EUS-Guided Antitumor Therapy for Pancreatic Tumors

Endoscopic ultrasound (EUS) is a very useful modality for the diagnosis and staging of pancreatic masses. With the advent of EUS-guided fine-needle aspiration technology, this modality has made a tremendous leap from imaging modality to histologic diagnosis and therapeutic intervention. EUS offers high-resolution images of and unparalleled access to the pancreas. After locating the tip of the echoendoscope in the duodenum or stomach, several drugs or local treatment modalities can be delivered directly into the pancreas. EUS-guided ethanol lavage with/without paclitaxel injection has been tested for the treatment of cystic tumors of the pancreas, with complete resolution of cystic tumor being observed in up to 70-80% of patients. Ethanol injection is also performed for the management of solid neuroendocrine tumors of the pancreas. Various type of EUS-guided injection have also been investigated for the treatment of pancreatic cancer. An activated allogenic mixed lymphocyte culture (Cytoimplant) was injected in patients with advanced pancreatic cancer. A replication-deficient adenovirus vector carrying the tumor necrosis factor-alpha gene was also delivered intratumorally by EUS. ONYX-015 is an oncolytic attenuated adenovirus that exhibits replication preferentially in malignant cells, causing cell death, and this has also been injected into pancreatic cancers under EUS guidance. EUS-guided local ablation therapies such as radiofrequency ablation, photodynamic therapy, and brachytherapy are also under investigation. EUS-guided fine-needle injection for various solid or cystic lesions is a rapidly expanding field. This article reviews the various applications of EUS for the treatment of pancreatic tumors.     

Efficacy and safety of scheduled early endoscopic ultrasonography-guided ethanol reinjection for patients with pancreatic neuroendocrine tumors: Prospective pilot study

Endoscopic ultrasonography (EUS)-guided ethanol injection was recently proposed for treatment of patients with small pancreatic neuroendocrine tumors (p-NET); however, tips on how to carry out safe and effective procedures are unclear. We launched a pilot study for scheduled early EUS-guided ethanol reinjection for small p-NET. Major eligibility criteria were presence of pathologically diagnosed grade (G) 1 or G2, tumor size ≤2 cm and being a poor or rejected candidate for surgery. For the treatment, we used a 25-gauge needle and pure ethanol. Contrast-enhanced computed tomography (CE-CT) was carried out on postoperative day 3, and if enhanced areas of the tumor were still apparent, an additional session was scheduled during the same hospitalization period. Primary endpoint was complete ablation rate at 1 month after treatment, and secondary endpoint was procedure-related adverse events. A total of five patients were treated. Median size of the tumor was 10 (range: 7–14) mm. Of the five patients, three underwent an additional session. Median volume of ethanol injection per session was 0.8 (range: 0.3–1.0) mL, and the total was 1.0 (0.9–1.8) mL. Complete ablation was achieved in four of the five tumors (80%) with no adverse events. During 1 year of follow up, none of the patients reported any procedure-related adverse events, and no recurrence of tumor. Scheduled early EUS-guided ethanol reinjection appears to be safe and effective for treating small p-NET (UMIN number: 000018834).     

Endoscopy-guided ablation of pancreatic lesions:Technical possibilities and clinical outlook

Endoscopic ultrasound(EUS) and endoscopic retrograde cholangiopancreatography(ERCP)-guided ablation procedures are emerging as a minimally invasive therapeutic alternative to radiological and surgical treatments for locally advanced pancreatic cancer(LAPC), pancreatic neuroendocrine tumours(PNETs), and pancreatic cystic lesions(PCLs). The advantages of treatment under endoscopic control are the real-time imaging guidance and the possibility to reach a deep target like the pancreas. Currently, radiofrequency probes specifically designed for ERCP or EUS ablation are available as wel as hybrid cryotherm probe combining radiofrequency with cryotechnology. To date, many reports and case series have confirmed the safety and feasibility of that kind of ablation technique in the pancreatic setting.Moreover, EUS-guided fine-needle injection is emerging as a method to deliver ablative and anti-tumoral agents inside the tumuor. Ethanol injection has been proposed mostly for the treatment of PCLs and for symptomatic functioning PNETs, and the use of gemcitabine and paclitaxel is also interesting in this setting. EUS-guided injection of chemical or biological agents including mixed lymphocyte culture, oncolytic viruses, and immature dendritic cells has been investigated for the treatment of LAPC. Data on the long-term efficacy of these approaches,and large prospective randomized studies are needed to confirm the real clinical benefits of these techniques for the management of pancreatic lesions.     

