Browse Articles

A phase II study of FOLFIRINOX (FFX) combined with the glycogen synthase kinase-3beta (GSK-3β) inhibitor elraglusib (ELRA) and the transforming growth factor beta (TGFβ) inhibitor losartan (LOS) in patients with untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).

4212 Background: Concurrent inhibition of GSK-3β and TGF-β signaling pathways aims to target epithelial-mesenchymal transition (EMT) plasticity, metabolic reprogramming, desmoplasia and immune escape mechanisms that underlie therapeutic resistance in mPDAC Methods: In this multi-institutional, open-label, four-arm (non-comparator) phase II trial conducted across three academic centers in the United States, 49 patients with newly diagnosed, treatment naive mPDAC were randomized to Arm 1: FFX alone (biomarker control, n=4) or Arm 2: FFX plus LOS (50 mg daily); Arm 3: FFX plus ELRA (9.3 mg/kg IV twice weekly); Arm 4: FFX plus LOS plus ELRA (n=15/arm). After 12 cycles of FFX without progression, patients transitioned to maintenance 5-FU (plus ELRA/LOS, based on the arm) and resumed full therapy at progression; treatment withdrawal required progression on full therapy or treatment-limiting toxicity. The primary endpoint was progression-free survival (PFS). Results: Between September 19, 2022, and January 2, 2025, 49 patients were enrolled (median age 65 years; 51% female; 74% White). At the data cutoff (July 6, 2025), 14 (28.6%) patients remained alive with a median follow-up of 9 months. Median PFS was 5.1 months (95% CI 1.1–NR) in Arm 1, 5.9 months (95% CI 1.6–9.9) in Arm 2, 6.0 months (95% CI 1.8–9.8) in Arm 3, and 6.5 months (95% CI 3.8–8.5) in Arm 4. 9-month PFS could not be calculated in arm 1, 29.3% (95% CI 9.2-53.3) in Arm 2, 37.3% (95% CI 13.6 – 61.5%) in Arm 3, and 21.7% (95% CI 5.3 –45.1) in Arm 4. Median overall survival (OS) was 7.7 months (95% CI 1.1–NR), 8.2 months (95% CI 3.3–14.5), 9.8 months (95% CI 4.3–NR), and 9.8 months (95% CI 5.6–15.6), respectively in each arm. Objective response rate 24.5% (12/49);stable disease 44.9% (22/49). 14/49 (28.5%) patients received maintenance therapy, with a median duration of 2.4 months. Treatment was generally well tolerated, grade ≥3 treatment-related adverse events occurred in 34.7% of patients; one treatment-related death due to sepsis occurred in Arm 3. Notably, a subset of patients in Arms 3 and 4 demonstrated deep and sustained clinical responses; Correlative biomarker analyses are ongoing to identify molecular and immune features associated with these long term responders. Conclusions: Although clinical outcomes with the novel combinations did not exceed historical standards of care, this non-comparator phase II study demonstrates the feasibility and tolerability of combinatorial pathway inhibition in mPDAC. This study enables ongoing correlative analyses of EMT plasticity, stromal remodeling, and immune escape in mPDAC and establishes a robust platform to define determinants of resistance and durable response. Clinical trial information: NCT05077800 .

A randomized phase II clinical trial on intratumoral autologous CD1c (BDCA-1) ⁺ /CD141 (BDCA-3) ⁺ myeloid dendritic cells (myDC) plus ipilimumab (IPI) and synthetic adjuvant AS01B combined with low-dose intravenous (IV) nivolumab (NIVO) in advanced pretreated melanoma patients.

e21514 Background: Many advanced melanoma patients (pts) will not obtain a durable response on immune checkpoint- (ICI) and BRAF/MEK-inhibitors (in case of a BRAFV600 mutation). Dendritic cells are crucial for ICI effectiveness and are often excluded from the tumor microenvironment in refractory melanoma. In a previous phase I clinical trial (NCT03707808), low-dose IV NIVO (10 mg) combined with intratumoral (IT) injections of autologous CD1c(BDCA-1)+/CD141(BDCA-3)+ myDC, IPI and synthetic adjuvant AS01B was proven feasible with a promising efficacy signal (DCR 50%) (Tijtgat et al, JITC 2024). We aimed to evaluate the added value of the myDC in a randomized trial. Methods: In this single-center, prospective, two-stage phase II clinical trial, advanced melanoma pts with injectable metastases progressive on standard-of-care life prolonging treatments were randomized 1:1 to receive weekly IT IPI and AS01B with (arm A) or without (arm B) a single IT injection of autologous myDC, and bi-weekly low-dose NIVO IV. At progression (PD), pts in arm B could cross-over to receive the single IT autologous myDC injection with continued study treatment. A sample size of 9 pts in each arm was determined according to a Simon’s two-stage study design. The 1-year PFS rate (1y PFS) served as primary endpoint. Key secondary endpoints were safety, ORR (per RECIST v1.1), PFS and OS. Results: At this interim analysis, 16 pts (8 in each arm) were enrolled (10 male, median (med) age 69, AJCC stage IIIB: 1, IIIC: 5; M1a: 6, M1c: 3, M1d: 1) between Jan ‘24 and DBL (20 Jan '26). There were no significant differences in treatment disposition between both study arms (med 6.5x IT (range 1-22) and 4x IV NIVO (range 1-12)). 13 pts were evaluable for response. The ORR was 28% in arm A (2 CR: 30 wks and 73+ wks), and 17% in arm B (1 CR: 48+ wks). 4 out of 5 pts crossed over at PD to receive myDC. After cross-over, there was one stable disease. After a median follow-up of 38 wks (range 2-101), 11 pts progressed (6 in arm A, 5 in arm B), and 6 had died (4 in arm A, 2 in arm B). Estimation of the 1y PFS is immature, requiring additional follow-up. Med PFS was 14 wks (95% CI 11-16) in arm A and 17 wks (95% CI 11-22) in arm B. All pts experienced at least one treatment-related adverse event (TRAE); most commonly low-grade fatigue (44%) and injection site reaction (56%) with equal frequency in both arms. 5 pts interrupted treatment temporary (4) or definitive (1) due to TRAE. No grade ≥4 TRAE occurred. Conclusions: Weekly IT IPI+AS01B and bi-weekly low-dose NIVO IV, with or without a single IT injection of myDC, is safe and results in durable tumor responses in a meaningful subset of advanced pretreated melanoma pts. Additional follow-up is needed to estimate the added value of IT myDC in this investigational IT immunotherapy regimen. Clinical trial information: EUDRACT 2017-003280-35.

