhibitors (ICIs). Therefore, this phase II randomized clinical trial (RCT) (ClinicalTrials.gov identifier: NCT05086627) aimed to evaluate the efficacy and safety of SCRT followed by CAPOX and tislelizumab in patients with LARC. Methods: Patients initially diagnosed rectal adenocarcinoma with cT1-2N+M0 or cT3-4NanyM0 were recruited, randomly assigned to receive SCRT (25Gy/5f), followed by four cycles of CAPOX combined with tislelizumab or CAPOX alone, respectively. After total mesorectal excision (TME), two cycles of postoperative adjuvant chemotherapy were given according to the patient's preferences. The pCR rate was set as the primary endpoint, and the major pathological response (MPR) (tumor regression grade (TRG) 0+1), 3-year progression free survival (PFS), 3-year overall survival (OS) and treatment safety were set as the secondary endpoints. R esults: Between September 2021 and March 2024, 118 patients were randomly assigned and 111 patients started allocated treatment, with 53 in the trial group and 58 in the control group. Ninety-six patients (86.5%) completed SCRT and 4 cycles of CAPOX chemotherapy with/without tislelizumab, including 49 patients (92.5%, 49/53) in the trial group and 47 patients (81.0%, 47/58) in the control group. Eighty-two patients (85.4%) had surgical resection, including 42 patients (85.7%, 42/49) in the trial group and 40 patients (85.1%, 40/47) in the control group. Among 82 patients who underwent surgery, 54.8% (23/42) patients in the trial group achieved pCR compared with 37.5% (15/40) in the control group. During the neoadjuvant treatment period, the incidence of grade 3-4 AEs were 9.4% in the trial group and 10.3% in the control group. Conclusions: SCRT-based TNT combined with tislelizumab followed by TME exhibited a favorable pCR rate in LARC. Clinical trial information: NCT05086627 . Surgical and postoperative pathological outcomes. Characteristic Experimental group (n= 42 ) Control group (n=4 0 ) R0 resection Yes 42 (100%) 40 (100%) No 0 (0%) 0 (0%) pCR Yes 23 (54.8%) 15 (37.5%) No 19 (45.2%) 25 (62.5%) TRG score 0 23 (54.8%) 15 (37.5%) 1 3 (7.1%) 2 (5%) 2 14 (33.3%) 15 (37.5%) 3 2 (4.8%) 8 (20%) Pathological T stage T0 24 (57.1%) 15 (37.5%) Tis 1 (2.4%) 0 (0%) T1 0 (0%) 1 (2.5%) T2 9 (21.4%) 6 (15%) T3 6 (14.3%) 10 (25%) T4 2 (4.8%) 8 (20%) Pathological N stage N0 39 (92.9%) 36 (90%) N1 3 (7.5%) 3 (7.5%) N2 0 (0%) 1 (2.5%) Type of surgery Anterior resection 36 (85.7%) 24 (60%) Abdominoperineal resection 6 (14.3%) 13 (32.5%) Hartmann procedure 0 (0%) 3 (7.5%) Anus preservation Yes 36 (85.7%) 27 (67.5%) No 6 (14.3%) 13 (32.5%)
Effects of neighborhood deprivation index on survival in gastric cancers.
