Browse Articles

Clinical and genomic characteristics of hepatocellular carcinoma-cholangiocarcinoma: Insights from real-world data.

556 Background: Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) is a rare and complex liver cancer with features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), making its management challenging. This study aims to analyze the clinical characteristics, genomic profiles, and treatment outcomes of cHCC-CCA patients in a real-world setting. Methods: We conducted a retrospective analysis of cHCC-CCA patients across three first-line treatment groups: chemotherapy alone(Gemcitabine/Cisplatin, FOLFOX), HCC-directed therapies (atezolizumab/bevacizumab, lenvatinib, nivolumab, durvalumab, sorafenib), and chemoimmunotherapy (Gemcitabine/Cisplatin combined with immunotherapy). This international study, involving Mayo Clinic and the National Cancer Center East (Japan), assessed overall survival (OS) using Kaplan-Meier and Cox regression models. Results: A total of 68 patients were included, with a mean age of 66 years; 74% were male and 66% were White Non-Hispanics. Cirrhosis was present in 74% of patients at diagnosis, and Hepatitis B and C were common etiologies in 57%. Prior primary resection and regional therapies (Transarterial chemoembolization (TACE), Transarterial radioembolization (TARE)) were recorded in 39% and 50% of patients, respectively. Advanced/metastatic disease was present in 52% of the cohort. The distribution of first-line treatments was as follows: 47% received chemotherapy alone, 39% received HCC-directed therapy, and 14% received chemoimmunotherapy. Genomic alterations were detected in 44% patients, with TP53 (28%), ARID1A (25%), and TERT (22%) being the most frequent. The HCC-directed therapy group demonstrated the best overall response rate (52%) and had a median OS of 15.8 months (mo), compared to 11.8 mo for chemotherapy and 4.7 mo for chemoimmunotherapy (p=0.8). Patients who received regional treatments had a longer median OS of 15.8 mo compared to those who did not (10.2 mo) (p=0.4). Conclusions: HCC-directed therapy showed a trend towards better survival outcomes compared to other treatments, though not statistically significant. A considerable proportion of patients had genomic alterations, which may have influenced survival outcomes. Ongoing research with larger cohorts is underway to further elucidate the impact of genomic variations on treatment efficacy and refine therapeutic strategies for this challenging malignancy. Baseline characteristics of patients with combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA). Total(N=68) Mean age at diagnosis, years (SD) 66(6.4) Gender, n (%) Male 50 (74%) Ethnicity, n (%) White, Non-Hispanic 45 (66%) Cirrhosis at diagnosis, n (%) 50 (74%) Etiology of Liver disease, n (%) Viral (Hepatitis B and C) 39 (57%) History of Primary resection, n (%) 27 (39%) Regional treatment, n (%) 34 (50%) Afp, n (%) < 200 23 (64%) ca19_9, n (%) < 50 27 (82%)

Prognostic implications and therapeutic response in GNAS-mutated colorectal adenocarcinoma: A retrospective cohort analysis.

244 Background: GNAS, a key regulator of the G-protein signaling pathway, is frequently mutated in colorectal adenocarcinomas and other malignancies. Despite its role in tumorigenesis, GNAS mutations remain understudied, with no established targeted therapies. Exploring the impact of GNAS alterations on therapeutic response and outcomes in colorectal cancer (CRC) is crucial for developing effective treatment strategies. Methods: We reviewed 531 CRC cases from our institutional Molecular Tumor Board database, identifying 8 patients with GNAS mutations. The prevalence ofGNASmutations in our cohort was 1.5%, which aligns with reported rates of 2-5% in various CRC cohorts. Comprehensive clinicopathologic data, including tumor histology, staging, treatment outcomes, and response rates, were analyzed. A detailed evaluation was conducted on stage IV patients to assess their response, progression-free survival (PFS), and overall survival (OS) in comparison to historical stage IV CRC benchmarks. Results: The cohort included 8 patients with a median age of 61 years (range: 33-73 years), with balanced gender representation (50% male, 50% female). The racial distribution was 50% Black or African American, 25% White, and 12.5% Asian or Pacific Islander. The majority of patients (62.5%) were diagnosed at stage IV, with primary tumor sites predominantly in the sigmoid colon and cecum. Among the 5 stage IV patients, while no patients achieved a complete or partial response, 3 exhibited stable disease, resulting in a 60% disease control rate (including stable disease). The median progression-free survival (mPFS) was 9 months, reflecting the duration of disease control before progression, while the median overall survival (mOS) was 15 months. These outcomes are notably lower than historical benchmarks for stage IV CRC, where response rates typically range from 40-50% with mOS of 20-24 months, highlighting the potentially adverse prognostic impact of GNAS mutations. Conclusions: Patients with GNAS-mutated colorectal adenocarcinoma appear to represent a unique subset with poorer therapeutic outcomes, even when achieving stable disease. The observed disease control in the absence of objective responses underscores the complexity of treating GNAS-mutated tumors and highlights the urgent need for targeted therapies tailored to this molecular subtype. Further research into the biological mechanisms underlying GNAS mutations and their impact on CRC treatment resistance is warranted to improve patient outcomes.

