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<i>TP53</i> Y220C mutations in colorectal carcinoma (CRC): A genomic landscape study.

239 Background: Inactivating genomic alteration (GA) of the TP53 tumor suppressor gene leads to inactivation of p53 protein and is currently the most frequently associated GA across all cancers. Colorectal cancer is a common and lethal subtype of cancer, in the top 5 for incidence, prevalence and cancer-related deaths worldwide. TP53 is the second most frequent GA identified in clinically advanced CRC. It has been postulated that GA in TP53 not only affects the molecular biology of malignant cells but also impacts the tumor microenvironment in CRC. This GA is currently untargetable by approved drugs however, recently a novel approach designed to revert to wild type functioning of TP53 inactivated by Y220C base substitution has gained significant clinical interest. Methods: 67,301 cases of clinically advanced CRC underwent hybrid capture based comprehensive genomic profiling to assess all classes of GA. Cases were sequenced to a mean coverage depth of 650X with microsatellite instability (MSI) status and tumor mutation burden (TMB) determined from the sequencing data and PD-L1 expression measured by immunohistochemistry using the DAKO tumor proportional staining system (low positive set at 1-49% staining and high positive set at ≥50% staining). Results: 422 (0.6%) of the CRC featured the TP53 Y220C GA (Y220C+). When compared with the CRC that were TP53 Y220C negative (Y220C-), the Y220C+ cases were of similar age, gender and number of GA per tumor. The Y220C- cases has significantly higher frequencies of MSI status (6.1% vs 2.2%; p=.0007) and TMB levels greater &gt;10 mutations/Mb (8.7% vs 4.7%; p=.004). The Y220C+ featured lower frequencies of GA in PIK3CA (12.9% vs 18.6%; p=.002), BRAF (8.8% vs 10.1%; NS) and PTEN (7.4% vs 8.3%, NS) and a higher frequency of ERBB2 amplification (5.0% vs 2.7%; p=.004). GA in APC , KRAS , NRAS , BRCA2 , EGFR and MET were similar in both Y220C+ and Y220C- CRC. PD-L1 low expression was similarly infrequent (12.1% to 16.7% range) in both groups. Conclusions: The potentially targetable TP53 Y220C short variant mutation is uncommon in clinically advanced CRC but is associated with unique genomic and biomarker characteristics. Further research might elucidate subpopulations or CRC subtypes with a greater frequency of this mutation who might benefit from a novel targeted therapy. CRC TP53 Y220C+(422 Cases) CRC TP53 Y220C-(66,879 Cases) P Value Gender 41.2% F/ 58.8% M 44.4% F/55.6% M NS Median Age (range) 62 (23-89+) 61 (8-89+) NS GA/tumor 6.1 6.5 NS TP53 non-Y220C GA 16.1% 75.7% &lt;.0001 PIK3CA 12.9% 18.6% .002 ERBB2 6.2% (5.0% amp) 5.1% (2.7% amp) .004 (amp) MSI High 2.2% 6.1% .0007 TMB &gt; 10 mut/Mb 4.7% 8.7% .004 PD-L1 Low (1-49%TPS)/ PD-L1 High (&gt;50% TPS) 16.7% (132 cases)/2.3% 12.1% (20,759 cases)/1.4% NS

Adjuvant capecitabine in resected biliary tract cancers: Real life data from a multicenter study (PRODIGE83-ACABi-PRONOBIL).

596 Background: Biliary tract cancers (BTCs) are rare and heterogeneous tumors with a poor survival even in early-stage patients treated with a curative surgery. Since 2019 the current standard of care in the adjuvant setting is oral chemotherapy (CT) with capecitabine for 6 months, as an option following BILCAP phase III trial results. Nevertheless, outside of this trial, real-world data are lacking. Methods: We conducted a French, retrospective, multicenter study from the ACABi-PRONOBIL cohort. Eligible patients had intrahepatic, perihilar, distal cholangiocarcinoma or gallbladder carcinoma treated by surgery with curative intent without prior therapy. Two groups were compared, patients who received capecitabine (Cape group) as adjuvant CT and patients without adjuvant treatment before 2017 (surveillance group). The primary endpoint was overall survival (OS). Secondary endpoints were disease-free survival (DFS) and toxicity. Results: 324 patients were included, 200 in the Cape group and 124 in the surveillance group. The median OS was 43.5 months (CI95%= 35.4-48.0) and 44.6 months (CI95% 37.7-54.8) in the Cape and surveillance group, respectively. ECOG performance status ≥ 2, pT3 stage, vascular and node invasion were associated with a poorer OS. The DFS was 15.8 months (CI95%= 14.1-20.3) in the Cape group and 13.3 months (CI95%= 10.1-17.5) in the surveillance group. In inverse probability of treatment weighting (IPTW) analysis we observed a significant statistical association between Cape group and DFS (IPTW HR (CI95%) Cape group vs surveillance group = 0.76 (0.60-0.96), pvalue=0.0224) but not with OS. In the Cape group, 49% of patients had at least one dose reduction, 35% had to discontinue treatment due to toxicity (mainly gastrointestinal,13.3% of grade 3-4; and cutaneous, 27% of grade 3-4). Conclusions: In this retrospective analysis, adjuvant capecitabine appears to increase DFS without statistically significant impact on OS in patients undergoing surgery for BTC, confirming in real life the BILCAP study results.

