Portal Venous Interventions: State of the Art 1

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1 This copy is for personal use only. To order printed copies, contact David C. Madoff, MD Ron C. Gaba, MD Charles N. Weber, MD Timothy W. I. Clark, MD Wael E. Saad, MD Online SA-CME See Learning Objectives: After reading the article and taking the test, the reader will be able to: n Discuss patient selection criteria, technical approaches, and novel strategies related to portal vein embolization utilization. n Explain clinical outcomes data, recent portal vein targeting techniques, and new indications for the use of trasjugular intrahepatic portosystematic shunts. n Clarify the indications and technical considerations for balloon retrograde transvenous obliteration. n Discuss patient selection, technical aspects, complications, and outcomes for patients undergoing pancreatic islet cell transplantation. Portal Venous Interventions: State of the Art 1 In recent decades, there have been numerous advances in the management of liver cancer, cirrhosis, and diabetes mellitus. Although these diseases are wide ranging in their clinical manifestations, each can potentially be treated by exploiting the blood flow dynamics within the portal venous system, and in some cases, adding cellular therapies. To aid in the management of these disease states, minimally invasive transcatheter portal venous interventions have been developed to improve the safety of major hepatic resection, to reduce the untoward effects of sequelae from end-stage liver disease, and to minimize the requirement of exogenously administered insulin for patients with diabetes mellitus. This state of the art review therefore provides an overview of the most recent data and strategies for utilization of preoperative portal vein embolization, transjugular intrahepatic portosystemic shunt placement, balloon retrograde transvenous obliteration, and islet cell transplantation. RSNA, 2016 REVIEWS AND COMMENTARY n STATE OF THE ART Accreditation and Designation Statement The RSNA is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The RSNA designates this journal-based SA-CME activity for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Disclosure Statement The ACCME requires that the RSNA, as an accredited provider of CME, obtain signed disclosure statements from the authors, editors, and reviewers for this activity. For this journal-based CME activity, author disclosures are listed at the end of this article. 1 From the Department of Radiology, Division of Interventional Radiology, New York-Presbyterian Hospital/Weill Cornell Medical Center, 525 E 68th St, P-518, New York, NY (D.C.M.); Department of Radiology, Interventional Radiology Section, University of Illinois Hospital, Chicago, Ill (R.C.G.); Department of Radiology, University of Pennsylvania School of Medicine, Penn Presbyterian Medical Center, Philadelphia, Pa (C.N.W., T.W.I.C.); and Department of Radiology, Division of Vascular and Interventional Radiology, University of Michigan Medical Center, Ann Arbor, Mich (W.E.S.). Received August 27, 2014; revision requested October 18; revision received January 23, 2015; accepted January 30; final version accepted March 24. Address correspondence to D.C.M. ( dcm9006@med.cornell.edu). q RSNA, 2016 Radiology: Volume 278: Number 2 February 2016 n radiology.rsna.org 333

2 In recent decades, there have been numerous advances in the management of liver cancer, cirrhosis, and diabetes mellitus. Although these diseases are wide ranging in their clinical manifestations, each can potentially be treated by exploiting the blood flow dynamics within the portal venous system, and in some cases, adding cellular therapies. To aid in the management of these disease states, minimally invasive transcatheter portal venous interventions have been developed to improve the safety of major hepatic resection, to reduce the untoward effects of sequalae from end-stage liver disease, and to minimize the requirement of exogenously administered insulin for patients with diabetes mellitus. This state of the art review therefore provides an overview of the most recent data and strategies for utilization of preoperative portal vein embolization (PVE), transjugular intrahepatic portosystemic Essentials nn Portal vein embolization allows for safe major hepatic resection in patients previously considered to have unresectable disease due to an inadequate anticipated future liver remnant volume. nn Multiple clinical trials for various indications show transjugular intrahepatic portosystemic shunt (TIPS) placement to be an effective, durable therapy for treating sequelae of portal hypertension. nn Balloon-occluded retrograde transvenous obliteration of ectopic varices is a procedure commonly practiced in Asia that is gaining acceptance in the United States as a potential alternative to TIPS placement in the management of variceal hemorrhage and hepatic encephalopathy. nn Percutaneous pancreatic islet cell transplantation is a promising cellular-based therapy aimed at longterm stabilization of glycemic control in type 1 diabetes and reduction of complications related to diabetes. shunt (TIPS) placement, balloon retrograde transvenous obliteration (BRTO), and islet cell transplantation. Portal Vein Embolization Despite advances in surgical methods in patients undergoing hepatic resection, patients remain at risk for developing postoperative complications such as liver insufficiency and bile leak. When planning for resection, the anticipated liver volume that remains in situ after surgery, termed the future liver remnant (FLR), has been shown to be a strong, independent predictor for postoperative complications related to liver dysfunction (1,2). PVE is a well-established technique that redirects portal blood flow to the FLR in patients who are potential candidates for extensive hepatic resection in an attempt to promote hypertrophy of nonembolized segments that will remain after resection (3 5). When needed, this increased FLR volume is associated with improved postoperative liver function and may improve the functional reserve of the FLR before surgery, allowing for safe, potentially curative hepatectomy in patients previously considered ineligible for resection based solely on small anticipated FLR volumes (6 10). Indications for PVE Multiple factors are considered when deciding which patients would benefit from PVE, including baseline liver function, liver volumetry, and the complexity of the planned surgery (for example, right hepatectomy or extended right hepatectomy). Accurate FLR volume calculation is essential in the triage of potential hepatectomy candidates for which PVE may be indicated. Liver volume is directly correlated with a patient s size; hence, normalizing the anticipated liver volume to a patient s size results in a more accurate FLR assessment (11,12). This principle led to the validation of a standardized FLR (sflr) by Vauthey et al (12), expressed as a ratio of the FLR over the total estimated functioning liver volume (TELV): sflr 5 FLR/TELV (Fig 1). Several methods have been used to measure total liver volume including those based on CT volumetry, body surface area, or body weight. Vauthey et al derived the following formula for estimating TELV by analyzing liver size and body surface area: TELV (body surface area) (13). Other formulas for determining total liver volume from CT volumetry are tedious and imprecise since tumor volume measurements must be performed and excluded from the overall liver volume. Outcomes in healthy livers. Multiple studies show that hepatectomy in the setting of sflr less than 20% in normal underlying liver is associated with increased postoperative complications (2,5,14) (Fig 2). As a result, the National Comprehensive Cancer Network treatment guidelines from 2013 endorse an sflr of 20% as a minimum threshold for patients without underlying liver disease to safely undergo hepatectomy, with consideration for PVE to be performed in patients below that threshold (15). In addition, patients who underwent PVE before surgery in order to increase their sflr from less than 20% to greater than 20% had statistically equivalent rates of liver insufficiency to patients with greater than 20% at baseline (14). Until recently, there was no adequate imaging metric used to assess FLR hypertrophy dynamically. Rather, FLR growth was a static measurement Published online /radiol Radiology 2016; 278: Content codes: Abbreviations: AASLD = American Association for the Study of Liver Disease BRTO = balloon retrograde transvenous obliteration FLR = future liver remnant HE = hepatic encephalopathy OLT = orthotopic liver transplantation PTFE = polytetrafluoroethylene PVE = portal vein embolization PVT = portal vein thrombosis sflr = standardized FLR TELV = total estimated functioning liver volume TIPS = transjugular intrahepatic portosystemic shunt Conflicts of interest are listed at the end of this article. 334 radiology.rsna.org n Radiology: Volume 278: Number 2 February 2016