Correlation between PD-L1 CPS and clinical outcomes in patients treated with first-line nivolumab plus chemotherapy for advanced gastric or gastroesophageal junction cancer: A multi-center retrospective study in Japan.

364 Background: The CheckMate 649 trial showed the superiority of first-line nivolumab plus chemotherapy (Nivo-CT) compared with chemotherapy alone for advanced gastric and gastroesophageal junction (GEJ) cancer with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) >5, while survival benefit was poor in PD-L1 CPS <1 and <5. However, there were few studies on correlation between PD-L1 CPS and efficacy of first-line Nivo-CT for advanced gastric or GEJ cancer in real world data. Methods: This multi-center retrospective study included patients with histologically confirmed advanced gastric or GEJ cancer who were started on first-line Nivo-CT between December 2021 and December 2023. PD-L1 CPS was assessed before the start of Nivo-CT by classified into three groups at each center: <1, 1~5 and >5, using the Dako PD-L1 immunohistochemistry 28-8 pharmDx assay. The efficacy was evaluated by overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Results: A total of 271 patients were included (median age, 70 [range 18–85] years; male/female, 64/36%; performance status (PS) 0/1/2, 47/49/4%; primary tumor site gastric/GEJ, 90/10%; status unresectable/recurrent, 81/19%; histology intestinal/diffuse, 30/70%). PD-L1 CPS status were evaluated 234 (86%) patients and PD-L1 CPS <1, 1~5 and >5 was found in 35 (15%), 76 (33%) and 123 (53%) patients, respectively. Median follow-up time was 11.3 (range 1-30) months. The median PFS was 9.7 (95%CI, 5.9-16.3), 8.8 (95%CI, 7.2-13.0) and 6.3 (95%CI, 5.3-9.0) months in the patient with PD-L1 CPS <1, 1~5 and >5, respectively. The median OS was 18.7 (95%CI, 17.4-NA), 23.4 (95%CI, 17.7-NA) and 18.3 (95%CI, 13.3-22.5) months, and the ORR were 30.8, 66.7 and 61.3% (p = 0.075) in the patient with PD-L1 CPS <1, 1~5 and >5, respectively. Liver metastases were found in 43 (35.0%) of the patients with PD-L1 CPS >5, significantly more than in the patients with PD-L1 CPS <5 (p < 0.001). Multivariate analysis indicated that PD-L1 CPS status was not associated with prognosis (PD-L1 CPS ≥5 vs. <1, HR 1.18 [95%CI, 0.75-1.86], p = 0.48). In the overall population, grade ≥3 adverse events were observed in 102 (37.6%) patients and grade ≥3 immune-related adverse events were observed in 26 (9.6%) patients. Conclusions: There were no significant differences in prognosis and response between PD-L1 CPS in first-line Nivo-CT for advanced gastric or GEJ cancer in real world data.

Man versus machine: Comparative analysis of ChatGPT’s colon cancer guidance and expert opinion.

299 Background: AI Chatbots, such as ChatGPT, are increasingly being utilized across various aspects of society, including healthcare. Despite this growing usage, their role within the field of oncology remains underdeveloped. The objective of this study is to evaluate ChatGPT’s ability to accurately respond to patient inquiries regarding colon cancer by comparing its responses to assessments from expert clinical oncologists. Methods: Ten comprehensive questions were compiled by reviewing commonly asked questions from reputable sources, including the American Society of Colon & Rectal Surgeons, Mount Sinai, the National Cancer Institute, Mayo Clinic, and the American Cancer Society. The questions were categorized into two categories based on their content: General Oncology Characteristics (covering symptoms, screening, and prevention) and for Diagnosis & Treatment. These questions were then entered into ChatGPT, with prompts designed to simulate patient inquiries. The AI-generated responses were subsequently evaluated by oncology experts using a 5-point Likert scale to assess their accuracy and relevance, with scores reflecting the experts' level of agreement with the answers. Results: On a five-point Likert scale, with 1 representing "strongly disagree" and 5 representing "strongly agree," the mean score was 4.72. ANOVA analysis was performed and there was no statistically significant difference in the mean score across all raters (p = 0.221). However, ratings between the two categories were statistically significant (p=0.034). Conclusions: This study demonstrates that ChatGPT can provide accurate and relevant responses to patient inquiries about colon cancer, as assessed by medical oncology experts. With an average rating of 4.72 on a 5-point Likert scale, ChatGPT’s responses closely align with expert opinion, particularly for general characteristics category which included symptoms, prevention, and screening. However, responses related to diagnosis and treatment showed a statistically significant difference between expert opinions and AI, indicating that the experts agreed less with this component of AI's responses. These findings highlight the potential of AI chatbots in supplementing patient education in oncology, though further research is necessary to explore its limitations and expand its clinical utilities.