MSC-EVs and UCB-EVs promote skin wound healing and spatial transcriptome analysis

Prenylation-dependent membrane localization of a deubiquitinating enzyme and its role in regulating G protein–mediated signaling in yeast

Comparison of risk factors, treatment strategy, and outcomes of early- vs. older-onset colorectal cancer within the prospective ColoCare study.

95 Background: The incidence of colorectal cancer among young adults aged 20-49 has continually increased in recent decades. Early-onset colorectal cancer (EOCRC) patients are more likely to be diagnosed at a more advanced stage of disease, have hereditary cancer syndromes, and have different molecular pathological features of disease than later-onset patients. Herein we compare the risk factors, treatment approaches, and responses to treatment of early-onset versus later-onset colorectal cancer within. Methods: The ColoCare Study is a prospective cohort enrolling individuals diagnosed with primary colorectal cancer at six different cancer centers in the United States and one in Germany. Serial questionnaires assess demographic characteristics and symptoms experienced prior to diagnosis, while clinical characteristics (including staging, pathology, treatments given) are abstracted from medical records. Restricting to patients with available age and stage, patients diagnosed &lt;50 years old were labeled as “early-onset” and ≥50yo as “later-onset.” Associations between patient age and characteristics of interest were tested using Fisher’s Exact Test for count data. Results: Of the3,173 patients included in this analysis, 78% were later-onset (mean: 65 years) and 22% were early-onset (mean: 42 years). Demographic data was comparable between the two groups, with 43% being female. Though similar rates of ever alcohol use were seen between the two groups, early-onset patients reported consuming fewer weekly alcoholic beverages than later-onset patients (mean (standard deviation) of 5.5 (6.6) vs. 8.4 (9.3)). Early-onset patients were less likely to have ever smoked tobacco (38% vs 51%, p&lt;0.001) and had lower rates of obesity (27% vs 31%) or overweight (34% vs 40%) than later-onset patients (p&lt;0.001). For stage II/III disease, early-onset patients were more likely to have received chemotherapy and/or radiation treatment compared to later-onset patients (87% vs 70%, p&lt;0.001), though both groups had similar rates of surgery. Despite this, younger patients did not appear to experience better outcomes, with 21% of younger patients experiencing a recurrence or new metastasis during follow-up versus 20% of later-onset patients. Conclusions: The risingincidence of colorectal cancer in early-onset patients does not appear to be explained by traditional risk factors such as alcohol use, tobacco use, or high BMI. Early-onset patients are more likely to receive chemotherapy or radiation, but observed outcomes are notably poorer compared to later-onset patients. Further statistical analysis on specifics of treatments by stage is ongoing.

Landscape of novel gene fusions in gastrointestinal tumors.

268 Background: Gene fusions are recognized as critical drivers of cancer and targets for precision therapies. The 2022 ASCO provisional clinical opinion on tumor genomic testing includes recommendations for fusion testing and recognizes the strengths of RNA-based approaches. Targeted DNA/RNA sequencing panels can be used to detect well characterized, clinically actionable fusions, but their ability to detect rare novel fusions (i.e., those with uncharacterized fusion partners) can be limited by assay design. Whole-exome, whole-transcriptome sequencing (WES/WTS) may improve the identification of actionable gene fusions by detecting both known and novel fusions. This work describes clinically actionable novel fusions detected in gastrointestinal (GI) cancers. Methods: The study included samples from GI cancers that were analyzed using the OncoExTra test between May 2018 and May 2024. The assay uses tumor-normal WES/WTS to identify somatic alterations, including gene fusions with known and unknown partners and breakpoints.Clinical data were queried foractionable fusions with novel fusion partners that were unique in the entire laboratory database and have not, to our knowledge, been previously reported in the existing scientific literature or public databases. Actionable fusions were defined as those associated with FDA-approved targeted therapies or those that made patients eligible for a clinical trial. Results: Tumor samples from 2,776 patients with GI cancers were evaluated with a total of 75 actionable fusions identified in samples from 74 patients. Of these, 25.3% (n=19) were novel, and 74.7% (n=56) were previously described or recurrent fusions. Novel fusions were detected in small bowel (2 of 81), colorectal (4 of 1,621), gastric/gastroesophageal junction (GEJ) (2 of 259), pancreatic (7 of 466) and biliary (4 of 131) cancers. Thirteen (63.2%) of the novel fusions involved genes associated with FDA-approved therapies, including FGFR2 (n=6), BRAF (n=3), MET (n=2), FGFR1 (n=1) and NTRK2 (n=1). Of the fusions associated with FDA-approved therapies, 20% (8/40) of recurrent fusions and 38.5% (5/13) of novel fusions were detected only by RNA sequencing. No fusions were identified in appendiceal or esophageal cancers. Conclusions: Gene fusions with novel fusion partners represented one fourth of all actionable fusions detected in GI tumors. Use of a comprehensive WES/WTS testing approach that detects fusions agnostic of the fusion partner may affect clinical care in GI cancers by increasing the number of patients eligible for targeted therapies.