Using lignin waste as additives to bitumen for the sustainability of the circular economy: A study of the interaction of mixture components

The growing role of the circular economy, the shortage of oil, and the expansion of its application areas have led to the search for and use of alternative raw materials that can replace/supplement petroleum products. One direction is the use of lignin, which is produced during cellulose production and can be used as a component/substitute for bitumen binders. Despite significant scientific research in this area, the use of oxidized long-term storage lignin has not been practically studied. Therefore, the purpose of this work was basic research on the interaction between bitumen and lignin, which can later serve as the basis for technologies for the use of this type of waste, obtained in Ukraine and stored for long periods in landfills. The initial lignin and the resulting mixtures with bitumen were characterized using differential thermal and thermogravimetric analysis (DTA/DTG), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). The results confirm that, despite structural and compositional changes induced by long-term storage, lignin actively interacts with bitumen, forming relatively stable chemical bonds. These results will also be used to develop effective technologies for the utilization of lignin waste accumulated in the Zaporizhzhia region, with direct environmental benefits.

Chemical Metabolomics: Chemical Biology Tools for Advanced Metabolism Investigations

ABSTRACT Human metabolism has been investigated to understand disease onset for the discovery of new selective pharmaceuticals and the development of diagnostics for early disease detection. Metabolomics, as an interdisciplinary research field, has been implemented to investigate the entirety of the complex metabolite profiles predominantly using mass spectrometry. In the past two decades, the development of chemical biology tools for the detailed metabolism investigation has received a boost to advance metabolomics analyses. Especially, the identification of the microbiome and its importance for human physiology were the main motivation for these strategies. These new tools at the intersection of Chemistry and Biology have especially aided to uncover previously unknown metabolites in humans and have slowly elucidated metabolites produced by microbial communities. These Chemical Biology tools, integrated with metabolomics tools and technologies, build the foundation for Chemical Metabolomics investigations, which have led to the discovery of important metabolites that are modulators or readouts for disease development and human homeostasis. This overview article focuses on the recent developments and the diversity of Chemical Biology tools and technologies, particularly methods involving chemoselective probes, in vivo analysis, host‐microbiome co‐metabolism, and activity metabolomics, in the context of understanding human metabolism at the molecular level.

Thermal conductance across bonded SiO <i>x</i> –SiO <i>x</i> interfaces in hybrid bonding process

Hybrid bonding is a pivotal technology for enabling three-dimensional integrated circuits (3D-ICs). Among the foremost challenges facing 3D-IC implementation is thermal management, where a deep understanding of heat conduction across bonded interfaces is essential for addressing heat dissipation and reliability issues. Nevertheless, the thermal conductance of bonded dielectric–dielectric interfaces remains poorly understood. In this study, we employ the low-temperature bonding technique integral to hybrid bonding to fabricate SiOx–SiOx interfaces and investigate their thermal boundary conductance (TBC) using time-domain thermoreflectance. Structural characterizations show high-quality bonded interfaces. By fitting the data with an equivalent multilayer thermal model, we establish a lower-limit TBC of 150 MW m−2 K−1 for the SiOx–SiOx interfaces, which corresponds to a thermal resistance lower than that of a 9.2-nm-thick dielectric layer. These findings offer valuable insights into thermal transport in hybrid-bonded structures and provide critical guidance for the thermal design of advanced packaging solutions.

Light attenuation and optical absorption characteristics of graphene-chitosan nanomaterials-based quandary nanocomposites

SMYD2 regulates lymph node metastasis derived from intrahepatic cholangiocellular carcinoma through CCR7-dependent chemotaxis