EUS-Guided Ethanol Ablation of Insulinomas: Case Series and Literature Review

Surgical resection is a standard treatment for insulinomas; however, it is associated with a high risk of complications and limited to specific suitable candidates. In recent years, endoscopic ultrasound (EUS)-guided ethanol ablation of insulinomas has emerged as a new therapeutic option, especially for elderly patients and candidates unfit for surgery. We aimed to evaluate the feasibility and safety of this technique for insulinomas.Four patients diagnosed with insulinomas based on EUS–fine-needle aspiration and immunohistochemistry results underwent EUS-guided 95% ethanol ablation. A comprehensive literature review was performed to understand the current status of the feasibility, safety, and effects of EUS-guided ethanol ablation of insulinomas.EUS-guided ethanol ablation of insulinomas was successfully completed in all the 4 patients. There were no perioperative or postoperative complications. The patients were discharged at 3 days after the procedure. No recurrence of hypoglycemia or tumors was noted during follow-up (range, 3–6 months). Literature review showed 8 patients with insulinomas who underwent EUS-guided ethanol ablation. All the procedures were successful, with no need for further surgical treatment. Among these reviewed cases, 6 patients had no post-procedural complications, while other 2 patients showed a mild increase in the serum levels of lipase and/or pancreatic enzymes within 48 h post-procedure; furthermore, 1 of these 2 patients presented at a later date with medically controllable hematoma and ulceration. During follow-up, 6 patients remained asymptomatic and normoglycemic, while the 2 patients who presented post-procedural complications developed occasional mild confusion.EUS-guided ethanol ablation of insulinomas is an effective and safe modality, with an acceptable level of post-procedural complications. However, the long-term effects of this new therapeutic option need to be validated in a large randomized controlled trial with longer follow-up.     

Endoscopic ultrasound guided tumor directed therapy and cyst ablation

Endoscopic ultrasonography (EUS) has become an interventional procedure for the diagnosis and treatment of various gastrointestinal and pancreatic tumors. Because of the unique anatomical location of the pancreas, EUS-guided therapies offer substantial promise for the delivery of targeted treatments. This article reviews the recent EUS-guided various therapeutic methods for pancreatic cyst and tumor ablation, especially focusing on cystic neoplasms.     

Echoendoscopic ablative therapy for solid pancreatic tumors

Initially, endoscopic ultrasound (EUS) was developed to inspect the pancreas and other organs adjacent to the gastrointestinal tract. After introduction of curvilinear‐array echoendoscopes, EUS has been used for a variety of interventions in gastroenterology, including fine needle aspiration, pancreatobiliary drainage and tumor ablation. EUS‐guided ablation of pancreatic cystic tumors with ethanol and with or without cytotoxic agents has been studied, showing its potential to become an alternative to surgery. However, only few attempts at using ethanol ablation to treat solid pancreatic tumors have been reported. Recently, EUS‐guided radiofrequency ablation was introduced and has been cautiously applied for pancreatic cancer. This article focuses on the clinical application of EUS for the ablation of solid pancreatic tumors.     

EUS-guided lauromacrogol ablation of insulinomas: a novel treatment

Background and aims: EUS-guided ablation with ethanol has been used to treat insulinoma since 2006 as a minimally invasive alternative for those who are unwilling or unsuitable for surgeries. However, pancreatic fistula, pancreatitis and other adverse effects were found after the procedure in these patients. Herein, we aimed to find a novel feasible injection.

Methods: Seven patients with different chief complaints were diagnosed with insulinoma by symptoms, lab results and pathology results from EUS fine needle aspiration. All the patients refused to have surgeries and were treated by EUS-guided ablation with lauromacrogol. The injection volume was calculated by tumor size. All the patients were followed up by at least 1 month to see if there is any adverse effect. Blood glucose (BG), insulin and C-peptide levels were monitored before and after the procedure.