A protein-based blood panel test for the early detection of colorectal cancer and advanced neoplasia.

46 Background: Early detection of colorectal cancer (CRC) is key to survival. CRC screening compliance is still low because of either the invasive procedure (colonoscopy) or the so-called "ick factor" (stool-based tests). Stool-based tests also lack ability to detect advanced adenoma (CRC precursor). A blood-based test could improve adherence to screening guidelines, but no one has so far been recommended due to a lack of sufficient sensitivity and specificity. Here we report the potential clinical utility of a blood-based biomarker panel providing high sensitivity (SE) and specificity (SP) for CRC and advanced adenomas (AA) as a screening triage option addressing positive patients to colonoscopy. Methods: A total of 241 retrospective serum samples (179 CRC, 22 adenoma, 40 healthy controls) were obtained from the Cooperative Human Tissue Network (CHTN) biobank and tested with a proprietary sandwich ELISA that detects dual CRC specific biomarkers (BF7 and CC3). A standard curve was generated and biomarkers concentration in the samples were calculated using a 4-parameter logistic method. The median biomarker concentration values in each patient group were compared to determine whether differences were statistically significant (p&lt; 0.05). Statistical analysis of two-group and multi-group comparisons was carried out using the non-parametric Mann-Whitney U test and the Kruskal-Wallis test, respectively. Receiver operating characteristic (ROC) curves were calculated to evaluate the diagnostic performance, by determining sensitivity (SE), specificity (SP), area under the curve (AUC), and confidence interval (CI). Statistical analysis, ROC curves and scatter plots were performed with GraphPad Prism 7.0. Results: Both biomarker's median concentration difference between CRC versus healthy samples groups were found to be statistically significant (p&lt;0.05). Both biomarkers were also elevated in AA as compared to healthy samples, but difference in median concentration was only statistically significant for CC3 (p&lt;0.0001). BF7 serum levels in cancer patients were significantly associated with TMN stage (p=0.019), N stage (p=0.039) and M stage (p=0.0006). No significant associations were found between this biomarker levels and other clinical characteristics of the CRC patients including age. Our test discriminated CRC (all stages) from healthy individuals with a SE of 80% and a SP of 90%. Sensitivity for early (n=95) and late-stage CRC (n=80) was 79% and 84%, respectively. Our test was also able to detect 81% of serum from advanced adenoma patients who are at increased risk of CRC. Conclusions: This study illustrates the potential clinical utility of our blood-based assay for the early detection of CRC which has a better sensitivity for advanced adenoma than tests in current clinical use. A large prospective cohort study is planned to further validate the clinical performance of this test.

Effect of ketorolac on serum GDF-15 and IL-8 in patients with pancreatic cancer with cachexia.

