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DNA-based vaccines have been safe but weakly immunogenic in humans to date. We sought to determine the safety, tolerability, and immunogenicity of ADVAX, a multigenic HIV-1 DNA vaccine candidate, injected intramuscularly by in vivo electroporation (EP) in a Phase-1, double-blind, randomized placebo-controlled trial in healthy volunteers. Eight volunteers each received 0.2 mg, 1 mg, or 4 mg ADVAX or saline placebo via EP, or 4 mg ADVAX via standard intramuscular injection at weeks 0 and 8. A third vaccination was administered to eleven volunteers at week 36. EP was safe, well-tolerated and considered acceptable for a prophylactic vaccine. EP delivery of ADVAX increased the magnitude of HIV-1-specific cell mediated immunity by up to 70-fold over IM injection, as measured by gamma interferon ELISpot. The number of antigens to which the response was detected improved with EP and increasing dosage. Intracellular cytokine staining analysis of ELISpot responders revealed both CD4+ and CD8+ T cell responses, with co-secretion of multiple cytokines. This is the first demonstration in healthy volunteers that EP is safe, tolerable, and effective in improving the magnitude, breadth and durability of cellular immune responses to a DNA vaccine candidate. ClinicalTrials.gov NCT00545987.

Background Modulation of the cardiac autonomic nervous system (ANS) is a promising adjuvant therapy in the treatment of atrial fibrillation (AF). In pre-clinical models, pulsed field (PF) energy has the advantage of selectively ablating the epicardial ganglionated plexi (GP) that govern the ANS. This study aims to demonstrate the feasibility and safety of epicardial ablation of the GPs with PF during cardiac surgery with a primary efficacy outcome of prolongation of the atrial effective refractory period (AERP). Methods In a single-arm, prospective analysis, patients with or without a history of AF underwent epicardial GP ablation with PF during coronary artery bypass grafting (CABG). AERP was determined immediately pre- and post- GP ablation to assess cardiac ANS function. Holter monitors were performed to determine rhythm status and heart rate variability (HRV) at baseline and at 1-month post-procedure. Results Of 24 patients, 23 (96%) received the full ablation protocol. No device-related adverse effects were noted. GP ablation resulted in a 20.7 ± 19.9% extension in AERP ( P  < 0.001). Post-operative AF was observed in 7 (29%) patients. Holter monitoring demonstrated an increase in mean heart rate (74.0 ± 8.7 vs. 80.6 ± 12.3, P  = 0.01). There were no significant changes in HRV. There were no study-related complications. Conclusions This study demonstrates the safety and feasibility of epicardial ablation of the GP using PF to modulate the ANS during cardiac surgery. Large, randomized analyses are necessary to determine whether epicardial PF ablation can offer a meaningful impact on the cardiac ANS and reduce AF. Trial registration Clinical trial registration: NCT04775264.

Purpose This study aims to evaluate the feasibility and efficacy of chemotherapy combined with irreversible electroporation (IRE) in patients with locally advanced gallbladder carcinoma (GBC) presenting as gallbladder masses. Materials and Methods Patients with unresectable GBC masses of size greater than 2 cm and less than 6 cm without evidence of distant metastases and with no contraindication to general anaesthesia will be enrolled in the study. They will be randomized using computer generated table into two arms with 1:1 allocation ratio to include 15 patients in each group. Group I will be the chemotherapy alone arm and Group II will be the combined image-guided irreversible electroporation of the tumour and chemotherapy arm. The primary outcome assessed shall be the clinical benefit rate (complete response, CR; partial response, PR and stable disease, SD) based on the mRECIST criteria and overall survival. The secondary outcome shall be feasibility and safety of the procedure and quality of life pre and post procedure. The quality of life will be assessed by a questionnaire as given by EORTC-Quality of Life Group before starting therapy and 4 weeks after completion of therapy. Expected Gain of Knowledge The combined local and systemic effects of irreversible electroporation and systemic chemotherapy respectively may improve the outcomes in inoperable cases of gallbladder carcinoma. Trial Registration Clinical Trials Registry – India ( https://ctri.nic.in/Clinicaltrials/advancesearchmain.php ). Identifier: CTRI/2021/05/033803. Primary Register of the International Clinical Trials Registry Platform (WHO ICTRP) ( http://www.who.int/ictrp/search/en/ ). Graphic Abstract

