[68Ga]Ga-FAPI-04 PET/MR imaging strategy in management of Krukenberg tumors (KTs) from gastric signet-ring-cell carcinoma: to overcome limitation of [68Ga]Ga-FAPI-04 PET imaging in KTs.

PURPOSE: To compare performance of whole-body [68Ga]Ga-FAPI-04 and [18F]FDG PET imaging in the detection of Krukenberg tumors (KTs), primary site and extra-ovarian metastases of gastric signet-ring-cell carcinoma (GSRCC), and evaluate the value of [68Ga]Ga-FAPI-04 PET/MR imaging strategy and its potential impact on the management of KTs from GSRCC. METHODS: Twelve patients with twenty-three KTs from GSRCC, who underwent both [68Ga]Ga-FAPI-04 pelvic PET/MR and whole-body [68Ga]Ga-FAPI-04 and [18F]FDG PET imaging were retrospectively analyzed. [68Ga]Ga-FAPI-04 and [18F]FDG uptakes were compared by using Wilcoxon signed-rank test or paired t test. McNemar's test was used to compare lesion detectability between two modalities. Two-tailed P<0.05 was considered statistically significant. Immunohistochemistry staining was utilized to analyze the fibroblast activation protein (FAP) expression in KTs. RESULTS: A total of 12 patients with 23 KTs from GSRCC (8 synchronous and 4 metachronous) were evaluated. [68Ga]Ga-FAPI-04 was superior to [18F]FDG PET in detecting primary sites of GSRCC (100% [11/11] vs. 18.2% [2/11], p = 0.002), involved lymph nodes (90.9% [10/11] vs. 54.5% [6/11], p = 0.046) and peritoneal metastases (100% [12/12] vs. 41.7% [5/12], p = 0.008), with higher SUVmax and TBR (all p < 0.005). Both tracers had limited value in identifying KTs, with 100% false negative rate on [68Ga]Ga-FAPI-04 PET and a low detection rate of 8.7% on [18F]FDG PET. Fap immunohistochemistry showed negative or slight FAP expression in neoplastic signet ring cells and ovarian stroma. [68Ga]Ga-FAPI-04 PET/MR imaging strategy greatly improved the detection rate of Krukenberg tumors (87%, 20/23). After adding diffusion-weighted imaging (DWI), the detection rate was further improved (87.5% vs. 100%, p = 0.083). [68Ga]Ga-FAPI-04 PET/MR imaging strategy either upgraded TNM staging or changed treatment management in twelve patients. CONCLUSIONS: [68Ga]Ga-FAPI-04 PET outperformed [18F]FDG PET in detecting primary site and most extra-ovarian metastases of GSRCC, but both tracers had limited value in identifying Krukenberg tumors. Pelvis MRI should be applied to compensate the limitation of [68Ga]Ga-FAPI-04 PET imaging to identify Krukenberg tumours. The [68Ga]Ga-FAPI-04 PET/MR imaging strategy has the potential to impact treatment decisions for GSRCC patients with KTs.

Conversion surgery intervention versus continued systemic therapy in patients with a response after PD-1/PD-L1 inhibitor-based combination therapy for initially unresectable biliary tract cancer: a retrospective cohort study.

