Ablation Of Pancreatic Tumors Research Articles

Chymotrypsin etched ultrasmall gold nanoclusters for dual response diagnosis and deeply penetrated chemodynamic therapy of pancreatic cancer

Pancreatic cancer (PC) is a highly invisible malignancy for which the early diagnosis is crucial to achieve the best treatment outcome. Abnormalities in serum chymotrypsin (ChT) are commonly associated with the development of PC, suggesting its potential role as a novel biomarker candidate. Herein, we report a ChT-responsive ultrasmall apo catalase-stabilized gold nanoclusters (AuCATapo NCs, core size ∼2 nm) with remarkable fluorescence and peroxidase (POD)-like activity. It can achieve "fluorescence" and "colorimetric" dual detection of ChT, with a wide detection range (0 – 100 μg/mL) and a low detection limit (0.029 μg/mL). Additionally, the weak acidity (pH 6.2 – 6.8) in the tumor microenvironment can meet the optimal catalytic capacity of deeply penetrated AuCATapo NCs, which generates cytotoxic reactive oxygen species to cause thorough tumor damage effects. The ChT-cleaved AuCATapo NCs may expose more catalytic active sites, resulting in higher tumor cytotoxicity, as demonstrated in both in vitro and in vivo models. Generally, these NCs probes can simultaneously realize accurate detection of ChT and efficient pancreatic tumor ablation via nanozyme based catalytic therapy, opening up a new idea of "diagnosis and treatment integration" for PC.

Endoscopic ultrasound-guided radiofrequency ablation of pancreatic tumors.

Surgery is a cornerstone in the management of pancreatic cancer and precancerous pancreatic lesions. However, many patients are not suitable candidates for surgery at the time of diagnosis for various reasons. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) appears to be a promising treatment option for patients who are ineligible for surgery for management of pancreatic adenocarcinoma (PDAC), and pancreatic neuroendocrine tumors (PNETs), and pancreatic cystic lesions (PCLs). EUS-RFA may serve as an adjunct to chemotherapy or palliative measures for inoperable cases of PDAC. Given its feasibility and efficacy, EUS-RFA has an evolving niche as a minimally invasive and potentially definitive treatment for PNETs and high-risk PCLs such as intraductal papillary mucinous neoplasms (IPMNs). EUS-RFA is a generally well tolerated procedure, with abdominal pain and acute pancreatitis being the most common adverse effects, though the risk can be mitigated through prophylactic measures. There is an increasing body of evidence to support the use of EUS-RFA in managing pancreatic lesions, either as definitive, adjunctive, or palliative treatment, depending on lesion type.

Iatrogenic Injuries Related to Thermal Ablation of the Liver and Pancreas

AbstractThermal ablation is a widely utilized treatment option for tumors of the liver and pancreas; procedures may be performed intraoperatively or percutaneously, under image guidance (more recently, endoscopy-guided ablation of pancreatic tumors has also been introduced). Through differing mechanisms, radiofrequency ablation, microwave ablation, and cryoablation aim to precisely eradicate tumor, with adequate margins and minimal injury to normal surrounding tissue. Knowledge of thermal ablative risks and complications is crucial for both therapeutic planning and postprocedural management to optimize outcomes and avoid significant patient injury. In this review, we discuss iatrogenic injuries related to thermal ablation of hepatic and pancreatic malignancies.

Endoscopic ultrasound guided biliary drainage: literature review

Mantas Markauskas1 1Vilnius City Clinical Hospital, Vilnius, Lithuania Abstract Background. The first echoendoscope was introduced only as diagnostic tool in 1980 and it was mainly used to diagnose tumors, located in mediastinum, pancreas, liver or biliary tree. Therapeutic procedures using endoscopic ultrasound became possible only in 1991, when first linear echoendoscope and needle compatible with it were introduced. During past two decades echoendoscope and its accessories were improved, therefore complex therapeutic procedures using endoscopic ultrasound, such as gallbladder and biliary drainage, pancreatic duct and peripancreatic fluid drainage, pancreatic tumor ablation, brachytherapy, celiac plexus neurolysis, gastroenterostomy and many others, became possible. Aim. To discuss the recent literature describing endoscopic ultrasound guided biliary drainage. Procedure is discussed in terms of its indications, technique, results and adverse events. Methods. The literature search was performed in the PubMed database by entering relevant keywords in various combinations into the regular and advanced search fields, as well as using the bibliographies of the articles found. A total of 38 publications were found during the review, with 24 scientific publications based on the inclusion criteria. Conclusion. Literature indicates that endoscopic ultrasound guided biliary drainage can be safely performed on patients with biliary obstruction after failed endoscopic retrograde cholangiopancreatography. Present studies allow to conclude that endoscopic ultrasound guided biliary drainage is safe and efficient. However, in order to confirm endoscopic ultrasound guided biliary drainage as first-line treatment on patients with biliary obstruction after failed endoscopic retrograde cholangiopancreatography, further large prospective multicenter studies are needed. Keywords: endoscopic ultrasound, therapeutic procedures, biliary drainage.

