Therapeutic EUS: today & tomorrow Pietro Fusaroli

Therapeutic EUS: today & tomorrow Pietro Fusaroli Gastroenterologia Università di Bologna AUSL di Imola, Castel S. Pietro Terme (BO) Direttore Prof. G. Caletti

EUS FNA: CONVEX ARRAY Olympus, Pentax, Toshiba

EUS FNA: CONVEX ARRAY Scanning Area Transducer

THERAPEUTIC EUS Established procedures Celiac plexus neurolysis Pseudocyst drainage Innovative procedures Cholangiography/pancreatography, direct CBD/PD drainage, rendez-vous techniques, fluid drainage, necrosectomy Experimental procedures Injective therapy: immune, viral, genetic Interventional techniques: tumor ablation, suturing, implantation of radiation seeds, fistula formation

THERAPEUTIC EUS Established procedures Celiac plexus neurolysis Pseudocyst drainage Innovative procedures Cholangiography/pancreatography, direct CBD/PD drainage, rendez-vous techniques, fluid drainage, necrosectomy Experimental procedures TODAY Injective therapy: immune, viral, genetic Interventional techniques: tumor ablation, suturing, implantation of radiation seeds, fistula formation

THERAPEUTIC EUS Established procedures Celiac plexus neurolysis Pseudocyst drainage Innovative procedures Cholangiography/pancreatography, direct CBD/PD drainage, rendez-vous techniques, fluid drainage, necrosectomy Experimental procedures TODAY TOMORROW Injective therapy: immune, viral, genetic Interventional techniques: tumor ablation, suturing, implantation of radiation seeds, fistula formation

PANCREATIC CANCER PAIN CONTROL 1 st line therapy Anti-inflammatory drugs +/- opioid drugs Opioid drugs: significant side effects (constipation, lethargy, and impaired mental status and quality of life) 2 nd line therapy Celiac plexus neurolysis Non-pharmacological method of pain control

EUS-guided CPN The first report on EUS-guided CPN Wiersema MJ et al. Endosonography-guided celiac plexus neurolysis Gastrointest Endosc 1996

CELIAC PLEXUS NEUROLYSIS PROBLEMS: TECHNIQUE (CLASSIC: Kappis) Nerve/vessel damage while advancing needle Alcohol causes arterial vasospasm : paraplegia

EUS CELIAC PLEXUS NEUROLYSIS ADVANTAGES Most direct access to celiac plexus Real time visualization of target Doppler capabilities

EUS CPN: TECHNIQUE - Needle is cleared with 3cc of Saline - Aspiration test to rule out vessel penetration - 10 ml (0.25%) bupivacaine, then 10/20ml (98%) ethanol - Needle flushed with 3cc Saline and removed < NEEDLE < ECHOGENIC CLOUD

EUS GUIDED CPN PANCREATIC CANCER VAS Mean Pain Scores 7 6 5 4 3 2 1 p<0.0005 n = 66 0 2 4 8 12 16 20 24 Time (weeks) Gunaratnam NT et al. Gastrointest Endosc 2001

EUS GUIDED CPN PANCREATIC CANCER Mean Morphine Use Over Time After CPN Mean Morphine (mg/day) 45 40 35 30 25 20 15 10 5 p=ns n = 66 0 2 4 8 12 16 20 24 Time (weeks) Gunaratnam NT et al. Gastrointest Endosc 2001

EUS GUIDED CPN: COMPLICATIONS Minor - 9% patients had transient abdominal pain post procedure (< 48 hours) - 16% patients diarrhea (48-72 hours) Major - No major complications observed Gunaratnam NT et al. Gastrointest Endosc 2001 Malick KJ et al. Gastroenterol Nurs 2003

PSEUDOCYST

PANCREATIC PSEUDOCYSTS: therapy SYMPTOMS WORSEN AND/OR SIZE INCREASES SYMPTOMS DIMINISH OR ARE MINIMAL AND SIZE IS STABLE OR DECREASING DRAINAGE WAIT-AND-SEE

PANCREATIC PSEUDOCYSTS: therapy 1. Surgical drainage 2. Percutaneous drainage under US or CT guidance 3. Endoscopic drainage 4. EUS drainage There are no randomized prospective trials comparing these options of therapy for pancreatic pseudocysts

PANCREATIC PSEUDOCYSTS: therapy Surgical drainage: the standard reference? Morbidity: 10-35% Mortality: 1-10%

PANCREATIC PSEUDOCYSTS: therapy Percutaneous drainage under US or CT guidance Aspiration alone ineffective: recurrence rates of up to 71% Continuous percutaneous drainage: complication rate from 5 to 60%

PANCREATIC PSEUDOCYSTS: therapy Endoscopic drainage Blind approach Morbidity: 15,6% Mortality: 3,1% Sarles et al. 1988

PANCREATIC PSEUDOCYSTS: therapy EUS-GUIDED PSEUDOCYST DRAINAGE Electronic curved linear (convex) array echoendoscopes Identification of the optimal site for puncture (broad surface contact/minimal distance) Ability to advance accessories into target lesion under real-time EUS-guidance Color Doppler imaging to scan the area of needle passage