3 Figure 1 [AQ4] Figure 1: FLR hypertrophy after PVE as determined by three-dimensional reconstruction of computed tomographic (CT) images. (a) Three-dimensional volumetric measurements determined by outlining hepatic segmental contours and then calculating the volumes as determined from the surface measurements of each section. (b) Formula for calculating total liver volume based on patient s body surface area ( ). (c) Before embolization (left), the volume of segments 2 and 3 was 282 cm 3 (14% of total liver volume [2036 cm 3 ]). After embolization (right), the volume of segments 2 and 3 was 440 cm 3 (21% of total liver volume [2036 cm 3 ]). (Adapted, with permission, from reference 12.) calculated before and up to 8 weeks after PVE. Two major issues therefore can be raised: One, evaluation of hypertrophy varies considerably between institutions, making technical comparisons of PVE difficult; two, assessment of the FLR s true functional capacity is limited. Therefore, Shindoh et al (16) proposed the kinetic growth rate, defined as the degree of hypertrophy at initial post- PVE volume assessment divided by num ber of weeks elapsed after PVE. They analyzed 107 patients who underwent PVE and subsequent right hepatectomy or extended right hepatectomy, and found kinetic growth rate to be the most accurate predictor of postopera- tive hepatic insufficiency and mortality when compared with sflr or degree of hypertrophy measurements. Of the three mea sures, a kinetic growth rate cutoff value of less than 2.0% per week showed the highest accuracy (81%), with sensitivity of 100% and specificity of 71% in predicting postoperative hepatic insufficiency. Outcomes in diseased livers. Liver regeneration occurs at a slower rate and with less capacity in diseased livers than with normal underlying liver, and this observation correlates to clinical outcomes (17 20). De Meijer et al (21) performed a meta-analysis of four studies involving 1000 patients and found that patients with greater than 30% steatosis of the liver had significantly higher risk of postoperative complications and postoperative death compared with patients without steatosis. Similarly, several series evaluating outcomes after extensive hepatic resection showed higher rates of both postoperative hepatic insufficiency and mortality in cirrhotic patients (22,23). Hence, higher sflr cut offs are considered for patients with additional risk factors such as hepatic steatosis, hepatotoxic chemotherapy expo sure, and compensated cirrhosis. Cirrhosis: For patients with wellcompensated cirrhosis (ie, Child-Pugh class A) who are considered for resection, an sflr greater than 40% is recommended. In support of this recommendation, Shirabe et al (23) showed that all cases (n 5 7) of postoperative hepatic insufficiency occurred when the FLR was calculated to be less than 250 ml/m 2 (which corresponds to a calculated sflr of less than 40%) in a series of 80 cirrhotic patients who underwent major hepatic resection (Fig 3). A prospective alternative allocation trial in which 28 patients with chronic liver disease were allocated to PVE or no PVE before resection further validated the higher minimum sflr cutoff of less than 40% (24). Chemotherapy: Accelerated tumor growth after PVE has been reported for both primary and metastatic liver tumors (25 28). Disease progression after PVE may preclude curative surgery; a 20% drop-out rate after first stage resection from disease progression was reported in two-stage hepatectomy series (29,30). Neoadjuvant chemotherapy can be administered to provide tumor control in the time between PVE and resection; however, concerns have been raised about its potential deleterious effect on liver function, hypertrophy, and lack of efficacy in preventing disease progression. Two studies have shown an association of oxaliplatin with sinusoidal dilation and irinotecan with steatohepatitis (31,32). In the study by Vauthey et al (32), the presence of steatohepatitis in patients who had undergone resec- Radiology: Volume 278: Number 2 February 2016 n radiology.rsna.org 335

4 Figure 2 Figure 3 Figure 3: Small liver volume correlates with poor outcome in patients with chronic liver disease. In this study, all deaths from liver failure occurred in patients with FLRs of less than 300 ml/m 2. (Reprinted, with permission, from reference 23.) Figure 2: Rates of hepatic insufficiency and death by preoperative sflr volume. (Reprinted, with permission, from reference 14.) tion was correlated to increased 90-day mortality (14.7% vs 1.6%; P 5.001). Given these findings, Shindoh et al (33) performed a retrospective analysis of nearly 200 patients with colorectal liver metastasis to determine the optimal FLR for patients treated with neoadjuvant chemotherapy. The authors found that both long duration of chemotherapy (defined as. 12 weeks) and sflr of 30% or less were predictors of hepatic insufficiency (odds ratio 5 5.4, P and odds ratio 5 6.3, P 5.019, respectively). No cases of postoperative mortality and only two cases of postoperative hepatic insufficiency were reported if the sflr was more than 30%, indicating that sflr greater than 30% may be a more appropriate cutoff value in patients who have received neoadjuvant chemotherapy, particular if the duration of treatment is longer than 12 weeks. In addition, the effect of systemic neoadjuvant chemotherapy on liver hypertrophy after PVE has been ad- dressed. Zorzi et al (34) reviewed FLR hypertrophy after PVE in patients with colorectal liver metastases who underwent PVE either with (n 5 43) or without (n 5 22) concomitant neoadjuvant chemotherapy before resection. The chemotherapy group, which included 26 patients treated in part with the vascular endothelial growth factor receptor blocker bevacizumab, showed comparable hypertrophy rates when compared with the no chemotherapy group 4 weeks after PVE. However, in a small series of 15 consecutive patients by Beal et al (35), the anticipated FLR volume increase was reduced in the setting of chemotherapy (P 5.016). Several studies have examined the effect of chemotherapy on disease progression after PVE prior to hepatectomy (36,37). Muratore et al (36) concluded that chemotherapy after stage 1 resection does not guarantee lower disease progression rates prior to stage 2 resection. However, Fischer et al (37) found similar findings though expanded on the utility of chemotherapy by showing overall survival benefit in a similar patient cohort. Though there was no statistical difference between the proportion of patients who ultimately underwent hepatic resection between two groups, the chemotherapy group had statistically lower rate of progression according to Response Evaluation Criteria In Solid Tumors, or RECIST, criteria (18.9% versus 34.2%; P 5.03). Of greater importance, the chemotherapy group demonstrated a clear survival benefit as compared with the no chemotherapy group (49% vs 24% 5-year survival; P 5.006) in both the surgical resection and nonsurgical cohorts. Technical Approaches for PVE PVE is typically performed traditionally either by means of an open surgical transileocolic approach (3) or, more commonly, with percutaneous transhepatic contralateral or ipsilateral techniques performed by using ultrasonography (US) and fluoroscopic guidance. The contralateral approach accesses the portal system via the FLR (4). This technique allows for straightforward catheter manipulation to the 336 radiology.rsna.org n Radiology: Volume 278: Number 2 February 2016