Minimally invasive image-guided therapy of primary and metastatic pancreatic cancer

Pancreatic cancer is a challenging malignancy with limited treatment options and poor life expectancy. The only curative option is surgical resection, but only 15%-20% of patients are resectable at presentation because more than 50% of patients has distant metastasis at diagnosis and the rest of them has locally advanced pancreatic cancer (LAPC). The standard of care first line treatment for LAPC patients is chemotherapy with or without radiation therapy. Recent developments in minimally invasive ablative techniques may add to the treatment armamentarium of LAPC. There are increasing number of studies evaluating these novel ablative techniques, including radiofrequency ablation, microwave ablation, cryoablation and irreversible electroporation. Most studies which included pancreatic tumor ablation, demonstrated improved overall survival in LAPC patients. However, the exact protocols are yet to set up to which stage of the treatment algorithm ablative techniques can be added and in what kind of treatment combinations. Patients with metastatic pancreatic cancer has dismal prognosis with 5-year survival is only 3%. The most common metastatic site is the liver as 90% of pancreatic cancer patients develop liver metastasis. Chemotherapy is the primary treatment option for patients with metastatic pancreatic cancer. However, when the tumor is not responding to chemotherapy or severe drug toxicity develops, locoregional liver-directed therapies can provide an opportunity to control intrahepatic disease progression and improve survival in selected patients. During the last decade new therapeutic options arose with the advancement of minimally invasive technologies to treat pancreatic cancer patients. These new therapies have been a topic of increasing interest due to the severe prognostic implications of locally advanced and metastatic pancreatic cancer and the low comorbid risk of these procedures. This review summarizes new ablative options for patients with LAPC and percutaneous liver-directed therapies for patients with liver-dominant metastatic disease.

Local ablation of pancreatic tumors: State of the art and future perspectives.

BACKGROUNDCurrently, the technologies most commonly used to treat locally advanced pancreatic cancer are radiofrequency ablation (RFA), microwave ablation, and irreversible (IRE) or reversible electroporation combined with low doses of chemotherapeutic drugs.AIMTo report an overview and updates on ablative techniques in pancreatic cancer.METHODSSeveral electronic databases were searched. The search covered the years from January 2000 to January 2021. Moreover, the reference lists of the found papers were analysed for papers not indexed in the electronic databases. All titles and abstracts were analysed.RESULTSWe found 30 studies (14 studies for RFA, 3 for microwave therapy, 10 for IRE, and 3 for electrochemotherapy), comprising 1047 patients, which were analysed further. Two randomized trials were found for IRE. Percutaneous and laparotomy approaches were performed. In the assessed patients, the median maximal diameter of the lesions was in the range of 2.8 to 4.5 cm. All series included patients unfit for surgical treatment, but Martin et al assessed a subgroup of patients with borderline resectable tumours who underwent resection with margin attenuation with IRE. Most studies administered chemotherapy prior to ablative therapies. However, several studies suggest that the key determinant of improved survival is attributable to ablative treatment alone. Nevertheless, the authors suggested chemotherapy before local therapies for several reasons. This strategy may not only downstage a subgroup of patients to curative-intent surgery but also support to recognize patients with biologically unfavourable tumours who would likely not benefit from ablation treatments. Ablation therapies seem safe based on the 1047 patients assessed in this review. The mortality rate ranged from 1.8% to 2%. However, despite the low mortality, the reported rates of severe post procedural complications ranged from 0%-42%. Most reported complications have been self-limiting and manageable. Median overall survival varied between 6.0 and 33 mo. Regarding the technical success rate, assessed papers reported an estimated rate in the range of 85% to 100%. However, the authors reported early recurrence after treatment. A distinct consideration should be made on whether local treatments induce an immune response in the ablated area. Preclinical and clinical studies have shown that RFA is a promising mechanism for inducing antigen-presenting cell infiltration and enhancing the systemic antitumour T-cell immune response and tumour regression.CONCLUSIONIn the management of patients with pancreatic cancer, the possibility of a multimodal approach should be considered, and conceptually, the combination of RFA with immunotherapy represents a novel angle of attack against this tumour.

