Daniel Y. Sze

Catheter-directed Therapy for the Treatment of Massive Pulmonary Embolism: Systematic Review and Meta-analysis of Modern Techniques

PURPOSE Systemic thrombolysis for the treatment of acute pulmonary embolism (PE) carries an estimated 20% risk of major hemorrhage, including a 3%-5% risk of hemorrhagic stroke. The authors used evidence-based methods to evaluate the safety and effectiveness of modern catheter-directed therapy (CDT) as an alternative treatment for massive PE. MATERIALS AND METHODS The systematic review was initiated by electronic literature searches (MEDLINE, EMBASE) for studies published from January 1990 through September 2008. Inclusion criteria were applied to select patients with acute massive PE treated with modern CDT. Modern techniques were defined as the use of low-profile devices (< or =10 F), mechanical fragmentation and/or aspiration of emboli including rheolytic thrombectomy, and intraclot thrombolytic injection if a local drug was infused. Relevant non-English language articles were translated into English. Paired reviewers assessed study quality and abstracted data. Meta-analysis was performed by using random effects models to calculate pooled estimates for complications and clinical success rates across studies. Clinical success was defined as stabilization of hemodynamics, resolution of hypoxia, and survival to hospital discharge. RESULTS Five hundred ninety-four patients from 35 studies (six prospective, 29 retrospective) met the criteria for inclusion. The pooled clinical success rate from CDT was 86.5% (95% confidence interval [CI]: 82.1%, 90.2%). Pooled risks of minor and major procedural complications were 7.9% (95% CI: 5.0%, 11.3%) and 2.4% (95% CI: 1.9%, 4.3%), respectively. Data on the use of systemic thrombolysis before CDT were available in 571 patients; 546 of those patients (95%) were treated with CDT as the first adjunct to heparin without previous intravenous thrombolysis. CONCLUSIONS Modern CDT is a relatively safe and effective treatment for acute massive PE. At experienced centers, CDT should be considered as a first-line treatment for patients with massive PE.

Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial

BACKGROUND JX-594 is a targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell-cycle abnormalities and epidermal growth factor receptor (EGFR)-ras pathway activation. Direct oncolysis plus granulocyte-macrophage colony-stimulating factor (GM-CSF) expression also stimulates shutdown of tumour vasculature and antitumoral immunity. We aimed to assess intratumoral injection of JX-594 in patients with refractory primary or metastatic liver cancer. METHODS Between Jan 4, 2006, and July 4, 2007, 14 patients with histologically confirmed refractory primary or metastatic liver tumours (up to 10.9 cm total diameter) that were amenable to image-guided intratumoral injections were enrolled into this non-comparative, open-label, phase I dose-escalation trial (standard 3x3 design; two to six patients for each dose with 12-18 estimated total patients). Patients received one of four doses of intratumoral JX-594 (10(8) plaque-forming units [pfu], 3x10(8) pfu, 10(9) pfu, or 3x10(9) pfu) every 3 weeks at Dong-A University Hospital (Busan, South Korea). Patients were monitored after treatment for at least 48 h in hospital and for at least 4 weeks as out-patients. Adverse event-monitoring according to the National Cancer Institute Common Toxicity Criteria (version 3) and standard laboratory toxicity grading for haematology, liver and renal function, coagulation studies, serum chemistry, and urinalysis were done. The primary aims were to ascertain the maximum-tolerated dose (MTD) and safety of JX-594 treatment. Data were also collected on pharmacokinetics, pharmacodynamics, and efficacy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00629759. FINDINGS Of 22 patients with liver tumours who were assessed for eligibility, eight patients did not meet inclusion criteria. Therefore, 14 patients, including those with hepatocellular, colorectal, melanoma, and lung cancer, were enrolled. Patients were heavily pretreated (5.6 previous treatments, SD 2.8, range 2.0-12.0) and had large tumours (7.0 cm diameter, SD 2.7, range 1.8-10.9). Patients received a mean of 3.4 (SD 2.2, range 1.0-8.0) cycles of JX-594. All patients were evaluable for toxicity. All patients experienced grade I-III flu-like symptoms, and four had transient grade I-III dose-related thrombocytopenia. Grade III hyperbilirubinaemia was dose-limiting in both patients at the highest dose; the MTD was therefore 1x10(9) pfu. JX-594 replication-dependent dissemination in blood was shown, with resultant infection of non-injected tumour sites. GM-CSF expression resulted in grade I-III increases in neutrophil counts in four of six patients at the MTD. Tumour responses were shown in injected and non-injected tumours. Ten patients were radiographically evaluable for objective responses; non-evaluable patients had contraindications to contrast medium (n=2) or no post-treatment scans (n=2). According to Response Evaluation Criteria in Solid Tumors (RECIST), three patients had partial response, six had stable disease, and one had progressive disease. INTERPRETATION Intratumoral injection of JX-594 into primary or metastatic liver tumours was generally well-tolerated. Direct hyperbilirubinaemia was the dose-limiting toxicity. Safety was acceptable in the context of JX-594 replication, GM-CSF expression, systemic dissemination, and JX-594 had anti-tumoral effects against several refractory carcinomas. Phase II trials are now underway.

