A Cascade-Amplified Pyroptosis Inducer: Optimizing Oxidative Stress Microenvironment by Self-Supplying Reactive Nitrogen Species Enables Potent Cancer Immunotherapy.

Selective generation of sufficient pyroptosis inducers at the tumor site without external stimulation holds immense significance for a longer duration of immunotherapy. Here, we report a cascade-amplified pyroptosis inducer CSCCPT/SNAP that utilizes reactive nitrogen species (RNS), self-supplied from the diffusion-controlled reaction between reactive oxygen species (ROS) and nitric oxide (NO) to potentiate pyroptosis and immunotherapy, while both endogenous mitochondrial ROS stimulated by released camptothecin and released NO initiate pyroptosis. Mechanistically, cascade amplification of the antitumor immune response is prompted by the cooperation of ROS and NO and enhanced by RNS with a long lifetime, which could be used as a pyroptosis trigger to effectively compensate for the inherent drawbacks of ROS, resulting in long-lasting pyroptosis for favoring immunotherapy. Tumor growth is efficiently inhibited in mouse melanoma tumors through the facilitation of reactive oxygen/nitrogen species (RONS)-NO synergy. In summary, our therapeutic approach utilizes supramolecular engineering and nanotechnology to integrate ROS producers and NO donors of tumor-specific stimulus responses into a system that guarantees synchronous generation of these two reactive species to elicit pyroptosis-evoked immune response, while using self-supplied RNS as a pyroptosis amplifier. RONS-NO synergy achieves enhanced and sustained pyroptosis and antitumor immune responses for robust cancer immunotherapy.

Celecoxib Augments Paclitaxel-Induced Immunogenic Cell Death in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks effective targeted therapies. Inducing immunogenic cell death (ICD) in tumor cells represents a promising strategy to enhance therapeutic efficacy by promoting antitumor immunity. Paclitaxel (PTX), a commonly used chemotherapy drug for TNBC, can induce ICD; however, the resulting immunogenicity is limited. Thus, there is an urgent need to explore strategies that improve the effectiveness of ICD in TNBC by incorporating immunoregulatory agents. This study investigated the potential of celecoxib (CXB) to enhance PTX-induced ICD by blocking the biosynthesis of PGE2 in the tumor cells. We observed that the combination of CXB and PTX promoted the maturation of dendritic cells and primed a T cell-dependent immune response, leading to enhanced tumor rejection in a vaccination assay. To further optimize drug delivery in vivo, we developed cRGD-modified liposomes for the targeted codelivery of CXB and PTX. This delivery system significantly improved drug accumulation and triggered robust antitumor immunity in an orthotopic mouse model of TNBC. Moreover, it served as an in situ vaccine to inhibit tumor recurrence and lung metastasis. Overall, our findings provide in-depth insights into the therapeutic mechanism underlying the combination of CXB and PTX, highlighting their potential as effective immune-based therapies for TNBC.

A biomimetic nanoplatform for precise reprogramming of tumor-associated macrophages and NIR-II mediated antitumor immune activation.

The therapeutic effects of photothermal therapy (PTT) are dependent on the photothermal conversion efficiency of photothermal agents (PTAs) in tumors and the subsequent activation of the antitumor immune system. However, the insufficient tumor accumulation of current PTAs and the inevitable recruitment of tumor-associated macrophages (TAMs) could further compromise the antitumor activities of PTT. To address these issues, a biomimetic photothermal nanoplatform Au@Fe-PM is developed for the targeted remodeling of TAMs, which promotes the antitumor immunity of PTT. Au nanorods with second near-infrared (NIR-II) absorptions are fabricated to serve as PTAs to induce immunogenic cell death in tumor cells. The ferric hydroxide shell coated on Au nanorods can release iron ions to repolarize M2-like TAMs into the tumoricidal M1 phenotype via P38 and STAT1-mediated signaling pathways. Moreover, the surface decoration of platelet membranes endows biomimetic nanoplatform with enhanced tumor targeting ability for precise tumor ablation and TAM regulation. Consequently, Au@Fe-PM under NIR-II laser irradiation exhibits significantly higher inhibitory effects in a poor immunogenic 4T1 tumor-bearing mouse model with a 50% complete remission rate compared to conventional PTT (0%). By simultaneously reversing the immunosuppressive tumor microenvironment, this biomimetic nanoplatform offers a promising strategy for enhancing the antitumor efficacy of PTT. STATEMENT OF SIGNIFICANCE: The therapeutic effects of current photothermal therapy (PTT) are hindered by the insufficient tumor accumulation of conventional photothermal agents and the recruitment of immunosuppressive tumor-associated macrophages (TAMs) after PTT. Herein, we report a biomimetic iron-based second near-infrared (NIR-II) photothermal nanoplatform (Au@Fe-PM) for targeted TAMs reprogramming and NIR-II mediated anti-tumor immunity. Au@Fe-PM can actively target the tumor site with the help of surface-decorated platelet membranes. Meanwhile, iron ions would be released from Au@Fe-PM in acidic lysosomes to reprogram TAMs into tumoricidal M1-like macrophages, which promotes the antitumor responses elicited by NIR-II PTT, thereby contributing to remarkable tumor inhibitory effects, with 50% higher complete remission rate than that of conventional PTT.