Abstract PR8: Irreversible electroporation is an effective tumor-ablation strategy that induces immunologic cell death and promotes systemic antitumor immunity

Abstract New therapeutic strategies are direly needed to treat pancreatic cancer. Over the last decade, tumor-ablation strategies, such as radiofrequency ablation, have emerged as promising therapeutic options. However, these strategies are associated with significant complications and treatment limitations. To circumvent these limitations, members of our research team developed a nonthermal tissue ablation modality, termed irreversible electroporation (IRE), for treating solid tumors. IRE delivers a series of low-energy, unipolar electric pulses through electrodes inserted directly into the tumor to produce structural defects in the target cell membrane and cell death. While the effectiveness of IRE in inducing targeted tumor ablation is well established, there is a paucity of data pertaining to immune system activation following IRE. Here, we hypothesize that IRE treatment will elicit robust proinflammatory cell death signaling and a strong anticancer immune response, ultimately leading to decreased disease burden. To evaluate this hypothesis, we utilized healthy pancreatic tissue, patient-derived xenograft (PDX) models, in vivo studies using immunocompetent mouse models, and studies in human patients. In healthy ex vivo pancreatic tissue, IRE induces predominately apoptotic cell death with limited proinflammatory effects. However, in ex vivo PDX tumors and in vivo murine pancreatic tumors, IRE induced voltage-dependent inflammatory cell death signaling, marked by the release of defined damage-associated molecular patterns (DAMPs). Mice treated with IRE exhibited 40% or more ablation of pancreatic tumors, significantly increased progression-free survival, and lower overall disease burden. IRE treatment also reduced local and systemic immunosuppressive cell populations, such as tumor-associated macrophages and T-regulatory cells, and increased proinflammatory signaling weeks after treatment. The increased proinflammatory signaling was, in part, associated with the generation of specific DAMPs and robust activation of the innate immune system. Additionally, we observed increased evidence of improved antigen presentation, altered immune checkpoint signaling pathways, and engagement of the adaptive immune system. Together, our data support a model whereby the unique cell death and tumor ablation following IRE treatment stimulate the local innate immune system, which shifts the tumor microenvironment from an anti-inflammatory state to a proinflammatory state. Likewise, the nonthermal nature of the ablation improves tumor antigen availability. Together, these mechanisms result in robust engagement of the adaptive immune system and improved systemic antitumor immune responses. We anticipate that IRE will be highly capable of improving conventional pancreatic cancer treatment strategies and complement emerging immunomodulatory approaches targeting primary tumors, metastatic lesions, and preventing recurrence. This abstract is also being presented as Poster A11. Citation Format: Rebecca M. Brock, Natalie Beitel-White, Melvin F. Lorenzo, Veronica M. Ringel-Scaia, Sheryl Coutermarsh-Ott, Navid Manuchehrabadi, Rafael V. Davalos, Irving C. Allen. Irreversible electroporation is an effective tumor-ablation strategy that induces immunologic cell death and promotes systemic antitumor immunity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR8.

Abstract No. 617 Nonthermal ablation of pancreatic cancer in a pig model, using vascular-targeted photodynamic therapy (VTP)

To examine whether pancreatic cancer in a pig model can be safely ablated using vascular-targeted photodynamic therapy (VTP), a nonthermal ablation modality that combines an intravascular photosensitizer (WST11) and percutaneous laser fibers. Pancreatic tumors (n=8) were induced in 5 Oncopigs (transgenic swine with Cre-inducible p53 and Kras mutations) using an adenoviral vector carrying the Cre recombinase gene. Non-thermal ablation of the tumors was performed using VTP: Intravenous infusion of WST11 (4 mg/kg, 10 min) was followed by near-infrared illumination (753 nm, 20 min) of the tumor through three optical fibers with 1-cm spacing, placed percutaneously into the tumor under CT guidance. Contrast-enhanced CT was performed immediately after, and at 7-days post ablation. Ablation sizes on CT were compared using a t test. Necropsy was performed 7 days post-ablation and lesions were examined histologically. There were no complications after ablation of pancreatic tumors (4 pancreatic head tumors, and 4 pancreatic tail tumors), based on imaging, laboratory results, and clinical evaluation. The average diameters of the ablation zones on contrast-enhanced CT increased from 1.2±0.1 cm at 200 mW/cm to 2.1±0.2 cm at 300 mW/cm (p<0.01). Pathology showed a zone of coagulative necrosis, hemorrhage, and occluded blood vessels. All vessels outside the ablation zone remained patent. VTP can be safely applied for reproducıble ablation of pancreatic tumors, while sparing large blood vessels outside the ablation zone. Preservation of nearby blood vessels could potentially enable ablation of unresectable pancreatic cancer with vascular involvement.

Histological analysis of human pancreatic carcinoma following irreversible electroporation in a nude mouse model.