BACKGROUND: The role of conversion surgery in patients with unresectable biliary tract cancer (BTC) who responded positively to PD-1/PD-L1 inhibitor-based therapy remains unclear. This study aimed to assess the outcomes in patients with or without conversion surgery. METHODS: In this cohort study, patients with advanced BTC who received combination therapy with PD-1/PD-L1 inhibitors from July 2019 to January 2023 were retrospectively. Patients who exhibited positive responses and met the criteria for conversion surgery were enrolled, and their surgical and oncological outcomes were analyzed. RESULTS: Out of 475 patients, 34 who met the conversion resection criteria were enrolled. The median follow-up was 40.5 months post-initiation of systemic therapy. Ultimately, 13 patients underwent conversion surgery, while 21 received continuation of systemic treatment alone (non-surgical group). The median interval from the initial antitumor therapy to surgery was 6.7 (interquartile range [IQR] 4.9-9.2) months. Survival with conversion surgery was significantly longer than the non-surgical cohort, with a median progression-free survival (PFS) (unreached vs. 12.4 mo; hazard ratio 0.17 [95% CI 0.06-0.48]; P=0.001) and overall survival (OS) (unreached vs. 22.4 mo; hazard ratio 0.28 [95% CI 0.09-0.84]; P=0.02), respectively. After a median postoperative follow-up of 32.2 months in the surgical cohort, 8 patients survived without recurrence. The estimated 3-year OS, PFS and recurrence-free survival rate in the surgical cohort were 59.9%, 59.2% and 60.6%, respectively. The R0 resection rate reached 92.3%, with 2 achieving a pathological complete response. One patient experienced a Clavien-Dindo grade 3 complication without surgery-related mortality. No serious adverse events or surgical delays were observed. Multivariate analysis indicated that conversion surgery was independently associated with OS (P=0.03) and PFS survival (P=0.003). CONCLUSION: Conversion surgery appears safe and offers survival benefits to patients responding to immune checkpoint inhibitors (ICIs)-based combinations. However, further studies are required to validate this strategy in the era of immunotherapy.

Neoadjuvant targeted immunotherapy followed by surgical resection versus upfront surgery for hepatocellular carcinoma with macrovascular invasion: A multicenter study.

Background: This study aimed to investigate the safety and efficacy of preoperative targeted immunotherapy followed by surgical resection for hepatocellular carcinoma (HCC) patients with macrovascular invasion. Method: Clinical information of HCC patients with macrovascular invasion was collected from four medical centers. These patients were divided into two cohorts: the upfront surgery group (n=40) and the neoadjuvant group (n=22). Comparisons between the two groups were made with appropriate statistical methods. Results: HCC Patients with macrovascular invasion in the neoadjuvant group were associated with increased incidence of postoperative ascites (72.73% vs. 37.5%, P=0.008), but shorter postoperative hospital stay (10 days vs. 14 days, P=0.032). Furthermore, targeted immunotherapy followed by surgical resection significantly reduced the postoperative recurrence rate at both 3 months and 1 year (9% versus 28.9%, 32.1% versus 67.9%, respectively; P=0.018), but increased the postoperative nononcologic mortality rate within 1 year (20.1% vs. 2.8%; P= 0.036). Conclusion: For HCC patients with macrovascular invasion, preoperative targeted immunotherapy significantly decreased the postoperative tumor recurrence rate while maintaining relative safety, but such a treatment may also result in chronic liver damage and increased risk of nononcologic mortality.

Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

Variation in placentophagy in golden snub-nosed monkeys (Rhinopithecus roxellana) reflects nutritional constraints.

Golden snub-nosed monkeys show inconsistent frequency of placentophagy between wild and captive populations, with almost all births in the wild but around half of the births in captivity accompanied by the female's consumption of placenta. This aligns with nutritional demands-driven placentophagy, as captive populations are generally under less nutritional constraints for breeding females than the wild population. Placentophagy is probably adaptive in the wild and under positive selection due to nutritional benefits to both mothers and infants.

Preclinical development of novel PD-L1 tracers and first-in-human study of [68Ga]Ga-NOTA-RW102 in patients with lung cancers.