5 Figure 4 Figure 4: Transhepatic ipsilateral right PVE extended to segment 4 in a 48-year-old woman with a cm intrahepatic cholangiocarcinoma involving segments 4 and 5 with a cm segment 7 metastasis. (a) Contrast-enhanced CT image with tumors in right liver and segment 4 prior to PVE; sflr/telv is 27%. (b) Anteroposterior flush portogram obtained through a 5-F flush catheter within the main portal vein using the ipsilateral approach. (c) Intraprocedural fluoroscopic image from PVE depicts coil placement into segment 4 branches. (d) Final portogram shows occlusion of the portal vein branches to segments 4 8 with continued patency of the veins supplying the left lateral liver. (e) CT scan 2 weeks after PVE shows hypertrophy with sflr/telv now 35% (degree of hypertrophy 5 8%, kinetic growth rate 5 4%). (f) CT image obtained after uncomplicated extended right hepatectomy shows massive hypertrophy of the remnant liver. tumor-bearing liver because of fewer acute angles between access and target portal branches. However, the contralateral approach risks damage to the FLR during needle access and catheter manipulation. The ipsilateral approach involves percutaneous access through the tumor-bearing liver, avoiding potential damage to the FLR during instrumentation (10). The difficulty in navigating acute angles necessary for embolization of adjacent liver segments can be overcome by using reverse curve catheters. However, care must be taken to avoid access through tumor to prevent peritoneal and/or hepatic tumor seeding. If a safe route is not visualized, the contralateral approach remains a reasonable alternative. Extent of embolization is also important to review. Before extended right hepatectomy, some authors ar- gue for extending right PVE to include segment 4 as a means of improving hypertrophy of segments 2 and 3 (38) (Fig 4). However, catheter manipulation into branches supplying segment 4 is more technically demanding, and inadvertent reflux of embolic material to the FLR has been reported (39,40). Capussotti et al (39) evaluated 26 patients who underwent right PVE alone (n 5 13) or combined right and segment 4 PVE (n 5 13). The authors found no difference in the volume increase or rate of increase (P 5.40) of segments 2 and 3 in the two groups, leading them to recommend against extended embolization. However, more recent studies showed improved hypertrophy of segments 2 and 3 when segment 4 embolization is performed, without an increased incidence of complications (2,41). It has been suggested that the disparate outcomes between these studies may reflect a difference in technical experience and sample size. PVE in Conjunction with Transarterial Therapy Although PVE usually leads to reliable FLR hypertrophy, liver regeneration can be variable, especially when comorbidities such as underlying hepatic dysfunction or diabetes exist. When FLR hypertrophy is inadequate after PVE, adjunct therapies such as transarterial embolization can be performed (Fig 5). The mechanism of transarterial embolization is complementary as a component of inflammation and necrosis add to the apoptosis-mediated cell death induced by PVE to stimulate liver hypertrophy. In fact, arterial embolization alone can induce FLR hypertrophy, though to a lesser degree compared with PVE (42). Radiology: Volume 278: Number 2 February 2016 n radiology.rsna.org 337

6 Figure 5 Figure 5: Images in a 68-year-old man with hepatocellular carcinoma and hepatitis C cirrhosis who underwent sequential transcatheter arterial embolization followed 3 weeks later by right PVE extended to segment 4 prior to an extended right hepatectomy. (a) Single image from pre-pve contrast-enhanced CT shows two hepatocellular carcinomas ( cm and cm) within segments 4B and 5. The sflr/telv is 31.3%. (b) Pre-embolization arteriogram shows hypervascularity within the right liver consistent with the tumors. (c) Pre-PVE portogram in craniocaudal position shows the right anterior sector portal vein arising from the left portal vein. (d) A single craniocaudal portogram shows coils within multiple branches of segment 4 and the right liver and complete diversion of flow to the FLR. (e) A single image from post-pve contrast-enhanced CT shows hypertrophy of the left lateral liver. FLR/TELV increased to 37.4% (degree of hypertrophy 5 6.1%; kinetic growth rate 5 2%). (f) The patient underwent an uncomplicated extended right hepatectomy with additional hypertrophy of the remnant liver seen at CT. Nagino et al (43) and Gruttadauria et al (44) each reported the use of selective transarterial embolization to improve FLR volume in two patients each with cholangiocarcinoma and colorectal liver metastases, respectively, who showed insufficient hypertrophy after PVE. In each report, the patients showed sufficient hypertrophy and underwent successful resection. Transarterial embolization can also be performed as a staged procedure prior to PVE (45,46). Aoki et al (45) reported the use of sequential transcatheter arterial chemoembolization (TACE) followed within 2 weeks by PVE in 17 patients with hepatocellular carcinoma. Sixteen (94%) patients underwent hepatectomy without episodes of postoperative hepatic insufficiency. Analy sis of the resected livers showed massive tumor necrosis without substantial injury to the nontumorous liver. The authors therefore encourage the aggressive use of this strategy in patients with large hepatocellular carcinoma and chronically injured livers. In this patient population, the rationale for performing TACE prior to PVE includes prevention of tumor progression after PVE, reduction of arterioportal shunts that may limit the effectiveness of the subsequent PVE, and boosting the regenerative stimulus in chronically diseased livers. Ogata et al (46) performed sequential TACE and PVE versus PVE alone in 36 patients with hepatocellular carcinoma and chronic liver disease prior to right hepatectomy. Patients in the combined TACE-PVE group (n 5 18) showed a higher mean increase in percentage of FLR volume (12% vs 8%; P 5.022) than those who underwent PVE alone (n 5 18). The incidence of complete tumor necrosis (83% vs 6%; P,.001) and 5-year disease-free survival rate (37% vs 19%; P 5.041) were also significantly higher in patients who underwent the combined approach. PVE with Adjuvant Stem Cell Transplantation Bone marrow derived stem cells play a role in liver regeneration and can repopulate damaged hepatocytes (47,48). Gehling et al (49) showed that partial hepatectomy induces mobilization of a distinct population of progenitor cells from bone marrow, identified as CD1331, which are capable of differentiation into hepatocytes. Researchers have therefore investigated the intra- 338 radiology.rsna.org n Radiology: Volume 278: Number 2 February 2016