AIMTo determine changes in the morphology and function of pancreatic cancer cells after irreversible electroporation (IRE) treatment, and to explore the clinical significance of IRE treatment for pancreatic cancer providing an experimental basis for the clinical application of IRE treatment.METHODSIRE was carried out in an athymic nude mouse model of pancreatic carcinoma generated with human pancreatic cancer cells 1. In therapy groups, IRE electrodes were inserted with 90 pulses per second at 800 V/cm applied to ablate the targeted tumor tissues. Histological assessment of the affected tissue was performed by hematoxylin and eosin staining (HE). Quantification of cell proliferation and apoptosis was performed by evaluating Ki67 and caspase-3 levels, respectively. Flow cytometry was used to assess cell apoptosis. Ultrasound imaging was carried out to evaluate IRE treatment results. Pathological correlation studies showed IRE is effective for the targeted ablation of pancreatic tumors in an orthotopic mouse model.RESULTSIRE was efficacious in removing tumors in the orthotopic mouse model. The IRE-ablated zone displays characteristics of nude mouse models at different time-points as assessed by hematoxylin and eosin staining. Immunohistochemical analysis of samples from the pancreatic cancer models showed significantly enhanced caspase-3 cleavage and Ki67. Flow cytometry data corroborated the above findings that apoptosis in tumor cells was observed immediately on the first postoperative day, and with time the middle and late stages of apoptosis were observed. For ultrasound imaging studies, the IRE ablation zone became a hyperechoic area due to increasing inflammatory and immunologic cellular contents.CONCLUSIONIRE is a promising new approach for pancreatic cancer, with many potential advantages over conventional ablation techniques.

Nano-Pulse Stimulation for the Treatment of Pancreatic Cancer and the Changes in Immune Profile.

A Pancreatic cancer is a notorious malignant neoplasm with an extremely poor prognosis. Current standard of care is rarely effective against late-stage pancreatic cancer. In this study, we assessed nanopulse stimulation (NPS) as a local treatment for pancreatic cancer in a syngeneic mouse Pan02 pancreatic cancer model and characterized corresponding changes in the immune profile. A single NPS treatment either achieved complete tumor regression or prolonged overall survival in animals with partial tumor regression. While this is very encouraging, we also explored if this local ablation effect could also result in immune stimulation, as was observed when NPS led to the induction of immune-mediated protection from a second tumor challenge in orthotopic mouse breast and rat liver cancer models. In the Pan02 model, there were insufficient abscopal effects (1/10) and vaccine-like protective effects (1/15) suggesting that NPS-induced immune mechanisms in this model were limited. To evaluate this further, the immune landscape was analyzed. The numbers of both T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSCs) in blood were significantly reduced, but memory (CD44+) T-cells were absent. Furthermore, the numbers of Tregs and MDSCs did not reduce in spleens compared to tumor-bearing mice. Very few T-cells, but large numbers of MDSCs were present in the NPS treated tumor microenvironment (TME). The number of dendritic cells in the TME was increased and multiple activation markers were upregulated following NPS treatment. Overall, NPS treatments used here are effective for pancreatic tumor ablation, but require further optimization for induction of immunity or the need to include effective combinational NPS therapeutic strategy for pancreatic cancer.

Microwave ablation of pancreatic tumors

Objectives: To evaluate the clinical performance of percutaneous microwave ablation (MWA) for treatment of locally-advanced-pancreatic-cancer (LAPC).Material and methods: Twenty-two MWA sessions (August 2015–March 2017) in 20 patients with primary pancreatic cancer (13 men, 7 women, mean-age: 59.9 ± 8.6 years, range: 46–73 years), who had given informed consent, were retrospectively evaluated. All procedures were performed percutaneously under CT-guidance using the same high-frequency (2.45-GHz) MWA device. Tumor location and diameter, ablation diameter and volume, roundness, duration, technical success and efficacy, output energy, complications, and local tumor progression defined as a tumor focus connected to the edge of a previously technically efficient ablation zone were collected.Results: Seventeen pancreatic malignant tumors (77.3%) were located in the pancreatic head and five (22.7%) in the pancreatic tail. Initial Mean Tumor Diameter was 30 ± 6 mm. Technical success and efficacy were idem (100%). No major complications occurred. Two patients (9.1%) showed minor complications of severe local pain related to MWA. Post-ablation diameter was on average 34.4 ± 5.8 mm. Mean ablation volume was 7.8 ± 3.8 cm³. The mean transverse roundness index was 0.74 ± 0.14. Mean ablation time was 2.6 ± 0.96 min. The mean applied energy per treatment was 9627 ± 3953 J. Local tumor progression was documented in one case (10%) of the 10/22 available three-month follow-up imaging studies.Conclusion: High-frequency (2.45 GHz) microwave ablation (MWA) for treatment of unresectable and non-metastatic locally-advanced-pancreatic-cancer (LAPC) shows promising results regarding feasibility and safety of percutaneous approach after short-term follow-up and should be further evaluated.

Porphysome nanoparticles for enhanced photothermal therapy in a patient-derived orthotopic pancreas xenograft cancer model: a pilot study.