Mitochondrial-Targeted Delivery of Polyphenol-Mediated Antioxidases Complexes against Pyroptosis and Inflammatory Diseases.

Excess accumulation of mitochondrial reactive oxygen species (mtROS) is a key target for inhibiting pyroptosis-induced inflammation and tissue damage. However, targeted delivery of drugs to mitochondria and efficient clearance of mtROS remain challenging. In current study, it is discovered that polyphenols such as tannic acid (TA) can mediate the targeting of polyphenol/antioxidases complexes to mitochondria. This affinity does not depend on mitochondrial membrane potential but stems from the strong binding of TA to mitochondrial outer membrane proteins. Taking advantage of the feasibility of self-assembly between TA and proteins, superoxide dismutase, catalase, and TA are assembled into complexes (referred to as TSC) for efficient enzymatic activity maintenance. In vitro fluorescence confocal imaging shows that TSC not only promoted the uptake of biological enzymes in hepatocytes but also highly overlapped with mitochondria after lysosomal escape. The results from an in vitro model of hepatocyte oxidative stress demonstrate that TSC efficiently scavenges excess mtROS and reverses mitochondrial depolarization, thereby inhibiting inflammasome-mediated pyroptosis. More interestingly, TSC maintain superior efficacy compared with the clinical gold standard drug N-acetylcysteine in both acetaminophen- and D-galactosamine/lipopolysaccharide-induced pyroptosis-related hepatitis mouse models. In conclusion, this study opens a new paradigm for targeting mitochondrial oxidative stress to inhibit pyroptosis and treat inflammatory diseases.

The circular RNA circSLC7A11 functions as a mir-330-3p sponge to accelerate hepatocellular carcinoma progression by regulating cyclin-dependent kinase 1 expression.

BACKGROUND: Circular RNAs (circRNAs), which are endogenous non-coding RNAs, are associated with various biological processes including development, homeostatic maintenance, and pathological responses. Accumulating evidence has implicated non-coding RNAs in cancer progression, and the role of circRNAs in particular has drawn wide attention. However, circRNA expression patterns and functions in hepatocellular carcinoma (HCC) remain poorly understood. METHODS: CircRNA sequencing was performed to screen differentially expressed circRNAs in HCC. Northern blotting, quantitative real-time polymerase chain reaction, nucleocytoplasmic fractionation, and fluorescence in situ hybridization analyses were conducted to evaluate the expression and localization of circSLC7A11 in HCC tissues and cells. CircSLC7A11 expression levels were modified in cultured HCC cell lines to explore the association between the expression of circSLC7A11 and the malignant behavior of these cells using several cell-based assays. The modified cells were implanted into immunocompetent nude mice to assess tumor growth and metastasis in vivo. We applied bioinformatics methods, RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays to explore the mechanisms of circSLC7A11 in HCC. RESULTS: CircSLC7A11 (hsa_circ_0070975) was conserved and dramatically overexpressed in HCC tissues and cells. HCC patients showing high circSLC7A11 expression had worse prognoses. Our in vitro and in vivo experiments showed that circSLC7A11 markedly accelerated HCC progression and metastasis through the circSLC7A11/miR-330-3p/CDK1 axis. CONCLUSIONS: The acceleration of HCC progression and metastasis by circSLC7A11 through the circSLC7A11/miR-330-3p/CDK1 axis suggests that circSLC7A11 is a potential novel diagnostic and therapeutic target for HCC treatment.