Resonant inter-mode second harmonic generation by backward spin waves in YIG nano-waveguides

We experimentally study the nonlinear generation of the second harmonic by backward volume spin waves propagating in microscopic magnonic waveguides fabricated from a low-loss magnetic insulator with a thickness of several tens of nanometers. We show that highly efficient resonant second harmonic generation is possible in the inter-mode regime at microwave powers of the order of 10−4 W. In contrast to previously observed second harmonic generation processes, the generation by backward waves is characterized by the nonlinearly generated waves propagating opposite to the initial waves and can be realized at zero bias magnetic field.

The viral serpin SPI-1 directly inhibits the host cell serine protease FAM111A

Shifting the paradigm: Early identification of colorectal cancer with C the Signs clinical decision support.

54 Background: The incidence of colorectal cancer is increasing rapidly, particularly amongst younger people. Despite a screening program being widely available, most patients are diagnosed with cancer through symptomatic presentation. Leveraging electronic medical records (EMRs) through clinical decision support platforms offers potential for identifying high-risk individuals before clinical suspicion develops. This study aims to explore the challenges associated with early colorectal cancer diagnosis and evaluate the effectiveness of the cancer case finding feature of a cancer management platform called C the Signs. Methods: A retrospective analysis was conducted using data from the Mayo Data Platform, comprising records of 894,275 patients, including 7,348 diagnosed with colorectal cancer. C the Signs was employed to identify patients at risk of colorectal cancer based on EMR data. Sensitivity and specificity analyses were performed to assess the platform's performance in identifying high-risk patients. Additionally, the study evaluated the temporal discrepancy in colorectal cancer diagnoses between those flagged by C the Signs and those detected by primary care physicians. Results: The C the Signs screening platform had a sensitivity of 93.8% and a specificity of 19.7% in identifying patients at risk of colorectal cancer. Notably, 29.4% of patients with colorectal cancer were identified as being at risk up to 5 years earlier by C the Signs compared to diagnoses made by primary care physicians, highlighting the platform's potential for early detection. Conclusions: Early identification of high-risk individuals holds promise for improving patient outcomes and reducing the burden of colorectal cancer. Whilst the specificity of the C the Signs platform for colorectal cancer is relatively low, the sensitivity is comparable to the most favorable rates reported for colonoscopy. In addition, if C the Signs was used in conjunction with a relatively cheap screening test such as Faecal Immunochemical Testing, this would significantly drive up the specificity whilst maintaining the sensitivity. Further studies are needed to assess its efficacy in conjunction with tests available in primary care.

Adjuvant chemoradiation combined with immunotherapy for patients with high-risk resectable extrahepatic cholangiocarcinoma and gallbladder cancer: A phase II, multicenter, randomized controlled trial (ACCORD trial).

570 Background: Extrahepatic cholangiocarcinoma (ECC) and gallbladder cancer (GBC), as the majority of biliary tract cancer (BTC), has a markedly high risk of recurrence after surgery. However, adjuvant treatments specifically for resectable ECC and GBC patients are scare and adjuvant chemotherapy alone delivers limited efficacy. Immunotherapy and radiotherapy are potential effective treatments and both of them may synergize with chemotherapy. Methods: ACCORD was a multicenter, phase 2, randomized controlled trial to assess the efficacy and safety of chemoradiation with immunotherapy as an adjuvant treatment in resectable ECC/GBC, compared to observation. The primary endpoint was overall survival (OS) and the secondary endpoints included recurrence-free survival (RFS) and safety. Patients in the chemoradiation-anti-PD-1 group received Camrelizumab intravenously every 3 weeks after surgery. Camrelizumab therapy was not terminated until disease progression, unacceptable toxic effects occurred or informed consent withdrawal. After 2 courses of Camrelizumab treatment, chemoradiation was carried out simultaneously. Patients in the observation group received no anticancer treatment unless relapse was detected. Results: From March 2020 to June 2022, a total of 93 ECC/GBC patients after curative resection were randomized 1:1 into chemoradiation-anti-PD-1 group ( n =46, Camrelizumab + concurrent Capecitabine and radiotherapy) and observation group ( n =47). The 1-year, 2-year and 3-year OS rate were 95.7%, 71.4%, and 58.2% in the chemoradiation-anti-PD-1 group, and 80.9%, 52.9%, 30.5% in the observation group (Hazard ratio (HR) 0.43, 95% confidence interval 0.24-0.79; P =0.004). The 1-year, 2-year and 3-year RFS rate were 78.3%, 54.0%, and 40.3% in the chemoradiation-anti-PD-1 group, and 55.3%, 27.0%, 17.2% in the observation group, with a hazard ratio of 0.46 (95% CI, 0.28 to 0.76; P < 0.001). In the chemoradiation-anti-PD-1 group, the main adverse effect ≥ grade 3 were anemia (7 [15.2%]), dermatitis radiation (5 [10.9%]), and nausea (5 [10.9%]); and 100% of patients completed the whole treatment. Conclusions: Chemoradiation combined with immunotherapy as an adjuvant therapy demonstrated superior survival outcomes over observation in resectable ECC/GBC patients with a well-tolerable safety profile, supporting the potential of this combination treatment as effective adjuvant therapy for these high-risk patients. Clinical trial information: NCT04333927 .