713 Background: Cancer cachexia deteriorates the quality of life, chemotherapy tolerance and survivability of pancreatic cancer (PC) patients. Although a prevalent condition affecting PC patients, there are no approved therapies for cachexia and its mechanism of action is poorly understood. Elevated growth differentiation factor 15 (GDF-15), a stress-induced cytokine, has been associated with the pathogenesis of cachexia. Similarly, prior studies have displayed positive correlations between the proinflammatory factor interleukin-8 (IL-8) and PC cachexia. This abstract focuses on the exploratory endpoints (serum GDF-15 and IL-8 levels) of a feasibility trial on ketorolac as a treatment for PC cachexia. Methods: Patients took ketorolac 10 mg PO QID for 5 consecutive days, with weights measured on Day 1 (D1) and Day 6 (D6). Serum cytokines were drawn on D1 and D6. IL-8 was measured using a HDF15 assay (Eve Technologies). GDF-15 was measured using a human R-plex GDF-15 assay. Activity (e.g., number of steps) was measured via Fitbit. Differences in weight, activity, GDF-15, and IL-8 were analyzed using two-sample paired t-tests. Results: Twenty-nine patients were enrolled, of which 19 were evaluable. Median age was 70, 47.4% (9/19) were female, and 94.7% (18/19) were adherent with ketorolac. Statistically significant increases in both weight per baseline BMI and activity were observed from D1 to D6 (0.0716±0.1079 kg/BMI, p=0.012; 1423±2477 steps, p=0.0221). Of the 19 evaluable patients, 16 patients provided complete D1 and D6 pairs of serum cytokines. From D1 to D6, the mean GDF-15 level decreased by 277.5 pg/mL (p=0.529) and mean IL-8 decreased by 65.13 pg/mL (p=0.103). In all patients who gained weight (n=14), a trend toward reduced IL-8 from D1 to D6 was observed (79.57±39.57 pg/mL, p=0.065). Similarly, for patients who gained ≥ 1-kg from D1 to D6 (n=10), a trend toward reduced GDF-15 was observed (951.2±482.3 pg/mL, p=0.080). Patients with increased activity from D1 to D6 (n=12) had mean reductions of 157.7 pg/mL (p=0.643) and 70.17 pg/mL (p=0.179) in GDF-15 and IL-8, respectively. Conclusions: Given the growing literature suggesting associations between inflammatory cytokines and cancer cachexia, it is critical to investigate treatments that may possibly alter cytokine levels. Although our findings suggest that ketorolac aids in weight gain and increased activity, larger sample sizes are needed to determine whether these differences are related to reductions of specific serum cytokines. However, given reductions that trended towards significance for both GDF-15 and IL-8 serum levels within subsets of patients that gained weight on ketorolac, further studies investigating these cytokines are warranted to hopefully provide insight on the mechanistic action of ketorolac in cachexia. Clinical trial information: NCT05336266 .

A hybrid Prairie INFO fission naked algorithm with stagnation mechanism for the parametric estimation of solar photovoltaic systems

Abstract This paper presents a study to enhance the performance of a recently introduced naked mole-rat algorithm (NMRA), by local optima avoidance, and better exploration as well as exploitation properties. A new set of algorithms, namely Prairie dog optimization algorithm, INFO, and Fission fusion optimization algorithm (FuFiO) are included in the fundamental framework of NMRA to enhance the exploration operation. The proposed algorithm is a hybrid algorithm based on four algorithms: Prairie Dog, INFO, Fission Fusion and Naked mole-rat (PIFN) algorithm. Five new mutation operators/inertia weights are exploited to make the algorithm self-adaptive in nature. Apart from that, a new stagnation phase is added for local optima avoidance. The proposed algorithm is tested for variable population, dimension size, and efficient set of parameters is analysed to make the algorithm self-adaptive in nature. Friedman as well as Wilcoxon rank-sum tests are performed to determine the effectiveness of the PIFN algorithm. On the basis of a comparison of outcomes, the PIFN algorithm is more effective and robust than the other optimization techniques evaluated by prior researchers to address standard benchmark functions (classical benchmarks, CEC 2017, and CEC-2019) and complex engineering design challenges. Furthermore, the effectiveness as well as reliability of the PIFN algorithm is demonstrated by testing using various PV modules, namely the RTC France Solar Cell (SDM, and DDM), Photowatt-PWP201, STM6- 40/36, and STP6-120/36 module. The results obtained from the PIFN algorithm are compared with various MH algorithms reported in the existing literature. The PIFN algorithm achieved the lowest root-mean-square error value, for RTC France Solar Cell (SDM) is 7.72E−04, RTC France Solar Cell (DDM) is 7.59E−04, STP6-120/36 module is 1.44E−02, STM6-40/36 module is 1.723E−03, and Photowatt-PWP201 module is 2.06E−03, respectively. In order to enhance the accuracy of the obtained results of parameter estimation of solar photovoltaic systems, we integrated the Newton-Raphson approach with the PIFN algorithm. Experimental and statistical results further prove the significance of the PIFN algorithm with respect to other algorithms.

Redox potential tuning by calcium ions in a novel c-type cytochrome from an anammox organism

Neoadjuvant immunotherapy for locally advanced/metastatic mismatch repair deficient colorectal cancer: A two-year institutional experience.

