Irreversible electroporation combined with chemotherapy and PD-1/PD-L1 blockade enhanced antitumor immunity for locally advanced pancreatic cancer.

Background: Irreversible electroporation (IRE) is a novel local tumor ablation approach with the potential to stimulate an antitumor immune response. However, it is not effective in preventing distant metastasis in isolation. This study aimed to compare the potential of augmenting the antitumor immune response in patients with locally advanced pancreatic cancer (LAPC) who underwent IRE combined with chemotherapy and PD-1/PD-L1 blockade with those who underwent IRE combined with chemotherapy. Methods: A retrospective review was conducted on LAPC patients treated either with IRE in combination with chemotherapy and PD-1/PD-L1 blockade (group A) or with IRE with chemotherapy alone (group B) from July 2015 to June 2021. The primary outcomes were overall survival (OS) and progression-free survival (PFS), with immune responses and adverse events serving as secondary endpoints. Risk factors for OS and PFS were identified using univariate and multivariate analyses. Results: A total of 103 patients were included in the final analysis, comprising 25 in group A and 78 in group B. The median duration of follow-up was 18.2 months (3.0-38.6 months). Group A patients demonstrated improved survival compared to group B (median OS: 23.6 vs. 19.4 months, p = 0.001; median PFS: 18.2 vs. 14.7 months, p = 0.022). The data suggest a robust immune response in group A, while adverse events related to the treatment were similar in both groups. The multivariate analysis identified the combination of IRE, chemotherapy, and PD-1/PD-L1 blockade as an independent prognostic factor for OS and PFS. Conclusion: The addition of PD-1/PD-L1 blockade to the regimen of IRE combined with chemotherapy enhanced antitumor immunity and extended survival in LAPC patients.

Clinical practice guidelines on image-guided thermal ablation of primary and metastatic lung tumors (2022 edition).

The main contents of the Clinical Practice Guidelines on Image-Guided Thermal Ablation (IGTA) of Primary and Metastatic Lung Tumors (2022 Edition) include the following: epidemiology of primary and metastatic lung tumors; the concepts of the IGTA and common technical features; procedures, indications, contraindications, outcomes evaluation, and related complications of IGTA on primary and metastatic lung tumors; and limitations and future development.

Astragalus polysaccharide (APS) attenuated PD-L1-mediated immunosuppression via the miR-133a-3p/MSN axis in HCC.

CONTEXT: Astragalus polysaccharide (APS) is a new tumour therapeutic drug, that has an inhibitory effect on a variety of solid tumours. Tumour cell immunosuppression is related to the up-regulation of programmed death ligand 1 (PD-L1). However, whether APS exerts its antitumor effect by regulating PD-L1 remains unclear. OBJECTIVE: To explore whether APS exerts its antineoplastic effect via regulating PD-L1-mediated immunosuppression in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: SMMC-7721 cells were subcutaneous injected into BALB/C mice for HCC model establishment. Mice were intraperitoneally injected with 100, 200 and 400 mg/kg APS for 12 days. Immunohistochemistry (IHC) was performed to assess CD8+ T cells' rate and PD-L1 level in HCC tissues. HCC cells were pre-treated with 0.1, 0.5 and 1 mg/mL APS for 4 h, then were treated with 10 ng/mL IFN-γ 24 h. PD-L1 level and cell apoptosis was detected by flow cytometry. PD-L1 and Moesin (MSN) proteins were measured by western blot. MiR-133a-3p and MSN mRNA levels were assessed by qRT-PCR. The targets of miR-133a-3p were predicted by starBase, and which was verified by dual-luciferase reporter assay. RESULTS: Our findings illustrated that APS dose-dependently inhibited HCC growth tested with IC50 values of 4.2 mg/mL, and IFN-γ-induced PD-L1 expression and attenuated PD-L1-mediated immunosuppression in HCC cells. APS attenuated PD-L1-mediated immunosuppression via miR-133a-3p in HCC cells. Besides, miR-133a-3p targeted to MSN, and MSN inhibited the antitumor effect of APS by maintaining the stability of PD-L1. Moreover, APS attenuated PD-L1-mediated immunosuppression via the miR-133a-3p/MSN axis. CONCLUSIONS: APS attenuated PD-L1-mediated immunosuppression via miR-133a-3p/MSN axis to develop an antitumor effect. APS may be an effective drug for HCC treatment.