Abstract Intrahepatic cholangiocellular carcinoma (ICC) has poor prognosis, especially with lymph node (LN) metastasis (LNM). Lysine methyltransferase SET and MYND domain-containing 2 (SMYD2) has critical roles and is reportedly associated with poor prognosis in various cancers, but the role of SMYD2 in ICC is unclear. Here, we examined the role of SMYD2 in the progression of LNM of ICC. We immunohistochemically analyzed SMYD2 expression using resected specimens first in primary ICC and then in metastatic LNs derived from ICC. For functional analyses, we then performed cell proliferation assay following SMYD2 inhibition using two ICC cell lines such as HuCCT-1 and HuH28. To explore the detailed mechanisms of LNM, immunocytochemistry and western blotting related to epithelial-mesenchymal transition (EMT) were first performed. Moreover, we performed clinically immunohistochemical staining of C-C motif chemokine receptor 7 (CCR7) in metastatic LNs, immunofluorescence staining and western blotting for functional analyses to evaluate the relationship between SMYD2 and CCR7. Finally, p65 of nuclear factor-kappa B (NF-κB) and phospho-p65 (Ser536) status were checked as the regulator of CCR7. Protein expression levels of SMYD2 in the primary ICC lesion were not associated with any clinicopathological characteristics or prognosis. However, SMYD2 was expressed in metastatic LNs of all cases and LNM was strongly associated with poor disease-free and overall survival also as previously reported. This study therefore aimed to clarify the molecular-biological roles for LNM by SMYD2. SMYD2 knockdown significantly inhibited ICC cell proliferation. According to subsequent EMT-related research, SMYD2 knockdown did not induce morphological changes or cadherin switching. Next, chemotaxis assay revealed that SMYD2 knockdown reduced chemotaxis in HuCCT-1 from metastatic ascites but not in HuH28 from the primary lesion. CCR7 expression in metastatic LNs was immunologically confirmed in all cases and had a positive correlation with SMYD2 expression. Decreased expression of CCR7 was observed in SMYD2-suppressed HuCCT-1 cells by immunofluorescence staining and western blotting simultaneously with the decreasing phosphorylation of p65 S536 . SMYD2 could be demonstrated to express in all metastatic LNs derived from ICC and may regulate this metastatic mechanism through CCR7-dependent chemotaxis rather than EMT via the SMYD2-phospho-p65 S536 -CCR7 pathway.

Photoreceptor outer segment disk rim curvature relies on a tetraspanin interaction web

Association of early cognitive decline with compromised delivery of adjuvant chemotherapy.

11010 Background: Cancer-related cognitive impairment (CRCI, “chemobrain”) is a common condition among patients (pts) receiving adjuvant chemotherapy (CT) and has been shown to negatively affect quality of life (QoL). However, the clinical relevance of early CRCI beyond symptom burden remains poorly characterized. We evaluated whether early CRCI is associated with compromised delivery of adjuvant CT, including reduced relative dose intensity (RDI). Methods: This prospective study was conducted at the University Hospital of Larissa and represents an expanded analysis of a previously reported population with treatment delivery endpoints. Pts with early stage (ES) breast (BC) or colorectal (CRC) cancer scheduled to receive adjuvant CT containing taxanes or oxaliplatin, respectively, were eligible for this study (C1). Two control groups were included: ES cancer pts that were not eligible for adjuvant CT (C2) and age-matched healthy controls (C3). Eligibility criteria included age &gt; 45 years and fluency in Greek; pts with pre-existing dementia or anxiety disorders were excluded. C1 pts were assessed at baseline and every 3 months (mo) up to 12 mo after CT initiation, while C2 and C3 were assessed at 3-mo intervals. CRCI was evaluated using the Greek Version of Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog). Early CRCI was defined as a ≥10-point decline in total FACT-Cog score at 3 mo after CT initiation, in the absence of severe anemia (CTCAE grade ≥3). Treatment delivery outcomes included RDI (reduced RDI: &lt; 85%), treatment delays, CT discontinuation, unplanned healthcare use and CT-related neurotoxicity (ntx). Results: Overall, 164 pts were included in C1 (111 BC, 63 CRC), 61 in C2 (38 BC, 23 CRC) and 25 in C3. Early CRCI was observed in a substantial proportion of pts receiving adjuvant CT (99/164, 60%). Pts with early CRCI were significantly more likely to receive reduced CT dose intensity compared to those without CRCI (OR 3.27, 95% CI 1.34-7.98). Early CRCI was also associated with an increased risk of clinically relevant concurrent treatment-related ntx (CTCAE grade &gt; 1; OR 4.05, 95% CI 1.81-9.08). CT discontinuation occurred more frequently among pts with early CRCI than among those without CRCI (12% vs 3%). In addition, these pts more frequently experienced treatment delays and unplanned healthcare use. These associations were independent of baseline ECOG PS. Early CRCI persisted beyond 3 mo in a substantial proportion of affected pts during follow up, while cognitive scores remained stable among controls. Conclusions: In this expanded cohort, early CRCI was associated with reduced RDI and higher rates of treatment discontinuation. Beyond its impact on QoL, early CRCI identifies a vulnerable subgroup of pts at risk for compromised treatment delivery and may represent a clinically actionable target for risk-adapted supportive strategies aimed at preserving curative-intent treatment intensity.

Outcome of chemotherapy among intubated patients with small cell lung cancer: A systematic review.

e20163 Background: Small cell lung cancer (SCLC) is characterized by rapid doubling time and early metastasis, often leading to acute physiological decompensation. The association of paraneoplastic syndrome with SCLC may necessitate airway management. This study aims to characterize the indications for intubation and the subsequent clinical outcomes in this high-risk population. Methods: A thorough systematic search was conducted to identify studies done on intubation in small cell lung cancer patients using Covidence. After appropriate exclusion of studies, data analysis was done using MS-Excel. Results: We identified a total of 1483 studies after thorough database searching. After excluding the studies, a total of 29 patients (M/F = 17/12) from 24 case reports and one case series were included in the qualitative analysis . Only 7 patients had been diagnosed with small cell lung cancer prior to the hospital presentation. For the remaining 22 patients, the median age at diagnosis was 57 years. 16 patients (55.17%) had a diagnosed paraneoplastic syndrome of which 15 patients were intubated for respiratory failure or airway protection and one was intubated for cardiac arrest. Other common indications were structural obstructions and procedural requirement. Liver metastases were reported in 3 patients and brain metastasis was reported in one patient. Patients were intubated for a mean duration of 7.16 days. 2 patients required tracheostomy following prolonged intubation. 8 patients (27.5%) succumbed to death while 21 patients (72.41%) were alive after receiving intubation and chemotherapy; of which 11 patients (37.93%) were either discharged home or to nursing home. Conclusions: Intubation in SCLC is not universally futile. Indications extend beyond simple respiratory failure to include reversible oncological emergencies and paraneoplastic neurological decline. Survival is possible, particularly when mechanical ventilation serves as a bridge to allow for the rapid initiation of systemic chemotherapy.

