Photonic Hyperthermia Synergizes with Immune-Activators to Augment Tumor-Localized Immunotherapy.

Photothermal immunotherapy, the combination of photothermal hyperthermia and immunotherapy, is a noninvasive and desirable therapeutic strategy to address the deficiency of traditional photothermal ablation for tumor treatment. However, insufficient T-cell activation following photothermal treatment is a bottleneck to achieve satisfactory therapeutic effectiveness. In this work, a multifunctional nanoplatform is rationally designed and engineered on the basis of polypyrrole-based magnetic nanomedicine modified by T-cell activators of anti-CD3 and anti-CD28 monoclonal antibodies, which have achieved robust near infrared laser-triggered photothermal ablation and long-lasting T-cell activation, realizing diagnostic imaging-guided immunosuppressive tumor microenvironment regulation following photothermal hyperthermia by reinvigorating tumor-infiltrating lymphocytes. By virtue of high-efficient immunogenic cell death and dendritic cell maturation combined with T-cell activation, this nanosystem markedly restrains primary and abscopal tumors as well as metastatic tumors with negligible side effects in vivo, exerting the specific function for suppressing tumor recurrence and metastasis by establishing a long-term memory immune response.

Percutaneous Ablation of Hepatic Tumors at the Hepatocaval Confluence Using Irreversible Electroporation: A Preliminary Study.

BACKGROUND: Tumors at the hepatocaval confluence are difficult to treat, either surgically or ablatively. METHODS: A retrospective longitudinal study on patients ineligible for thermal ablation who underwent computed tomography-guided IRE for hepatic tumors at the hepatocaval confluence was conducted. Factors analyzed included patient and tumor characteristics, IRE procedure details, treatment-related complications, and prognosis. RESULTS: Between 2017 and 2021, 21 patients at our institute received percutaneous IRE. Of the 38 lesions, 21 were at the hepatocaval confluence. Complete ablation was achieved in all cases. Local and distant recurrence was observed in 4.8% (1/21) and 42.6% (9/21) of the ablated tumors, respectively. All postcava remained perfused at follow-up, except for 1 (4.8%) hepatic vein near the lesion found to be temporarily occluded and restored within 1 month. The ratio of the maximum diameter of ablation area at 1, 3, and 6 months post procedure compared to that immediately after IRE was 0.68 (0.50-0.84), 0.49 (0.27-0.61), and 0.38 (0.25-0.59), respectively. Progression-free survival of the patients with recurrence was 121 (range, 25-566) days. Four (19.0%) patients died at the end of follow-up with median overall survival of 451.5 (range, 25-716) days. CONCLUSIONS: IRE could be a safe and effective treatment for hepatic tumors at the hepatocaval confluence. This article provides valuable prognostic data; further clinical research is needed for better prognosis.

Inhibition of Endoplasmic Reticulum Stress-Mediated Autophagy Enhances the Anticancer Effect of Iodine-125 Seed Radiation on Esophageal Squamous Cell Carcinoma.

Autophagy has been reported to play a radioresistance role in high-dose-rate irradiation. However, its mechanisms and roles in continuous low-dose-rate (CLDR) irradiation have not been clearly understood. Iodine-125 (I-125) seed brachytherapy is a modality of CLDR irradiation and has been used in the treatment of various cancers. In this study, we investigated the mechanisms and roles of autophagy induced by I-125 seed radiation in human esophageal squamous cell carcinoma (ESCC) cell lines (Eca-109 and EC-109) and a xenograft mouse model. The results of this work showed that I-125 seed radiation induced a dose-dependent increase in autophagy in both cell lines. In Eca-109 cells, I-125 seed radiation-induced endoplasmic reticulum (ER) stress, manifesting as the increased levels of intracellular Ca2+ and Grp78/BiP, and activated PERK-eIF2α, IRE1, and ATF6 pathways of the unfolded protein response. Knockdown of PERK led to the decreased expression of autophagy marker, LC3B-II. Inhibition of autophagy by chloroquine or knockdown of ATG5 enhanced I-125 seed radiation-induced cell proliferation inhibition and apoptosis. Interestingly, chloroquine did not aggravate ER stress but promoted apoptosis via the mitochondrial pathway. The animal experiment showed that inhibition of autophagy by chloroquine improved the efficacy of I-125 seed radiation. In summary, our data demonstrate that I-125 seed CLDR radiation induces ER stress-mediated autophagy in ESCC. Autophagy plays a pro-survival role in I-125 seed CLDR irradiation, and chloroquine is a potential candidate for use in combination therapy with I-125 seed radiation treatment to improve efficacy against ESCC.