Local disease control is a major challenge in pancreatic cancer treatment, because surgical resection of the primary tumor is only possible in a minority of patients and radiotherapy cannot be delivered in curative doses. Despite the promise of photothermal therapy (PTT) for focal ablation of pancreatic tumors, this approach remains underinvestigated. Using photothermal sensitizers in combination with laser light irradiation for PTT can result in more efficient conversion of light energy to heat and improved spatial confinement of thermal destruction to the tumor. Porphysomes are self-assembled nanoparticles composed mainly of pyropheophorbide-conjugated phospholipids, enabling the packing of ∼80,000 porphyrin photosensitizers per particle. The high-density porphyrin loading imparts enhanced photonic properties and enables high-payload tumor delivery. A patient-derived orthotopic pancreas xenograft model was used to evaluate the feasibility of porphysome-enhanced PTT for pancreatic cancer. Biodistribution and tumor accumulation were evaluated using fluorescence intensity measurements from homogenized tissues and imaging of excised organs. Tumor surface temperature was recorded using IR optical imaging during light irradiation to monitor treatment progress. Histological analyses were conducted to determine the extent of PTT thermal damage. These studies may provide insight into the influence of heat-sink effect on thermal therapy dosimetry for well-perfused pancreatic tumors.

Harmonic motion imaging for abdominal tumor detection and high-intensity focused ultrasound ablation monitoring: an in vivo feasibility study in a transgenic mouse model of pancreatic cancer.

Harmonic motion imaging (HMI) is a radiationforce- based elasticity imaging technique that tracks oscillatory tissue displacements induced by sinusoidal ultrasonic radiation force to assess the resulting oscillatory displacement denoting the underlying tissue stiffness. The objective of this study was to evaluate the feasibility of HMI in pancreatic tumor detection and high-intensity focused ultrasound (HIFU) treatment monitoring. The HMI system consisted of a focused ultrasound transducer, which generated sinusoidal radiation force to induce oscillatory tissue motion at 50 Hz, and a diagnostic ultrasound transducer, which detected the axial tissue displacements based on acquired radio-frequency signals using a 1-D cross-correlation algorithm. For pancreatic tumor detection, HMI images were generated for pancreatic tumors in transgenic mice and normal pancreases in wild-type mice. The obtained HMI images showed a high contrast between normal and malignant pancreases with an average peak-to-peak HMI displacement ratio of 3.2. Histological analysis showed that no tissue damage was associated with HMI when it was used for the sole purpose of elasticity imaging. For pancreatic tumor ablation monitoring, the focused ultrasound transducer was operated at a higher acoustic power and longer pulse length than that used in tumor detection to simultaneously induce HIFU thermal ablation and oscillatory tissue displacements, allowing HMI monitoring without interrupting tumor ablation. HMI monitoring of HIFU ablation found significant decreases in the peak-to-peak HMI displacements before and after HIFU ablation with a reduction rate ranging from 15.8% to 57.0%. The formation of thermal lesions after HIFU exposure was confirmed by histological analysis. This study demonstrated the feasibility of HMI in abdominal tumor detection and HIFU ablation monitoring.

Preoperative ultrasound ablation for borderline resectable pancreatic cancer: A report of 30 cases

Background and objectivesCurrently, extended resection and preoperative neoadjuvant chemotherapy are the two main modalities for improvement of the resection rate and R0 resection rate of borderline resectable pancreatic cancer. The past few years, however, have witnessed some progress in the treatment of unresectable pancreatic cancer with high intensity focused ultrasound (HIFU). The aim of this study is twofold: first, to evaluate the feasibility and safety of HIFU ablation as a preoperative adjuvant therapy for borderline resectable pancreatic cancer, and second, to conduct pathological analyses to verify the safety and effectiveness of HIFU treatment of pancreatic cancer. MethodsFrom January 2011 to December 2012, 30 patients with borderline resectable pancreatic cancer underwent HIFU ablation by Haifu Model-JC200 Focused Ultrasound Tumor Therapeutic System prior to radical surgery. The effect of pre-operative HIFU ablation was evaluated by post-HIFU functional imaging results, operation time of radical surgery, blood loss volume, R0 resection rate, postoperative 1-year survival rate and Ca199 curve. Postoperative pathological specimens were obtained for histological examination. ResultsAll 30 patients with borderline resectable pancreatic cancer had completed the treatments and follow-ups. Functional image assessment after HIFU treatment showed a mean tumor ablation rate of (61.5±24.3)%. 28 patients underwent radical resection of pancreatic cancer 7–9days after HIFU treatment (23 cases underwent pancreaticoduodenectomy. 4 patients underwent pancreatectomy and 1 patient had total pancreatectomy). 7 patients underwent combined resection and reconstruction of portal-superior mesenteric vein (23.3%), with the resectability rate of 93.3%, the R0 resection rate of 92.7%, and the 1-year survival rate of 96.7%. The biological coagulative necrosis regions identified by the postoperative pathological examination matched well with the necrosis foci identified by post-operative functional imaging. ConclusionThe effectiveness of HIFU ablation of pancreatic tumors, as well as interstitial tissues within he main vascular spaces was confirmed by post-operative pathological examinations. Based on these observations, we conclude that preoperative HIFU ablation of borderline resectable pancreatic cancer can significantly improve the resection rate, R0 resection rate, and reduce the difficulty and risk of surgery. Therefore, HIFU may be a valuable pre-operative adjunct therapy for resectable pancreatic cancer. However, the safety and the efficacy on the improvement of the surgery need to established with future multicenter, randomized studies.