Results: Insulinoma size ranged from 0.76?cm ×0.84?cm to 3.39?cm ×1.84?cm. With a mean injection volume of 1.9?ml (range from 0.9 to 3.9?ml), all the patients showed relief in symptoms after the procedure. During the follow up, their BG, insulin and C-peptide levels went back to normal. None of the patients had any adverse effect.

Conclusions: EUS-guided ablation with lauromacrogol showed good treatment results and received no adverse effect after the procedure. Hence, we consider it as an effective and safe method to treat insulinoma.     

Appraisal of needle-based confocal laser endomicroscopy in the diagnosis of pancreatic cysts

Nearly 2.5% of cross-sectional imaging studies will report a finding of a cystic pancreatic lesion. Eventhough most of these are incidental findings, it remains very concerning for both patients and treating clinicians. Differentiating and predicting malignant transformation in pancreatic cystic lesions is clinically challenging. Current evaluation of suspicious cystic lesions includes a combination of radiologic imaging, endoscopic ultrasound(EUS) and cyst fluid analyses. Despite these attempts, precise diagnostic stratification among nonmucinous, mucinous, and malignant cystic lesions is often not possible until surgical resection. EUS-guided needle based confocal laser endomicroscopy(n CLE) for evaluation of pancreatic cysts is emerging as a powerful technique with remarkable potential. Though limited imaging data from 3 large clinical trials(INSPECT, DETECT and CONTACT) are currently the reference standard for n CLE imaging, nonetheless these have not been validated in large studies. The aim of this review article is to review the evolving role of EUS-guided n CLE in management of pancreatic cystic lesions in terms of its significance, adverse events, limitations, and implications.     

Últimos avances sobre los tumores pancreáticos

Pancreatic cancer (PC) continues to have a very poor prognosis. New epidemiological trials suggest that statins could play a protective role in smokers, while HbsAg-positive hepatitis B virus could be a risk factor. Endoscopic ultrasound (EUS) is the main diagnostic tool for PC, and new technologies associated with this technique have emerged, such as quantitative elastography, intravenous contrasts or, more recently, LASER confocal endomicroscopy. New markers in urine or pancreatic juice have appeared to distinguish between PC and chronic pancreatitis. The role of the “on site” cytopathologist to increase the diagnostic yield of EUS-guided pancreatic sampling is completely supported by new prospective trials and some multicenter studies have been reported that compare the standard cytologic needles with the new procore-histology needles. Regarding cystic pancreatic tumors, most studies have aimed to validate the 2012 Sendai international guidelines and to ascertain predictive factors of malignancy in cystic lesions, mainly intraductal papillary mucinous neoplasm (IPMN). The role of intracystic CEA levels in determining malignancy is challenged. From a therapeutic point of view, EUS-guided radiofrequency ablation of cystic and solid lesions has emerged as a feasible and safe procedure in specific circumstances.     

EUS-guided alcohol ablation of an insulinoma

BACKGROUND: Surgical resection is currently considered to be the criterion standard for treatment of insulinomas. Alternative treatments, despite medication with diazoxide, are lacking. EUS-guided ethanol ablation of endocrine tumors has not been reported before. INTERVENTION: A 78-year-old woman was referred with typical symptoms of an insulinoma. Diagnosis was confirmed by laboratory findings, EUS, and EUS-guided FNA. Because of severe complications during several hypoglycemic episodes, a poor general condition, and strict refusal of surgical resection, the decision was made to ablate the insulinoma by EUS-guided alcohol injection. A total of 8 mL 95% ethanol was injected into the tumor. RESULTS: The patient was discharged and exhibited no further hypoglycemic episodes, and her general condition improved rapidly. Based on clinical, morphologic, and biochemical criteria, we achieved a durable complete remission of the tumor. CONCLUSIONS: EUS-guided ablation may become a minimally invasive alternative for patients with insulinomas in whom surgery is not feasible.     