Modeling MEN1 with Patient-Origin iPSCs Reveals GLP-1R Mediated Hypersecretion of Insulin.

Multiple endocrine neoplasia type 1 (MEN1) is an inherited disease caused by mutations in the MEN1 gene encoding a nuclear protein menin. Among those different endocrine tumors of MEN1, the pancreatic neuroendocrine tumors (PNETs) are life-threatening and frequently implicated. Since there are uncertainties in genotype and phenotype relationship and there are species differences between humans and mice, it is worth it to replenish the mice model with human cell resources. Here, we tested whether the patient-origin induced pluripotent stem cell (iPSC) lines could phenocopy some defects of MEN1. In vitro ß-cell differentiation revealed that the percentage of insulin-positive cells and insulin secretion were increased by at least two-fold in MEN1-iPSC derived cells, which was mainly resulted from significantly higher proliferative activities in the pancreatic progenitor stage (Day 7-13). This scenario was paralleled with increased expressions of prohormone convertase1/3 (PC1/3), glucagon-like peptide-1 (GLP-1), GLP-1R, and factors in the phosphatidylinositol 3-kinase (PI3K)/AKT signal pathway, and the GLP-1R was mainly expressed in ß-like cells. Blockages of either GLP-1R or PI3K significantly reduced the percentages of insulin-positive cells and hypersecretion of insulin in MEN1-derived cells. Furthermore, in transplantation of different stages of MEN1-derived cells into immune-deficient mice, only those ß-like cells produced tumors that mimicked the features of the PNETs from the original patient. To the best of our knowledge, this was the first case using patient-origin iPSCs modeling most phenotypes of MEN1, and the results suggested that GLP-1R may be a potential therapeutic target for MEN1-related hyperinsulinemia.

Simultaneous Gemcitabine and Percutaneous CT-Guided Irreversible Electroporation for Locally Advanced Pancreatic Cancer.

Background: Irreversible electroporation (IRE) is a new local ablation technique for pancreatic cancer. The aim of this study is to analyse the safety and effectiveness of simultaneous gemcitabine and percutaneous CT-guided IRE for locally advanced pancreatic cancer (LAPC). Materials and Methods: From October 2016 to January 2018, 61 patients with LAPC who received simultaneous gemcitabine and IRE therapy (GEM-IRE group, n = 31) or IRE alone therapy (IRE group, n = 30). Routine intravenous gemcitabine chemotherapy was performed 2 weeks after IRE in both groups. Results: Technical success rates were 90.0% (27/30) and 93.3% (28/30) in the GEM-IRE and IRE groups. Compared with the IRE group, the GEM-IRE group exhibited longer overall survival (OS), local tumor progression free survival (LTPFS), and distant disease free survival (DDFS) from IRE (OS, 17.1 vs. 14.2 months, p=0.031; LTPFS, 14.6 vs. 10.2 months, p=0.045; DDFS, 15.4 vs. 11.7 months, p=0.071). Multivariate Cox regression analysis results suggested that tumor volume ≤37 cm3 and simultaneous gemcitabine with IRE were significant independent prognostic factors of OS, LTPFS, and DDFS. Four major adverse reactions occurred; all of them were resolved after symptomatic treatment. Conclusions: Simultaneous gemcitabine and percutaneous CT-guided IRE therapy model was effective and well-tolerated therapeutic strategy in LAPC patients.

Irreversible Electroporation for Hepatocellular Carcinoma Abutting the Diaphragm: A Prospective Single-center Study.