Endovascular Management of Iliac Vein Compression (May-Thurner) Syndrome

PURPOSE To evaluate the feasibility of endovascular techniques in treating venous outflow obstruction resulting from compression of the iliac vein by the iliac artery of the left lower extremity (May-Thurner syndrome). MATERIALS AND METHODS A retrospective analysis of 39 patients (29 women, 10 men; median age, 46 years) with iliac vein compression syndrome (IVCS) was performed. Nineteen patients presented with acute deep vein thrombosis (DVT) and 20 patients presented with chronic symptoms. All patients presented with leg edema or pain. In the acute group, patients were treated with catheter-directed thrombolysis (120,000-180,000 IU urokinase/h) and angioplasty followed by stent placement. In the chronic group, patients were treated with use of angioplasty and stent placement alone (n = 8), or in combination with thrombolysis (n = 12). Patients were then followed-up with duplex ultrasound and a quality-of-life assessment. RESULTS Initial technical success was achieved in 34 of 39 patients (87%). The overall patency rate at 1 year was 79%. Symptomatically, 85% of patients were completely or partially improved compared with findings before treatment. Thirty-five of 39 patients received stents. The 1-year patency rate for patients with acute symptoms who received stents was 91.6%; for patients with chronic symptoms who received stents, the 1-year patency rate was 93.9%. Five technical failures occurred. Major complications included acute iliac vein rethrombosis (< 24 hours) requiring reintervention (n = 2). Minor complications included perisheath hematomas (n = 4) and minor bleeding (n = 1). There were no deaths, pulmonary embolus, cerebral hemorrhage, or major bleeding complications. CONCLUSION Endovascular reconstruction of occluded iliac veins secondary to IVCS (May-Thurner) appears to be safe and effective.

Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial

Both replication-incompetent and replication-selective adenoviruses are being developed for the treatment of cancer and other diseases. Concerns have been raised about the safety of intra-vascular adenovirus administration following a patient death on a clinical trial with a replication-defective adenovirus. In addition, the feasibility of vascular delivery to distant tumors has been questioned. dl1520 (ONYX-015) is a replication-selective adenovirus that has previously shown safety and antitumoral activity following intratumoral injection. This is the first report of intra-vascular administration with a genetically engineered, replication-selective virus. A phase I dose-escalation trial was performed in patients with liver-predominant gastrointestinal carcinoma (n = 11 total; primarily colorectal). dl1520 was infused into the hepatic artery at doses of 2 × 108–2 × 1012 particles for two cycles (days 1 and 8). Subsequent cycles of dl1520 were administered in combination with intravenous 5-fluorouracil (5-FU) and leucovorin. No dose-limiting toxicity, maximally tolerated dose or treatment-emergent clinical hepatotoxicity were identified following dl1520 infusion. Mild to moderate fever, rigors and fatigue were the most common adverse events. Antibody titers increased significantly in all patients. Viral replication was detectable in patients receiving the highest two doses. An objective response was demonstrated in combination with chemotherapy in a patient who was refractory to both 5-FU and dl1520 as single agents. Therefore, hepatic artery infusion of the attenuated adenovirus dl1520 was well-tolerated at doses resulting in infection, replication and chemotherapy-associated antitumoral activity.