Performance of endosonography-guided fine needle aspiration and biopsy in the diagnosis of pancreatic cystic lesions

OBJECTIVE: Preoperative diagnosis of cystic lesions of the pancreas remains difficult despite improvement in imaging modalities and cystic fluid analysis. The aim of our study was to assess the performance of endoscopic ultrasonography (EUS) and EUS-guided fine needle aspiration (FNA) in the diagnosis of pancreatic cystic lesions. METHODS: Data from a series of 127 consecutive patients with pancreatic cystic lesions were prospectively studied. EUS and EUS-guided FNA were performed in all patients, and cystic material was used for cytological and histological analysis as well as for biochemical and tumor markers analysis. Performance of EUS diagnosis, biochemical and tumor markers, and FNA diagnosis were compared with the final histological diagnosis obtained at surgery or postmortem examination. Sixty-seven patients underwent surgery and therefore constituted our study group. RESULTS: EUS provided a tentative diagnosis in 113 cases (89%). Cytohistological FNA provided a diagnosis in 98 cases (77%). When the results of EUS and EUS-guided FNA were compared with the final diagnosis (67 cases), EUS correctly identified 49 cases (73%), whereas FNA correctly identified 65 cases (97%). Sensitivity, specificity, positive predictive value, and negative predictive value of EUS and EUS-guided FNA to indicate whether a lesion needed further surgery were 71% and 97%, 30% and 100%, 49% and 100%, and 40% and 95%, respectively. Carbohydrate antigen 19-9 > 50,000 U/ml had a 15% sensitivity and a 81% specificity to distinguish mucinous cysts from other cystic lesions, whereas it had a 86% sensitivity and a 85% specificity to distinguish cystadenocarcinoma from other cystic lesions. CONCLUSIONS: EUS-guided FNA is a valuable tool in the preoperative diagnostic assessment of pancreatic cystic lesions.     

Concentration-dependent ablation of pancreatic tissue by EUS-guided ethanol injection

BACKGROUND: Ethanol is a commonly available agent and has been used to successfully and safely ablate cystic lesions of various organs. OBJECTIVE: The aim of this study was to determine the short-term effects of an EUS-guided injection of ethanol into the pancreas of pigs by using 2 mL ethanol, in increasing concentration of 0% to 100%. DESIGN: Six pigs were sedated by general anesthesia, and ethanol was injected, under EUS-guidance, with a 22-gauge needle into the pancreatic tail. MAIN OUTCOME MEASUREMENTS: End points of this study were gross and microscopic evidence of pancreatitis and clinical tolerance. During the 7-day observational period, the animals were monitored by serum levels of amylase and lipase and by a CT on day 4. RESULTS: At euthanasia, there was no pancreatic lesion in the animals that received normal saline solution or 20% ethanol. The injection of 40% to 100% ethanol led to a visible necrotic area in the pancreatic tail. By histology, the average maximal diameter of the lesions was 20.8 +/- 4.3 mm. The cross-sectional area of necrosis was proportional to the concentration of ethanol (r = 0.961). CT demonstrated a localized site of nonenhancing pancreatic tissue, with an average diameter of 19.4 +/- 10.5 mm; 40% to 100% ethanol. Clinically, the animals appeared to tolerate the procedure without sequelae. Serum levels of amylase and lipase were normal. CONCLUSIONS: The EUS-guided injection of ethanol into the pig pancreas resulted in a localized concentration-dependent tissue necrosis without complications.     

New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection

BACKGROUND: Cystic tumors of the pancreas are frequently detected and encompass a wide pathologic spectrum, ranging from benign to malignant. A substantial proportion of cystic tumors cannot be histologically classified, even after extensive diagnostic evaluation, and, therefore, ultimately require surgical resection. Recently, complete resolution of cystic tumors by EUS-guided ethanol lavage was reported in a pilot study. OBJECTIVES: The aim of this study was to evaluate the safety, feasibility, and response after EUS-guided ethanol lavage with paclitaxel injection (EUS-EP) for cystic tumors of the pancreas. DESIGN: A prospective study. SETTING: A tertiary care, academic medical center, from July 2005 to November 2006. PATIENTS: Fourteen patients who underwent EUS-EP were observed for more than 6 months. They were analyzed in terms of procedure safety, feasibility, and response. INTERVENTION: EUS-EP. MAIN OUTCOME MEASUREMENTS: To compare changes of cyst volume before and after an EUS-EP. RESULTS: An EUS-EP was successfully performed in all cases except one patient in whom the cyst fluid was so viscous that it could not be sufficiently aspirated. Acute pancreatitis occurred in one patient, and minor complications, including hyperamylasemia (n = 6) and vague abdominal pain (n = 1), were observed. Complete resolution of a cystic tumor was observed in 11 patients and partial resolution in two patients, and a cyst persisted in one patient. LIMITATIONS: A small patient number, a short follow-up time, a single treatment arm. CONCLUSIONS: EUS-EP appears to be a safe, feasible, and effective method for treating cystic tumors of the pancreas. Further studies that involve larger populations and longer follow-ups are warranted.     