Clinicopathological characteristics and prognosis of pheochromocytomas and paragangliomas (PPGLs) in 235 patients.

e15175 Background: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors. Clinical and pathological features are closely interrelated with prognosis. To study the Clinicopathological characteristics and prognosis of pheochromocytomas and paragangliomas (PPGLs) in 235 patients. Methods: We conducted a retrospective analysis of 235 patients with PPGLs who were treated and followed up for 66 months in a single Oncology center. Analyze the relationship between clinicopathological features and survival. Results: Patients presented with various symptoms: hypertension (57%), headache, palpitations and sweating (20%), Stomachache/abdominal distension (15.3%), Neck mass (5.1%), backache 10 (4.3), Asymptomatic 88/235 (37.4%). Among 235 patients, 110 (47%) were male and 125 (53%) were female, with mean (SD) age 50±12 years. There were 135 cases of adrenal pheochromocytoma and 100 cases of extra-adrenal paraganglioma (68 retroperitoneal, 16 carotid body, and 16 at other sites). Recurrence occurred in 21 patients (14 retroperitoneal, 6 adrenal, 1 carotid body; tumor size (6.33 ± 3.99) cm; 18 cases with SDHB negative, Ki67 proliferation index (8.39 ± 10.69)%; hypertension 11/21). 5 patients died (4 retroperitoneal, 1 adrenal; mean tumor size 9.46 cm; 2 with SDHB negative, 3 with weak diffuse expression; mean Ki67 19%; 3 with hypertension, 1 had hypertension complicated by cerebral hemorrhage). SDHB immunohistochemistry was performed on 217 of the 235 cases. Negative/weak diffuse expression was observed in 37 cases (17%). The recurrence rate was 43% in the SDHB negative/weak diffuse expression group and 2% in the positive group. 5-year DFS 93%, 5-year OS 98%; 10-year DFS 83%, 10-year OS 94%. Younger age (48 years) and extra-adrenal location were predictors of poor prognosis. Large tumor size (6cm), high Ki67 index (5%), and SDHB negative/weak diffuse expression were independent risk factors for postoperative recurrence in PPGLs. Conclusions: Large tumor size, high Ki67 index, and SDHB negative/weak diffuse expression are independent risk factors for postoperative recurrence in PPGLs.

AGIBOT AM1000 versus da Vinci Xi systems for robot-assisted partial nephrectomy: A retrospective propensity score–matched noninferiority study.

e16540 Background: Robot-assisted partial nephrectomy (RAPN) has become a new standard option for clinical T1 renal tumors. Whether outcomes with the AGIBOT AM1000 system are comparable to those with the da Vinci Xi platform remains uncertain. Methods: This single-center, retrospective, propensity score-matched noninferiority study included adults who underwent RAPN between December 2023 and December 2025. The primary endpoint was the operative success rate, defined as completion of the planned RAPN without conversion to laparoscopy or open surgery. Secondary endpoints included docking time, operation time, warm ischemic time (WIT), estimated blood loss (EBL), intraoperative complications, postoperative complications, hemoglobin, serum creatinine, eGFR level, surgical workload assessed by NASA-TLX, and surgical margin status. Postoperative complications were evaluated using the Clavien-Dindo classification. The caliper width for propensity score matching was set at 0.02. The noninferiority margin was set at -10%. Results: Overall, 54 patients in AGIBOT group and 521 patients in da Vinci group were enrolled. After propensity score-matching, 49 patients were matched in each group. All procedures were completed without conversion. Operative success was 100% in both groups; the risk difference was 0.0% (95% CI, -7.3% to 7.3%), meeting the noninferiority criterion. No significant difference was found in operation time, WIT, docking time, intraoperative complications, postoperative complications, serum creatinine, eGFR level, or positive surgical margin. AGIBOT AM1000 was associated with lower EBL (median 30 vs 50 mL; p = 0.014) and a smaller hemoglobin decrease (-3.60% vs -6.02%; p = 0.017). As for the NASA-TLX, significant differences were found in temporal demand and effort. Higher temporal demand when operating with the da Vinci Xi system could be attributed to the high-volume and demanding surgical schedule, while higher effort likely reflected the surgeons’ intension to achieve optimal outcomes while adapting to a new surgical platform. Conclusions: The AGIBOT AM1000 system is safe and effective for RAPN, and its operative success rate, short-term functional and oncological outcomes are comparable to those of da Vinci Xi robotic system.