Background and Aims: Irreversible electroporation (IRE) is an emerging local ablation therapy which may be effective for unresectable tumors. This study aimed to evaluate the safety and efficacy of percutaneous IRE in the treatment of hepatocellular carcinoma (HCC) abutting the diaphragm. Methods: A total of 26 participants with 39 tumors abutting the diaphragm were prospectively evaluated between July 2015 and September 2018. Complications associated with IRE were recorded, and the survival benefit of IRE was analyzed. The factors associated with time to local tumor progression (LTP) were analyzed using univariate and multivariate Cox regression models. Results: No major complications or treatment-related deaths occurred. The technical success rate was 96.2% (25/26) and complete ablation rate was 92.3% (36/39). The median follow-up period was 16.7 months (range: 3.0-43.0 months), the LTP occurred in 15.2% of tumors and median time to LTP was 20.4 months. Overall, tumor size (hazard ratio: 1.24 [95% confidence interval: 0.38, 3.81], p=0.03) was the only factor associated with time to LTP. Conclusions: This study shows for the first time that percutaneous IRE is a safe and effective ablation technology for HCC abutting the diaphragm.

CT-Guided Percutaneous Cryoablation in Patients with Lung Nodules Mainly Composed of Ground-Glass Opacities.

PURPOSE: To assess the safety and efficacy of cryoablation in patients with lung nodules mainly composed of ground-glass opacities (GGOs). MATERIALS AND METHODS: In this retrospective study, 50 patients (mean age, 65.0 years ± 12.3; 28 women) with a diagnosis of lung GGO nodules who underwent cryoablation were included (from June 2016 to June 2021). The local recurrence rate, incidence of regional metastases to lymph nodes, incidence of distant metastases, adverse events, and lung function condition were analyzed. RESULTS: Follow-up computed tomography (CT) was performed at a mean of 33 months (range, 3-60 months) after the cryoablation procedure. Outcomes were only evaluated in 30 patients. A total of 20 patients were excluded. Of these 20 patients, 10 patients had no cancer detected by histopathological analysis and a diagnosis was made using CT or positron emission tomography (PET)-CT, The other 10 patients had nodules with a diameter of <10 mm and a consolidation-to-tumor ratio of >0.25; thus, histopathological analysis was not performed because of the small nodule size, and patients were diagnosed using CT or PET-CT. The local recurrence rate was 0% (0 of 30). Evidence of regional metastases of lymph nodes was not found in any patients (0%; 0 of 30), and the incidence of distant metastases was 0% (0 of 30). No major adverse events were noted. Lung function recovered to normal within 1 month after cryoablation in all patients. CONCLUSIONS: Cryoablation may serve as a safe and feasible option for the treatment of lung nodules mainly composed of GGOs.

A developed non-smooth coordinate transformation for general bilateral vibro-impact systems.

Discontinuity and non-smoothness of system displacement and velocity caused by mechanical impact make the related research on dynamics of vibro-impact systems very difficult and complex. For the sake of bypassing the problems resulting from impact to some extent, Zhuravlev and Ivanov coordinate transformations were proposed, which can effectively convert the vibro-impact system to one without impact terms. In this paper, a more direct and universal transformation for general bilateral rigid vibro-impact systems is proposed. It is inspired by the main technique of Ivanov transformation, which makes the trajectories remain continuous in an auxiliary phase space. It can be directly applied to common vibro-impact systems, whether the positions of barriers are symmetrical or the restitution coefficients of barriers on both sides are consistent. In particular, this method can also be applied to the unilateral vibro-impact system. Validity of the proposed methodology is examined by means of case studies.

Clinical Safety and Efficacy of Locoregional Therapy Combined with Adoptive Transfer of Allogeneic γδ T Cells for Advanced Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma.

PURPOSE: To investigate the safety and efficacy of locoregional therapy plus adoptive transfer of allogeneic gamma delta (γδ) T cells for patients with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). METHODS: Thirty patients with HCC and 29 patients with ICC were randomly assigned to receive locoregional therapy (HCC, Group A, n = 15; ICC, Group C, n = 15) or locoregional therapy plus γδ T cell therapy (HCC, Group B, n = 15; ICC, Group D, n = 14). Groups A and C only received locoregional ablation (cryoablation or irreversible electroporation), whereas Groups B and D received locoregional therapy followed by adoptive transfer of allogeneic γδ T cells. The primary endpoints were safety, distant progression-free survival (PFS), local PFS, and overall survival (OS). RESULTS: The median distant PFS was significantly longer in the combined treatment groups than the locoregional treatment groups (HCC: 8 vs 4 months, P = .04; ICC: 8 vs 4 months, P = .021). There was no significant difference in local PFS between the 2 treatment modalities. Patients with HCC in the combined treatment group had a longer OS (median OS: 13 vs 8 months, P = .029). However, there was no significant difference in OS in patients with ICC between the 2 treatment modalities (median OS: 9.5 vs 8 months, P = .546). All adverse events were manageable with no significant difference in incidence between groups. CONCLUSIONS: The novel combination of locoregional ablation with adoptive transfer of allogeneic γδ cells was safe, with encouraging clinical efficacy against HCC and ICC.