179 Background: MMRd is a tumour agnostic biomarker predictive of response to immune checkpoint inhibitors (ICIs). Given the poor response to 5-FU based chemotherapy, ICIs are now being explored in early MSI-H CRC. The outcomes on this strategy are limited. Methods: We retrospectively evaluated early outcomes for patients receiving neoadjuvant ICIs for unresectable locally advanced/oligometastatic MMRd colorectal cancer (CRC), where intention of treatment was downstaging to permit curative resection. Following discussion at regional MDT, suitable patients were administered a PD-1 inhibitor 6-weekly until disease progression or improvement rendering suitability for surgical resection (to max of 2 years). Results: From October 2022-September 2024, ten patients with MMRd CRC were commenced on neoadjuvant ICIs. These comprised six right, one left sided colonic and three rectal tumours. Median age at diagnosis was 59 (IQR54–68). Four patients had family history of CRC. One patient had clinical stage II, seven stage III and two patients oligometastatic stage IV disease. All were patients with initially unresectable disease, with potential for curative resection pending response to ICI. Histologically, two tumours were poorly differentiated, two mucinous phenotype and six moderately differentiated adenocarcinomas. BRAF mutation was identified in three patients. None had KRAS mutation. Three rectal cancers received radiotherapy in addition to immunotherapy. Five required a defunctioning stoma either prior to or on ICI. Median follow-up was 12.5 months (IQR7-17). Objective response rate by RECIST 1.1 was 100%, with significant downstaging in 9 of 10 patients. The remaining patient is early in treatment course with no reimaging. To date, complete clinical response (cCR) has been observed in three patients (33%). All 10 patients are alive. Grade 3-4 treatment-related adverse events occurred in two patients (20%) who developed treatment-related strictures (one also had tumour perforation). This was successfully managed with defunctioning ileostomy and antibiotics, with subsequent cCR. Conclusions: We report impressive early outcomes of immunotherapy for locally advanced/metastatic MMRd CRC, with excellent downstaging and high predicted cCR. This highlights the importance of screening all CRC for MSI-H/MMRd. In the setting of initially unresectable CRC, an ICI-first approach can render patients eligible for surgery, however deep responses can result in local effects including strictures and/or perforation.

Randomized study to assess colonic microbiome changes in response to energy drink consumption (ROSANNA Trial).

TPS325 Background: Colorectal cancer (CRC), the second leading cause of cancer deaths in the US, is increasingly diagnosed in individuals under 50. This rise in early-onset CRC (eoCRC) led the U.S. Preventative Services Task Force to recommend a reduction in the age to begin colorectal cancer screening in average-risk persons, from 50 to 45. The etiology of eoCRC is multifaceted, with one postulated theory pointing to alterations in the young adult colonic microbiome. Hydrogen sulfide (H 2 S) producing bacteria, like Bilophila wadsworthia , Fusobacterium nucleatum and Atopobium parvulum , are typically minor gut microbiota components but are overrepresented in CRC cases, linked to inflammation, and may promote a pro-carcinogenic environment. These bacteria preferentially use taurine, an essential amino acid, as a primary energy source. Energy drinks represent one of the largest dietary sources (6-16x normal daily intake) of taurine in contemporary diets. Our hypothesis is that high taurine levels in energy drinks could exacerbate CRC risk by promoting preferential growth and metabolic activities of already present H 2 S-producing bacteria, contributing to the rise of eoCRC. Methods: This randomized open-label trial is actively enrolling up to 60 young adults (18-40 years) without personal or family history of CRC, other major GI disease/distress, and baseline infrequent energy drink consumption. Group 1 (Arm A; n=30), will consist of subjects consuming at least one of two protocol-specified energy drinks daily for 4 weeks. Group 2 (Arm B; n=30), will consist of usual dietary intake. Enrollments are randomized 1:1 and stratified, by gender, age (18-25 vs. 26-40), and baseline energy drink consumption (rare/none vs. 1-2 per week). Every subject will complete: 1) a daily dietary and fitness log, 2) a weekly wellness log, 3) collection of stool/saliva/skin/urine at 3 sequential time points (baseline, after 2 weeks, after 4 weeks), and 4) blood collection at the same time points. The primary endpoint is the change in H 2 S-metabolizing bacterial communities between baseline and 1 month of energy drink exposure within Arm A and also compared to those in Arm B using microbiome analysis (diversity, taxonomy, sulfur-enriched gene pathways). Several secondary and exploratory assessments include changes related to subject demographic and dietary differences, concordance of microbiome changes with dietary logs and in other biospecimens beyond stool, H 2 S-production measurements, and analyses of subject metabolic and immune function. Trial opened in February 2024 with active enrollment ongoing. Updated data on trial status and any amendment modifications will be presented at the meeting. Clinical trial information: NCT06137248 .

The Oncopig hepatocellular carcinoma model: An innovative large animal platform for evaluating treatment effects.