Internal Iliac Artery Embolization in the Stent-Graft Treatment of Aortoiliac Aneurysms: Analysis of Outcomes and Complications

PURPOSE To analyze the complications of internal iliac artery (IIA) embolization in conjunction with stent-graft treatment of aortoiliac aneurysms. MATERIALS AND METHODS Seventy-one patients with aortoiliac ( n = 47) or iliac ( n = 24) aneurysms were treated with endoluminal placement of stent-grafts. Thirty-two patients (31 men, one woman; mean age, 73 years; range, 56–88 years) had embolization or occlusion of one ( n = 27) or both ( n = 5) IIAs. Status of the IIAs and the collateral circulation was assessed by retrospective review of angiographic images. Follow-up consisted of a standardized patient questionnaire and review of radiologic and medical records. RESULTS The mean follow-up time was 35 months (range, 5–64 months). Eleven of the 47 patients with abdominal aortic aneurysms (AAA) (23%) and 19 of the 24 patients with iliac aneurysms (79%) required IIA embolization. One patient with AAA and another with iliac aneurysm had unintentional occlusion of an IIA by extension of the stent-graft over their origins. A total of seven patients had bilateral occlusion of the IIAs after the procedure. Additionally, the inferior mesenteric arteries (IMAs) of two other patients with AAA were also embolized. In six patients, all three vessels were occluded after placement of the stent-grafts. Symptoms were reported in nine of the 20 (45%) patients with iliac aneurysms and in three of the 12 (25%) patients with AAA. Symptoms consisted of buttock claudication (nine of 32, 28%), new sexual dysfunction (two of 16, 12%), and transient urinary retention (3%). Seven of the claudicants had resolution of symptoms after a mean interval of 14 months (range, 1–36 months). There were no instances of bowel ischemia, neurologic sequelae, or buttock necrosis related to these procedures. CONCLUSION Embolization of the IIA is associated with symptoms in a significant number of patients. While symptoms are transient in most patients, they can be problematic. Efforts should be made to preserve the pelvic circulation if possible.

Delayed Complications after Esophageal Stent Placement for Treatment of Malignant Esophageal Obstructions and Esophagorespiratory Fistulas

PURPOSE To evaluate delayed complications after esophageal expandable metallic stent placement. MATERIALS AND METHODS From April 1993 to December 1997, 90 expandable metallic stents were placed in 82 consecutive patients with inoperable malignant esophageal obstruction (n = 49) or malignant esophagorespiratory fistula (n = 33). Stents used included covered Gianturco-Rosch Z stents (n = 20), Wallstents (covered, n = 31; uncovered, n = 13), and Ultraflex stents (covered, n = 8; uncovered, n = 10). Patients were followed prospectively and monitored for delayed complications, defined as major (hemorrhage, tracheal compression, stent migration, perforation or fistula formation, granulomatous obstruction, tumor ingrowth and overgrowth, funnel phenomenon, and stent covering disruption) or minor (reflux, chest pain, and food impaction). RESULTS Mean survival was 4.5 months after stent placement (range, 3 weeks to 26 months). The overall incidence of delayed complications was 64.6%, with 17 patients (20.7%) experiencing more than one complication. The rates of delayed complications in patients with Z stents, Wallstents, and Ultraflex stents were 75.0%, 68.1%, and 44.4%, respectively (P <.05). Most complications were life-threatening and occurred more frequently when stents were placed in the proximal third of the esophagus, compared with more distally (P <.05). Thirteen patients (15.9%) died from complications directly related to stent placement. CONCLUSION Esophageal stent placement for malignant obstruction or fistula is associated with a substantial incidence of delayed complications.

Research Reporting Standards for Radioembolization of Hepatic Malignancies

Primary Liver Tumors Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver; its incidence is increasing worldwide. It ranks as the sixth most common tumor and third most common cause of cancer-related mortality (1,2). Primary liver tumors include HCC and intrahepatic cholangiocarcinoma. Surgical resection is preferred over transplantation and is considered potentially curative in patients with resectable HCC and normal liver function (3). Transplantation is considered the gold standard for patients with unresectable HCC and whose disease is within the Milan criteria (4). Resection and transplantation have limited roles, given advanced disease (chronic liver disease and/or tumor extent) at presentation and limited organ availability (5–7). Chemoembolization and radiofrequency ablation represent standard therapies in treating patients and serve as a bridge to transplantation in selected patients (8,9). Radioembolization has an emerging role in “bridging” patients within criteria by delaying tumor progression. It has also been shown to downstage disease beyond the Milan, to within, transplant criteria (10–12). A recent study has demonstrated that radioembolization leads to longer time-to-progression and better toxicity profile when compared with chemoembolization (13). Patients with macrovascular tumor involvement have also exhibited evidence of clinical benefit after radioembolization (14).