Expert consensus on thermal ablation therapy of pulmonary subsolid nodules (2021 Edition).

The Expert Consensus reviews current literatures and provides clinical practice guidelines for thermal ablation of pulmonary subsolid nodules or ground-glass nodule (GGN). The main contents include the following: (1) clinical evaluation of GGN; (2) procedures, indications, contraindications, outcomes evaluation, and related complications of thermal ablation for GGN; and (3) future development directions.

Chemotherapy plus concurrent irreversible electroporation improved local tumor control in unresectable hilar cholangiocarcinoma compared with chemotherapy alone.

INTRODUCTION: Unresectable hilar cholangiocarcinoma (UHC) is a malignant tumor and has a poor prognosis. IRE is a novel non-thermal ablative therapy that causes cellular apoptosis via electrical impulses. To compare the curative effect for UHC, chemotherapy plus concurrent IRE and chemotherapy alone were set up. MATERIALS AND METHODS: From July 2015 to May 2019, 47 patients with UHC were analyzed to chemotherapy + IRE group (n = 23) or chemotherapy alone group (n = 24) in this study. Treatment response was assessed with computed tomography (CT) or magnetic resonance imaging (MRI) 1 month after treatment and every 3 months thereafter. Local tumor progression (LTP), time to LTP, overall survival (OS) and procedure-related complications were compared between the two groups. RESULTS: Chemotherapy plus concurrent IRE group showed a tendency toward a decreased rate of LTP (16.7% vs. 39.5%; p = 0.039) and an increased complete response rate (52.2% vs. 12.5%; p = 0.011) compared with chemotherapy alone group. Time to LTP was significantly longer in the chemotherapy plus concurrent IRE group compared to chemotherapy alone group (11.2 months vs. 4.2 months; p = 0.001). Median OS was significantly longer in the chemotherapy plus concurrent IRE group compared to chemotherapy alone group (19.6 months vs. 10.2 months; p = 0.001). CONCLUSIONS: Chemotherapy plus concurrent IRE improved local control and prolonged time to LTP and OS in patients with UHC.

Transient response of the time-delay system excited by Gaussian noise based on complex fractional moments.

In this paper, the transient response of the time-delay system under additive and multiplicative Gaussian white noise is investigated. Based on the approximate transformation method, we convert the time-delay system into an equivalent system without time delay. The one-dimensional Ito stochastic differential equation with respect to the amplitude response is derived by the stochastic averaging method, and Mellin transformation is utilized to transform the related Fokker-Planck-Kolmogorov equation in the real numbers field into a first-order ordinary differential equation (ODE) of complex fractional moments (CFM) in the complex number field. By solving the ODE of CFM, the transient probability density function can be constructed. Numerical methods are used to ascertain the effectiveness of the CFM method, the effects of system parameters on system response and the level of error vary with time as well as noise intensity are investigated. In addition, the CFM method is first implemented to analyze transient bifurcation, and the relation between CFM and bifurcation is discussed for the first time. Furthermore, the imperfect symmetry property appear on the projection map of joint probability density function.

Chinese expert consensus of image-guided irreversible electroporation for pancreatic cancer.

Pancreatic cancer (PC) is a lethal disease with extremely high mortality. Although surgical resection is the optimal therapeutic approach for PC, about 30%-40% of those patients are not candidates for surgical resection when diagnosed. Chemotherapy and radiotherapy also could not claim a desirable effect on PC. The application of interventional radiology approaches is limited by unavoidable damage to the surrounding vessels or organs. By the superiority of mechanism and technology, IRE could ablate the tumor by creating irreversible pores on the membrane of PC cells with other tissues like vessels and pancreatic ducts untouched. This consensus gathers the theoretical basis and clinical experience from multiple Chinese medical centers, to provide the application principles and experience from Chinese experts in the IRE field.