BACKGROUND: The programmed cell death protein-1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis critically facilitates cancer cells' immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 axis have shown remarkable efficacy in various tumors. Immuno-positron emission tomography (ImmunoPET) imaging of PD-L1 expression may help reshape solid tumors' immunotherapy landscape. METHODS: By immunizing an alpaca with recombinant human PD-L1, three clones of the variable domain of the heavy chain of heavy-chain only antibody (VHH) were screened, and RW102 with high binding affinity was selected for further studies. ABDRW102, a VHH derivative, was further engineered by fusing RW102 with the albumin binder ABD035. Based on the two targeting vectors, four PD-L1-specific tracers ([68Ga]Ga-NOTA-RW102, [68Ga]Ga-NOTA-ABDRW102, [64Cu]Cu-NOTA-ABDRW102, and [89Zr]Zr-DFO-ABDRW102) with different circulation times were developed. The diagnostic efficacies were thoroughly evaluated in preclinical solid tumor models, followed by a first-in-human translational investigation of [68Ga]Ga-NOTA-RW102 in patients with non-small cell lung cancer (NSCLC). RESULTS: While RW102 has a high binding affinity to PD-L1 with an excellent KD value of 15.29 pM, ABDRW102 simultaneously binds to human PD-L1 and human serum albumin with an excellent KD value of 3.71 pM and 3.38 pM, respectively. Radiotracers derived from RW102 and ABDRW102 have different in vivo circulation times. In preclinical studies, [68Ga]Ga-NOTA-RW102 immunoPET imaging allowed same-day annotation of differential PD-L1 expression with specificity, while [64Cu]Cu-NOTA-ABDRW102 and [89Zr]Zr-DFO-ABDRW102 enabled longitudinal visualization of PD-L1. More importantly, a pilot clinical trial shows the safety and diagnostic value of [68Ga]Ga-NOTA-RW102 immunoPET imaging in patients with NSCLCs and its potential to predict immune-related adverse effects following PD-L1-targeted immunotherapies. CONCLUSIONS: We developed and validated a series of PD-L1-targeted tracers. Initial preclinical and clinical evidence indicates that immunoPET imaging with [68Ga]Ga-NOTA-RW102 holds promise in visualizing differential PD-L1 expression, selecting patients for PD-L1-targeted immunotherapies, and monitoring immune-related adverse effects in patients receiving PD-L1-targeted treatments. TRIAL REGISTRATION NUMBER: NCT06165874.

Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial.

BACKGROUND: Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC. METHODS: In this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon's two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy. RESULTS: Sixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6-51.9) and 90.3% (56/62, 95% CI, 80.1-96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8-not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7-94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients. CONCLUSIONS: Tislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04401800).

Patients with hepatocellular carcinoma extrahepatic metastases can benefit from hepatic arterial infusion chemotherapy combined with lenvatinib plus programmed Death-1 inhibitors.

BACKGROUND: Lenvatinib plus Programmed Death-1 (PD-1) inhibitors (LEN-P) have been recommended in China for patients with advanced hepatocellular carcinoma (HCC). However, they provide limited survival benefits to patients with extrahepatic metastases. We aimed to investigate whether combining hepatic arterial infusion chemotherapy (HAIC) with LEN-P could improve its efficacy. MATERIALS AND METHODS: This multi-center cohort study included patients with HCC extrahepatic metastases who received HAIC combined with LEN-P (HAIC-LEN-P group, n=127) or LEN-P alone (n=103) as the primary systemic treatment between January 2019 and December 2022. Baseline data were balanced using a one-to-one propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). RESULTS: After PSM, the HAIC-LEN-P group significantly extended the median overall survival (mOS) and median progression-free survival (mPFS), compared with the LEN-P group (mOS: 27.0 months vs. 9.0 months, P<0.001; mPFS: 8.0 months vs. 3.0 months, P=0.001). After IPTW, the mOS (hazard ratio (HR)=0.384, P<0.001) and mPFS (HR=0.507, P<0.001) were significantly higher in the HAIC-LEN-P group than in the LEN-P group. The HAIC-LEN-P group's objective response rate was twice as high as that of the LEN-P group (PSM cohort: 67.3% vs. 29.1%, P<0.001; IPTW cohort: 66.1% vs. 27.8%, P<0.001). Moreover, the HAIC-LEN-P group exhibited no noticeable increase in the percentages of grade 3 and 4 adverse events compared with the LEN-P group (P>0.05). CONCLUSION: HAIC can improve the efficacy of LEN-P in patients with HCC extrahepatic metastases and may be an alternative treatment for advanced HCC management.

Understanding cellulose pyrolysis via ab initio deep learning potential field.