Safety and Efficacy of Percutaneous Fiducial Marker Implantation for Image-guided Radiation Therapy

PURPOSE To evaluate the safety and technical success rate of percutaneous fiducial marker implantation in preparation for image-guided radiation therapy. MATERIALS AND METHODS From January 2003 to January 2008, we retrospectively reviewed 139 percutaneous fiducial marker implantations in 132 patients. Of the 139 implantations, 44 were in the lung, 61 were in the pancreas, and 34 were in the liver. Procedure-related major and minor complications were documented. Technical success was defined as implantation enabling adequate treatment planning and computed tomographic simulation. RESULTS The major and minor complication rates were 5% and 17.3%, respectively. Pneumothorax after lung implantation was the most common complication. Pneumothoraces were seen in 20 of the 44 lung implantations (45%); a chest tube was required in only seven of the 44 lung transplantations (16%). Of the 139 implantations, 133 were successful; in six implantations (4.3%) the fiducial markers migrated and required additional procedures or alternate methods of implantation. CONCLUSIONS Percutaneous implantation of fiducial marker is a safe and effective procedure with risks that are similar to those of conventional percutaneous organ biopsy.

Incomplete endograft apposition to the aortic arch: bird-beak configuration increases risk of endoleak formation after thoracic endovascular aortic repair.

PURPOSE To determine the clinical importance of the bird-beak configuration after thoracic endovascular aortic repair (TEVAR). MATERIALS AND METHODS The institutional review board approved this retrospective study and waived the requirement to obtain informed consent from patients. Sixty-four patients (40 men, 24 women; mean age, 64 years) who underwent TEVAR were evaluated. The treated diseases included dissection (n = 29), degenerative aneurysm (n = 13), acute traumatic transection (n = 8), pseudoaneurysm (n = 4), penetrating aortic ulcer (n = 6), intramural hematoma (n = 2), and mycotic aneurysm (n = 2). Bird-beak configuration, defined as the incomplete apposition of the proximal endograft with a wedge-shaped gap between the device and the aortic wall, was assessed with postprocedural CT angiography. The presence and length of the bird-beak configuration were compared with the formation of endoleaks and adverse clinical events. RESULTS Endoleaks were detected in 26 (40%) of the 64 patients, including 14 with type Ia endoleak formation, one with type Ib endoleak formation, six with type II endoleak formation (from the left subclavian artery), two with type IIo endoleak formation (from other arteries), and three with type III endoleak formation. Bird-beak configuration was observed in 28 (44%) of 64 patients and correlated significantly with the risk of developing a type Ia or IIa endoleak (P < .01). Mean bird-beak length was significantly longer (P < .01) in patients with a type Ia or II endoleak (mean length, 14.3 and 13.9 mm, respectively) than in patients without endoleaks (mean length, 8.4 mm). Adverse events included early aortic-related death in three patients, additional treatment for endoleak in eight patients, and stent-graft collapse or infolding in six patients. CONCLUSION Detection of bird-beak configuration is helpful in the prediction of adverse clinical events after TEVAR.

Complicated acute type B aortic dissection: Midterm results of emergency endovascular stent–grafting

OBJECTIVE This study assessed midterm results of emergency endovascular stent-grafting for patients with life-threatening complications of acute type B aortic dissection. METHODS Between November 1996 and June 2004, 16 patients with complicated acute type B aortic dissections (mean age 57 years, range 16-88 years) underwent endovascular stent-grafting within 48 hours of presentation. Complications included contained rupture, hemothorax, refractory chest pain, and severe visceral or lower limb ischemia. Stent-graft types included custom-made first-generation endografts and second-generation commercial stent-grafts (Gore Excluder or TAG; W. L. Gore & Associates, Inc, Flagstaff, Ariz.). Follow-up was 100% complete, averaged 36 +/- 36 months, and included postprocedural surveillance computed tomographic scans. RESULTS Early mortality was 25% +/- 11% (70% confidence limit), with no late deaths. No new neurologic complications occurred. According to the latest scan, 4 patients (25%) had complete thrombosis of the false lumen; the lumen was partially thrombosed in 6 patients (38%). Distal aortic diameter was increased in only 1 patient. Actuarial survival at 1 and 5 years was 73% +/- 11%; freedom from treatment failure (including aortic rupture, device fault, reintervention, aortic death, or sudden, unexplained late death) was 67% +/- 14% at 5 years. CONCLUSION With follow-up to 9 years, endovascular stent-grafting for patients with complicated acute type B aortic dissection conferred benefit. Consideration of emergency stent-grafting may improve the dismal outlook for these patients; future refinements in stent-graft design and technology and earlier diagnosis and intervention should be associated with improved results.