Efficacy and safety of intraperitoneal paclitaxel based regimens in patients with gastric cancer and peritoneal metastasis: A systematic review and meta-analysis.

373 Background: Peritoneal metastasis (PM) occurs in about 5% - 20% of patients with gastric cancer (GC) at the time of diagnosis, and prognosis remains poor with limited treatment options. There are conflicting results on the efficacy of intra-peritoneal (IP) paclitaxel in patients with gastric cancer with PM. We performed a meta-analysis to examine the current evidence on the effectiveness of IP paclitaxel-based regimens in this patient population. Methods: A comprehensive search was conducted across Pubmed, EMBASE, Cochrane library, and Clinicaltrials.gov, resulting in the initial identification of 253 articles. Following screening, 35 articles, comprising only clinical trials (CT) and Randomized Controlled Trials (RCTs), were selected for detailed analysis. Screening and data extraction were conducted by two reviewers concurrently, with quality assessment performed using RoB (Risk of Bias) 2.0 tool and NIH quality assessment questionnaire. Proportional meta-analysis was done to estimate the pooled efficacy of IP paclitaxel based on the Median Survival Time (MST) and 1-year Overall Survival (OS), and tumor response was assessed using RECIST criteria. Subgroup analysis was conducted for patients who underwent conversion gastrectomy. Safety was assessed through the analysis of adverse events. Results: A total of 855 patients were included in the evaluation of MST, revealing an overall pooled MST of 20.21 months for GC patients with PM treated with IP paclitaxel-based regimens. Additionally, 1-year OS data was available for 785 patients, revealing an overall cumulative 1-year OS of 71% (95% CI: 66-76). Furthermore, among the 332 patients who underwent conversion gastrectomy, the pooled overall MST was 27 months. For 168 participants who underwent conversion gastrectomy after receiving therapy with IP PAC-based regimens, the 1-year OS was 84% (95% CI: 77-89). The most common adverse events (AE) observed were alopecia (75%) and anemia (60%). Overall, most studies exhibited low RoB, with only a few demonstrating poor quality. Conclusions: IP paclitaxel-based regimens demonstrate both safety and encouraging efficacy in the treatment of GC patients with PM. Subsequent conversion gastrectomy in eligible patients can further improve the survival outcomes.

AGITG ASCEND: Randomised, double-blind phase II study of certepetide or placebo added to gemcitabine plus nab-paclitaxel in patients with untreated metastatic pancreatic ductal adenocarcinoma: Initial results.