PANCREATIC PSEUDOCYSTS: therapy One-step procedure FNA Needles: 22-19 gauges Contrast filling of the pseudocyst under fluoroscopy Guide-wire: 0.018-0.035 Needle-Knife/Cystotome/Balloon dilation Stents (7, 8.5,10 Fr; double pig-tail) Diagnostic aspiration of cyst fluid

Stents (7, 8.5,10 Fr; double Pig-tail) and/or nasocystic catheter

EUS: pancreatic pseudocysts 33 pts. with a mean age of 43 years Median pseudocyst size 8.5 cm (4-20 cm) 14 pts. (42%) had infected pseudocysts, 8 pts. (24%) had gastric varices, and 16 pts. (48%) had no visible endoscopic bulge Stent placement successful in 31 patients (94%) Complete resolution in 82%; partial resolution in 12% 2 major complications and 3 minor complications Recurrence: only 1 patient (median follow-up 46 weeks) Antillon et al. Gastrointest Endosc 2006

EUS-guided pseudocyst drainage A novel prototype forward-viewing US endoscope Puncturing at an angle sometimes hampers successful completion of the procedure Seven patients were treated; drainage was successfully performed without complications In 2 cases, the procedure was initially started with a conventional EUS scope, but it proved impossible to puncture the pseudocyst. With the forward-viewing EUS scope both pseudocysts were successfully punctured Voermans RP et al. Gastrointest Endosc 2007

EUS-guided necrosectomy Aggressive endoscopic therapy for pancreatic necrosis and pancreatic abscess EUS-guided multiple transmural and/or transpapillary drainage; daily endoscopic necrosectomy and lavage; sealing of pancreatic fistula by N-butyl-2-cyanoacrylate Pancreatic necrosis and pancreatic abscesses were successfully drained in 13 patients Complications included minor bleeding after balloon Seewald S et al. Gastrointest Endosc 2005

EUS-guided cholangiography The first report on cholangiography obtained with an echoendoscope Wiersema MJ et al. Endosonography-guided cholangiopancreatography. Gastrointest Endosc 1996

INNOVATIVE THERAPEUTIC EUS Cholangiography and duct drainage Either a combination of EUS and ERCP ( rendezvous technique ) or an entirely EUS-guided procedure 1) Puncture a dilated common bile duct; 2) perform cholangiography; 3) guide wire and stent to form an enterocholedochal fistula biliary decompression Kahaleh et al. Gastrointest Endosc 2004 Puncture of a dilated left hepatic duct via trans-gastric route, creating a hepaticogastrostomy Giovannini et al. Endoscopy 2003

EUS GUIDED HEPATICO-GASTROSTOMY Giovannini et al. Endoscopy 2003

EUS GUIDED CHOLEDOCHODUODENOSTOMY Kahaleh et al. Gastrointest Endosc 2004

Interventional EUS-cholangiography 28 patients with a failed ERCP were offered an IEUC EUS biliary system guidewire across the obstruction retrograde or antegrade drainage IEUC successful in 23 patients, with a transgastrictranshepatic or transenteric-transcholedochal approach 18 successful stent deployment, 3 choledochoenteric fistula formation 1 case of bile leak, 2 self-limited pneumoperitoneum, and 1 minor bleeding Kahaleh M et al. Gastrointest Endosc 2006

Interventional EUS-cholangiography Kahaleh M et al. Gastrointest Endosc 2006

INNOVATIVE THERAPEUTIC EUS Pancreatography and duct drainage Either a combination of EUS and ERCP or an entirely EUS-guided procedure Pain and pancreatic duct dilation caused by severe chronic pancreatitis or malignancy 1) Needle advanced through the stomach into the duct; 2) pancreatography; 3) guidewire introduced; 4) stent improvement of pts. signs and symptoms Francois et al. Gastrointest Endosc 2002 Mallery et al. Gastrointest Endosc 2004 Kahaleh et al. Gastrointest Endosc 2003

EUS GUIDED PANCREATICO-GASTROSTOMY PANC DUCT OBST. Francois et al. Gastrointest Endosc 2002

EUS-guided pancreaticogastrostomy 13 pts with failed ERCP were offered EPG EUS transgastric puncture and opacification of the pancreatic duct guidewire ductal decompression with a plastic endoprosthesis 10 successful endoprosthesis placement Pain score decreased from 7.3 to 3.6 (P =.01) 1 bleeding (hemoclip), 1 contained perforation Kahaleh M et al. Gastrointest Endosc 2007

EUS-guided pancreaticogastrostomy Kahaleh M et al. Gastrointest Endosc 2007

EUS-guided therapies of PC EUS-guided injection (FNI) Allogeneic mixed lymphocyte culture (Cytoimplant) ONYX-015 Chang et al. Cancer 2000 Hecht et al. Clin Cancer Res 2003 TNFerade: gene transfer therapy EUS-guided brachytherapy Chang. Endoscopy 2006 Sun et al. Endoscopy 2006