7 Figure 6 Figure 6: Stent graft for TIPS. (a) Stent graft after deployment from its delivery catheter. The PTFE fabric of the device covers the intrahepatic portion of the device, while the bare stent edge at right (arrow) is intended to preserve flow within the portal vein segment of the device. (b) Portogram obtained during TIPS placement performed with market pigtail catheter to enable sizing of stent graft device. (c) Portogram immediately following TIPS creation with stent graft. portal infusion of bone marrow stem cells in conjunction with PVE to improve rapidity of FLR growth (50,51). In a series of 11 patients treated with PVE and stem cell transplantation and 11 patients treated with PVE alone (52), both absolute and relative increases in FLR volumes 14 days after PVE were significantly greater in patients undergoing PVE and stem cell transplantation than in patients treated with PVE alone. TIPS Procedure In the 3 decades since its inception, the TIPS procedure has become established as an effective, durable therapy for treating sequalae of portal hypertension such as refractory ascites, variceal bleeding, Budd-Chiari syndrome, and portal vein thrombosis (PVT). A transformational point in TIPS history was the development of polytetrafluoroethylene (PTFE)-covered stent-grafts (Fig 6), which showed superior patency over bare metal stents and nearly eliminated the problems related to shunt stenosis and thrombosis (53 55). The American Association for the Study of Liver Disease (AASLD) Practice Guidelines now recommend routine use of PTFE stent-grafts over bare metal stents (56). However, outcomes continue to be greatly influenced by patient comorbidities and underlying hepatic function. TIPS also causes hepatic encephalopathy (HE) and hepatic insufficiency in a small but important subset of patients. TIPS Clinical Trials Variceal bleeding. First-line therapy for acute variceal bleeding is pharmacologic and endoscopic therapy, then, if refractory, TIPS placement for portal decompression (56). Level I evidence supporting early TIPS placement among other first-line therapies has shown significantly decreased 1-year mortality versus standard of care, 31% versus 65% (57) and 14% versus 39% (58). In light of these studies, the Baveno V conference in 2010 recommended considering early TIPS placement (ie, within 72 hours) in patients at high risk of treatment failure, although the AASLD Practice Guidelines remain unchanged (59). Among patients with very high Child-Pugh scores (C14 15), most centers do not perform salvage TIPS procedures because of the high associated mortality. However, Rudler et al (60) reported a small cohort of patients with improved survival when rapid transplant (within 2 weeks) was coordinated. For prevention of recurrent variceal bleeding, AASLD Practice Guidelines recommend that TIPS should not be placed in patients who have bled only once and should be limited to those who fail pharmacologic and endoscopic therapy (59). A recent randomized controlled trial and a meta-analysis reported lower incidences of recurrent variceal bleeding when TIPS placement was combined with variceal embolization (61,62). Refractory ascites. TIPS placement is also effective in treating refractory ascites, with response rates between 54% 93% (63 67). This improvement in the ranges of clinical success may be secondary to use of PTFE-covered stents (55). Current AASLD Practice Guidelines recommend TIPS procedures only in those patients who are intolerant of repeat large-volume paracentesis (56). Although this recommendation remains unchanged since the original 2005 guidelines, recent data support a more aggressive practice. A meta-analysis of four randomized controlled trials comparing TIPS versus large volume paracentesis favored TIPS in clinical efficacy including recurrence of tense ascites (42% vs 89%) and number of subsequent paracenteses (1.6 vs 7.1) (68). Similarly, a recent randomized controlled trial reported complete or partial response rates within 1 year of 67% 87% and 27% 30% for TIPS and large volume paracentesis, respectively (69). However, of greater clinical importance is the improvement in survival among patients with refractory ascites (68,70). A recent randomized controlled trial confirmed these conclusions, reporting TIPS versus large Radiology: Volume 278: Number 2 February 2016 n radiology.rsna.org 339

8 volume paracentesis 1-year survival of 80% versus 49% (69). Refractory ascites is associated with higher post-tips mortality compared with those manifesting variceal bleeding, as this indicates greater severity of end-stage liver disease (71,72). Other pre-tips prognostic markers for increased mortality in patients manifesting bleeding or ascites include increased serum creatinine, serum bilirubin, Model for End-Stage Liver Disease (MELD), MELD-Na, and Child scores, and portosystemic gradient, as well as age over 70 years and decreased urine sodium (64 66,71,73,74). Refractory hepatic hydrothorax. Since the source of hepatic hydrothorax is direct passage of peritoneal fluid through the diaphragm, TIPS efficacy is by means of treatment of the underlying cause, refractory ascites. As for ascites, TIPS placement is considered second-line therapy after failure of a low salt diet and diuretics (56). In small studies, 30-day mortality is 19% 29% (75). Clinical success (complete and partial response) has been reported at 58% 82% (76,77). A recent study including four patients with hepatic hydrothorax reported resolution in all of the patients following TIPS procedures (63). Hepatorenal syndrome. The AASLD Practice Guidelines state that TIPS placement is of investigatory use for the treatment of hepatorenal syndrome (HRS) especially type 1 HRS (56). TIPS procedures alter hemodynamic variables, reducing activity of the renin-angiotensin-aldosterone axis and sympathetic nervous systems and thereby improving renal conductance, with a gradual improvement in circulatory dysfunction (78,79). TIPS placement has been shown to improve renal function in both type 1 and 2 HRS (80,81). TIPS may also prevent de novo HRS or progression of type 2 to type 1 HRS compared with paracentesis plus albumin therapy (82). Recent studies support the concepts that TIPS placement in general improves renal function; however, this benefit is not as well realized in patients with organic renal failure (compared with prerenal failure which is associated with HRS) (66,83,84). Type 1 HRS has higher associated mortality than type 2, reported to be 80% and 30% at 1 year, respectively (79). Although controversial, and randomized trials are lacking, it has been suggested that TIPS decreases mortality in HRS patients (85,86). Budd-Chiari syndrome. The 2009 AASLD Practice Guidelines were updated to address management of Budd- Chiari syndrome and recommend TIPS placement in those patients with moderate disease that fails to improve with anticoagulation. Mild disease should be managed medically, and severe disease or acute hepatic failure is best managed by means of liver transplantation (56). Although randomized controlled trials are lacking, 5-year survival in Budd-Chiari syndrome patients who have undergone TIPS placement approaches 80% (87 89). A stepwise approach to therapy (anticoagulation, recanalization, TIPS, transplant) proved beneficial with 5-year survival of up to 89% (89). Hepatic encephalopathy. HE is a known complication of TIPS placement, with recent studies reporting an incidence of 8% 43% (mean, 22%) (53 55,67,90). Moderate to severe HE requir ing TIPS reduction occurs in up to 7% of cases (91,92). Although controversial, several studies report similar rates of moderate and severe HE regardless of placement of uncovered or covered stents (53 55,67,93). A variety of suggested approaches to reduce incidence of HE include the use of 10-mm stent-grafts dilated with 8-mm balloons for nonemergent indications (94). A recent randomized controlled trial designed to compare 8-mm versus 10-mm diameter stent-grafts was stopped prematurely because the 8-mm shunt arm was inferior in controlling complications of portal hypertension (95). Predictors of HE include increased age, advanced liver disease, history of HE prior to TIPS, and low serum sodium (79). Recent studies suggest functional magnetic resonance (MR) imaging and cerebral blood flow imaging may help indicate development of HE, although the utility and practicality of these modalities remain to be determined (96,97). Update on Portal Vein Targeting Technologies for TIPS With improvement in technical skills, development of dedicated devices for TIPS creation, and widespread availability of dedicated stent-grafts, complications arising from TIPS placement have been substantially reduced. However, some complications continue to arise from needle access of the portal vein from the hepatic vein, which can result in abdominal bleeding, hemobilia, and hepatic artery injury (79,98). This step is also the most time-consuming, exposing the patient and radiology personnel to increased radiation if the portal vein cannot be cannulated quickly, and represents the point in the procedure at which attempted TIPS placement may be aborted. Different techniques have been used to optimize localization of the portal vein, including wedged hepatic venography with CO 2 or iodinated contrast material to define the portal vein anatomy. These techniques are helpful but are not without limitations, as the images provide only a transient twodimensional representation of hepatic and portal anatomy. US for TIPS. US can be used in portal vein targeting during TIPS procedures. This is particularly helpful in US in technically difficult TIPS procedures, such as in patients with altered or distorted anatomy, Budd-Chiari syndrome, or PVT. Transabdominal US is used to guide percutaneous puncture of both the portal and hepatic veins in the same sonographic frame, followed by placement of a traversing guidewire, which is then snared from the transjugular access (99). Intravascular US has also been used to successfully place TIPS in patients in whom the traditional transjugular technique failed (100). MR imaging. Both MR imaging and MR-fluoroscopy hybrid systems have shown promise in guiding TIPS procedures, although only animal studies and small clinical series have been published ( ). 340 radiology.rsna.org n Radiology: Volume 278: Number 2 February 2016