336 Background: Previous studies have shown that living in disadvantaged neighborhoods resulted in poor outcomes in several malignancies. Neighborhood Deprivation Index (NDI) identifies key variables from 13 measures, including the following dimensions of socioeconomic (SES) status: wealth and income, education, occupation, and housing conditions. In this study, we aimed to investigate the effect of NDI among patients with gastric cancer (GC). Methods: We conducted a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database from 1996-2015. NDI was divided into two groups: less disadvantaged areas (NDI <60) and highly disadvantaged areas (NDI >60), respectively. Demographic and clinical characteristics were summarized by NDI groups. All associations were compared using Kruskal-Wallis and Chi-Square tests, respectively. Kaplan Meier curves were summarized by the NDI group for overall survival (OS) and disease-specific survival (DSS). All associations were compared using a log-rank test. Cox multivariate regression was performed to measure the association between NDI and OS/DSS. All analyses were conducted in RStudio v4.2.3 at a significance level of ≤ 0.05. Results: A total of 19,205 GC (11,137 patients with NDI<60 and 8,068 NDI>60) patients were analyzed. Disadvantaged areas (NDI>60) had a higher proportion of Black and Hispanic, single, uninsured, rural patients with later disease stage as compared to NDI <60. Median OS was 10.0 months for patients with NDI <60 versus 9.0 months for those with NDI >60 (p=0.0007). Median DSS was 12.0 months for NDI <60 and 10.0 months for NDI >60 (p=0.010). Multivariate analysis revealed that factors associated with worse OS included NDI >60 [HR 1.044, p=0.009], age (>60) [HR 1.28, p<0.001], male sex [HR 1.082, p<0.001], single marital status [HR 1.21, p<0.001], uninsured status [HR 1.13], p <0.001], advanced disease stage (III/IV) [HR 2.05, p<0.001], and higher grade [HR 1.32, p<0.001]. On the other hand, non-Hispanic Black [HR 0.98] and Hispanic [HR 0.94] race and urban location [HR 0.91, p<0.001] were associated with improved OS. Factors associated with inferior DSS included NDI >60 [HR 1.037, p=0.038], age (p<0.001), male sex [HR 1.05, p=0.005], single marital status [HR 1.15, p<0.001], advanced disease stage (III/IV) [HR 2.375, p<0.001], and advanced grade (III/IV) [HR 1.40, p<0.001). In contrast, Hispanic [HR 0.94], non-Hispanic Black [0.96], and urban location [HR 0.90, p<0.001] were associated with improved DSS. Conclusions: Patients from areas with higher NDI had worse OS and DSS for GC. Tailored healthcare policies that aim to improve healthcare delivery to areas with high deprivation may help improve GC outcomes.
Short- and long-term outcomes of conversion surgery for initially unresectable advanced gastric cancer: A Japanese multicenter retrospective cohort study.
402 Background: The efficacy of conversion surgery in patients with unresectable advanced gastric cancer at the initial diagnosis who converted to be resectable due to remarkable response to chemotherapy is unclear. To evaluate short- and long-term outcomes of conversion surgery for initially unresectable cStage IVB/pStage IV gastric cancer as the basic data for the JCOG2301 trial, which is a randomized controlled trial comparing conversion surgery with continuation of chemotherapy, a multicenter retrospective cohort study was conducted in the Stomach Cancer Study Group of the Japan Clinical Oncology Group. Methods: Inclusion criteria were as follows; (1)gastric cancer with at least one of following distant metastasis at the initial diagnosis; (i) peritoneal metastasis (PER) diagnosed by imaging examination or P1b or P1c disease diagnosed by laparoscopy or laparotomy, (ii) multiple liver metastasis (HEP) more than three lesions, and (iii) distant lymph node metastasis (LYM) beyond paraaortic lymph node station 16a2/b1, (2) conversion to be resectable after systemic chemotherapy, (3) surgery aiming at an R0 resection of the primary and remaining lesions between April 2010 and September 2017. Clinical data were retrospectively obtained from electronic patient records of 58 institutions. Results: Atotal of 241 patients were included to the study. Initial unresectable factors were PER, HEP, and LYM in 132(55%), 37(15%), and 63(26%) patients, respectively, and 9(4%) patients had two or more factors. Conversion to be resectable obtained during the first and second/later line chemotherapy was in 209 (87%) patients and 32 (13%), respectively. 182(76%), 29(12%), and 30(12%) patients underwent R0, R1, and R2 resection, respectively. The incidence of postoperative complication of Clavien-Dindo Grade II or higher was 24% and no surgery-related death was observed. The median overall survival (mOS) from surgery was 45.4 (95%CI 30.9-61.4) months in R0 resection, 16.6 (11.5-18.5) months in R1, and 20.9 (11.3-35.6) months in R2. In case of R0 resection, the mOS from surgery was 34.4 (95%CI 26.5-59.2) months in PER, 55.9 (21.8-96.7) months in HEP, 54.6 (30.9-98.3) months in LYM, and not reached (19.7-NA) in two or more factors. Conclusions: Conversion surgery appears to be safe and a promising treatment strategy for patients who have initially unresectable advanced gastric cancer and presented remarkable response to systemic chemotherapy.
Effect of changes in body composition and sociodemographic factors on colon cancer survival.