728 Background: Gemcitabine (GEM) plus nab-paclitaxel (NAB-PAC) is a standard first-line chemotherapy regimen for advanced/metastatic pancreatic ductal adenocarcinoma (PDAC), with median Progression Free Survival (mPFS) and Overall Survival (mOS) of 5.5 & 8.7 in the MPACT trial and 5.6 & 9.2 months (mo) in the NAPOLI 3 trial, respectively. Certepetide (formerly LSTA1 or CEND-1) is a novel cyclic peptide that improves targeted penetration of co-administered drugs into tumor and stroma, leading to potentially increased anti-neoplastic activity. ASCEND is a randomized phase II trial designed to investigate the impact of adding certepetide to GEM/NAB-PAC. (NCT05042128). Methods: Eligible participants (pts) with histologically confirmed advanced PDAC and ECOG 0-1 were randomized 2:1 to receive GEM/NAB-PAC plus certepetide (3.2 mg/kg) or placebo (PLA) on days 1, 8, & 15 of a 28-day cycle. Stratification was by age (<65/≥65 years), ECOG (0/1), presence of liver metastasis (Y/N) and trial site. The primary objective was to determine the effect of adding certepetide to GEM/NAB-PAC on PFS. Objective tumor response rate (OTRR), safety and OS were secondary objectives. This non-comparative phase II design targeted a PFS increase of 17% at 6 mo from 47% to 63%. A sample size of 65 patients in the certepetide arm was expected to have 80% power, with 95% confidence to exclude an uninteresting 6-mo PFS rate of 47%. Results: 95 pts (66 certepetide, 29 PLA) were enrolled between May 2022 to December 2023. 6-mo PFS in the certepetide and PLA groups was 49.0% (95% CI 36.4%, 60.5%) and 40.8 (95% CI 22.6%, 58.3%) respectively, with mPFS of 5.5 mo in both groups. mOS was 12.42 mo for the certepetide and 9.72 mo for the PLA. An OTRR of 38.3% (certepetide) and 26.9% (PLA) was observed. Of note, 4 complete responses were observed in the certepetide group vs. 0 in PLA group. In subjects with ECOG 0, 6 mo PFS was 68.1% (95% CI 48.7%, 81.4%) in the certepetide compared to 36.4% (95% CI 11.2%, 62.7%) in the PLA. Grade ≥3 toxicities were similar in both groups at 16% (certepetide) and 15% (PLA). Conclusions: The addition of certepetide is safe and despite showing no improvement in 6-mo PFS, a possible signal of benefit in OS and OTRR, including the 4 complete responses was observed, warranting further investigation. A further cohort of the ASCEND study evaluating the addition of a second dose of certepetide is ongoing. Clinical trial information: NCT05042128 .

Vertical Al2O3/GaN MOS capacitors with PEALD-GaO<i>x</i> interlayer passivation

In this Letter, we report high-quality vertical GaN metal–oxide–semiconductor (MOS) capacitors with sulfur passivation and a plasma-enhanced atomic layer deposition -grown GaOx interlayer, exhibiting a low interface trap density (Dit) of ∼8 × 1010 cm−2 eV−1 and a low frequency-dependent flatband voltage shift [ΔVFB (f)] of ∼20 mV (from 1 kHz to 1 MHz). The introduction of the GaOx interlayer effectively suppresses the leakage current (from ∼10−3 to ∼10−6 A/cm2 under 10 V positive bias) and passivates nitrogen/oxygen-related vacancies and dangling bonds. The demonstrated controllable and low-destructive passivation technique provides the insights and methodologies for the fabrication of high-performance GaN MOS structure-based devices.

A physicochemical rationale for the varied catalytic efficiency in RNase J paralogues

A global comparative study on MDT practices in the management of hepatocellular carcinoma in high-income countries (HICs) and low- and middle-income countries (LMICs).

562 Background: As the sixth most common malignancy worldwide, hepatocellular carcinoma (HCC) accounted for 4.7% of all new cancer diagnoses in 2022. Low- and middle-income countries seem to bear a disproportionate burden of the disease, with over 50% of new HCC cases estimated to occur in China and Africa. Research on multidisciplinary team (MDT) practices in these regions is limited. The objective of this study is to compare MDT practices in the management of HCC in HICs and LMICs. Methods: Data on MDT practices from hospitals that manage HCC in Italy, Spain, Switzerland, Germany, Denmark, Canada and the USA, representing HICs, and in China, South Africa and Egypt, representing LMICs were collected through virtual semi-structured interviews and workshops. Results: Ten key areas of differences were identified (Table 1) that could be categorized as organizational/regulatory or clinical. In HIC institutions, the focus currently is on optimizing MDTs as standard of care approach accessible to all patients with HCC; MDT principles are often integrated into national policies. In LMICs, emphasis is on establishing MDTs and expanding their capacity; patient access to MDT care is not a mandatory requirement, nor regulated in national policy. Of note, LMICs are seeking early technology adoption to overcome some potential barriers to MDT interactions; online formats are more often explored to facilitate participation and AI-assisted diagnostic tools are explored to compensate for absence of radiologists. Absence of screening and surveillance for early detection in HCC is more common in LMICs, and therefore likely that patients more often present with advanced stage disease. Also, with limited diagnostic modalities, diagnostic work-up and staging may be sub-optimal. Conclusions: Significant variation exists in HCC MDT practices between HICs and LMICs. The ultimate goal of this study is to develop a format for clinical MDTs that will facilitate interaction between HICs and LMICs. Consideration for the differences highlighted above is crucial for the development of this concept. 10 key areas highlighting differences identified between HICs and LMICs. MDT development direction: Standard of Care for all patients vs. specific session for complex cases National/regional regulatory requirements Institutionalizing MDT principles MDT composition (specialists) Use of digital tools Reimbursement Access to therapeutic options Stage presentation of HCC patients Use of clinical staging Patient follow-up after MDT discussion

Racial disparities in receipt of guideline concordant pancreatic cancer care among older adults in the US.