内镜超声引导下细针穿刺对胰腺占位病变的诊断价值

目的 通过超声内镜结合细针穿刺活检确定胰腺占位病变的性质，并评价该法对胰腺病变的诊断价值。方法 对经CT、MRI、体表腹部超声及内镜超声发现的23例胰腺局限性占位病变进行内镜超声检查，以明确病变大小、形态、位置，并观察有无淋巴结转移。在内镜超声引导下对病变行细针穿刺活检。结果 23例患者中，21例得到了充足的细胞量，15例得到组织块，12例最终确定为胰腺肿瘤的患者，经组织细胞学检查10例为阳性（其中胰腺癌8例；胰腺囊腺瘤癌1例；无功能神经内分泌肿瘤1例），敏感性为83％，特异性为100％。全部结果经手术（16例）及临床随访（7例）证实。无1例出现不良反应。结论 超声内镜结合细针穿刺是诊断胰腺病变安全、有效的方法。     

Endoscopic ultrasound guided radiofrequency ablation for pancreatic tumors: A critical review focusing on safety,efficacy and controversies

The role of endoscopic ultrasound (EUS) in the last two decades has shifted from a diagnostic tool to an important therapeutic tool treating mainly pancreato-biliary disorders. In recent years, its applications for treating pancreatic diseases have broadened, including the implementation of radiofrequency ablation (RFA), which has been traditionally used for treating solid tumors. In this critical in-depth review, we summarized all the papers throughout the literature regarding EUS-RFA for pancreatic neuroendocrine neoplasms, adenocarcinoma, and pancreatic cystic lesions. Overall, for pancreatic neuroendocrine neoplasms we identified 16 papers that reported 96 patients who underwent EUS-RFA, with acceptable adverse events that were rated mild to moderate and a high complete radiological resolution rate of 90%. For pancreatic adenocarcinoma, we identified 8 papers with 121 patients. Adverse events occurred in 13% of patients, mostly rated mild. However, no clear survival benefit was demonstrated. For pancreatic cystic lesions, we identified 4 papers with 38 patients. The adverse events were mostly mild and occurred in 9.1% of patients, and complete or partial radiological resolution of the cysts was reported in 36.8%. Notably, the procedure was technically feasible for most of the patients. Nevertheless, a long road remains before this technique finds its definite place in guidelines due to several controversies. EUS-RFA for pancreatic tumors seems to be safe and effective, especially for pancreatic neuroendocrine neoplasms, but multicenter prospective trials are needed to consider this treatment as a gold standard.     

Interventional endoscopic ultrasound for pancreatic neuroendocrine neoplasms

The proximity of the endoscopic ultrasound (EUS) transducer to the pancreas and the possibility to place needles or other accessories into a target located adjacent to the wall of the GI tract have encouraged researchers to develop various EUS-guided local treatments directed towards pancreatic neuroendocrine neoplasms (PanNENs). The use of pre-operative EUS-guided tattooing or fiducial marker placement to facilitate intraoperative tumor localization has proven effective in reducing operative time of laparoscopic surgeries. To reduce the mortality and morbidity rates of surgical resection, which is presently the mainstay treatment of PanNENs. EUS-guided loco-regional treatments, such as injection of alcohol and radiofrequency ablation have been proposed and results are hitherto promising. The present paper summarizes currently available data in the field of EUS-guided interventions to pancreatic neuroendocrine tumors, as well as possible future applications.     