Number of Positive Lymph Nodes Is Superior to LNR and LODDS for Predicting the Prognosis of Pancreatic Neuroendocrine Neoplasms.

Background: The American Joint Committee on Cancer (AJCC) staging for pancreatic neuroendocrine neoplasms (PanNENs) based on the number of positive lymph nodes (PLNs) is the most widely accepted nodal staging system. New nodal staging schemes that take both the number of PLNs and the number of examined lymph nodes into consideration have emerged as useful prognostic tools. The aim of the current study was to determine the most effective nodal staging system, among the 8th edition AJCC N staging (or PLN staging), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS), for predicting the cause-specific survival of patients with PanNENs. Methods: The clinicopathological and prognostic data of 2,295 patients from the Surveillance, Epidemiology, and End Results (SEER) database, diagnosed with PanNENs between 1988 and 2015, were reviewed retrospectively. Results: A multivariate analysis identified PLN and LNR staging as independent prognostic factors, but not LODDS. The PLN staging exhibited higher C-index and area under the curve values than those of the LNR and LODDS, indicating better predictive discriminatory capacity. No significant difference in the survival of patients was observed within the same PLN staging subgroup according to the number (high or low) of examined lymph nodes. In contrast, intra-group heterogeneity was seen with use of LNR and LODDS staging, due to overestimation of the risk of insufficient examined lymph nodes, and LODDS failed to stratify patients without lymph nodes metastasis into different risk groups. Conclusions: The PLN staging is more reliable than LNR and LODDS staging for predicting the cause-specific survival of PanNENs.

The Role of Tumor Associated Macrophages in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and represents a classic paradigm of inflammation-related cancer. Various inflammation-related risk factors jointly contribute to the development of chronic inflammation in the liver. Chronic inflammation, in turn, leads to continuous cycles of destruction-regeneration in the liver, contributing to HCC development and progression. Tumor associated macrophages are abundant in the tumor microenvironment of HCC, promoting chronic inflammation and HCC progression. Hence, better understanding of the mechanism by which tumor associated macrophages contribute to the pathogenesis of HCC would allow for the development of novel macrophage-targeting immunotherapies. This review summarizes the current knowledge regarding the mechanisms by which macrophages promote HCC development and progression, as well as information from ongoing therapies and clinical trials assessing the efficacy of macrophage-modulating therapies in HCC patients.

Preoperative Portal Vein Embolization for Liver Resection: An updated meta-analysis.

Background: Portal vein embolization (PVE) is performed before major liver resection to increase liver volume remnant, controversy remains on the adverse effect of PVE on liver tumor patients. The current study highlighted the effect of PVE on the degree of hypertrophy of future liver remnant (FLR) and summarized PVE-related complications, aiming to provide a guideline for surgeons. Methods: A search of current published studies on PVE was performed. Meta-analysis was conducted to assess the effect of PVE on hypertrophy of FLR and summarized PVE-related complications. Results: 26 studies including 2335 patients were enrolled in the meta-analysis. All enrolled studies reported data regarding FLR hypertrophy rate, pooled effect size (ES) for FLR hypertrophy rate using a fixed-effect model was 0.105 (95%CI: 0.094-0.117, p=0.000), indicating PVE is favored in inducing FLR hypertrophy. Metatrim method indicated no obvious evidence of publication bias in the present meta-analysis. 247 (10.6%) patients exhibited PVE-related complications, receiving expectant treatment without affecting planned liver resection. Total 1782 patients (76%) underwent a subsequent liver resection after PVE, which is an encouraging result comparing with traditional resection rate in liver tumor patients. Conclusions: PVE is a safe and effective procedure with a low occurrence of related complications for inducing sufficient hypertrophy of FLR in liver tumor patients, which could elevate the resection rate of liver tumor patients. Careful patient cohort selection is crucial to avoid overuse of PVE in technically resectable patients. Further multiple central clinical trials are conducive to select optimal patient cohorts and provide a guideline for surgeons.

The prognostic value of external vs internal pancreatic duct stents after pancreaticoduodenectomy in patients with FRS ≥ 4: a retrospective cohort study.