679 Background: Patients racialized as Black experience higher incidence and mortality from pancreatic cancer (PC). The aim of this study was to examine differences in receipt of guideline concordant care (GCC) among older adults with PC racialized as Black, White, or Hispanic ethnicity. Methods: Patients 65 years and older with incident PC racialized as White, Black, or Hispanic ethnicity were identified in the SEER-Medicare database from 2004-2019. The primary outcome was receipt of GCC (stage I/II: surgery+chemotherapy+/-radiation; stage III: chemotherapy+/-surgery+/-radiation; stage IV: chemotherapy+/-radiation). Multivariable logistic regression was used to identify factors associated with GCC. Oaxaca-Blinder decomposition was used to examine the contribution of measured and unmeasured variables to racial disparities in receipt of GCC. Results: Of 12,772 patients included, 85.5% of patients racialized as White (n=10,915), 7.8% Black (n=992), and 6.8% Hispanic ethnicity (n=865). Patients racialized as Hispanic ethnicity and Black were more often dual-eligible for Medicare/Medicaid than patients racialized as White (38.6%, 26.9%, and 7.5%, respectively). In total, 56.3% received GCC. On adjusted analysis, patients racialized as Black were less likely to receive GCC for early stage (stage I/II) disease compared to patients racialized as White (OR 0.66; 95% CI 0.53-0.83), but not for stage III (OR 0.65; 95% CI 0.41-1.01) or stage IV (OR 0.87; 95% CI 0.66-1.14) disease. No difference in GCC was observed among patients of Hispanic ethnicity when compared to patients racialized as White. Increased age and dual-eligibility were associated with decreased likelihood of GCC across stages. Differences in receipt of GCC among patients racialized as Black and White remain largely unexplained. Of the measured factors, comorbidities, dual-eligibility, and area level poverty contributed most to the disparity in GCC (Table). Conclusions: Just over half of an insured population with PC receive GCC. Despite an increased focus on equity in cancer care, Black-White racial disparities in receipt of GCC are prevalent, particularly among patients with early-stage disease. Further studies are critical to identify and address the unmeasured factors driving treatment disparities. Contributing factors to racial disparities in guideline concordant care for patients with pancreatic cancer. Stage I/II Stage III Stage IV Difference (White-Black) 11.6% 9.4% 4.1% Explained Age -3.0% -2.0% -1.0% Sex 0.1% 0.8% 0.1% Dual-Eligibility 2.0% 3.1% 0.8% Charlson Comorbidity Index 1.3% 0.2% 0.7% Area Level Poverty 2.2% -0.8% 0.7% Hospital/Practice Volume 1.2% -0.3% -0.03% Region 0.4% 0.9% -0.2% Year of Diagnosis -0.1% 0.5% 0.1% Unexplained 7.5% 7.0% 3.0% Positive values indicate these factors increased the measured disparity, while negative values indicate these decreased the measured disparity.

AGX101: A TM4SF1-directed tubulin inhibitor conjugate in ongoing first-in-human trial including GI cancers.

829 Background: TM4SF1 (Transmembrane-4 L-Six-Family-Member-1) is an endothelial marker with critical roles in angiogenesis, as well as a tumor cell antigen that contributes significantly to invasion and metastasis. TM4SF1 is upregulated 20-fold in angiogenic tumor vascular endothelium compared to normal vasculature endothelium and exhibits a unique nuclear internalization pathway. AGX101 is a novel tubulin inhibitor conjugate specifically directed against TM4SF1, delivering a potent maytansinoid payload directly to the nucleus of cells within the tumor microenvironment. Delivery to both the vascular and tumor cell compartments of the tumor results in three mechanisms of action (MoAs): (1) activation of tumor immune surveillance, (2) tumor blood supply deprivation, and (3) direct tumor cell killing. Methods: TM4SF1 expression was assessed using immunohistochemistry. Safety and pharmacokinetics of AGX101 were evaluated in non-human primates (NHP), with escalating doses to determine the highest non-severely toxic dose (HNSTD). Efficacy studies were also conducted in mouse models, enabling assessment of the minimum effective dose (MED) needed to engage each of the three MoAs. The combination of HNSTD and MED enables calculation of a therapeutic index (TI). The potential for synergy with immune checkpoint inhibitors (ICIs) was also investigated. A first-in-human study of AGX101 in patients with advanced solid tumors with the primary objective of safety and dose-limiting toxicities (DLTs) has initiated. Results: Notable cancers with high TM4SF1 scoring intensity include pancreatic adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, and gastric cancer. In esophageal cancer, 20% of patients have a TM4SF1 copy number amplification, and these have worse prognosis. In NHP, AGX101 exhibited a favorable safety profile. In preclinical efficacy studies, monotherapy demonstrated robust efficacy through each of the three MoAs in syngeneic models in mice including CT26 colon carcinoma, and human tumor xenograft models including MIA PaCa-2 pancreatic cancer. Measured by exposure, TI was large. In syngeneic mouse models including CT26, the effects of ICIs were potentiated, suggesting a potential synergistic approach in cancer therapy. The first two dose levels of AGX101 monotherapy in humans has cleared without DLTs. Three patients with pancreatic adenocarcinoma have been treated thus far. Conclusions: AGX101, targeting the TM4SF1 antigen, represents a promising new approach in cancer therapy. The preclinical data suggest that AGX101 could provide a significant therapeutic benefit by novel and differentiated mechanisms of action, namely selectively targeting the tumor vasculature and potentiating immune-based therapies. Further clinical development of AGX101 is ongoing and initial outcome data will become available by the conference. Clinical trial information: NCT06440005 .