Iodine­125 seed radiation induces ROS­mediated apoptosis, autophagy and paraptosis in human esophageal squamous cell carcinoma cells.

Iodine­125 (125I) seed brachytherapy has been proven to be a safe and effective treatment for advanced esophageal cancer; however, the mechanisms underlying its actions are not completely understood. In the present study, the anti­cancer mechanisms of 125I seed radiation in human esophageal squamous cell carcinoma (ESCC) cells (Eca­109 and KYSE­150) were determined, with a particular focus on the mode of cell death. The results showed that 125I seed radiation significantly inhibited cell proliferation, and induced DNA damage and G2/M cell cycle arrest in both ESCC cell lines. 125I seed radiation induced cell death through both apoptosis and paraptosis. Eca­109 cells were primarily killed by inducing caspase­dependent apoptosis, with 6 Gy radiation resulting in the largest response. KYSE­150 cells were primarily killed by inducing paraptosis, which is characterized by extensive cytoplasmic vacuolation. 125I seed radiation induced autophagic flux in both ESCC cell lines, and autophagy inhibition by 3­methyladenine enhanced radiosensitivity. Furthermore 125I seed radiation induced increased production of reactive oxygen species (ROS) in both ESCC cell lines. Treatment with an ROS scavenger significantly attenuated the effects of 125I seed radiation on endoplasmic reticulum stress, autophagy, apoptosis, paraptotic vacuoles and reduced cell viability. In vivo experiments showed that 125I seed brachytherapy induced ROS generation, initiated cell apoptosis and potential paraptosis, and inhibited cell proliferation and tumor growth. In summary, the results demonstrate that in ESCC cells, 125I seed radiation induces cell death through both apoptosis and paraptosis; and at the same time initiates protective autophagy. Additionally, 125I seed radiation­induced apoptosis, paraptosis and autophagy was considerably mediated by ROS.

PD-L1-targeted microbubbles loaded with docetaxel produce a synergistic effect for the treatment of lung cancer under ultrasound irradiation.

Immunotherapy is gradually becoming as important as traditional therapy in the treatment of cancer, but adverse drug reactions limit patient benefits from PD1/PD-L1 checkpoint inhibitor drugs in the treatment of non-small cell lung cancer (NSCLC). As a chemotherapeutic drug for NSCLC, docetaxel (DTX) can synergize with PD1/PD-L1 checkpoint inhibitors but increase haematoxicity and neurotoxicity. Herein, anti-PD-L1 monoclonal antibody (mAb)-conjugated and docetaxel-loaded multifunctional lipid-shelled microbubbles (PDMs), which were designed with biologically safe phospholipids to produce synergistic antitumour effects, reduced the incidence of side effects and promoted therapeutic effects under ultrasound (US) irradiation. The PDMs were prepared by the acoustic-vibration method and then conjugated with an anti-PD-L1 mAb. The material features of the microbubbles and their cytotoxic effects, cellular apoptosis and cell cycle inhibition were studied. A subcutaneous tumour model was established to test the drug concentration-dependent and antitumour effects of the PDMs combined with US irradiation, and an orthotopic lung tumour model simultaneously confirmed the antitumour effect of this synergistic treatment. The PDMs achieved higher cellular uptake than free DTX, especially when combined with US irradiation. The PDMs combined with US irradiation also induced an increased rate of cellular apoptosis and an elevated G2-M arrest rate in cancer cells, which was positively correlated with PD-L1 expression. An in vivo study showed that synergistic treatment had relatively strong effects on tumour growth inhibition, increased survival time and decreased adverse effect rates. Our study possibly provides a well-controlled design for immunotherapy and chemotherapy and has promising potential for clinical application in NSCLC treatment.

Thyroid cancer MR molecular imaging via SHP2-targeted nanoparticles.