Real-world landscape of PTEN protein expression and its relationships with HER2 and PSMA in Chinese hormone-sensitive prostate cancer.

e17102 Background: This study aimed to characterize the prevalence of PTEN loss and explore its associations with HER2 and PSMA in a large Chinese hormone-sensitive prostate cancer (HSPC) cohort. Methods: This retrospective real-world cohort study included patients with hormone-sensitive prostate cancer diagnosed by prostate biopsy at Peking University First Hospital between 2021 and 2025. PTEN, HER2 and PSMA protein expression were assessed by immunohistochemistry (IHC). Clinicopathologic variables were collected, and statistical analyses were performed to characterize PTEN expression patterns and evaluate associations with clinical features and the expression of clinically actionable biomarkers. Results: A total of 1,080 patients with HSPC were retrospectively included in the final analysis. Baseline clinicopathologic characteristics of the study population are summarized in Table 1. Clinical T stage at diagnosis was predominantly cT2 (n = 781, 72.7%), followed by cT3a (n = 201, 18.7%), cT3b (n = 60, 5.6%), and cT4 disease (n = 32, 3.0%). PTEN protein expression assessed by immunohistochemistry was available in all patients (n = 1,080). PTEN-negative, low, moderate, and strong expression was identified in 46 (4.3%), 495 (45.8%), 282 (26.1%), and 257 (23.8%) cases, respectively. Spearman rank correlation analyses demonstrated that PTEN expression levels were not significantly associated with age, serum total PSA levels, clinical T stage (p = 0.347), ISUP grade group, or MRI PI-RADS score (p = 0.104).In contrast, PTEN loss was inversely associated with HER2 expression and PSMA expression, as reflected by a positive correlation between PTEN expression levels and HER2 (ρ = 0.222, p &lt; 0.001) and PSMA expression (ρ = 0.808, p &lt; 0.001). Conclusions: Absolute PTEN loss was rare ( &lt; 5%) in the Chinese HSPC population, whereas low PTEN expression was more common. The complementary relationship between PTEN loss and HER2 and PSMA expression underscores molecular heterogeneity and may provide a reference for future precision treatment strategies in hormone-sensitive prostate cancer. Clinicopathologic characteristics according to PTEN expression status in HSPC. Variable PTEN=0 PTEN=1 PTEN=2 PTEN=3 P value Age, y 69(63-72) 69 (63-74) 69 (64.00-74) 70 (65-75) 0.066 PSA, ng/mL 14.82 (7.38-44.68) 14.95 (8.09-50.23) 18.48 (9.45-66.92) 14.51 (8.46-46.09) 0.510 ISUP group=1-2 18 (39.1%) 155 (31.3%) 99 (35.1%) 89 (34.6%) 0.372 ISUP group=3-5 28 (60.9%) 340 (68.7%) 183 (64.9%) 168 (65.4%) 0.372 HER2 status=0/1 5 (10.9%) 56 (11.3%) 43 (15.2%) 90 (35.0%) &lt;0.001 HER2 status=2/3 41 (89.1%) 439 (88.7%) 239 (84.8%) 167 (65.0%) &lt;0.001 PSMA status=0/1 3 (20.0%) 10 (3.8%) 42 (95.5%) 176 (89.3%) &lt;0.001 PSMA status=2/3 12 (80.0%) 256 (96.2%) 2 (4.5%) 21 (10.7%) &lt;0.001 Data are presented as median(Q1-Q3) for continuous variables and n(%) for categorical variables.

Bortezomib plus gemcitabine-cisplatin versus gemcitabine-cisplatin as first-line treatment for advanced biliary tract cancers: A randomized phase II clinical trial with exploratory analysis of PTEN status.

4112 Background: Biliary tract cancers (BTCs) are aggressive malignancies with limited treatment and poor prognosis, including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (perihilar and distal), gallbladder cancer and ampullary cancer. Our previous research indicated that bortezomib is a promising treatment option as proteasome inhibitor in PTEN-loss iCCA patients (Clin Transl Med. 2024 May;14(5): e1675). In this randomized phase II clinical trial, we expanded the indication to BTCs and explored clinical benefit and safety of bortezomib plus gemcitabine-cisplatin (GPB) compared with gemcitabine-cisplatin (G based) as first line treatment for advanced BTCs and further evaluated the potential predictive value of PTEN status. Methods: Between September 1, 2020, and December 31,2023, a total of 105 patients were screened. 59 patients were enrolled. The 59 patients were randomly assigned to either GPB group (n = 32) or G based group (n=27). PTEN status was not known at the time of randomization. PTEN immunohistochemical staining was subsequently performed in all patients identifying 18 patients (30.5%) with PTEN loss (PTEN=0) and 41 patients (69.5%) with PTEN expression (PTEN=1). The GPB regimen consisted of gemcitabine 1000 mg/m 2 day 1,8, cisplatin 75 mg/m 2 day 1, 8, plus bortezomib 1.3 mg/m 2 day 1, 4, 8, and 11 of a 21-day cycle. The G based group received gemcitabine based regimens including G-cisplatin (GP), G-Oxaliplatin (GMOX) or G-S-1 (GS). The primary endpoint was mediate progress-free survive (mPFS) according to RECIST v 1.1. Statistical analyses were performed using SPSS. The last follow-up date was July 25, 2025. Results: With a median follow-up of 31.8 months (95% CI, 21.3–42.3), the mPFS was 5.49 months in the GPB group and in 5.95 months in the G-based group, with no significant statistically significant difference (HR, 0.86; 95% CI, 0.50–1.47; P = 0.59). The median overall survival (OS) was 16.23 months with GPB and 15.01 months with G-based group (HR, 0.88;95% CI, 0.47–1.67; P = 0.70). Biomarker analyses showed that within the GPB group, patients with PTEN loss had significantly longer PFS than those with PTEN expression (9.26 vs. 3.35 months; HR, 0.64; 95% CI, 0.42–0.96; P = 0.03). Among PTEN=0 patients, GPB was associated with improved mPFS compared with G-based (9.26 vs. 3.59 months; HR, 0.25; 95% CI, 0.08–0.78; P = 0.01). Grade ≥3 CTCAE AEs were mainly hematologic, with thrombocytopenia most common (50.0% vs 14.8%). Conclusions: Although no significant survival benefit was observed in the overall GPB group, a clinically meaningful improvement in mPFS was identified in the PTEN-loss subgroup. PTEN status may serve as a promising biomarker for identifying patients more likely to benefit from GPB therapy, warranting further prospective validation. Clinical trial information: ChiCTR2000035916.