Comprehensive and dynamic studies of cellulose pyrolysis reaction mechanisms are crucial in designing experiments and processes with enhanced safety, efficiency, and sustainability. The details of the pyrolysis mechanism are not readily available from experiments but can be better described via molecular dynamics (MD) simulations. However, the large size of cellulose molecules challenges accurate ab initio MD simulations, while existing reactive force field parameters lack precision. In this work, precise ab initio deep learning potentials field (DPLF) are developed and applied in MD simulations to facilitate the study of cellulose pyrolysis mechanisms. The formation mechanism and production rate of both valuable and greenhouse products from cellulose at temperatures larger than 1073 K are comprehensively described. This study underscores the critical role of advanced simulation techniques, particularly DLPF, in achieving efficient and accurate understanding of cellulose pyrolysis mechanisms, thus promoting wider industrial applications.

A toroidal SAW gyroscope with focused IDTs for sensitivity enhancement.

A surface acoustic wave (SAW) gyroscope measures the rate of rotational angular velocity by exploiting a phenomenon known as the SAW gyroscope effect. Such a gyroscope is a great candidate for application in harsh environments because of the simplification of the suspension vibration mechanism necessary for traditional microelectromechanical system (MEMS) gyroscopes. Here, for the first time, we propose a novel toroidal standing-wave-mode SAW gyroscope using focused interdigitated transducers (FIDTs). Unlike traditional SAW gyroscopes that use linear IDTs to generate surface acoustic waves, which cause beam deflection and result in energy dissipation, this study uses FIDTs to concentrate the SAW energy based on structural features, resulting in better focusing performance and increased SAW amplitude. The experimental results reveal that the sensitivity of the structure is 1.51 µV/(°/s), and the bias instability is 0.77°/s, which are improved by an order of magnitude compared to those of a traditional SAW gyroscope. Thus, the FIDT component can enhance the performance of the SAW gyroscope, demonstrating its superiority for angular velocity measurements. This work provides new insights into improving the sensitivity and performance of SAW gyroscopes.

The superior detection rate of total-body [68Ga]Ga-PSMA-11 PET/CT compared to short axial field-of-view [68Ga]Ga-PSMA-11 PET/CT for early recurrent prostate cancer patients with PSA < 0.2 ng/mL after radical prostatectomy.

BACKGROUND AND PURPOSE: [68Ga]Ga-PSMA PET imaging has been extensively utilized for the detection of biochemical recurrence (BCR) in prostate cancer. However, the detection rate declines to merely 10-40% when PSA levels are < 0.2 ng/mL employing short axial field-of-view (SAFOV) PET. Prior studies exhibited superior detection rates with total-body [68Ga]Ga-PSMA-11 PET compared to SAFOV [68Ga]Ga-PSMA-11 PET in BCR patients with PSA > 0.2 ng/mL. Nevertheless, the diagnostic utility of total-body [68Ga]Ga-PSMA-11 PET for BCR patients when PSA is < 0.2 ng/mL remains unclear. This study aimed to assess whether total-body [68Ga]Ga-PSMA-11 PET/CT could improve the detection rate compared to SAFOV [68Ga]Ga-PSMA-11 PET/CT in BCR patients with PSA < 0.2 ng/mL. METHODS: Eighty BCR patients with PSA < 0.2 ng/mL underwent total-body [68Ga]Ga-PSMA-11 PET/CT. These patients were matched by baseline qualities to another 80 patients who received SAFOV [68Ga]Ga-PSMA-11 PET/CT. The detection rates of total-body [68Ga]Ga-PSMA-11 PET/CT and SAFOV [68Ga]Ga-PSMA-11 PET/CT were compared utilizing a chi-square test and stratified analysis. Image quality of total-body [68Ga]Ga-PSMA PET/CT and SAFOV [68Ga]Ga-PSMA-11 PET/CT was assessed based on subjective scoring and objective parameters. The objective parameters measured were SUVmax, SUVmean, standard deviation (SD) of SUV, and signal-to-noise ratio (SNR) of liver and gluteus maximus. RESULTS: The image quality of total-body [68Ga]Ga-PSMA PET/CT was superior to that of SAFOV [68Ga]Ga-PSMA-11 PET/CT in both early and delayed scans. The detection rate of total-body [68Ga]Ga-PSMA PET/CT for BCR patients with PSA < 0.2 ng/mL was significantly higher than that of SAFOV [68Ga]Ga-PSMA-11 PET/CT (73.75% vs. 43.75%, P < 0.001). Total-body [68Ga]Ga-PSMA PET/CT resulted in noteworthy modifications to the treatment regimen when contrasted with SAFOV [68Ga]Ga-PSMA-11 PET/CT. CONCLUSIONS: In BCR patients with PSA < 0.2 ng/mL, total-body [68Ga]Ga-PSMA-11 PET/CT not only demonstrated a significantly higher detection rate compared to SAFOV [68Ga]Ga-PSMA-11 PET/CT but also led to significant alterations in treatment regimens.