A phase 1/2 study to evaluate CHM-2101, an autologous cadherin 17 (CDH17) chimeric antigen receptor (CAR) T cell therapy for the treatment of relapsed or refractory gastrointestinal cancers.

TPS844 Background: Patients with advanced gastrointestinal (GI) malignancies have poor prognoses and limited treatment options. Cadherin 17 (CDH17) is a cell membrane-associated protein important for GI cell-cell interactions that is expressed in proximity to epithelial tight junctions. In some GI malignancies, CDH17 expression is also expressed diffusely across the cancer cell membrane, thus providing access to CDH17 directed CAR T-cells. CHM CDH17 is a third generation autologous CAR T-cell product candidate that was designed to target and eradicate CDH17+ solid tumors. Notably, expression of CDH17 varies across indications in the cancer setting CDH17– TABLE 1. Methods: Clinical Trial NCT06055439 is a seamless Phase 1/2 clinical trial of autologous CHM CDH17 CAR T-cells for patients with advanced gastric cancer (GC), colorectal (CRC) cancer or neuroendocrine tumors (NETs) of the midgut or hindgut. As CDH17 expression in GC is heterogenous, GC subjects will be screened for CDH17 expression. In preparation for receiving CDH17 CAR T-cells, subjects receive 3-days of lymphodepleting intravenous (IV) chemotherapy (fludarabine and cyclophosphamide). The Phase 1 portion of the clinical trial uses a 3+3 dose escalation and a starting dose of 50 million CAR-T cells in a single IV infusion. Decisions regarding dose escalation/de-escalation are based on real-time dose-limiting toxicity evaluation during the first 28 days of treatment during dose escalation. After establishing a recommended Phase 2 dose, three indication-specific Simon 2-Stage cohorts will be initiated in (1) GC (2) CRC and (3) NETs of the midgut or hindgut to further characterize the safety and assess the efficacy of CHM CDH17 CAR T-cells. This is an ongoing first-in-human multi-center clinical trial of CHM CDH17, a CDH17 directed autologous CAR T-cell product candidate, enrolling subjects with advanced GI cancers that express CDH17. Clinical trial information: NCT06055439 . Expression of CDH17 in selected gastrointestinal cancer indications. Indication Sample size CDH17Expression %* Colorectal cancer 821 96% Neuroendocrine tumors of the midgut and hindgut 119 97% Gastric cancer 1,409 64% *Expression of total tumors tested for CDH17 by immunohistochemistry (CHM data on file).

Anomalous shot noise in a bad metal β-tantalum

We investigate the electronic shot noise produced by nanowires of β-Ta, an archetypal “bad” metal with resistivity near the Ioffe–Regel localization limit. The Fano factor characterizing the shot noise exhibits a strong dependence on temperature and is suppressed compared to the expectations for quasiparticle diffusion, but hopping transport is ruled out by the analysis of scaling with the nanowire length. These anomalous behaviors closely resemble those of strange metal nanowires, suggesting that β-Ta may host a correlated electron liquid. This material provides an accessible platform for exploring exotic electronic states of matter.

Protein kinase a suppresses antiproliferative effect of interferon-α in hepatocellular carcinoma by activation of protein tyrosine phosphatase SHP2

Disparities in clinical trial enrollment among LGBTQ+ individuals and its impact on cancer treatment and management: A systematic review.