Evaluation of Resistance as a Measure of Successful Tumor Ablation During Irreversible Electroporation of the Pancreas

Intraoperative evaluation of successful pancreatic tumor ablation using irreversible electroporation (IRE) is difficult secondary to lack of visual confirmation. The IRE generator provides feedback by reporting current (amperage), which can be used to calculate changes in tumor tissue resistance. The purpose of the study was to determine if resistance can be used to predict successful tumor ablation during IRE for pancreatic cancers. All patients undergoing pancreatic IRE from March 2010 to December 2012 were evaluated using a prospective database. Intraoperative information, including change in tumor resistance during ablation and slope of the resistance curve, were used to evaluate effectiveness of tumor ablation in terms of local failure or recurrence (LFR) and disease-free survival (DFS). A total of 65 patients underwent IRE for locally advanced pancreatic cancer. Median follow-up was 23 months. Local failure or recurrence was seen in 17 patients at 3, 6, or 9 months post IRE. Change in tumor tissue resistance and the slope of the resistance curve were both significant in predicting LFR (p = 0.02 and p = 0.01, respectively). The median local disease-free survival was 5.5 months in patients who had recurrence compared with 12.6 months in patients who did not recur (p = 0.03). Neither mean change in tumor tissue resistance nor the slope of the resistance curve significantly predicted overall DFS. Mean change in tumor tissue resistance and the slope of the resistance curve could be used intraoperatively to assess successful tumor ablation during IRE. Larger sample size and longer follow-up are needed to determine if these parameters can be used to predict DFS.

Abstract No. 129: Percutaneous irreversible electroporation (IRE) in the treatment of hepatocellular carcinoma (HCC) and metastatic colorectal cancer (mCRC) to the liver

Purpose: Pancreatic carcinoma is surgically unresectable and without distant metastatic disease in 30% of newly diagnosed cases. We present our initial safety experience with percutaneous IRE in unresectable pancreatic carcinoma. Materials and Methods: Four consecutive patients (3 male,1 female), age 49-78, with surgically unresectable pancreatic carcinoma (stage III) were treated under general anesthesia. Average Eastern Cooperative Oncology Group (ECOG) grade was 1.5 (range 0-3). American Society of Anesthesiology (ASA) class was 3 in all patients. Seven percutaneous ablations were performed of five primary pancreatic tumors. Clinical evaluation, laboratory and imaging was performed at baseline, 24 hours, 1 month and 3 months. Results: Seven technically successful ablations were performed in the four patients. No mortalities occurred at 30 days. No episodes of intraoperative arrhythmia occurred. Intraoperative transient hypertension occurred with all treatments (7/7). No patients had prolonged hypertension after completion of electroporation. There were no incidents of hemorrhage, infection, pancreatic fistula, or bowel injury. One treatment (1/7) was complicated by partial splenic infarction, which required no treatment. Average length of stay was 1.3 days. No patients required analgesics on discharge. Conclusion: Percutaneous pancreatic IRE appears to be a safe method for pancreatic tumor ablation. Further studies will be needed to evaluate efficacy.

Initial experience using percutaneous irreversible electroporation (IRE) in the treatment of locally advanced pancreatic adenocarcinoma (LAPC) with vascular encasement.