Echo-endoscopy: new therapeutic frontiers

Endoscopic ultrasound (EUS) has been established as a valuable diagnostic modality as it offers high-resolution imaging and fine-needle biopsy, which is essential in detecting and staging malignancies. Since the introduction of EUS-guided fine needle aspiration (EUS-FNA) in 1992, numerous novel EUS-based interventions and techniques have emerged. Currently, established interventional EUS techniques include celiac plexus block and neurolysis, drainage of pancreatic pseudocysts and pelvic fluid collections, and implantation of fiducial markers and radioactive seeds into the malignant tumors. Emerging EUS-guided experimental techniques include antitumor injection, ablation of tumors, and vascular access. Diagnostic and therapeutic access to the biliary tree and pancreatic duct is increasingly being used for failed ERCP procedures or inaccessible ducts. Interventional EUS is a very promising technique with many potential applications. The future holds promise for substantial progress in EUS-guided therapeutic interventions and their applications in clinical gastroenterology.     

The safety and efficacy of endoscopic ultrasound-guided ablation therapy for solid pancreatic tumors: a systematic review

Abstract

Background and aims

Recently, endoscopic ultrasound (EUS)-guided ablation therapy, as a minimally invasive technique, has shown its potential to substitute surgery in treating solid pancreatic tumors, such as small potential malignant pancreatic tumors, small insulinomas and locally advanced pancreatic ductal adenocarcinoma (LAPDAC). Therefore, we conducted this systematic review to assess the safety and efficacy of EUS-guided ablation therapy for solid pancreatic tumors.     

Endoscopic ultrasound in pancreatic diseases

There are many indications for the use of endoscopic ultrasound (EUS) in the management of patients with pancreatic diseases. High-resolution imaging of the pancreas is achievable due to the close proximity between luminal structures and the pancreas. Since its introduction, EUS has had a significant impact on the diagnosis of pancreatic diseases. The detection of small lesions and neuroendocrine pancreatic tumors as well as the preoperative staging of pancreatic adenocarcinoma have been improved employing EUS. For the detection of small pancreatic tumors <2 cm in diameter, EUS appears to be the most sensitive method. EUS adds significant information to the differential diagnosis between pancreatic cancer and chronic pancreatitis, and it may be further enhanced by EUS-guided fine-needle aspiration. While the role of EUS in distinguishing between benign and malignant cystic pancreatic tumors is under discussion, EUS-guided drainage of pancreatic pseudocysts is an accepted treatment option for symptomatic individuals. One of the most important advantages of EUS apart from tumor staging is the early detection of chronic pancreatitis. EUS is as good as endoscopic retrograde cholangiopancreatography in diagnosing chronic pancreatitis in advanced stages. In early stages of the disease, when the ductal system remains normal, EUS appears to be a superior diagnostic modality because it can detect features of chronic pancreatitis in the parenchyma not visible by other techniques.     

Frequency and significance of acute intracystic hemorrhage during EUS-FNA of cystic lesions of the pancreas

BACKGROUND: Complications from EUS-guided FNA of cystic lesions of the pancreas are infrequent. Although several studies have evaluated infectious complications of EUS-guided FNA in this setting, the frequency and the clinical significance of intracystic hemorrhage have not been determined. This study assessed the frequency of acute intracystic hemorrhage during EUS-guided FNA of pancreatic cystic lesions. The characteristic EUS appearance is described. METHODS: EUS-guided FNA of pancreatic cyst lesions was performed in 50 patients (July 2000 to June 2003). Patients were followed prospectively for the development of complications. OBSERVATIONS: Acute intracystic hemorrhage occurred during EUS-guided FNA at the site of aspiration in 3 patients (6%: 95% confidence interval [1.3%, 16.6%]). Endosonographically, the bleeding manifested as a small hyperechoic area at the puncture site that progressed gradually over a few minutes to involve the majority of the cyst cavity. EUS-guided FNA was terminated when bleeding was observed. One patient was asymptomatic, but two patients experienced abdominal pain transiently. All patients were treated with a short course of orally administered antibiotics and were observed as outpatients. Clinical history and laboratory parameters did not predict which patients were at risk for intracystic hemorrhage. CONCLUSIONS: Acute intracystic hemorrhage is a rare complication of EUS-guided FNA; it has a characteristic EUS appearance. Recognition of this event is important, because it permits termination of the procedure and thereby minimizes the potential for more serious bleeding.