BACKGROUND: The prognostic value of external vs internal pancreatic duct stents after pancreaticoduodenectomy remains controversial. This study aimed to evaluate the benefits of external and internal stents using the Fistula Risk Score system with regard to the incidence of clinically relevant postoperative pancreatic fistula. METHODS: A total of 382 patients who underwent pancreaticoduodenectomy with duct to mucosa pancreaticojejunostomy were retrospectively enrolled from January 2015 to October 2019. The receiver operating characteristic curve was performed for subgroup analysis of the patients at different levels of risk for pancreatic fistula. RESULTS: There were no significant differences in terms of pancreatic fistula or other postoperative complications. According to the receiver operating characteristic curve threshold of 3.5, 172 patients with a Fistula Risk Score ≥ 4 and 210 patients with a Fistula Risk Score < 4 were divided into separate groups. The number of valid cases was insufficient to support the subsequent research in patients with a Fistula Risk Score < 4. In patients with a Fistula Risk Score ≥ 4, the use of an external pancreatic duct stent was significantly more effective than the use of an internal stent, especially with regard to the risk for pancreatic fistula (Grade C) (P = 0.039), at ameliorating the incidence of clinically relevant postoperative pancreatic fistula (P = 0.019). Additionally, the incidence of lymphatic leakage was significantly higher in the external stent group compared with the internal stent group (P = 0.040). CONCLUSIONS: Compared with internal stents, the use of an external stent could reduce the incidence of clinically relevant postoperative pancreatic fistula in patients with a Fistula Risk Score ≥ 4. More large-scale prospective clinical trials are warranted to further clarify our results.

Prevalence, diagnosis, and treatment of primary hepatic gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GIST), which is the most common mesenchymal tumor of the digestive tract, account for 1%-3% of gastrointestinal tumors. Primary stromal tumors outside the gastrointestinal tract are collectively referred to as extra GISTs, and stromal tumors in different regions often have different prognoses. A primary hepatic GIST is a rare tumor with an unknown origin, which may be related to interstitial Cajal-like cells. Although primary hepatic GIST has certain characteristics on imaging, it lacks specific symptoms and signs; thus, the final diagnosis depends on pathological and genetic evidence. This review summarizes all cases of primary hepatic GIST described in the literature and comprehensively analyzes the detailed clinical data of all patients. In terms of treatment, local resection alone or with adjuvant therapy was the prioritized choice to obtain better disease-free survival and longer survival time. For advanced unresectable cases, imatinib mesylate was applied as the first-line chemotherapy agent. Moreover, transcatheter arterial chemoembolization, radiofrequency ablation, and microwave ablation were shown to improve overall survival for selected patients. Liver transplantation was a final treatment option after resistance to chemotherapy developed.

Primary leiomyoma of the inferior vena cava mimicking a cystic neoplasm of the pancreas: a case report.

Benign smooth muscle tumors of the inferior vena cava (IVC) are unusual, but mostly consist of intravenous leiomyomatosis, which arises from the uterus. Primary leiomyoma of the IVC is extremely rare. Here, we report a primary leiomyoma of the IVC, misleadingly reported as a cystic neoplasm of the pancreas in images. Immunohistochemical analysis was positive for (estrogen receptor) ER and (progesterone receptor) PR, indicating gynecologic leiomyomas. The use of ER and PR immunostaining is recommended to help distinguish between somatic and gynecologic leiomyomas, whose criteria of malignancy differ.

Integrative Analysis of ceRNA Network Reveals Functional lncRNAs in Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is the second most common lethal liver cancer worldwide. Currently, despite the latest developments in genomics and transcriptomics for ICC in recent years, the molecular pathogenesis promoting ICC remains elusive, especially in regulatory mechanisms of long noncoding RNAs (lncRNAs), which acts as competing endogenous RNA (ceRNA). In order to elucidate the molecular mechanism of functional lncRNA, expression profiles of lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) were obtained from The Cancer Genome Atlas (TCGA) database and an integrative analysis of the ICC-associated ceRNA network was performed. Moreover, gene oncology enrichment analyses for the genes in the ceRNA network were implemented and novel prognostic biomarker lncRNA molecules were identified. In total, 6,738 differentially expressed mRNAs (DEmRNAs), 2,768 lncRNAs (DElncRNAs), and 173 miRNAs (DEmiRNAs) were identified in tumor tissues and adjacent nontumor ICC tissues with the thresholds of adjusted P < 0.01 and |logFC| > 2. An ICC-specific ceRNA network was successfully constructed with 30 miRNAs, 16 lncRNAs, and 80 mRNAs. Gene oncology enrichment analyses revealed that they were associated with the adaptive immune response, T cell selection and positive regulation of GTPase activity categories. Among the ceRNA networks, DElncRNAs ARHGEF26-AS1 and MIAT were found to be hub genes in underexpressed and overexpressed networks, respectively. Notably, univariate Cox regression analysis indicated that DElncRNAs HULC significantly correlated with overall survival (OS) in ICC patients (P value < 0.05), and an additional survival analysis for HULC was reconfirmed in an independent ICC cohort from the Gene Expression Omnibus (GEO) database. These findings contribute to a more comprehensive understanding of the ICC-specific ceRNA network and provide novel strategies for subsequent functional studies of lncRNAs in ICC.