291 Background: Neoadjuvant chemoradiation therapy can convert some patients (pts) with borderline or unresectable LAPC to resectability. Persistent vascular encasement after neoadjuvant therapy usually contraindicates resection. IRE using the Nanoknife is more versatile than other ablative modalities in that tumors abutting vascular structures can be treated with IRE without compromise of the vessels or concern for the heat sink effect of nearby blood flow. Methods: We examined the records of pts referred for IRE for LAPC. The procedures were all done percutaneously under general anesthesia using a standard protocol. The primary endpoint was safety. Secondary endpoints included survival and resection rate after the procedure. Results: Between 12/2010 and 8/2011, 8 pts with biopsy-proven PC underwent percutaneous ablation of pancreatic tumors using IRE. The median age was 53 years (range 51-72), the median time from diagnosis to IRE was 8.8 months (range 2.4-29.2) and the median tumor size treated was 2.8cm (range 2.5-6.8). All pts had prior chemotherapy and 7 had prior radiation, with a median of 2 lines of prior therapies (range 1-4). Two pts went to surgery after IRE after 4 and 5 months respectively. Both had margin-negative (R0) resections and one had a pathologic complete response. Both remain disease-free at 1 and 5 months after resection respectively. Among the 6 remaining pts, 2 were lost to follow-up, one had progressive disease after 3 months and 3 remain under follow-up to determine resectability. One of these 3 pts had a negative follow-up PET scan and surgery is planned. The procedure was complicated by a spontaneous pneumothorax during anesthesia in one patient, and another developed pancreatitis; both recovered completely. Conclusions: Percutaneous ablation of pancreatic tumors appears to be feasible and safe using the IRE modality. In our initial experience, 2 out of 8 pts with unresectable LAPC due to persistent vascular encasement after neoadjuvant therapy achieved a margin-negative resection after IRE. One had a pathological complete response. A prospective neoadjuvant trial in LAPC incorporating IRE is planned.

Microwave Ablation with Percutaneous Approach for the Treatment of Pancreatic Adenocarcinoma

Pancreatic adenocarcinoma, characterized by a late presentation and by high aggressiveness, is one of the most lethal human cancers and currently the fifth most common cause of cancer-related death in men [1]. Only 10% of the tumors are confined to the pancreas at the time of presentation, 30–40% are locally advanced, and 50% have distant metastases [1, 2]. Only approximately 20% of pancreatic cancers are found to be resectable at the time of presentation. Surgical resection is the only potentially curative treatment for pancreatic cancer [2]. Some palliative therapeutic modalities have been applied in treatment of unresectable locally advanced pancreatic carcinoma, such as chemotherapy and chemoradiation [3]. In a few patients, thermal ablative techniques, such as radiofrequency ablation (RFA) and microwave ablation (MWA), have been reported, especially in association with surgery [4, 5]. Date RS [6] reviewed the results of local ablative therapies for the treatment of pancreatic cancer; photodynamic therapy (PDT), high-intensity ultrasound (HIFU), cryoablation, and RFA may have role in ablation of pancreatic tumors. Wu et al. [7] reported encouraging results on the feasibility of HIFU ablation of pancreas tumor, but they excluded patients with carcinoma located in the head to avoid damage of the biliary duct. Photodynamic therapy has major disadvantages of organizational and technical difficulties in setting up the treatments and potential side effects, such as skin photosensitivity reaction [8]. Matsui et al. [9] performed laparotomy and radiofrequency heating in 20 patients with unresectable pancreatic carcinomas. They have reported an intraperitoneal abscess in one patient who died of septic shock. Potential benefits of these techniques include treatment of patients who are not surgical candidates and reduced morbidity compared with surgery. Ablation with microwave has several intrinsic advantages over RFA, including the capability to generate very high tissue temperature, less intraprocedural pain, larger coagulation zones, less sensitivity to tissue type and charring, improved performance near blood vessels, and no requirement of ground pads [10–12]. Recently, this technique has been proposed in different organs, such as liver, lung, and kidney [10]. However, only few cases regarding the use of MWA in pancreatic cancer have been published and they were performed under laparotomy [5]. To the best of our knowledge, our case G. Carrafiello (&) A. M. Ierardi F. Piacentino N. Lucchina C. Fugazzola Interventional Radiology, Department of Radiology, Insubria University, Viale Borri, 57, 21100 Varese, Italy e-mail: gcarraf@tin.it