296 Background: Muscle mass, muscle quality, and adipose tissue volumes have been shown to affect colon cancer survival. Further research is required to understand how change in body composition during treatment impacts colon cancer outcomes, and how covariables such mental health and socioeconomic status affect this relationship. The aim of this project was to examine how changes in body composition during chemotherapy for colon cancer impact the duration of disease-free survival (DFS) and how sociodemographic covariables (age, sex, social isolation, depression, anxiety, income, community size) influence this relationship. Methods: Computed tomography (CT) scans from the time of diagnosis and the end of chemotherapy were obtained from individuals treated for stage III colon cancer with oxaliplatin at BC Cancer between 2012 and 2016. Whole body tissue volumes were estimated based on CT images at the level of the third lumbar vertebra, analysed using DAFS Express (Voronoi Health Analytics Inc., Vancouver BC). Muscle quantity was measured as skeletal muscle index (SMI), and muscle quality was measured as skeletal muscle density (SMD) and skeletal muscle gauge (SMG). Quantity of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intermuscular adipose tissue (IMAT), and total adipose tissue (TAT) were also measured. Social isolation, anxiety, and depression symptoms were measured using the validated Psychosocial Screen for Cancer–Revised. Neighbourhood income and community population were estimated using postal codes. Cox proportional hazard models were calculated for the effect of body composition variables on DFS, and interactions with sociodemographic variables. Results: Significant reductions in SMI, SMD, SMG, VAT, IMAT and TAT were observed between diagnosis and post-chemotherapy (n=282). Improved survival was associated with higher SMD and lower IMAT at diagnosis and post-chemotherapy, lower VAT at diagnosis, and an increase in VAT or TAT during chemotherapy. Body composition had a more significant effect on survival in individuals who were older, female, or lived in smaller communities. Conclusions: Significant reductions in SMI, SMD, SMG, VAT, IMAT and TAT were observed between diagnosis and post-chemotherapy (n=282). Improved survival was associated with higher SMD and lower IMAT at diagnosis and post-chemotherapy, lower VAT at diagnosis, and an increase in VAT or TAT during chemotherapy. Body composition had a more significant effect on survival in individuals who were older, female, or lived in smaller communities.
Engineering Atom‐Scale Cascade Catalysis via Multi‐Active Site Collaboration for Ampere‐Level CO<sub>2</sub> Electroreduction to C<sub>2+</sub> Products
AbstractElectrochemical reduction of CO2 to value‐added multicarbon (C2+) productions offers an attractive route for renewable energy storage and CO2 utilization, but it remains challenging to achieve high C2+ selectivity at industrial‐level current density. Herein, a Mo1Cu single‐atom alloy (SAA) catalyst is reported that displays a remarkable C2+ Faradaic efficiency of 86.4% under 0.80 A cm−2. Furthermore, the C2+ partial current density over Mo1Cu reaches 1.33 A cm−2 with a Faradaic efficiency surpasses 74.3%. The combination of operando spectroscopy and density functional theory (DFT) indicates the as‐prepared Mo1Cu SAA catalyst enables atom‐scale cascade catalysis via multi‐active site collaboration. The introduced Mo sites promote the H2O dissociation to fabricate active *H, meanwhile, the Cu sites (Cu0) far from Mo atom are active sites for the CO2 activation toward CO. Further, CO and *H are captured by the adjacent Cu sites (Cu&+) near Mo atom, accelerating CO conversion and C─C coupling process. Our findings benefit the design of tandem electrocatalysts at atomic scale for transforming CO2 to multicarbon products under a high conversion rate.
Surufatinib combined with locoregional therapies and immune checkpoint inhibitor (ICI) for treating unresectable or metastatic intrahepatic cholangiocarcinoma.