619 Background: Hepatocellular carcinoma (HCC) is an aggressive disease associated with poor prognosis and limited treatment options. Systemic therapies for advanced HCC include sorafenib, lenvatinib, and atezolizumab plus bevacizumab. However, given the limited efficacy of systemic treatment options, novel treatment approaches including combination of systemic and locoregional therapies (LRTs) is required to improve patient outcomes. These approaches require advanced large animal models to prove effectiveness. Pigs represent an ideal platform that provide both regulatory acceptable and clinically relevant large animal cancer models due to their similar physiology, size, genetics, immunity, and metabolism in relation to humans. The Oncopig HCC model is an ideal tool for testing LRT and other oncolytic based treatments. Methods: The Oncopig cancer model develops tumors following induced expression of KRAS G12D and TP53 R167H driver mutations utilizing an adenoviral vector encoding Cre recombinase (AdCre). Oncopig HCC cell lines were developed by isolating hepatocytes from Oncopig liver biopsies and transformed in vitro via exposure to AdCre. Transgene expression and hepatocyte cell origin were validated by RT-PCR and arginase-1 staining, respectively. Comparison of in vitro Oncopig, human, and murine HCC cell line phenotypes (proliferation, migration, and chemotherapeutic response) was performed. Oncopig HCC tumor formation was performed via autologous intrahepatic injection of Oncopig HCC cells. Tumor formation was evaluated using ultrasound and CT imaging. Results: Oncopig and human HCC cell lines displayed similar cell cycle lengths and migration rates. Oncopig HCC cells were consistently more predictive of human HCC responses than murine cells when treated with standard chemotherapeutic agents (doxorubicin, cisplatin, mitomycin C, and sorafenib). Importantly, consistent with human HCC, Oncopig HCC cells were non-responsive to 5-fluorouracil, while murine HCC cells were responsive. Intrahepatic injection of Oncopig HCC cells resulted in tumors visible on ultrasound and CT scan within 2-4 weeks. Resulting tumors were consistent with human tumors on imaging. Histological analysis of tumor biopsies confirmed the identity of the resulting masses as HCC tumors based on positive arginase-1 and KRAS G12D staining. Conclusions: The Oncopig HCC model may be more predictive of human HCC chemotherapeutic responses than currently employed murine models. Tumors develop rapidly (within 2-4 weeks) and are readily identified on ultrasound and CT imaging, making this an ideal model for evaluation of novel therapeutic approaches. Further exploration and development of additional tumor models including further translational characterization will be important for broader utility.

Updated trends in incidence and mortality of pancreatic cancer. an analysis of the Surveillance, Epidemiology, and End Results (SEER) database.

786 Background: Pancreatic cancer is the fourth leading cause of cancer deaths in the United States. The prognosis for pancreatic cancer remains poor despite advances in cancer therapy. In this study, we provide updated trends in pancreatic cancer incidence and mortality using the SEER database, with a subset analysis of age and gender. Methods: Using the SEER Stat software, we gathered data from the Surveillance, Epidemiology, and End Results (SEER) database (2000–2021). We employed Jointpoint regression to analyze the secular trend of incidence and incidence-based mortality (IBM), which we classified and arranged according to age and sex. Results: 235,116 cases met the inclusion criteria for our study. These included diagnosed cases of pancreatic cancer from 2000 to 2001. The total age-adjusted incidence rate was 12.5 per 100,000. 118,791 (50.5%) were males and 116,325 (49.5%) were female. While the annual percentage change (APC) from 2000-2019 was 0.92 (p &lt; 0.05), signifying an annual cumulative increase, APC from 2019-2021 was -0.085, signifying an annual cumulative decrease. For males, the APC was 0.94 (p &lt; 0.05) from 2000 to 2018 and -0.55 from 2018-2021, and for females, the APC was -0.89 (p &lt; 0.05) from 2019-2021. The pancreatic cancer IBM APC from 2000-2022 was 22.60 (p &lt; 0.05) and 0.54 (p &lt; 0.05) from 2002-2021. For males, IBM APC was 21.10 (p &lt; 0.05) from 2000-2002 and 0.58 from 2002-2021. For females, IBM APC was 25.15 from 2000-2002 and 0.42 from 2002-2021. We also studied pancreatic cancer IBM based on age. For 30-49 years, APC from 2000-2002 was 34.65 (p &lt; 0.05), and -0.64 (p &lt; 0.05) from 2002-2021. For 50-69 years, APC from 2000-2002 was 28.05 (p &lt; 0.05) and 0.3 from 2002-2021. For 70+ years, APC from 2000-2002 was 21.28 (p &lt; 0.05) and 0.73 from 2002-2021. Conclusions: There was a statistically significant rise in incidence and incidence-based mortality across the board, underscoring the need for improved diagnostic and therapeutic modalities of management of pancreatic cancer.

Multi-branch convolutional neural network with cross-attention mechanism for emotion recognition

Between scents and sterols: Cyclization of labdane-related diterpenes as model systems for enzymatic control of carbocation cascades

Exploring Nectin-4 expression in hepatocellular carcinoma.