[Expert Consensus for Thermal Ablation of Pulmonary Subsolid Nodules (2021 Edition)].

"The Expert Group on Tumor Ablation Therapy of Chinese Medical Doctor Association, The Tumor Ablation Committee of Chinese College of Interventionalists, The Society of Tumor Ablation Therapy of Chinese Anti-Cancer Association and The Ablation Expert Committee of the Chinese Society of Clinical Oncology" have organized multidisciplinary experts to formulate the consensus for thermal ablation of pulmonary subsolid nodules or ground-glass nodule (GGN). The expert consensus reviews current literatures and provides clinical practices for thermal ablation of GGN. The main contents include: (1) clinical evaluation of GGN, (2) procedures, indications, contraindications, outcomes evaluation and related complications of thermal ablation for GGN and (3) future development directions.
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Gemcitabine plus concurrent irreversible electroporation vs gemcitabine alone for locally advanced pancreatic cancer.

BACKGROUND: Locally advanced pancreatic cancer (LAPC) is a common malignant digestive system tumor that ranks as the fourth leading cause of cancer-related death in the world. The prognosis of LAPC is poor even after standard treatment. Irreversible electroporation (IRE) is a novel ablative strategy for LAPC. Several studies have confirmed the safety of IRE. To date, no prospective studies have been performed to investigate the therapeutic efficacy of conventional gemcitabine (GEM) plus concurrent IRE. AIM: To compare the therapeutic efficacy between conventional GEM plus concurrent IRE and GEM alone for LAPC. METHODS: From February 2016 to September 2017, a total of 68 LAPC patients were treated with GEM plus concurrent IRE n = 33) or GEM alone n = 35). Overall survival (OS), progression free survival (PFS), and procedure-related complications were compared between the two groups. Multivariate analyses were performed to identify any prognostic factors. RESULTS: There were no treatment-related deaths. The technical success rate of IRE ablation was 100%. The GEM + IRE group had a significantly longer OS from the time of diagnosis of LAPC (19.8 mo vs 9.3 mo, P < 0.0001) than the GEM alone group. The GEM + IRE group had a significantly longer PFS (8.3 mo vs 4.7 mo, P < 0.0001) than the GEM alone group. Tumor volume less than 37 cm3 and GEM plus concurrent IRE were identified as significant favorable factors for both the OS and PFS. CONCLUSION: Gemcitabine plus concurrent IRE is an effective treatment for patients with LAPC.

Irreversible electroporation plus allogenic Vγ9Vδ2 T cells enhances antitumor effect for locally advanced pancreatic cancer patients.

Immunotherapy has limited efficacy against locally advanced pancreatic cancer (LAPC) due to the presence of an immunosuppressive microenvironment (ISM). Irreversible electroporation (IRE) can not only induce immunogenic cell death, but also alleviate immunosuppression. This study aimed to investigate the antitumor efficacy of IRE plus allogeneic γδ T cells in LAPC patients. A total of 62 patients who met the eligibility criteria were enrolled in this trial, then randomized into two groups (A: n = 30 and B: n = 32). All patients received IRE therapy and after receiving IRE, the group A patients received at least two cycles of γδ T-cell infusion as one course continuously. Group A patients had better survival than group B patients (median OS: 14.5 months vs. 11 months; median PFS: 11 months vs. 8.5 months). Moreover, the group A patients treated with multiple courses of γδ T-cell infusion had longer OS (17 months) than those who received a single course (13.5 months). IRE combined with allogeneic γδ T-cell infusion is a promising strategy to enhance the antitumor efficacy in LAPC patients, yielding extended survival benefits.ClinicalTrials.gov ID: NCT03180437.

Prevention of Procedural Hypertension in the Irreversible Electroporation Ablation of Liver and Pancreatic Tumors Based on Distance from the Adrenal Gland.