Background At present, the main clinical application of local ablation therapy, such as radiofrequency ablation (RFA), is to heat the tissue to a certain temperature. However, high temperature will cause thermal damage. Irreversible electroporation (IRE) is a novel minimally invasive local ablation technology for tumors. By high-frequency pulse, the tumor cell membrane can be irretrievably perforated, resulting in the destruction of the intracellular environment, which can preserve important structures in the treatment area. However, there are no randomized controlled clinical trials comparing the efficacy of IRE with traditional local ablation in the treatment of liver cancer. Aims This study aims to conduct a randomized controlled clinical trial comparing the efficacy of IRE with RFA in the treatment of liver cancer. Methods We will conduct a multicenter, randomized, parallel-controlled non-inferiority clinical trial to compare the efficacy and safety of IRE and RFA for hepatocellular carcinoma (HCC). One hundred and ninety patients with HCC from five academic medical centers will be enrolled. The patients will be randomized into treatment arm (IRE) and control arm (RFA). The primary outcome is the progress -free survival (PFS) and the key secondary outcome is the Overall survival (OS). Results Forty-eight patients had been recruited from 5 centers, of which, 33 patients (median age, 59.1 years) with 38 tumors had completed the 1-month follow-up and 21 patients have complete the 3-month follow up, with 2.3 months median follow up period. The mean largest tumor diameter is 3.9 cm. No end point was observed for PFS or OS in both groups, and the complete ablation rate was 100% in both groups. The lesions in the IRE group showed obvious shrinkage 1 month after procedure. One major adverse event (AE) was occurred in the control group. Conclusion This is the first randomized controlled clinical trial to compare the clinical effects of IRE and RFA. The preliminary results suggest that both RFA and IRE are effective in the treatment of HCC, which can provide strong evidence for the use of IRE in HCC and provide more options for the treatment of patients with HCC. Clinical Trial Registration ClinicalTrials. gov, identifier NCT05451160.

BackgroundIrreversible electroporation (IRE) and stereotactic ablative body radiotherapy (SABR) are cytoreductive therapies for locally advanced pancreatic cancer (LAPC). Both may signify immunogenic cell death. We aimed to compare systemic immune responses between the treatments.MethodsAs part of the randomized phase II CROSSFIRE trial (NCT02791503), comparing the oncological efficacy of IRE to SABR in patients with LAPC, pre- and post-treatment (2 weeks and 3 months) peripheral blood samples were collected. Frequency and activation status of lymphocytic and myeloid subsets were determined using flow cytometry. T cell responses to pancreatic cancer associated with Wilms tumor-1 (WT-1) and survivin tumor antigens were determined by interferon-γ enzyme-linked immunospot assay.ResultsIn total, 20 IRE and 20 SABR-treated participants were analyzed (20 men; median age 65 (IQR 55–70)). IRE induced immediate decreases in systemic regulatory T cell (Treg) and conventional type-1 dendritic cell rates, coinciding with CD4+/CD8+ T cell activation by upregulation of PD-1, which was associated with improved overall survival (OS). SABR similarly induced immediate CD4+/CD8+ T cell activation by upregulation of Ki67 and CD25 but resulted in asynchronously delayed Treg downregulation. SABR also induced a durable increase in CD4+ EM T cells, associated with improved OS. Ablation-induced WT-1 or survivin-specific T cell responses were observed in 9/16 (56%) immune competent participants (IRE n=5, SABR n=4) and were associated with longer OS.ConclusionDistinct immune stimulatory responses associated with improved OS, suggest that SABR might benefit from combined Treg depletion strategies while IRE could benefit from PD-1 checkpoint inhibition.Trial registration numberThe trial was registered on clinical trials.gov (NCT02791503).

Background Current surgical and ablative treatment options for prostate cancer (PCa) may result in a high incidence of (temporary) incontinence, erectile dysfunction and/or bowel damage. These side effects are due to procedure related effects on adjacent structures including blood vessels, bowel, urethra and/or neurovascular bundle. Ablation with irreversible electroporation (IRE) has shown to be effective and safe in destroying PCa cells and also has the potential advantage of sparing surrounding tissue and vital structures, resulting in less impaired functional outcomes and maintaining men’s quality of life. Methods/Design In this randomized controlled trial (RCT) on IRE in localized PCa, 200 patients with organ-confined, unilateral (T1c-T2b) low- to intermediate-risk PCa (Gleason sum score 6 and 7) on transperineal template-mapping biopsies (TTMB) will be included. Patients will be randomized into focal or extended ablation of cancer foci with IRE. Oncological efficacy will be determined by multiparametric Magnetic Resonance Imaging, Contrast-Enhanced Ultrasound imaging if available, TTMP and Prostate Specific Antigen (PSA) follow-up. Patients will be evaluated up to 5 years on functional outcomes and quality of life with the use of standardized questionnaires. Discussion There is critical need of larger, standardized RCTs evaluating long-term oncological and functional outcomes before introducing IRE and other focal therapy modalities as an accepted and safe therapeutic option for PCa. This RCT will provide important short- and long-term data and elucidates the differences between focal or extended ablation of localized, unilateral low- to intermediate-risk PCa with IRE. Trial registration Clinicaltrials.gov database registration number NCT01835977 . The Dutch Central Committee on Research Involving Human Subjects registration number NL50791.018.14.