Biomimetic Dual-Network Collagen Fibers with Porous and Mechanical Cues Reconstruct Neural Stem Cell Niche via AKT/YAP Mechanotransduction after Spinal Cord Injury.

Tissue engineering scaffolds can mediate the maneuverability of neural stem cell (NSC) niche to influence NSC behavior, such as cell self-renewal, proliferation, and differentiation direction, showing the promising application in spinal cord injury (SCI) repair. Here, dual-network porous collagen fibers (PCFS) are developed as neurogenesis scaffolds by employing biomimetic plasma ammonia oxidase catalysis and conventional amidation cross-linking. Following optimizing the mechanical parameters of PCFS, the well-matched Young's modulus and physiological dynamic adaptability of PCFS (4.0 wt%) have been identified as a neurogenetic exciter after SCI. Remarkably, porous topographies and curving wall-like protrusions are generated on the surface of PCFS by simple and non-toxic CO2 bubble-water replacement. As expected, PCFS with porous and matched mechanical properties can considerably activate the cadherin receptor of NSCs and induce a series of serine-threonine kinase/yes-associated protein mechanotransduction signal pathways, encouraging cellular orientation, neuron differentiation, and adhesion. In SCI rats, implanted PCFS with matched mechanical properties further integrated into the injured spinal cords, inhibited the inflammatory progression and decreased glial and fibrous scar formation. Wall-like protrusions of PCFS drive multiple neuron subtypes formation and even functional neural circuits, suggesting a viable therapeutic strategy for nerve regeneration and functional recovery after SCI.

A Fairness-Enhanced Federated Learning Scheduling Mechanism for UAV-Assisted Emergency Communication.

As the frequency of natural disasters increases, the study of emergency communication becomes increasingly important. The use of federated learning (FL) in this scenario can facilitate communication collaboration between devices while protecting privacy, greatly improving system performance. Considering the complex geographic environment, the flexible mobility and large communication radius of unmanned aerial vehicles (UAVs) make them ideal auxiliary devices for wireless communication. Using the UAV as a mobile base station can better provide stable communication signals. However, the number of ground-based IoT terminals is large and closely distributed, so if all of them transmit data to the UAV, the UAV will not be able to take on all of the computation and communication tasks because of its limited energy. In addition, there is competition for spectrum resources among many terrestrial devices, and all devices transmitting data will bring about an extreme shortage of resources, which will lead to the degradation of model performance. This will bring indelible damage to the rescue of the disaster area and greatly threaten the life safety of the vulnerable and injured. Therefore, we use user scheduling to select some terrestrial devices to participate in the FL process. In order to avoid the resource waste generated by the terrestrial device resource prediction, we use the multi-armed bandit (MAB) algorithm for equipment evaluation. Considering the fairness issue of selection, we try to replace the single criterion with multiple criteria, using model freshness and energy consumption weighting as reward functions. The state of the art of our approach is demonstrated by simulations on the datasets.