805 Background: There is a significant gap in oncologic research, which arises from the exclusion of LGBTQ+ individuals from cancer clinical trials, compromising the development of personalized cancer therapies and limiting the generalizability of findings. Despite known health disparities in this population, including higher cancer risk factors and unique psychosocial stressors, data on clinical trial participation remains sparse. This study aims to elucidate the extent of underrepresentation of LGBTQ+ individuals in cancer clinical trials and examine its impact on treatment efficacy, safety, and overall management. Methods: We conducted a systematic review of literature and clinical trial databases, including PubMed, ClinicalTrials.gov, and other registries, focusing on cancer trials from 2010 to 2024. We extracted data on LGBTQ+ enrollment, analyzed demographic inclusivity criteria, and identified barriers to participation. Subgroup analyses evaluated the correlation between LGBTQ+ representation and treatment outcomes, considering variables such as trial design, recruitment strategies, and data collection on sexual orientation and gender identity. The review also examined policy changes and inclusivity initiatives aimed at improving trial access for this community. Results: The review identified a significant underrepresentation of LGBTQ+ individuals in cancer trials, with sexual orientation and gender identity data reported in only 6.2% of trials. Structural and sociocultural barriers, including heteronormative trial designs, lack of inclusive recruitment strategies, and pervasive discrimination, were frequently cited as impediments. Trials that included LGBTQ+ participants rarely conducted stratified analyses to assess differential treatment responses, leading to a paucity of data on drug safety, efficacy, and toxicity profiles specific to this population. The absence of these data may contribute to suboptimal therapeutic decision-making and potential adverse outcomes in clinical practice. Conclusions: The substantial underrepresentation of LGBTQ+ individuals in cancer clinical trials impairs the ability to develop inclusive, evidence-based oncology care. Addressing this gap requires systematic changes, including the integration of sexual and gender minority data collection, implementation of LGBTQ+-specific recruitment frameworks, and stratified analyses of treatment outcomes. Enhancing trial inclusivity will not only improve the external validity of oncologic research but also support the development of tailored therapeutic approaches that address the unique needs of LGBTQ+ cancer patients, ultimately advancing health equity in cancer care.

INSIGHT: A phase 3, randomized, open-label study of ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib with <i>KIT</i> exon 11 + 17/18 mutations.

TPS848 Background: Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal sarcoma, with approximately 80% of cases driven by KIT mutations. Most patients (pts) with advanced GIST experience disease progression following first-line treatment with imatinib due to KIT secondary resistance mutations occurring most commonly in the ATP-binding pocket (exons 13/14) and/or activation loop (exons 17/18). Sunitinib is approved as second-line therapy for advanced GIST. Ripretinib is a switch-control tyrosine kinase inhibitor approved for pts with GIST who received prior treatment with 3 or more kinase inhibitors, including imatinib. In the INTRIGUE phase 3 study (NCT03673501) in second-line therapy for advanced GIST, ripretinib was not superior to sunitinib in terms of progression-free survival (PFS); however, a more favorable safety profile was observed with ripretinib vs sunitinib (Bauer S et al. J Clin Oncol . 2022). Exploratory mutational analysis from INTRIGUE using baseline circulating tumor DNA (ctDNA) demonstrated that pts harboring primary KIT exon 11 mutations with secondary resistance mutations exclusively in KIT exons 17/18 derived PFS benefit with ripretinib vs sunitinib (median, 14.2 vs 1.5 months; HR, 0.22; 95% CI, 0.11 to 0.44; nominal P &lt;0.0001; Heinrich MC et al. Nat Med . 2024). Here, we describe an ongoing phase 3 study for pts with advanced GIST previously treated with imatinib harboring KIT exon 11 + 17/18 mutations. Methods: INSIGHT (NCT05734105) is a phase 3, randomized, open-label study designed to evaluate the efficacy of ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib and who harbor KIT exon 11 + 17/18 mutations. Eligible pts must be ≥18 years old with histologically confirmed GIST and co-occurring KIT exon 11 + 17/18 mutations confirmed by ctDNA analysis. Pts must also have advanced disease with ≥1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, radiologic progression on imatinib, and an Eastern Cooperative Oncology Group performance status ≤2. Key exclusion criteria include a KIT exon 9, 13, or 14 mutation confirmed via ctDNA analysis at screening and prior treatment with another line of therapy in addition to imatinib for advanced GIST. A total of 54 pts will be randomized (2:1) to receive ripretinib 150 mg once daily (QD; continuous) or sunitinib 50 mg QD (4 weeks on/2 weeks off) in 6-week cycles. The primary endpoint is PFS by independent radiologic review (IRR) per mRECIST v1.1; key secondary endpoints are objective response rate by IRR using mRECIST v1.1 and overall survival. Safety and patient-reported outcome measures will also be assessed. Pts randomized to the sunitinib arm may cross over to the ripretinib arm upon disease progression. This abstract was originally presented at ASCO 2023. Clinical trial information: NCT05734105 .