9 Cone-beam CT. C-arm or conebeam CT uses flat-panel fluoroscopy systems to acquire and display threedimensional images and is now widely available in many interventional suites. An important advantage over frontal projection digital subtraction angiography is that the operator is able to view the images in any projection and slab thickness, allowing improved delineation of vascular and soft-tissue structures of interest. For TIPS placement, during CO 2 portography or the mesenteric venous phase of superior mesenteric artery angiography, a cone-beam CT scan three-dimensional roadmap of the portal vein is superimposed over the working fluoroscopy screen (104). This can prevent possible repeat digital subtraction angiography at various projections and theoretically permit more efficient routine TIPS procedures. Examples in which cone-beam CT has been utilized to overcome placing TIPS in challenging anatomic situations include patients with polycystic liver disease, altered anatomy such as split liver transplant for biliary atresia, and portal vein occlusion requiring shunting to the superior mesenteric vein (105,106). Electromagnetic tracking. Solomon et al (107) reported TIPS placement in four of five pigs, each with only one to two passes of the needle. Levy et al (108) used a system of abdominal fiducials to successfully place a TIPS in a pig by using respiratory-gated image registration in a single needle pass. No studies have yet been reported in humans using this technology. New Horizons in TIPS Prevention of PVT to lengthen the bridge to transplantation. An important role of TIPS developed over the past several years is that of a bridge to orthotopic liver transplantation (OLT). Many patients with end-stage cirrhosis are now treated with TIPS for their refractory symptoms of portal hypertension. Improved patency of PTFE-covered stent-grafts means that more patients are living longer with their TIPS, permitting a larger surgical window for eventual transplantation. A recent review suggests TIPS should be proposed in symptomatic patients awaiting transplantation, as insertion of the stent-grafts has not been associated with higher intraoperative or postoperative complication rates (109). PVT is found in 5% 26% of cases being evaluated for transplantation (110). PVT had previously been considered a contraindication for TIPS (111). If PVT is found peri- or intraoperatively, interventional radiologists may coordinate with the transplant surgery team for endovascular treatment ( ). The main objective in management of PVT in OLT candidates is to achieve recanalization so that portal flow to the transplant liver can be restored through a conventional end-to-end portal vein anastomosis at transplantation. Anticoagulation therapy and TIPS placement are two therapeutic options for portal recanalization. Anticoagulation therapy can result in complete recanalization and may prevent extension of recent PVT (115). However, concerns remain about this approach because of increased risk of gastrointestinal bleeding in these patients with advanced liver failure and who often have varices. Furthermore, anticoagulation therapy artificially raises the internationalized normalized ratio, spuriously elevating the Model for End-Stage Liver Disease score which is crucial to prioritizing the OLT waiting list. Since the low-flow state in the portal venous system is the main predisposing condition to thrombus formation in patients with liver cirrhosis (116), the rationale for treatment is to correct the portal hypertension and reestablish adequate portal blood flow. By enhancing portal venous blood flow, TIPS may enable clearance of PVT and preservation of portal venous patency in cirrhotic OLT candidates. Pooled technical success was 100% in 129 patients with partial PVT ( ). Notably, D Avola et al (118) reported patent portal systems at transplantation in all 15 patients. Luca et al (121) reported complete recanalization was achieved in 57% of patients, and a marked decrease in thrombosis in another 30%. Furthermore, there was no PVT or increase in procedural difficulty in 15 patients who eventually underwent OLT. These studies demonstrate that TIPS may help recanalize portal venous systems and prevent progression of PVT in liver transplantation candidates, providing them a longer bridge to OLT. Chronic occlusion of the portal vein and creating a new patient population eligible for transplant. Complete PVT in the recipient has been previously considered to be an absolute contraindication to OLT. A variety of surgical options have been developed to overcome this problem and allow graft placement (122). However, the presence of complete PVT remains associated with substantial morbidity and mortality (123). If the main portal vein cannot be recanalized prior to transplantation, less ideal surgical options for graft placement must be entertained. The completely occluded and fibrotic portal vein is difficult or impossible to access from a transjugular approach, and therefore, in the past, com plete PVT and cavernous transformation as contraindications to TIPS creation (111,124) unfortunately meant that most of these patients were ineligible for OLT. There have been multiple reports showing TIPS placement in patients with portal cavernoma with varying success, with a few larger studies showing technical success of 59% (45 of 76) (120, ). Multiple techniques were used for TIPS placement, including transjugular with or without transhepatic or transsplenic approaches. A number of shunt variations were incorporated, such as TIPS extending from a dilated collateral vessel of the portal cavernoma or other splanchnic vessels such as the superior mesenteric vein that bypass the main portal vein. Recent studies have attempted to assess the role of TIPS in patients with complete PVT (Fig 7). Senzolo et al reported 61% (14 of 23) technical success and attempted thrombectomy was successful in 58% (11 of 19) of patients. Three patients who went on to undergo OLT had no thrombus identified at surgery (119). Han et al (120) reported 57% (eight of 14) technical success, however, zero of eight were successful if a fibrotic cord replaced the main portal Radiology: Volume 278: Number 2 February 2016 n radiology.rsna.org 341