EUS-guided Injection (FNI) of Allogeneic Mixed Lymphocyte Culture (Cytoimplant) for the treatment of Patients with Advanced Pancreatic Carcinoma Cytoimplant Tumors are immuno- suppressive Allogeneic mixed lymphocyte culture (Cytoimplant) produces activated T- cells and cytokines which, in turn, support T-cell proliferation and differentiation Placement of Cytoimplant directly into tumor may block tumor immunosuppression and enhance host immune response Tumor Cells Chang et al. Cancer 2000

EXPERIMENTAL THERAPEUTIC EUS EUS injection of pancreatic cancer with ONYX-015 Hecht et al. Clin Cancer Res 2003

EXPERIMENTAL THERAPEUTIC EUS

EXPERIMENTAL THERAPEUTIC EUS EUS injection of pancreatic cancer with ONYX-015 18 pts each receiving 8 injections over 8 wks Concomitant gemcitabine on wks 5-8 > 100 viral injections by EUS guidance 3 minor responses (> 50% tumor reduction) 2 sepsis, 1 abscess, 2 duodenal perforations No clinical pancreatitis Hecht et al. Clin Cancer Res 2003

EXPERIMENTAL THERAPEUTIC EUS EUS-FNI of TNFerade: a novel gene transfer therapy Replication-deficient adenovector containing human TNFα gene, regulated by a radiation-inducible promoter Five weekly treatments, continuous 5FU One grade 3 adverse event; all other grade 1-2 3-month f-up: 53% of pts. alive without disease progression; >25% tumor reduction in 33%; >50% tumor reduction in 13%; 1 pt. pathologic response Chang et al. Gastrointest Endosc 2004 (DDW AB92)

EUS GUIDED RADIO-FREQUENCY TUMOR ABLATION Goldberg et al. Gastrointest Endosc 1999

EXPERIMENTAL THERAPEUTIC EUS EUS-guided photodynamic therapy of the pancreas Injection of porfimer sodium a small diameter quartz optical fiber inserted through a 19-ga. needle into the pancreas, the liver, the kidney, and the spleen in pigs Localized tissue necrosis was achieved in all organs without significant complications Chan et al. Gastrointest Endosc 2004

EXPERIMENTAL THERAPEUTIC EUS EUS-guided suturing: transgastric gastropexy and hiatal hernia repair for GERD Stitches were placed through the gastric wall into the median arcuate ligament in pigs Stitches were tied together and locked against the gastric wall Median LES pressure was 11 mm Hg before surgery and 21 mm Hg after stitch placement (p=0.0002) Length of the LES increased from a median of 2.8 cm before the procedure to 3.5 cm after the procedure Fritscher-Ravens et al. Gastrointest Endosc 2004

EXPERIMENTAL THERAPEUTIC EUS Fritscher-Ravens et al. Gastrointest Endosc 2004

EUS-FNA of cardiac diseases: : future? Needle in the left atrium Needle in the coronary artery No visible damage was observed in the heart in 8 pigs The needle could be introduced repeatedly into the left atrium, aortic valve, and coronary artery Of the 3 pts. pericardial fluid was successfully aspirated in 2 and a left atrial mass was punctured in the 3rd excluding neoplasia (thrombus) Fritscher-Ravens et al. Endoscopy 2007

EUS training in a live pig model A significant improvement between a pre-test and post-test was observed for diagnostic procedures For lymph node FNA, a significant improvement was observed in the duration of the procedure (84 seconds vs. 60 seconds; P = 0.01), and precision (4.2 mm vs. 1.8 mm; P = 0.009), but not for the rate of technical error (29 % vs. 6 %; not significant [n. s.]) For celiac neurolysis, a significant improvement was observed in procedure time (150 seconds vs. 84 seconds; P = 0.003), but not in the rate of technical error (6 % vs. 6 %; n. s.) or precision (4.2 mm vs. 2.8 mm; n. s.) EUS-FNA EUS-CPN Giovannini et al. Endoscopy 2007

EXPERIMENTAL THERAPEUTIC EUS EUS-guided formation of permanent anastomoses between hollow organs Suturing under EUS control to any desired depth and to allow fixation of adjacent hollow organs Cholecystogastrostomy and gastrojejunostomy in the presence of an obstructing cancer: 19-gauge needle balloon over a wire fill it with a ferromagnetic fluid release without deflation; magnet in the stomach to exert compressive force on the magnetic fluid filled balloon Anastomoses of 1.5-2 cm providing instant drainage Fritscher-Ravens et al. Gastrointest Endosc 2002 Fritscher-Ravens et al. Gastrointest Endosc 2003 (DDW AB76)

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Endoscopy. 2007 Apr;39(4):287-91. Epub 2007 Mar 15. Transgastric endoscopic ultrasonography-guided biliary drainage: results of a pilot study. Bories E, Pesenti C, Caillol F, Lopes C, Giovannini M.

Endoscopy. 2007 Apr;39(4):292-5. Epub 2007 Mar 15. Treatment of biliary obstruction in selected patients by endoscopic ultrasonography (EUS)-guided transluminal biliary drainage. Will U, Thieme A, Fueldner F, Gerlach R, Wanzar I, Meyer F.