593 Background: Advanced metastatic ICC, characterized by poor survival and limited therapeutic options, may benefit from the combined use of surufatinib—a selective tyrosine kinase inhibitor targeting VEGFR 1, 2, and 3, FGFR1, and CSF-1R—and ICIs, alongside locoregional treatments like TACE, DEB-TACE, and HAIC. Methods: Eligible pts who were 18 -75 years old with histologically confirmed unresectable or metastatic intrahepatic cholangiocarcinoma were enrolled. Pts received surufatinib (250mg, orally daily), ICI, and locoregional therapies until surgery, disease progression, death, intolerable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), overall survival (OS), conversion to surgical resection rate and safety. Results: By July 31, 2024, 20 pts were enrolled and 10 pts were evaluated. Median age was 56.4 years (range: 36-69), with a majority being male (70%). 9 pts were pathologically confirmed as adenocarcinoma, 1patient was small bile tract type. Treatment included DEB-TACE (20%), TACE (30%), and HAIC (50%). 50% (5/10) pts achieved partial response (PR), 20% (2/10) pts accepted conversion surgery, 30% (3/10) pts achieved stable disease (SD), and the confirmed ORR was 50%, DCR was 80%. The median PFS (95%Cl: 6.9-NA months) had not yet matured, with no significant differences in survival benefits based on age or gender, though TACE showed potential benefits. The most common AEs of all grades were nausea (30%), dizziness (30%), and headache (10%), No grade ≥ 3 TEAEs or new safety signals occurred. Conclusions: Surufatinib plus immune checkpoint inhibitor, along with locoregional therapies showed preliminary anti-tumor activity and manageable toxicity for the 1L treatment of ICC, providing an additional treatment option for pts with ICC. Clinical trial information: NCT05236699 .
Clinical outcomes and changes in body composition following endoscopic submucosal dissection versus total gastrectomy in patients with proximal early gastric cancer.
415 Background: Sarcopenia is associated with poor surgical outcomes and prognosis in patients with gastric cancer. However, the relationship between changes in skeletal muscle following endoscopic submucosal dissection (ESD) versus total gastrectomy (TG) in patients with proximal early gastric cancer (EGC) remains unclear. This study aimed to investigate the clinical outcomes and skeletal muscle mass changes between ESD and TG in patients with proximal EGC. Methods: We retrospectively reviewed 329 patients who underwent either ESD (n=127) or TG (n=202) for cT1N0M0 gastric cancer in the upper third of the stomach between 2015 and 2019 at a tertiary care center. The skeletal muscle index (SMI), visceral/subcutaneous fat, and abdominal circumference were measured preoperatively, and at 1 and 3 years after surgery, using cross-sectional computed tomography. We compared these parameters between the two groups and assessed both short- and long-term outcomes, as well as prognostic factors. Results: No significant differences were observed between the two groups with respect to overall survival (P=0.266), recurrence-free survival (P=0.079), or disease-specific survival (P=0.24). The recurrence rate was four (3.1%) in the ESD group and two (0.9%) in the TG group. Of the four recurrences in the ESD group, two were cured by gastrectomy, and two by ESD. Two recurrences in the TG group died of cancer progression. In the ESD group, all deaths were unrelated to gastric cancer, compared to 83.3% in the TG group (P=0.376). Patients in the ESD group showed more preserved SMI (P<0.001), visceral/subcutaneous fat (P<0.001), and abdominal circumference (P<0.001) at 1 and 3 years after surgery, compared to the TG group. The incidence of sarcopenia was significantly lower in the ESD group at postoperative years 1 (22.2% vs. 34.7%, P=0.02) and years 3 (25.7% vs. 40.6%, P=0.001). Sarcopenia had a significant impact on survival, with 5-year OS rates being lower in patients with preoperative sarcopenia (85.3% vs. 95.6%, P=0.005). Multivariate analysis revealed that the prognostic nutritional index was significantly associated with OS (hazard ratio, 0.86; 95% confidence interval: 0.75–0.99, P=0.03). Conclusions: Although OS was comparable between the ESD and TG groups, ESD was associated with better preservation of skeletal muscle and visceral/subcutaneous fat. These results suggest that ESD should be considered for patients with proximal EGC who are at high risk for sarcopenia.
Real-world microscopic residual disease (MRD) monitoring with circulating tumor DNA (ctDNA) in pancreatic adenocarcinoma (PDAC).