Germline genetic correlates in metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT) plus non-steroidal anti-androgen (NSAA) or enzalutamide (ENZA): Correlative study of ENZAMET (ANZUP 1304).

5099 Background: The international, randomized, phase III ENZAMET trial (n=1125) showed improved overall survival (OS) with ADT plus ENZA vs ADT plus NSAA for mHSPC. Observational studies showed that the mHSPC genetic landscape is comparable to castration resistant prostate cancer (CRPC). Prognostic and predictive impact of inherited pathogenic variants (PVs), including those affecting BRCA1 , BRCA2 and other DNA damage and repair (DDR) genes, on androgen receptor pathway inhibitor (ARPI)-treated mHSPC is under investigation. Methods: Whole exome sequencing of germline DNA prospectively obtained from ENZAMET pts. Variant annotation and effect prediction identified PVs (altered “+” vs wild-type “-”). Prognostic effect of PVs was assessed within arms. Endpoints: clinical progression-free survival (PFS) and OS by Kaplan-Meier method. Hazard ratios (HRs) were estimated using Cox models. Multivariable analyses (MVA) adjusted for Gleason score (GS), volume (vol), metachronous vs synchronous and docetaxel (D) use. Results: All 847 available samples were successfully sequenced. 123 PVs were identified in 117 (13.8%) pts, of which 46 (5.43%) pts harbored a PV in ≥1 DDR gene. The rate of pathogenic germline BRCA1 / BRCA2 (BRCA) PVs was 2.13% (39.1% of DDR PVs). Proportions of arm, D use, vol and visceral disease were similar between DDR+ vs DDR- and BRCA+ vs BRCA-. Synchronous mHSPC in DDR+ vs DDR- and BRCA+ vs BRCA- was 41.3% vs 63.0% and 44.4% vs 62.2%, respectively. PFS and OS estimates were similar between BRCA+ and BRCA- groups in the overall cohort (5-yr OS: 55.6% vs 61%; 3-yr PFS: 50% vs 53.5%, respectively) and in the ENZA arm, but differed in the NSAA arm (Table). BRCA+ treated with ADT+NSAA (67% D use) had shortest PFS (median PFS: 11.3m vs 24.9m [BRCA-], HR 1.85, 95% CI: 0.95-3.6). D use associated with poorer outcomes. In MVA, the HR(PFS) for BRCA+ in NSAA arm was 1.47 (95% CI 0.71-3.04, p=0.3) vs ENZA arm: HR 0.98, (95% CI 0.31-3.08, p=0.97). Vol and GS were independently significant in both arms. Conclusions: In one of the largest germline genetic studies from a phase III mHSPC trial, we observed recurrent DDR and BRCA PVs at a lower rate than institutional cohorts. Germline BRCA PVs are associated with a shorter PFS on ADT+NSAA – an effect which may be mitigated by ENZA. Validation in independent trial cohorts is ongoing. Outcomes by arm/docetaxel and BRCA status. n 5y-OS % (95% CI) 3y-PFS % (95% CI) NSAA only BRCA- 238 56.6 (50.0-62.7) 42.9 (36.5-49.1) NSAA only BRCA+ 3 66.7 (5.4-94.5) 66.7 (5.4-94.5) NSAA+D BRCA- 176 54.7 (47.0-61.8) 32.5 (25.7-39.6) NSAA+D BRCA+ 6 33.3 (4.6-67.6) 16.7 (0.8-51.7) ENZA only BRCA- 228 70.6 (64.2-76.0) 73.3 (67.0-78.5) ENZA only BRCA+ 7 71.4 (25.8-92.0) 71.4 (25.8-92.0) ENZA+D BRCA- 187 60.7 (53.2-67.3) 62.3 (54.9-58.8) ENZA+D BRCA+ 2 NE 50.0 (0.6-91.0)

Perioperative therapy with tifcemailmab plus toripalimab and chemotherapy for resectable thoracic esophageal squamous cell carcinoma (BT-NICE trial): A prospective phase II study.