10 Figure 7 Figure 7: Portal vein recanalization TIPS in a 68-year-old-woman with nonalcoholic steatohepatitis cirrhosis, refractory ascites, and esophageal varices. The patient was not a candidate for liver transplantation due to chronic PVT. (a) Axial gadolinium-enhanced T1-weighted image shows PVT with cavernous vein transformation (arrow). (b) The occluded portal venous system was accessed percutaneously and a directional catheter manipulated through the main portal vein (arrows). Contrast agent injected through the tip of the catheter opacifies left gastric varices, confirming access to the portal-mesenteric venous system. (c) A snare was placed through a sheath introduced through the transhepatic access and used to target the confluence of the right and left portal veins. A TIPS access needle was inserted through the right hepatic vein and captured by the snare (arrow). This step enables transhepatic guidewire access into the portal system so that a TIPS can be created. (d) Digitally subtracted TIPS portogram with a widely patent TIPS. The portal vein (arrow) has been recanalized through simple balloon angioplasty. (e) TIPS portogram 4 weeks later shows decompressed varices and a widely patent main portal vein (arrow). The patient was relisted for OLT on the basis of successful portal vein recanalization. (Case courtesy of Riad Salem, MD, Chicago, Ill.) vein. All successful TIPS were placed by means of a combination of transjugular with transhepatic or transsplenic approaches resulting in main portal vein recanalization. Similarly, a case report described a combined transjugular with transhepatic approach to place a TIPS in a cavernous portal vein occlusion by using a balloon-targeting technique (128). Balloon-occluded Retrograde Transvenous Obliteration BRTO of ectopic varices (commonly described for gastric varices) is a procedure that is commonly practiced in Asia and is gaining acceptance in the Unit- ed States (129). In the field of BRTO and closure of portosystemic shunts, updates on popular clinical research trends are along three lines: (a) management of HE, (b) accelerated BRTO without indwelling balloon occlusion, and (c) combining BRTO with portal modulators such as TIPS or splenic embolization. The latter is in the continuum of another clinical research trend which is combining TIPS and variceal embolization in portal hypertensive patients with variceal bleeding. Hepatic Encephalopathy From a clinical standpoint, HE related to liver disease is categorized as either persistent or recurrent HE ( ). HE has a poor prognosis, with a 1-year survival after the initial encephalopathy episode of approximately 40% (133,134). HE is usually overlooked and its diagnosis is often delayed (commonly 1 year after onset) (132). HE is due to systemic accumulation of intestinal-derived neurotoxins due to either impaired hepatocellular dysfunction and/or bypassed liver detoxification (ie, portosystemic shunting) (135,136). In turn, from a pathogenesis standpoint, there are two types of HE: that related to hepatic synthetic function (associated with hepatic failure, terminal HE or type A) and that associated with portosystemic shunting (type B or bypass type). Type B HE is part of the 342 radiology.rsna.org n Radiology: Volume 278: Number 2 February 2016

11 constellation of symptoms and findings referred to as portosystemic shunt syndrome although both types of HE can potentially coexist in end-stage portosystemic shunt syndrome (137,138). The early stage of the type B syndrome is characterized by HE, lack of ascites, relatively preserved hepatic synthetic function, and paucity of the portal vein branches. The later stages of the syndrome are characterized by portal vein diminution/thrombosis, liver atrophy, hepatic failure, and type A and type B HE (138). Endovascular management. Spontaneous portosystemic shunts can be classified into either shunts directly associated with varices (such as gastrorenal shunts that are invariably associated with gastric varices) or shunts not associated with varices (ie, do not course through the walls/submucosa of the gastrointestinal tract) such as splenorenal shunts (138). Those spontaneous portosystemic shunts that are associated with a patent portal vein and varices should be sclerosed with the BRTO technique (138,139). Spontaneous portosystemic shunts that are not directly associated with varices can be occluded with standard embolic material and do not have to be sclerosed. However, regardless of whether the shunt is directly related to ectopic varices or not, all patients must undergo endoscopy of the esophagus and stomach for diagnosis and potential prophylactic management of varices. This is due to occlusion of the portosystemic shunt and invariably aggravates portal hypertension and, in turn, increases the risk of variceal bleed ing (up to 30% 35% at 5 years) (140,141). By subjective criteria in retrospective studies, BRTO for HE has had excellent results signified by the clinical resolution of HE. Clinical success is defined objectively as improvement in HE preferably by objective psychometric/cognitive criteria, a reduction in serum ammonia levels, and reduction or independence of anti-he medications. These criteria are very difficult to achieve objectively and consistently with retrospective studies. Recently, a multicenter study by Laleman et al (132) evaluated 37 patients who had undergone endovascular closure of spontaneous portosystemic shunts and showed good outcomes utilizing objective criteria including ammonia level reduction. At approximately 2-year follow-up, the portosystemic shunts had complete and partial resolution of HE at 75% and 50%, respectively. However, there was a gradual decline in symptom resolution over the 2-year period. Similarly, Mukund et al (139) evaluated 20 patients who underwent BRTO specifically for HE. The clinical response was 80% at 24 months, with a significant reduction in serum ammonia levels. An interesting study evaluated the value of adjunctive partial splenic artery embolization as an augment to spontaneous portoststemic shunt occlusion for the management of type B HE (142). Splenic embolization was shown to have added benefit for reduction in the HE 1 year after the procedures as well as the reduction in the serum ammonia levels. Accelerated BRTO without indwelling balloon occlusion. The conventional BRTO procedure entails that a balloon-occlusion catheter remain inflated for 6 12 hours for sclerosis and thrombosis to take effect in the gastric variceal system (141,143) and thus requires the patient to be monitored in an intensive care unit, step-down unit, or the angiography recovery area for a prolonged period of time (143). Saad and Nicholson (143) discussed the logistical advantages of an accelerated BRTO practice and described two techniques of placing metallic embolic agents, coils, or Amplatzer vascular plugs (St Jude Medical) coaxially through balloon occlusion catheters (Figs 8, 9). Two other techniques described for successful accelerated BRTO have been described, one by Darwish et al (144) in which they coaxially deployed a thick absorbable gelatin sponge (Gelfoam; Pfizer, New York, NY) through the balloon occlusion catheter before deflating the balloon. This is only technically feasible and safe in small gastric variceal systems based on a previously described gastric variceal scoring system Figure 8 Figure 8: The combined balloon guide-catheter (Merci Device; Concentric Medical, Mountain View, Calif) and a coaxially placed 16-mm Amplatzer vascular plug (AGA Medical, Plymouth, Minn). The balloon of the balloon-occlusion guide-catheter is inflated to 12 mm (recommended industry inflation diameter limit is 10 mm). (Reprinted, with permission, from reference 143.) (Table 1) (143). Gwon et al (145) describe a technique in which a balloonocclusion catheter was not required, by using metallic embolic materials such as Amplatzer vascular plugs deployed first, followed by a Gelfoam plug. Technical success was 100% in 20 patients by utilizing this technique, with obliteration of the gastric variceal system beyond 2 months in 18 of 20 patients. BRTO and Portal Modulators Combining BRTO and TIPS. Recent studies have evaluated the effectiveness of variceal embolization as an adjunct to TIPS in reducing the risk of variceal rebleeding (140,141). This is especially true in the setting of subsequent TIPS dysfunction (146). However, with the introduction of expanded-ptfe covered stents, the need to occlude varices in case of subsequent TIPS dysfunction may be less important (93,147). Recently, there is increasing data that supports variceal embolization as having an Radiology: Volume 278: Number 2 February 2016 n radiology.rsna.org 343