Biomarkers and prognostic factors of PD-1/PD-L1 inhibitor-based therapy in patients with advanced hepatocellular carcinoma.

Systemic therapies using programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors have demonstrated commendable efficacy in some patients with advanced hepatocellular carcinoma (HCC); however, other individuals do not respond favorably. Hence, identifying the biomarkers, the prognostic factors, and their underlying mechanisms is crucial. In this review, we summarized the latest advancements in this field. Within the tumor microenvironment, PD-L1 expression is commonly utilized to predict response. Moreover, the characteristics of tumor-infiltrating lymphocytes are associated with the effectiveness of immunotherapy. Preclinical studies have identified stimulatory dendritic cells, conventional dendritic cells, and macrophages as potential biomarkers. The emergence of single-cell sequencing and spatial transcriptomics has provided invaluable insights into tumor heterogeneity through the lens of single-cell profiling and spatial distribution. With the widespread adoption of next-generation sequencing, certain genomic characteristics, including tumor mutational burden, copy number alterations, specific genes (TP53, CTNNB1, and GZMB), and signaling pathways (WNT/ß-catenin) have been found to correlate with prognosis. Furthermore, clinical features such as tumor size, number, and metastasis status have demonstrated prognostic value. Notably, common indicators such as the Child-Pugh score and Eastern Cooperative Oncology Group score, which are used in patients with liver diseases, have shown potential. Similarly, commonly employed laboratory parameters such as baseline transforming growth factor beta, lactate dehydrogenase, dynamic changes in alpha-fetoprotein (AFP) and abnormal prothrombin, CRAFITY score (composed of C-reactive protein and AFP), and immune adverse events have been identified as predictive biomarkers. Novel imaging techniques such as EOB-MRI and PET/CT employing innovative tracers also have potential. Moreover, liquid biopsy has gained widespread use in biomarker studies owing to its non-invasive, convenient, and highly reproducible nature, as well as its dynamic monitoring capabilities. Research on the gut microbiome, including its composition, dynamic changes, and metabolomic analysis, has gained considerable attention. Efficient biomarker discovery relies on continuous updating of treatment strategies. Next, we summarized recent advancements in clinical research on HCC immunotherapy and provided an overview of ongoing clinical trials for contributing to the understanding and improvement of HCC immunotherapy.

Lenvatinib combined with PD-1 inhibitor plus Gemox chemotherapy versus plus HAIC for advanced biliary tract cancer.

OBJECTIVE: To compare the treatment efficacy and safety of lenvatinib and programmed cell death 1 (PD-1) inhibitor combined with oxaliplatin plus gemcitabine (Gemox) chemotherapy or hepatic arterial infusion chemotherapy (HAIC) for patients with advanced biliary tract cancer (BTC). METHOD: This study involved 86 patients with advanced BTC receiving PD-1 inhibitor and lenvatinib combined with HAIC (P-L-H group) or Gemox chemothrapy (P-L-G group). Propensity score matching (PSM) (1:1) analysis was used to balance potential bias. The primary endpoints were overall survival (OS) and progression-free survival (PFS), whereas the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and safety. RESULT: After PSM, a total of 60 patients were enrolled with 30 in the P-L-G group and 30 in the P-L-H group. The median PFS was significantly longer with P-L-G group (13.7 versus 6.0 months, p < 0.0001) than with the P-L-H group. The median OS was 23.8 months in the P-L-G group versus 11.6 months in the P-L-H group (p < 0.0001). Patients in the P-L-G group exhibited a better ORR (73.3 % vs 30 %, p = 0.002) compared to the P-L-H group. The DCR was the same in both groups, 96.7 %, respectively. The P-L-G group had a higher incidence of grade 3-4 AEs than the P-L-H group. However, there was no significant difference in the any grade or grade 3-4 of AEs between the two groups. CONCLUSION: PD-1 inhibitor plus lenvatinib and Gemox are promising first-line regimens for the treatment of advanced BTC in the multicenter retrospective real-world study.

Data-Driven Controlled Synthesis of Oriented Quasi-Spherical CsPbBr3 Perovskite Materials.