IntroductionTransurethral resection of the prostate (TURP) is the gold standard surgical treatment to lower urinary tract symptoms and benign prostatic obstruction (LUTS/BPO). Although it has been proven to have substantial efficacy in improving functional outcomes, it has shown a high incidence of complications, including transurethral resection syndrome, massive bleeding, urinary incontinence and sexual dysfunction. High-frequency irreversible electroporation (H-FIRE) is a novel non-thermal ablation technique that delivers pulsed high-voltage but low-energy electric current to the cell membrane, thereby leading to cell death. H-FIRE has been reported to be tissue-selective, which leads to fewer side effects. However, no data are available on whether H-FIRE is non-inferior compared with TURP in treating patients with LUTS/BPO regarding safety and efficacy.Methods and analysisThis trial is a prospective, single-centre, randomised controlled, double-blinded and non-inferiority study in which all men with LUTS/BPO are included. This study aims to determine whether the HI-FIRE is non-inferior to TURP for achieving better functional outcomes as measured by the co-primary outcome of the change from baseline in maximal flow rate (Qmax) and the urinary symptoms by questionnaire of International Prostate Symptom Score (IPSS) scoring at 3 months after surgical treatment. The main inclusion criteria are men with prostatic volume range 30 to 100 mL, Qmax<15 mL/s and IPSS>8. A sample size of 118 participants is required, accounting for a 20% loss. All participants will be randomly allocated at a ratio of 1:1 to the H-FIRE arm (n=59) and the TURP arm (n=59). The primary outcome is to assess the change from baseline in Qmax and IPSS scoring at 3 months after surgical treatment.Ethics and disseminationEthical approval was obtained from the ethics committee of Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China. The results of the study will be disseminated and published in international peer-reviewed journals.Trial registration numberClinicalTrials.gov: NCT05306145.

BackgroundApproximately 30% of patients with pancreas cancer have unresectable locally advanced disease, which is currently treated with systemic chemotherapy. A new treatment option of irreversible electroporation (IRE) has been investigated for these patients since 2005. Cohort studies suggest that IRE confers a survival advantage, but with associated, procedure-related complications. Selection bias may account for improved survival and there have been no prospective randomised trials evaluating the harms and benefits of therapy. The aim of this trial is to evaluate the feasibility of a randomised comparison of IRE therapy with chemotherapy versus chemotherapy alone in patients with locally advanced pancreatic cancer (LAPC).Methods and analysisEligible patients with LAPC who have undergone first-line 5-FluoroUracil, Leucovorin, Irinotecan and Oxaliplatin chemotherapy will be randomised to receive either a single session of IRE followed by (if indicated) further chemotherapy or to chemotherapy alone (standard of care). Fifty patients from up to seven specialist pancreas centres in the UK will be recruited over a period of 15 months. Trial follow-up will be 12 months. The primary outcome measure is ability to recruit. Secondary objectives include practicality and technical success of treatment, acceptability of treatment to patients and clinicians and safety of treatment. A qualitative study has been incorporated to evaluate the patient and clinician perspective of the locally advanced pancreatic cancer with percutaneous irreversible electroporation trial. It is likely that the data obtained will guide the structure, the primary outcome measure, the power and the duration of a subsequent multicentre randomised controlled trial aimed at establishing the clinical efficiency of pancreas IRE therapy. Indicative procedure-related costings will be collected in this feasibility trial, which will inform the cost evaluation in the subsequent study on efficiency.Ethics and disseminationThe protocol has received approval by London-Brent Research Ethics Committee reference number 21/LO/0077.Results will be analysed following completion of trial recruitment and follow-up. Results will be presented to international conferences with an interest in oncology, hepatopancreaticobiliary surgery and interventional radiology and be published in a peer-reviewed journal.Trial registration number ISRCTN14986389.

DNA vaccines are cost-effective and versatile, though intracellular delivery has been challenging in humans. Alternative delivery modalities such as electroporation have demonstrated improved immune responses, but are painful. In this single-center, double-blind, medical device trial, we evaluated the safety and tolerability of Easy Vax™ dermal electroporation system, alone (without DNA) in healthy adults. Three randomized protocol doses were administered to 10 subjects (80% white, 60% female, mean age: 32.1 years) in each of two areas (total of six doses). Two subjects complained of shooting pain, burning and/or tingling when doses were administered to the forearm region, but not the lateral deltoid regions. Subsequent doses for the remaining eight subjects were restricted to the deltoid regions only. Tolerability pain scores never exceeded 3 of 10 in the 11-Point Pain Rating scale, and 12 of 100 in the Visual Analog Scale (VAS), and lower in follow-up evaluations (P < 0.0001), with no significant difference between the three dosing protocols. Electrical properties of the skin, measured automatically by the device, showed no correlation between pain intensity and skin conductance. In conclusion, the Easy Vax™ electroporation device is safe and well tolerated when administered over the lateral deltoid skin regions in healthy volunteers.

Irreversible electroporation (IRE) is a novel image-guided ablation technique that is rapidly gaining popularity in the treatment of malignant tumors located near large vessels or bile ducts. The presence of metal objects in the ablation zone, such as Wallstents, is generally considered a contraindication for IRE, because tissue heating due to power conduction may lead to thermal complications. This report describes a 66-year-old female with a Bismuth–Corlette stage IV unresectable cholangiocarcinoma with a metallic Wallstent in the common bile duct, who was safely treated with percutaneous IRE with no signs for relapse 1 year after the procedure.