12 Figure 9 Figure 9: Substituting a Merci balloon-occlusion guide-catheter with coaxial 16-mm Amplatzer vascular plugs. (a) Fluoroscopic image during Sotradecol sclerosant mixture (black arrows) injection through the Merci balloon-occlusion guide-catheter (white arrow). The balloon (white arrowhead) is inflated with one-third strength contrast agent. The balloon-occlusion guide-catheter has been passed coaxially through a reinforced 10-F sheath. The black arrowheads point to coils in the inferior phrenic vein. (b) Fluoroscopic image of a 16-mm Amplatzer vascular plug (arrow) being advanced coaxially through the balloon-occlusion guide-catheter (white arrowhead). At this time, the 16-mm Amplatzer vascular plug has not been deployed. It is still tethered at its stalk (black arrowhead). (c) Fluoroscopic image while a 16-mm Amplatzer vascular plug (black arrow) is being deployed through the balloon-occlusion guide-catheter. The balloon of the balloon-occlusion catheter has ruptured (arrowhead). At this point in time the 16-mm Amplatzer vascular plug has not been deployed. It is still tethered at its stalk. Noted is the reinforced sheath of which the entire Merci device and Amplatzers are advanced coaxially through (white arrow at sheath tip). (d) Fluoroscopic image while a second 16-mm Amplatzer vascular plug (white arrow) is being advanced coaxially through the balloon-occlusion guide-catheter. The first 16 mm Amplatzer vascular plug has keeled off to the side (black arrow). (e) Fluoroscopic image while a third 16-mm Amplatzer vascular plug (arrow) is being advanced coaxially through the balloon-occlusion guidecatheter. (f) Digitally subtracted venogram after three Amplatzer plug deployments (arrows) demonstrating patent distal gastrorenal shunt (GRS) and left renal vein (LRV). Contrast agent is seen readily flowing out of the left renal vein and into the inferior vena cava (IVC). added benefit by reducing the post-tips hemorrhagic rates (140,141). Multiple studies show superior outcomes of combined TIPS and BRTO compared with BRTO alone (148,149). The advantage of combining BRTO with TIPS is that the spontaneous gastrorenal portosystemic shunt, which is occluded during the BRTO, is compensated for by the creation of a TIPS (148). Thus, the aggravated portal pressure that is a common feature after BRTO is ameliorated. As a result, combining TIPS with BRTO showed decreased transudative complications related to portal hypertension (ascites/hydrothorax, 57% at 1 year for BRTO alone vs 0% at 1 year for BRTO plus TIPS), reduced esophageal variceal bleeding, and reduced overall gastric variceal rebleed rates (148). The upper gastrointestinal bleeding rate at 1 year after the procedure for TIPS alone, BRTO alone, and TIPS with BRTO combined was greater than 11%, 9%, and 0%, respectively (148,150). Combining BRTO and splenic embolization. Secondary to BRTO of gas- 344 radiology.rsna.org n Radiology: Volume 278: Number 2 February 2016

13 Table 1 Gastric Variceal Size Classification System Size Category Score* Recommended Embolic Material Size A Thick Gelfoam plug and/or coils Size B Thick Gelfoam plug and/or coils Size C Coils/ Amplatzer vascular plug Size D Coils/ Amplatzer vascular plug Size E Coils/ Amplatzer vascular plug Size F.751 Probably safer to perform conventional BRTO with indwelling balloon Source. Reference 143. * The score is the product of the diameter of the gastrorenal shunt at the site of balloon occlusion (must be within 2 cm from the confluence of the shunt and the left renal vein) and the total volume of sclerosant (diameter in millimeters 3 sclerosant volume in milliliters). Thick gelfoam plug as recommended by Darwish and co-workers (144). tric varices, the spontaneous gastrorenal shunt is also obliterated (148). This spontaneous portosystemic shunt leads to an increase in portal pressure. To temper this predicted increase in portal pressure, partial splenic embolization has been performed (150, 151). Chikamori et al (150) compared the wedged hepatic pressure gradient before and after BRTO, comparing patients who underwent concomitant partial splenic embolization versus those who did not, and showed that the wedged hepatic pressure gradient is not significantly increased with partial splenic embolization; however, it is increased after BRTO without partial splenic embolization. Moreover, there was a significant increase in the platelet count after combined BRTO and splenic embolization. Waguri et al (151) made a similar evaluation, with the combined therapy group showing significantly reduced esophageal variceal exacerbation. Transient splenic artery balloon occlusion has also been described and found to be particularly helpful in complex gastric varices that are associated with high portal pressure (152,153). The splenic artery occlusion reduces the portal pressure and allows adequate and uniform sclerosant distribution within the gastric varices (153). This is particularly true with complex and high-pressure gastric varices (152,153). One can argue that an alternative to partial splenic embolization in complex high-pressure gastric varices (with risk of incomplete obliteration and/or aggravation of esophageal varices) would be combining the BRTO with TIPS in patients who are TIPS candidates. Certainly, the TIPS will also provide access to the gastric varices from the portal venous side that may allow additional access for sclerosant obliteration (148). Moreover, it is still unclear what the indications are for partial splenic embolization during BRTO. Chikamori et al suggest partial splenic embolization be considered when there is splenic and/or portal vein thrombosis as well as in pediatric cases where gastric varices are more commonly associated with splenoportal vein thrombosis and/or prehepatic (extrahepatic) portal hypertension with large spleens and hypersplenism (150). Pancreatic Islet Cell Transplantation Percutaneous pancreatic islet cell transplantation is a promising cellular-based therapy for type 1 diabetes mellitus that affords stable long-term glycemic control without the need for exogenous insulin in up to 60% 70% of recipients (154) and also curtails the progression of diabetic complications (155). This procedure, which involves portal venous injection of islet cells, has historically been driven by transplant surgeons. However, the development and widespread adoption of imaging-guided approaches and transcatheter techniques has fostered radiologic cooperation and transformed islet cell transplantation into a minimally invasive intervention (156). Nearly 600 recipients have undergone approximately 1100 islet cell infusions worldwide between 1999 and 2009 (154). Patient Selection Currently, islet cell transplantation is performed in the context of a controlled research study (157) for patients with type 1 diabetes mellitus of at least 5-year duration who have no endogenous C-peptide secretion and severe glycemic lability with frequent episodes of undetected hypoglycemia or progressive diabetic complications despite optimization of insulin injection therapy. Renal transplantation is frequently performed concomitantly in patients with imminent or established end-stage renal disease. Contraindications to islet cell transplantation include age younger than 18 or older than 70 years, diabetes mellitus duration less than 5 years, residual C-peptide secretion, untreated proliferative diabetic retinopathy, portal hypertension, coexisting prohibitive cardiovascular disease, active infection, known substance abuse, active or planned pregnancy, obesity with body mass index greater than 28 kg/m 2, and relative insulin resistance. Procedure Technique Pancreatic islet cell transplantation is performed in the interventional radiology suite by using intravenous moderate sedation and hemodynamic monitoring. Patients typically undergo periprocedural antimicrobial and antiviral therapy (156). With US and/or fluoroscopic guidance ( ) and a right transhepatic approach (159,160), a second- or third-order portal vein branch is punctured by using a gauge needle with dilation to a 5 6-F vascular sheath with tip positioned in the main portal vein. Inability to catheterize the main portal vein, while very uncommon, may compel segmental infusion (Fig 10). Systemic anticoagulation is initiated with 5000 units of heparin, followed by direct portography and baseline Radiology: Volume 278: Number 2 February 2016 n radiology.rsna.org 345