Controlled synthesis of lead-halide perovskite crystals is challenging yet attractive because of the pivotal role played by the crystal structure and growth conditions in regulating their properties. This study introduces data-driven strategies for the controlled synthesis of oriented quasi-spherical CsPbBr3, alongside an investigation into the synthesis mechanism. High-throughput rapid characterization of absorption spectra and color under ultraviolet illumination was conducted using 23 possible ligands for the synthesis of CsPbBr3 crystals. The links between the absorption spectra slope (difference in the absorbance at 400 nm and 450 nm divided by a wavelength interval of 50 nm) and crystal size were determined through statistical analysis of more than 100 related publications. Big data analysis and machine learning were employed to investigate a total of 688 absorption spectra and 652 color values, revealing correlations between synthesis parameters and properties. Ex situ characterization confirmed successful synthesis of oriented quasi-spherical CsPbBr3 perovskites using polyvinylpyrrolidone and Acacia. Density functional theory calculations highlighted strong adsorption of Acacia on the (110) facet of CsPbBr3. Optical properties of the oriented quasi-spherical perovskites prepared with these data-driven strategies were significantly improved. This study demonstrates that data-driven controlled synthesis facilitates morphology-controlled perovskites with excellent optical properties.

Molecular characterization and functional roles of circulating cell-free extrachromosomal circular DNA.

Circular DNA segments isolated from chromosomes are known as extrachromosomal circular DNA (eccDNA). Its distinct structure and characteristics, along with the variations observed in different disease states, makes it a promising biomarker. Recent studies have revealed the presence of eccDNAs in body fluids, indicating their involvement in various biological functions. This finding opens up avenues for utilizing eccDNAs as convenient and real-time biomarkers for disease diagnosis, treatment monitoring, and prognosis assessment through noninvasive analysis of body fluids. In this comprehensive review, we focused on elucidating the size profiles, potential mechanisms of formation and clearance, detection methods, and potential clinical applications of eccDNAs. We aimed to provide a valuable reference resource for future research in this field.

Development and validation of web-based nomograms for predicting survival status in patients with intrahepatic cholangiocarcinoma depending on the surgical status: a SEER database analysis.

This study aimed to develop and validate prognostic nomograms that can estimate the probability of 1-, 3- and 5-year overall survival (OS) as well as cancer-specific survival (CSS) for Intrahepatic cholangiocarcinoma (ICCA) patients. Clinical data of 1446 patients diagnosed with ICCA between 2010 and 2017 from the Surveillance, Epidemiology, and End Results (SEER) database were analyzed. In both the OS and the CSS group, the training cohort and validation cohort were divided into a 7:3 ratio. Age, sex, AJCC T stage, AJCC N stage, AJCC M stage, surgical status, and tumor grade were selected as independent prognostic risk factors to build the nomograms. To compare the efficacy of predicting 1-, 3-, and 5-year OS and CSS rates of the nomogram with the 8th edition of the American Joint Committee on Cancer (AJCC) staging system, we evaluated the Harrell's index of concordance (C-index), area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA) in both cohorts. The results showed the nomogram for 1-, 3-, and 5-year OS and CSS prediction performed better than the AJCC staging system. In the subgroup analysis for patients could not receive surgery as the primary treatment. We developed two nomograms for predicting the 1-, and 2-year OS and CSS rates following the same analysis procedure. Results indicate that the performance of both nomograms, which contained sex, AJCC T stage, AJCC M stage, chemotherapy, and tumor grade and prognostic factors, was also superior to the AJCC staging system. Meanwhile, four dynamic network-based nomograms were published. The survival analysis showed the survival rate of patients classified as high-risk based on the nomogram score was significantly lower compared to those categorized as low-risk (P < 0.0001). Finally, accurate and convenient nomograms were established to assist clinicians in making more personalized prognosis predictions for ICCA patients.

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma.

BACKGROUND: Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA. METHODS: We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA. RESULTS: Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy. CONCLUSIONS: MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).