632 Background: Nectin cell adhesion protein 4 (Nectin-4) is overexpressed in various malignancies, contributing to cancer progression and poor prognosis. We aimed to assess Nectin-4 expression in hepatocellular carcinoma (HCC). Methods: Patients who underwent primary liver tumor resection for HCC upon initial diagnosis at National Taiwan University Hospital in 2019 were included. Exclusion criteria consisted of prior systemic or loco-regional therapy, or death within three months post-surgery. Immunohistochemical (IHC) staining for Nectin-4 (EPR15613-68, Abcam) was conducted and independently reviewed by two pathologists. Nectin-4 expression patterns (membranous, cytoplasmic, and nuclear) and intensity were scored on a 0–3 scale, with normal eccrine glands (2+) serving as a positive control. Nectin-4 expression was further assessed in primary and paired progressive or metastatic tissue samples from patients with available paired samples. Results: Of the 193 patients, 175 had specimens available for IHC analysis. Nectin-4 expression was detected in 22.9% of these patients, with intensity scores of 0 in 77.1%, 1 in 22.3%, and 2 in 0.6%. The majority of staining pattern was cytoplasmic (94.3%), with membranous staining observed in 5.1% of cases. Nectin-4 expression was significantly associated with higher pathological grades ( p = 0.005) but showed no correlation with recurrence-free survival ( p = 0.771) or overall survival ( p = 0.396) after surgery. Importantly, Nectin-4 expression intensity significantly increased in paired progressive or metastatic samples compared to initial HCC specimens ( p = 0.046; n = 27). Conclusions: Nectin-4 expression is associated with higher pathological grades but not related to clinical outcomes in HCC. Increased Nectin-4 expression in progressive or metastatic disease highlights its potential as a therapeutic target.

Real-world survival comparison of second-line treatment strategies for patients with RAS/RAF wild-type, right-sided metastatic colorectal cancer.

73 Background: For patients with RAS/RAF wild type metastatic colorectal cancer (mCRC), systemic therapy usually includes fluoropyrimidine-based chemo + anti-VEGF or anti-EGFR targeted therapy. The PARADIGM trial established tumor sidedness as an important predictive biomarker for patients with RAS/RAF wild-type disease; in right-sided tumors, there was no survival difference between first-line chemo + anti-EGFR vs. chemo + anti-VEGF. However, there is no comparative data to guide second-line treatment decisions in this population. We aim to compare the effectiveness of second-line chemo + anti-EGFR versus chemo + anti-VEGF therapy for patients with RAS/RAF wild-type, right-sided mCRC who received first-line chemo + anti-VEGF. Methods: We used the nationwide Flatiron Health electronic health record-derived database, comprising de-identified patient-level structured and unstructured data obtained from ~280 cancer clinics and curated via technology-enabled abstraction. Patients ≥18 years old with RAS/RAF wild-type, right-sided mCRC who received first-line therapy consisting of chemotherapy ((FOLFIRI or FOLFOX or CAPEOX) + anti-VEGF and initiated second-line chemotherapy with either anti-EGFR or anti-VEGF targeted therapy between January 2013-May 2024 were included. Multiple imputation with chained equations imputed missing values for sidedness, RAS/RAF status, and propensity score covariates (age, gender, year of diagnosis, synchronous/metachronous disease, MMR/MSI status, ECOG score, CEA level, and first-line therapy duration). Cox proportional hazards modeling with stabilized inverse probability of treatment weighting (IPTW) assessed the association of anti-EGFR vs anti-VEGF treatment with overall survival. Results: 4,444 patients received appropriate first-line treatment and received chemo + anti-EGFR or chemo + anti-VEGF in the second line. Across 25 imputations, an average of 444 patients met inclusion criteria: 175 patients received chemo + anti-EGFR and 269 patients received chemo + anti-VEGF. Following IPTW, baseline characteristics were balanced between treatment groups. Patients who received chemotherapy + anti-EGFR had a 24% increased hazard of death when compared with patients who received chemotherapy + anti-VEGF, though this was not statistically significant (HR 1.24, 95% CI 0.96 – 1.61, p=0.097). Conclusions: Among patients with RAS/RAF wild-type, right-sided mCRC who received first-line chemotherapy + anti-VEGF, there is some evidence to support continuing anti-VEGF therapy vs. switching to anti-EGFR therapy in the second line, though the result was not statistically significant. Future studies should explore predictive biomarkers for EGFR vs VEGF-directed treatment for this population to determine the patients most likely to benefit from anti-EGFR therapy during their disease course.

Single agent olaparib in advanced oesophago-gastric cancer: Primary results from the SOlar clinical phase II single arm trial.