466 Levels of Evidence in Endoscopic Ultrasonography (EUS): A Survey of the Literature

EUS has evolved into a valuable implement of modern clinical practice with critical impact on patients' management. We recorded all the studies on EUS published during the last decade and evaluated them in terms of scientific quality based on levels of evidence (LE). All articles on EUS published between January 2001 and June 2010 were retrieved using a Pubmed search. The following classification was used to determine LE. Ia: meta-analysis of randomized controlled trials; Ib: at least one randomized controlled trial; IIa: at least one well designed controlled study without randomization; IIb: at least one other type of well designed quasi-experimental study; III: well designed non-experimental descriptive studies (comparative studies, correlation studies or case studies); IV: expert committee reports or opinions, or clinical experiences of respected authorities. 1,692 relevant papers constituted the material of our analysis. An overview of the studies, according to the subject and LE, is presented in Table 1.Over the course of the past 10 years a progressively increasing number of publications was recorded. Although the majority comprised retrospective studies, reviews and case series, a considerable number of prospective controlled trials, RCTs and meta-analyses was also noted, especially during the last 5 years. These consolidated the value of EUS in the diagnosis and staging of luminal cancers, documented its efficacy in the pancreatobiliary area and the mediastinum, clarified many of the technical aspects of EUS-FNA, and extended the role of EUS towards therapy (celiac plexus neurolysis, fluid drainage, pancreatic tumor ablation).Table 1Levels of Evidence per SubjectIAIBIIAIIBIIIIVTotalPancreatic tumors and cysts2 (0.5%)6 (1.5%)18 (4.5%)52 (12.5%)224 (53.7%)114 (27.3%)416EUS in general⁎Technical aspects of instrumentation and EUS-fine needle aspiration (FNA), complications, sedation., Experimental studies0 (0%)12 (3.9%)12 (3.9%)44 (14.6%)103 (34.3%)130 (43.3%)301Esophageal, Gastric and Rectal cancer9 (3.6%)4 (1.6%)12 (4.8%)43 (17.2%)119 (47.6%)63 (25.2%)250Emerging and Other indications⁎⁎Liver, adrenals, kidneys, celiac ganglia, Barrett's, Crohn's, gastric ulcer, sarcoidosis, ascites.0 (0%)2 (1.4%)10 (7%)37 (26.1%)73 (51.4%)20 (14%)142Extrahepatic biliary tree4 (2.9%)4 (2.9%)17 (12.3%)28 (20.3%)50 (36.2%)35 (25.4%)138Therapeutic EUS2 (1.7%)5 (4.2%)2 (1.7%)14 (11.9%)53 (44.9%)42 (35.6%)118Lung cancer, mediastinum, lymph nodes2 (1.7%)2 (1.7%)12 (10.3%)20 (17.2%)56 (48.3%)24 (20.7%)116Submucosal tumors0 (0%)0 (0%)3 (3.4%)13 (14.6%)53 (59.5%)20 (22.5%)89Chronic and Acute pancreatitis0 (0%)1 (1.2%)8 (9.5%)13 (15.5%)31 (36.9%)31 (36.9%)84Portal hyper tension0 (0%)2 (5.3%)1 (2.6%)11 (28.9%)16 (42.1%)8 (21.1%)38Total19 (1.1%)38 (2.2%)95 (5.6%)275 (16.2%)778 (45.9%)487 (28.8%)1692 Technical aspects of instrumentation and EUS-fine needle aspiration (FNA), complications, sedation. Liver, adrenals, kidneys, celiac ganglia, Barrett's, Crohn's, gastric ulcer, sarcoidosis, ascites. Open table in a new tab The available literature on EUS keeps expanding, encompassing not only its well-established diagnostic role throughout the gastrointestinal tract, but also novel indications and therapeutic interventions. A trend towards well-structured studies, demonstrating the clinical impact of EUS, is now obvious.

Preclinical in vivo Evaluation of an Extracorporeal HIFU Device for Ablation of Pancreatic Tumors

Extracorporeal high-intensity focused ultrasound (HIFU) can be used to ablate tissue noninvasively by delivering focused ultrasound energy from an external source. HIFU for clinical treatment of pancreatic cancer has been reported; however, systematic evaluation of the safety and efficacy of pancreatic ablation with HIFU has not been performed. The objectives of this in vivo study are as follows: (1) assess the safety and feasibility of targeting and ablating pancreatic tissue using the FEP-BY02 HIFU system (Yuande Bio-Medical Engineering, Beijing, China); (2) evaluate a method for estimating in situ acoustic treatment energy in an in vivo setting; and (3) identify the optimal treatment parameters that result in safe and effective ablation of the pancreas. The pancreata of 12 common swine were treated in vivo. Prior to therapy, blood was drawn for laboratory analysis. Animals were then treated with extracorporeal HIFU at three different acoustic treatment energies (750, 1000 and 1250 J). Endoscopy was performed prior to and immediately following HIFU therapy to assess for gastric injury. Blood was drawn after completion of the treatment and on days 2 and 7 following treatment to assess for biochemical evidence of pancreatitis. Animals were then euthanized 7 d following treatment and a necropsy was performed to assess for unintended injury and to obtain pancreatic tissue for histology to assess efficacy of HIFU ablation. Histologic scoring of pancreatic tissue changes was performed by a pathologist blinded to the treatment energy delivered. The degree of ablation identified on histology correlated with the treatment energy. No collateral tissue damage was seen at treatment energies of 750 and 1000 J. At 1250 J, thermal injury to the abdominal muscles and gastric ulcers were observed. There were no premature deaths, serious illnesses, skin burns or evidence of pancreatitis on biochemical analysis. HIFU treatment of the pancreas is feasible, safe and can be used to ablate tissue noninvasively. A clinical trial in humans examining the use of extracorporeal HIFU for palliation of pain related to pancreatic cancer is planned. (E-mail: jooha@u.washington.edu)