14 Figure 10 Figure 10: Failure to achieve catheterization of the main portal vein in 46-year-old woman owing to circuitous vessel course and small size. Right anterior segment portal venogram reveals patent segmental branch vessels into which islet cells successfully infused, without significant portal vein pressure increase (8 10 mm Hg). Although patient is currently insulin independent 1-year after transplant, main portal vein infusion preferred to avert saturating segmental portal vasculature and risk venous thrombosis; careful preprocedure US selection of target vessel showing straight course into main portal vein optimizes chance for successful catheterization. portal venous pressure measurement, which should be below 20 mm Hg to avoid disproportionate risk for portal venous thrombosis. Islet cells (from deceased donors) are then infused; patients typically receive at least islet equivalents or islets measuring at least 150 mm in diameter per kilogram of body weight (157). Islet cells are instilled during minutes using either gravity flow or direct syringe injection, with intermittent portal venous pressure measurement. A persistent pressure rise to more than double baseline or to greater than 22 mm Hg warrants infusion termination to avert thrombotic complications or excessive risk for tract bleeding (Fig 11). After infusion, the liver parenchymal tract is embolized by using gelatin sponge torpedoes, metallic coils, or other hemostatic material; this procedure step commands extreme care and technical attention to ensure hemostasis without hemorrhagic complication (Fig 12) (161). Figure 11 Figure 11: Portal venogram in a 42-year-old woman with significant portal venous pressure increase following islet cell infusion. Portal vein pressure increased from baseline 11 mm Hg to peak 29 mm Hg, necessitating delay in vascular access removal for 2 hours until portal vein pressure spontaneously reduced to 18 mm Hg to lessen bleeding risk; such pressure elevation would typically prompt termination of infusion, but must be weighed against total islet equivalents infused and chance for successful cure. Postprocedure Care After transplant procedures, serum glucose levels are closely monitored for target fasting glucose levels of 140 mg/dl. Low-dose insulin is administered for 1 month to avoid stressing engrafting islet cells, and insulin is tapered and discontinued as glucose levels normalize. Posttransplant monitoring of islet function is performed by measurement of a variety of serum markers at basal and stimulated levels, and inability to achieve or maintain insulin independence indicates need for repeat islet cell transplantation (155). All patients are immunosuppressed, and current protocols which are steroid-free to minimize diabetogenic effects consist of induction with a T-cell depleting agent and IL-2 monoclonal antibody receptor blocker followed by maintenance with calcineurin and m-tor inhibitors (157), although other agents have also been used. Transplantation Efficacy Numerous studies have described islet cell transplantation outcomes since the seminal Edmonton series was reported in 2000 (Table 2). The seventh Annual Report of the National Institute of Diabetes and Digestive and Kidney Diseases Collaborative Islet Transplant Registry (154) summarized the results of 1072 total islet allograft infusions performed for 571 recipients between 1999 and 2009, representing 86% of all allogeneic islet infusion procedures and 87% of recipients during this time period. Among the study cohort, 178 (31%), 268 (47%), 115 (20%), and 10 (2%) recipients received 1, 2, 3, and 4 or more infusions, respectively, and 1- and 2-year insulin independence achievement rates were 65% and 75%, respectively. Some positively influencing factors include older recipient age, lower insulin requirements, islets cultured greater than 6 hours, islet transplant alone, two total infusions, higher total islet equivalents infused over all procedures, and immunosuppression using T-cell depleting agents, TNF-ainhibitors, calcineurin inhibitors, and inosine 59-monophosphate dehydrogenase inhibitors. To this end, properly selected patients and donor organs with favorable characteristics have a very high likelihood of long-term success, with 5-year insulin independence rates approximating 60% 70%. Similarly, graft survival defined as fasting C-peptide of greater than or equal to 0.3 ng/ml can also reach 80% at 5 years. Encouragingly, outcomes of islet cell transplantation have also continued to improve over time (182), indicating progressive advancement in candidate selection, cellular isolation, and procedure technique, and, similar to whole pancreas transplantation, contribute to reversal or stabilization of long-term diabetes mellitus complications (157), including diabetic retinopathy, nephropathy, and neuropathy (161). Complications Serious adverse events occur in approximately 20% of islet cell transplant recipients within 30 days, although only 13% of patients fail to completely recover (154). Among clinically relevant risks, intraperitoneal or liver subcapsular bleeding is most common, occurring in up to 13% of cases (160); hemorrhage risk is increased with cumulative transplant procedure number and heparin dose equal to or greater than 45 units per kilogram (160). Partial PVT 346 radiology.rsna.org n Radiology: Volume 278: Number 2 February 2016

15 Figure 12 Figure 12: Successful liver tract embolization in 42-year-old woman. (a) Pretransplant US used to identify portal vein branch target (arrowhead); a deep vessel and a long (4 5 cm, 5.4 cm in this case) liver parenchymal tract desirable to accommodate ample embolic material necessary to attain secure tract embolization at procedure conclusion. Following islet cell infusion, sheath withdrawn using US and fluoroscopy until tip positioned in liver tract, confirmed with (b) tractogram, which delineates extravascular sheath tip (white arrowhead) and tract opacification (black arrowhead). Embolic agent, in this case microfibrillar collagen (Avitene; C. R. Bard, Murray Hill, NJ) mixed with iodinated contrast material, then slowly injected into entire liver tract over 2 3 minutes with concurrent sheath retraction (injection across whole tract ensures hemostasis of any small inadvertently traversed vessels); material is readily visible (arrowheads) on (c) US and (d) fluoroscopic images and results in immediate hemostasis. complicates less than 5% of islet cell transplants (183) and complete portal venous thrombosis, while potentially devastating, is rare. Other adverse events include liver enzyme elevation, abdominal pain, focal hepatic steatosis, and severe hypoglycemia. Recent Progress and Future Directions In recent years, the field of islet cell transplantation has been progressed by several exciting advances. First, development of the Clinical Islet Transplant Consortium with a 13-center multinational membership by the National Institutes of Health has led to better standardization of islet isolation and transplant procedures. Second, improved islet isolation techniques with superior purification methods and better enzymes have resulted in enhanced recovery of highly pure human islets (184). Third, application of more secure embolic materials, such as microfibrillar collagen (Avitene; C. R. Bard, Murray Hill, NJ), for liver tract embolization has boosted the safety of transhepatic portal venous access by reducing bleeding complications. Fourth, contemporary data further supports the proof of concept that chronic diabetes complications, such as atherosclerosis, can be prevented through islet trans- Radiology: Volume 278: Number 2 February 2016 n radiology.rsna.org 347