4087 Background: Tifcemailmab is a first-in-class humanized monoclonal antibody targeting B- and T-lymphocyte attenuator (BTLA), a novel inhibitory immune checkpoint. This phase II BT-NICE trial represents the first clinical study designed to evaluate the efficacy and safety of a perioperative treatment regimen that combines a BTLA inhibitor (tifcemailmab), a PD-1 inhibitor (toripalimab), and chemotherapy for resectable thoracic ESCC. Methods: Patients(pts) with histologically confirmed, resectable thoracic ESCC (clinical stage cT1b-3N1-3M0 or cT2-3N0M0) were enrolled. They received 2 cycles of neoadjuvant therapy with tifcemailmab, toripalimab, and standard chemotherapy (every 3 weeks). Following radical esophagectomy, pts with a pathological complete response (pCR) received up to 15 cycles of adjuvant dual immunotherapy (tifcemailmab + toripalimab). Pts without a pCR received 2 cycles of adjuvant chemotherapy plus dual immunotherapy, followed by dual immunotherapy for up to 13 cycles. The primary endpoint was pCR rate. Secondary endpoints included major pathological response (MPR) rate, objective response rate (ORR), R0 resection rate, adverse events (AEs), event-free survival (EFS), and overall survival (OS). Results: Between October 20, 2024, and September 30, 2025, a total of 25 patients were successfully enrolled and underwent surgery after completing neoadjuvant therapy. The median age was 63 years (range 53-75), and 19 (76.0%) were male. Most pts (23/25, 92.0%) had stage III disease. The R0 resection rate was 100% (25/25). The ORR (neoadjuvant) was 96.0% (24/25). The MPR rate was 56.0% (14/25), and the pCR rate was 40.0% (10/25). Pathologic downstaging was achieved in 84.0% of patients. Grade 3-4 treatment-related AEs occurred in 24.0% (6/25) of pts, and grade 3-4 immune-related AEs occurred in 20.0% (5/25); the most common were rash and hypothyroidism. Overall postoperative complications were 20% (5/25). One pt experienced postoperative complications (pulmonary infection and anastomotic leakage). No treatment-related surgical delays or 30-day mortality occurred. Conclusions: The BT-NICE regimen demonstrates promising efficacy and is feasible with a manageable safety profile in pts with locally advanced, resectable ESCC. This study provides the first clinical evidence supporting the incorporation of a BTLA inhibitor into a perioperative treatment paradigm for ESCC. Clinical trial information: NCT06588335 .

Impact of AI-augmented histopathology review on next-generation sequencing (NGS) success.

1618 Background: Insufficient nucleic acid quantity (QNS) can compromise NGS success (QNS rates can be &gt;20%), necessitating re-biopsies and delaying therapy. While interventions like extended de-crosslinking (EXT) can rescue samples with low total nucleic acid (TNA) yield tissues, they prolong processing times, demanding a precise method to identify samples requiring such processing. We developed an AI system, Paige Predict (PP), that analyzes digitized H&amp;E slides to predict NGS QNS and recommend tissue input quantity. This study evaluates PP in two contexts: (1) optimizing internal lab workflows by selectively routing high-risk samples to EXT, and (2) exploring its utility in an external setting, Cedars-Sinai (CS), to triage samples for comprehensive Tempus genomic profiling (CGP), requiring &gt;50ng input, vs targeted low-input assays (&gt;5ng) performed at CS. Methods: We conducted a validation study in the Tempus lab comparing a baseline period prior to introduction of EXT (July 2024 - Sept 2024 n=17,026) against an intervention period (Oct 2025 - Nov 2025, n=12,975) where PP automatically routed at-risk samples to EXT. To evaluate external utility, we also performed a retrospective analysis on a cohort of CS pts. We assessed PP’s ability to predict CGP QNS, and compared it against pathologist assessment for inter-institutional sample referral. Results: In the validation study, PP-guided EXT routing reduced joint DNA+RNA QNS rates by 19.6%, with a number needed to test (NNT; 1/Absolute Rate Reduction) indicating that for every 40.2 pts, one received a result that would otherwise not have. RNA QNS rates reduced by 15.9% (NNT 63.7) relative to the baseline period. This reduction was achieved while decreasing net tissue input by 16.7% and increasing TNA yields in the optimal range (100–1500ng) by 19.0% (NNT 10.1). Similar benefits were observed in the NSCLC subset. In the external CS cohort, PP could have triaged 74% of samples that failed Tempus CGP to low input sequencing at CS. Conversely, PP indicated that over 70% of samples sequenced at CS could have succeeded with Tempus CGP. Conclusions: PP significantly reduces NGS failure rates and improves tissue stewardship by deploying rescue workflows only when necessary. These analyses lay the groundwork for a future multi-institution prospective trial and establish PP as a scalable AI tool to amplify access to precision oncology. (Tempus) EXT routing validation metrics (N=12,975 all / 3,530 NSCLC) PP % change vs. baseline (p-value) / NSCLC subset NNT vs. baseline / NSCLC subset (Cedars-Sinai) retrospective analysis metrics(N=1,082) PP % flagged for QNS (50ng) DNA+RNA QNS rate -19.6% (2.0e-9) / -30.4% (8.6e-9) 40.2 / 24.4 DNA QNS 74% DNA pass &amp; RNA QNS rate -15.9% (1.1e-4) / -3.1% (7.0 e-1) 63.7 / 384.6 DNA Pass 16.4% Optimal TNA range +19.0% (2.0e-12) / +21.0% (5.3e-11) 10.1 / 9.0 Not referred 28.6% Median N input slides -16.7% (3.0e-11) / -14.3% (6.4e-7) N/A

Risk of lung cancer in systemic lupus erythematosus patients with interstitial lung disease: A retrospective cohort study.