BACKGROUND: Molecular imaging has generated a great demand to develop targeted contrast agents for MR imaging. MATERIALS AND METHODS: In this study, we synthesized Src homology 2-containing phosphotyrosine phosphatase 2 (SHP2)-targeted and polylactic-co-glycolic acid--based nanoparticles (NPs), which encapsulated perfluoropentane and being chelated with gadolinium (Gd3+) as an efficient molecular probe for targeting MR imaging on thyroid carcinoma. RESULTS: These NPs displayed practical properties and favorable biocompatibility in vitro. Furthermore, they showed abilities to specifically target thyroid cancer and enhance MRI as a contrast agent in both in vitro and in vivo experiments. CONCLUSION: This novel MR molecular imaging based on this SHP2-targeted contrast agent provides a useful and non-invasive method for the early detection of thyroid carcinoma.

A New Fully Covered Irradiation Stent Versus a Partially Covered Irradiation Stent for Unresectable Malignant Dysphagia: A Single-Center Experience.

PURPOSE: To assess the efficacy and safety of a newly developed fully covered irradiation stent (FCIS) compared with a partially covered irradiation stent (PCIS) in patients with unresectable malignant dysphagia. MATERIALS AND METHODS: Data of 195 patients [158 (81.0%) males, median age of 75 years (range 49-89 years)] who underwent FCIS or PCIS placement for unresectable malignant dysphagia from January 2012 to November 2017 were retrospectively analyzed. The median follow-up time was 181 days (range 4-547 days). Outcomes were measured in terms of recurrent dysphagia (primary), technical success, clinical success, overall survival, and adverse events. Recurrent dysphagia was analyzed by Fine-Gray regression model. RESULTS: The technical success rate was 97.8% (87/89) in the FCIS group and 99.1% (105/106) in the PCIS group (P = 0.59). The clinical success rate was 100.0% in both groups. There was no statistically significant difference in the recurrent dysphagia rate between the FCIS and PCIS groups (21.8% vs. 28.6%; P = 0.12). Compared with PCISs, FCISs were associated with a decrease in tissue/tumor growth rate (11.5% vs. 21.9%; P = 0.01), while stent migration rates were statistically comparable (11.5% vs. 5.7%; P = 0.23). The median overall survivals were comparable between the FCIS and PCIS groups (164 days vs. 162 days; P = 0.70). A dysphagia score of 4 and metastasis were risk factors for survival. No significant differences were observed in the rates of adverse events, including chest pain, fistula formation, hemorrhage, and aspiration pneumonia (P > 0.05). CONCLUSION: For patients with unresectable malignant dysphagia, this newly developed FCIS can provide efficacy and safety comparable to those of a PCIS. Compared with PCIS, this FCIS is more successful in preventing tissue/tumor growth, with a comparable stent migration rate.

Thyroid Cancer Detection by Ultrasound Molecular Imaging with SHP2-Targeted Perfluorocarbon Nanoparticles.

Background: Contrast-enhanced ultrasound imaging has been widely used in the ultrasound diagnosis of a variety of tumours with high diagnostic accuracy, especially in patients with hepatic carcinoma, while its application is rarely reported in thyroid cancer. The currently used ultrasound contrast agents, microbubbles, cannot be targeted to molecular markers expressed in tumour cells due to their big size, leading to a big challenge for ultrasound molecular imaging. Phase-changeable perfluorocarbon nanoparticles may resolve the penetrability limitation of microbubbles and serve as a promising probe for ultrasound molecular imaging. Methods: 65 thyroid tumour samples and 40 normal samples adjacent to thyroid cancers were determined for SHP2 expression by IHC. SHP2-targeted PLGA nanoparticles (NPs-SHP2) encapsulating perfluoropentane (PFP) were prepared with PLGA-PEG as a shell material, and their specific target-binding ability was assessed in vitro and in vivo, and the effect on the enhancement of ultrasonic imaging induced by LIFU was studied in vivo. Results: In the present study, we verified that tumour overexpression of SHP2 and other protein tyrosine phosphatases regulated several cellular processes and contributed to tumorigenesis, which could be introduced to ultrasound molecular imaging for differentiating normal from malignant thyroid diagnostic nodes. The IHC test showed remarkably high expression of SHP2 in human thyroid carcinoma specimens. In thyroid tumour xenografts in mice, the imaging signal was significantly enhanced by SHP2-targeted nanoparticles after LIFU induction. Conclusion: This study provides a basis for preclinical exploration of ultrasound molecular imaging with NPs-SHP2 for clinical thyroid nodule detection to enhance diagnostic accuracy.