BACKGROUND AND OBJECTIVE: When irreversible electroporation (IRE) ablation of abdominal tumors, procedural hypertension often occurs, which often affects the progress of the ablation. Until now, there is no reasonable explanation for this phenomenon. The objective of this research was to explore the cause and solution of procedural hypertension in percutaneous IRE. METHODS: In this study, the treatment data of 4 consecutive groups of patients were used to confirm the cause of intraoperative hypertension and then verify the solution. A total of 155 patients with procedural hypertension were screened based on their medical records of pancreatic or hepatic IRE treatment. Procedural hypertension was monitored in 21 new patients, the correlation between serum catecholamines and hypertension was recorded and evaluated using regression analysis. Forty new patients were divided into two groups (distance from needle tip to adrenal gland, < 2 cm vs ≥ 2 cm), and the blood pressure was recorded and compared with two-way ANOVA. Eleven patients with ablative distance <2 cm were treated in advance with phentolamine to observe for the occurrence of procedural hypertension. RESULTS: Of the 21 re-enrolled patients with ablation of the pancreas and liver tumors, 9 developed intraoperative hypertension with significantly elevated serum catecholamines levels, epinephrine, norepinephrine and dopamine are all positively associated with hypertension, with P values were 0.0003, 0.0253, and 0.0015, respectively. For the two groups with different needle-insertion distances, hypertension in the < 2 cm group was more significant than that in the other group (for procedural hypertension, P< 0.01; for heart rate, P< 0.05), which was considered as a high-risk group. The occurrence of intraoperative hypertension could be completely prevented by using phentolamine prior to treatment. CONCLUSION: Hypertension occurs frequently during hepatic and pancreatic IRE because of the damage of adrenal gland. The safe distance of ablation probe for the adrenal gland was 2 cm. For high-risk patients, early drug prevention works well.

Irreversible electroporation for liver metastasis from pancreatic cancer: A case report.

BACKGROUND: Pancreatic cancer has a poor prognosis; 40%-50% of patients have liver metastases at the time of initial diagnosis and only 15%-20% undergo surgical resection. Irreversible electroporation (IRE) is a new, non-thermal local ablation method for solid tumors, which can induce cell membrane permeabilization, resulting in unrecoverable nanoscale perforation and apoptotic cell death without damaging the structural components of tissues. CASE SUMMARY: We report the case of a 66-year-old female patient with liver metastasis from pancreatic cancer with a pathological diagnosis of poorly differentiated adenocarcinoma. Carbohydrate antigen 19-9 was elevated to 420.3 U/mL. Computed tomography showed a pancreas mass of 2.7 cm × 2.5 cm and single liver metastasis of 1.4 cm × 1.1 cm in the S6 area. The patient underwent IRE and arterial infusion chemotherapy and received tegafur. The therapeutic effect of the combination treatment has been evaluated as complete response. To date, the patient has survived for > 12 mo and is receiving tegafur as maintenance therapy (at the time this case report was written). CONCLUSION: IRE plus arterial infusion chemotherapy and tegafur may be synergistic, providing a reference for treating liver metastasis from pancreatic cancer.

Cryoablation for liver metastasis from solid pseudopapillary tumor of the pancreas: A case report.

BACKGROUND: Solid pseudopapillary tumor (SPT) of the pancreas is a rare pancreatic tumor and 10% to 15% of cases are associated with metastasis. Cryoablation is a new method that can induce tumor necrosis, and treatment of tumors by cryoablation can cause anti-tumor immune responses. CASE SUMMARY: A 16-year-old woman with SPT of the pancreas developed liver metastases 5.3 years after complete resection of the primary pancreatic tumor. She was admitted with chief complaints of abdominal pain in the upper abdomen and a weight loss of approximately 5 kg over 4 mo. Carbohydrate antigen (CA) 125, carcinoembryonic antigen, and CA 199 were normal. An abdominal computed tomography scan found multiple nodules in the right lobe of the liver that measured approximately 13.5 cm × 10.8 cm × 21.4 cm. Immunohistochemical staining results showed that CD10 and CD56 were positive, and the patient was diagnosed with SPT of the pancreas with liver metastasis. The patient underwent percutaneous cryoablation and interventional embolization. During the 5-year follow-up, the patient remained disease-free after cryoablation, with relatively normal immune function. CONCLUSION: Herein, we for the first time report the treatment of liver metastasis from SPT of the pancreas using cryoablation plus interventional embolization, which could be a promising alternative therapy for pancreatic SPT liver metastasis.