Giant nonfunctional ectopic adrenocortical carcinoma on the anterior abdominal wall: A case report.

BACKGROUND: Adrenocortical cancer (ACC) is an infrequent and often aggressive malignancy with a very poor prognosis. It can be classified as functional or nonfunctional. Nonfunctional ACC is hampered by the absence of specific signs or symptoms; only abdominal pain with or without incidental adrenal occupation is typically present. CASE SUMMARY: We report a rare case of a patient with a 30 cm × 15 cm × 8 cm ectopic ACC on the anterior abdominal wall without organ adhesion. A 77-year-old male was admitted to our hospital because of a huge abdominal mass, which, by ultrasonography, had an unclear border with the liver. Computed tomography showed that the mass was not associated with any organ but was adherent to the anterior abdominal wall. The patient underwent tumor resection, and a postoperative pathology examination showed a neuroendocrine tumor, which was diagnosed as ACC. The patient was disease-free at the 9-mo follow up. CONCLUSION: The anterior abdominal wall is a rare site of ACC growth.

Spindle cell hemangioma of the spleen: A case report.

RATIONALE: Spindle cell hemangioma (SCH) is considered a benign vascular lesion. It typically develops as a solitary nodule or multiple masses located in the dermal or subcutaneous layers of the distal extremities. To the best of our knowledge, there are no prior reports of SCH in the spleen. PATIENT CONCERNS: A 41-year-old male was admitted to our hospital with recurrent headaches, nausea, and vomiting persisting for 5 days. Ultrasound, computed tomography, and magnetic resonance imaging revealed multiple space-occupying lesions in the spleen, and the biggest lesion was 4.8 cm × 5.4 cm in size. INTERVENTIONS: The patient underwent laparoscopic splenectomy. DIAGNOSIS: A diagnosis of spindle cell hemangioma of the spleen was made based on the histopathology. OUTCOMES: No evidence of local recurrence or distant metastases was observed over 4-year follow-up. LESSONS: Splenic SCH may exhibit relatively high proliferative activity and be comorbid with epithelioid hemangioendothelioma or angiosarcoma, raising the possibility of malignant potential. However, the patient remained alive and disease-free 4 years after the operation. The nature of SCH in deep soft tissues requires further study.

Sarcomatoid carcinoma of the pancreas: A case report.

BACKGROUND: Sarcomatoid carcinoma of the pancreas (SCP) is a rare and aggressive epithelial tumor that has both epithelial and mesenchymal features. It is characterized by sarcomatous elements with evidence of epithelial differentiation. And the term "sarcomatoid carcinoma" is often confused with "carcinosarcoma". CASE SUMMARY: We present a case of SCP with lymph node metastasis in a 59-year-old male patient. He had experienced darkening of the urine, scleral icterus, and fatigue for 4 weeks. Computed tomography and magnetic resonance imaging revealed a mass in the pancreatic head, and laboratory tests revealed elevated serum bilirubin levels. The patient underwent pancreaticoduodenectomy after biliary decompression. Histologically, spindle cells with marked nuclear atypia and brisk mitotic activity arranged in a storiform or fascicular pattern were present in the bulk of the tumor. Immunohistochemical analysis found that the spindle cells exhibited strong diffuse positivity for epithelial markers, indicative of epithelial differentiation. Accordingly, the pathologic diagnosis of the pancreatic neoplasm was SCP. CONCLUSION: Although sarcomatoid carcinomas and carcinosarcomas have different pathologic features, both have epithelial origin.