427 Background: A subset of pts with advanced oesophago-gastric adenocarcinoma (OGA) are characterised by deficient DNA damage repair (DDR) providing a rationale for PARP inhibition (PARPi) in these tumours. Potential activity was observed in the phase 3 gastric cancer trial with Olaparib + paclitaxel, however the efficacy of Olaparib monotherapy and response biomarkers have not been established. Herein we report the primary clinical results from the SOlar trial. Methods: SOlar is a prospective, open label, single arm phase II trial using a Simon’s two stage optimal design, evaluating the efficacy and safety of Olaparib 300mg twice daily in pts with locally advanced/metastatic OGA who had previously progressed on ≥1 line of therapy in the advanced setting. Pts with measurable disease by RECIST v1.1 amenable to mandatory baseline biopsy were included. The primary end point was disease control rate (DCR) at 8 weeks from Olaparib initiation by RECIST v1.1. In this two-stage optimal design, if ≥5/27 pts had disease control in stage 1, a further 27 pts were to be recruited in stage 2. If ≥12/54 evaluable pts achieved disease control, Olaparib would warrant further investigation. Other key endpoints include; overall response rate, progression free survival and overall survival, and translational biomarker analyses (NCT03829345). Results: Between July 2019 - February 2024, 55 pts with locally advanced/metastatic OGA were enrolled. 51 pts received Olaparib and 50 were evaluable for the primary endpoint (5 withdrew). The median age was 61yrs (range: 54-67), 7 (14%) were HER2 -positive and 2 had a known germline BRCA mutation. 19 (38%) pts had received ≥3 lines of therapy and 22 (44%) pts had received prior immunotherapy for OGA. 30 (60%) pts had objective responses to prior platinum chemotherapy (CR + PR). The DCR at 8-weeks was 28% (91% one-sided confidence interval lower bound: 19.4) with 14/50 evaluable pts having stable disease. No objective response was observed. 36/51 (71%) treated pts experienced a treatment-related adverse event (TRAE) of any grade, and 9 (18%) experienced a grade ≥3 TRAE (most common being anaemia, fatigue, vomiting). Two serious adverse events were reported as treatment-related: definitely related grade 1 pneumonitis, and possibly related grade 4 lung infection. Conclusions: In SOlar, Olaparib met its primary endpoint with 28% DCR in this heavily pre-treated group. No new safety concerns were observed. Ongoing translational analyses include; homologous repair deficiency scoring, whole exome sequencing, RNA expression, serial ctDNA, and multiplex immunofluorescent assessment of the tumour micro-environment, with a view to identify a subgroup who might benefit from PARPi to support ongoing PARPi combinatorial studies in advanced OGA. Clinical trial information: NCT03829345 .

Comparison of efficacy and safety of PD-1 and PD-L1 antibodies in combination with hepatic arterial infusion chemotherapy and target therapy for unresectable intrahepatic cholangiocarcinoma: A multicenter retrospective study.

553 Background: Immune checkpoint inhibitors (ICIs) in combination with hepatic arterial infusion chemotherapy (HAIC) and target therapy have shown promising antitumor activity in unresectable intrahepatic cholangiocarcinoma (iCCA). The present study aimed to compare the efficacy and safety of programmed cell death protein 1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors in this setting. Methods: In this multicenter retrospective study, we included patients with iCCA who received ICIs + HAIC + target therapy from June 2018 to June 2023. Propensity score matching (PSM) was performed to reduce confounding factors. Patients were divided into two groups: those treated with PD-L1 antibody + HAIC + target therapy (Group A) and those treated with PD-1 antibody + HAIC + target therapy (Group B). Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were compared between the two groups. Adverse events were assessed according to CTCAE v5.0. Results: A total of 336 patients met the inclusion criteria and were enrolled for analysis. There were no significant differences in OS, PFS, or ORR between the two groups (median OS: 17.7 vs. 25.3 months, P=0.139; median PFS: 8.3 vs. 10.0 months, P=0.534; ORR: 48.4% vs. 31.1%, P=0.051). Following PSM (ratio = 3, caliper = 0.2), 30 patients in Group A and 83 patients in Group B were included. The ORR, according to the modified RECIST criteria, was significantly higher in Group A compared to Group B (50% vs. 28.9%, P=0.037). However, no significant difference in PFS (median 10.0 vs. 9.0 months, P=0.29) or OS (median 17.6 vs. 22.8 months, P=0.293) was observed between the two groups. Adverse events (AEs) occurred in all 113 patients (100%), wherein grade 3–4 AEs were reported for 12 (10.6%) patients in group A and 45 (39.8%) in group B. There was a tendency for Group A to have a lower incidence of grade 3–4 AEs compared to Group B (40.0% vs. 54.2%, P=0.182),although this difference was not statistically significant. Conclusions: This study found that in the treatment combining ICIs with HAIC and target therapy for unresectable iCCA, Group A demonstrated a superior tumor response and a more favorable safety profile.