696 Background: ctDNA is a powerful tool that can detect MRD with limited but emerging data in patients (pts) with PDAC. We describe the clinical outcomes of pts with PDAC who underwent real-world MRD testing at our institutions. Methods: We retrospectively analyzed pts at 2 institutions with ≥1 tumor-informed ctDNA test (Natera, Inc) ordered for MRD testing post-operation (post-op) between June 2020-August 2024. Descriptive statistics were used to characterize clinicopathologic factors, ctDNA positivity (ctDNA+), and relapse rates (RR). Median relapse-free survival (mRFS) and overall survival (mOS) were calculated using Kaplan-Meier methods, comparisons between groups by log-rank test, and hazard ratios (HR) by Cox proportional hazard models. Associations between clinicopathologic factors and outcomes were assessed by Fisher’s exact and Chi-square tests. Results: Of the 54 pts who underwent MRD testing, 48 pts (88.9%) had successful tests. Failures were due to insufficient tissue. Patients with successful tests were staged as follows: 31.2% stage 1, 50.0% stage 2, and 18.8% stage 3, with 12.5% having R1/2 resections and 46.8% being node-positive. With a median follow-up of 21.0 months (mo), 22 (45.8%) pts had relapsed and 22 (45.8%) were anytime-ctDNA+. Sensitivity and specificity of ctDNA for relapse was 77.3% and 86.4%, respectively. Between anytime- and never-ctDNA+ pts, RR were 77.0% vs. 23.1%, mRFS 14.2 mo vs. not reached (NR) (HR 4.9, 95% CI 1.9-12.9), and mOS 31.7 mo vs. NR (HR 3.3, 95% CI 1.0-10.9), respectively. For 27 pts tested in the MRD window (2-12 weeks post-op), mRFS was 6.6 vs. 25.0 mo (HR 3.1, 95% CI 1.0-9.4) and mOS was 25.5 mo vs. NR (HR 2.5, 95% CI 0.6-10.2) in ctDNA+ vs. negative pts. ctDNA+ preceded radiographic relapse in 54.5% of patients with a median lead time of 166 days (IQR 70-332). In anytime-ctDNA+ pts, there were non-statistically significant trends for improved RFS and OS based on ctDNA decrease and clearance (table). No clinicopathologic factors predicted ctDNA+. Post-op ctDNA+ (p <0.001) and CA 19-9 (p=0.03) were the only factors that had a significant association with RFS. Conclusions: Post-op ctDNA is a strong prognostic marker for survival in PDAC, predicting relapse about five months before imaging. ctDNA+ status is independent of clinicopathologic factors and the strongest predictor of recurrence. These findings highlight a window where novel therapies could be tested to eradicate MRD. Longer follow up and prospective studies are needed to validate its predictive role with therapies in the MRD setting to improve outcomes in high-risk pts. RFS events/total mRFS (mo) HR (95% CI) p OS events/total mOS (mo) HR (95% CI) p ctDNA clearance Yes 6/9 17.0 0.61 (0.2-1.7) 0.35 2/9 NR 0.37 (0.08-1.8) 0.20 No 11/13 10.3 8/13 31.7 ctDNA MTM/mL reduction ≥50% 8/11 15.5 0.93 (0.3-2.9) 0.90 3/11 NR 0.54 (0.1-2.4) 0.42 <50% 6/8 13.6 4/8 31.7
A Phase‐Transition–Free Sodium Vanadium Phosphate Cathode via Medium‐Entropy Engineering for Superior Sodium Ion Batteries
Abstract Na 3 V 2 (PO 4 ) 3 , based on multi‐electron reactions between V 3+ /V 4+ /V 5+ , is a promising cathode material for SIBs. However, its practical application is hampered by the inferior conductivity, large barrier of V 4+ /V 5+ , and stepwise phase transition. Herein, these issues are addressed by constructing a medium‐entropy material (Na 3.2 V 1.1 Ti 0.2 Al 0.2 Cr 0.2 Mn 0.2 Ni 0.1 (PO 4 ) 3 , ME‐NVP) with strong ME─O bond and highly occupied Na2 sites. Benefiting from the medium‐entropy effect, ME‐NVP manifests a phase‐transition–free reaction mechanism, two reversible plateaus at 3.4 (V 3+ /V 4+ ) and 4.0 V (V 4+ /V 5+ ), and small volume change (2%) during Na + insertion/extraction processes, as confirmed by comprehensive in/ex situ characterizations. Moreover, kinetics analysis illuminates the superior Na + diffusion ability of ME‐NVP. Thus, the ME‐NVP cathode realizes remarkable rate capability of 67 mA h g −1 at 50C and a long‐term lifespan over 10 000 cycles (capacity retention of 81.3%). Theoretical calculations further illustrate that the weak binding of Na + ion in the channel is responsible for the rapid Na + diffusion, accounting for the superior reaction kinetics. Moreover, rigid MEO 6 octahedral and feasible rearrangement of Na + ions can suppress the phase transition, thus endowing an ultrastable ME‐NVP cathode. This work highlights the significant role of medium‐entropy engineering in advancing the output voltage, cycling stability, and rate capability of polyanionic cathodes.