e20088 Background: Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disease that may affect virtually any organ system including the joints, skin, kidneys, heart, and lungs. Interstitial lung disease (ILD) is an uncommon pulmonary manifestation of SLE and is seen in other rheumatological diseases such as rheumatoid arthritis (RA). While ILD is a well-established risk factor for lung cancer in RA, its association with lung cancer in SLE remains poorly characterized. This study aims to assess whether ILD in SLE is associated with an increased risk of lung cancer. Methods: We conducted a retrospective cohort study using TriNetX, a multi-institutional, de-identified EHR database, restricted to adults aged ≥18 years. The exposure cohort included SLE patients with ILD while the control cohort included SLE patients without ILD. Patients with drug induced lupus erythematosus, systemic sclerosis, dermatopolymyositis, and prior history of lung cancer were excluded. One-to-one propensity score matching was performed based on age, sex, race, tobacco use, obesity, hypertension, type 2 diabetes mellitus, chronic kidney disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, connective tissue diseases, and exposures to medications such as glucocorticoids, immunosuppressants, and antineoplastics. The primary outcome was defined as the development of lung cancer, and the secondary outcome was defined as all cause mortality. Results: After matching, 10,773 patients were included per cohort. Lung cancer occurred in 143 patients in the exposure cohort and 62 patients in the control cohort with a risk ratio of 2.31 (95% CI 1.71-3.10) and an odds ratio of 2.32 (95% CI 1.72-3.14). All-cause mortality occurred in 1947 patients in the exposure group and 1316 patients in the control group with a risk ratio of 1.48 (95% CI 1.39-1.58) and an odds ratio of 1.59 (95% CI 1.47-1.71). Conclusions: ILD in SLE is associated with a 2.3-fold increased risk of lung cancer and a 1.5-fold increased risk of all-cause mortality, with an absolute risk of 1.33% and 18.14% respectively. These findings suggest that chronic pulmonary inflammation and fibrosis in SLE-ILD may drive lung carcinogenesis as is well described in idiopathic pulmonary fibrosis and RA-ILD. Collectively, these results highlight ILD as a clinically meaningful risk marker in SLE patients, supporting targeted lung cancer surveillance in this population.

Beyond the tumor: Cardiovascular mortality in female ovarian cancer patients—A retrospective analysis of the last 2 decades (1999-2020).

e17594 Background: Cardiovascular disease (CVD) is the leading cause of death among women with ovarian cancer. This study investigates cardiovascular mortality in women with ovarian cancer across the United States, assessing trends by geography and urbanization. Methods: Mortality data from the CDC WONDER database (1999–2020) were analyzed. Females with ovarian cancer listed on the death certificate and cardiovascular disease as the cause of death were identified using ICD-10 codes. Age-adjusted mortality rates (per 100,000) were calculated and stratified by census region and urbanization. Trends were evaluated using Average Annual Percent Change (AAPC) calculated by the Joinpoint Regression Program V5.4.0. Results: From 1999 to 2018, cardiovascular mortality in ovarian cancer patients declined, with an APC of –2.09%, consistent across regions and urbanization levels. However, from 2018 to 2020, a concerning reversal occurred, with mortality increasing by +3.79% per year. The abrupt rise in mortality is observed in the Midwest region, with an APC of +3.99, and in small and medium metro regions, with APCs of +7.38 and +6.46, respectively. This reversal in cardiovascular mortality in ovarian cancer from 2018 to 2020 is likely due to the COVID-19 pandemic that disrupted screening and treatment. Conclusions: This 21-year analysis demonstrates a long-term decline in cardiovascular mortality among women with ovarian cancer, followed by a sharp reversal from 2018 to 2020. This increase suggests the urgent need for public health interventions to reduce cardiovascular risk among ovarian cancer patients.

Comparative clinical outcomes with lenvatinib versus cabozantinib post-progression on first-line immunotherapy in patients with advanced hepatocellular carcinoma.

e16246 Background: First line systemic therapy for advanced hepatocellular carcinoma (HCC) includes immune checkpoint inhibitor (ICI) combination therapy, with tyrosine kinase inhibitors (TKIs), lenvatinib or cabozantinib, commonly used as second line therapy. However, there is limited data comparing efficacy of TKIs following first line ICI therapy. In the present study, we compared survival and risk of hospitalization in a propensity score matched analysis of patients who received lenvatinib or cabozantinib following progression on first line ICI therapy in patients with advanced HCC. Methods: We performed a retrospective cohort study using data from TriNetX, a healthcare database of over 150 million patients in the United States. We identified adult patients with a history of HCC who received atezolizumab plus bevacizumab (A+B) or durvalumab plus tremelimumab (D+T) as first line treatment. We then stratified patients by use of lenvatinib or cabozantinib in the subsequent line setting. Propensity score matching (PSM) was conducted between those who received lenvatinib and those who received cabozantinib, matching for demographic factors (age, sex, race), clinical characteristics (history of alcohol use, ascites, esophageal varices, or viral hepatitis), and laboratory parameters [platelets, albumin, bilirubin, INR and alpha-1-fetoprotein (AFP)]. Results: We identified 416 patients who were initially treated with either A+B or D+T, with 327 patients receiving A+B and 89 patients receiving D+T. Of these, 336 patients (80.8%) subsequently received lenvatinib and 80 patients (19.2%) received cabozantinib. Baseline characteristics of demographic factors, clinical characteristics, and laboratory parameters were comparable between patients in the lenvatinib arm and cabozantinib arm with all standardized mean differences (SMD) &lt; 0.10. After PSM, 76 patients were included in the analyses, with all variables adequately balanced. There was no significant difference in the risk of hospitalization between those receiving lenvatinib or cabozantinib at 3 months [31.6% vs 34%, odds ratio (OR) 1.13, 95% confidence interval (CI) 0.57-2.2]. There was also no significant difference in mOS between those receiving lenvatinib and cabozantinib [9.5 vs 9.0 months, hazard ratio (HR) 1.03, 95% CI 0.62-1.7]. Conclusions: In patients with HCC who received lenvatinib or cabozantinib as second-line therapy following first-line ICI combination therapy, we found no significant differences in rate of hospitalization or survival. These findings suggest that either option may be appropriate, and decisions may be based in side effect profile and patient preferences. Prospective studies will be important to further assess differences in patient outcomes.