Ziv Neeman

Phase I Study of Heat-Deployed Liposomal Doxorubicin during Radiofrequency Ablation for Hepatic Malignancies

PURPOSE A phase I dose escalation study was performed with systemically delivered lyso-thermosensitive liposomal doxorubicin (LTLD). The primary objectives were to determine the safe maximum tolerated dose (MTD), pharmacokinetic properties, and dose-limiting toxicity (DLT) of LTLD during this combination therapy. MATERIALS AND METHODS Subjects eligible for percutaneous or surgical radiofrequency (RF) ablation with primary (n = 9) or metastatic (n = 15) tumors of the liver, with four or fewer lesions as large as 7 cm in diameter, were included. RF ablation was initiated 15 minutes after starting a 30-minute intravenous LTLD infusion. Dose levels between 20 mg/m(2) and 60 mg/m(2) were evaluated. Magnetic resonance imaging, positron emission tomography, and computed tomography were performed at predetermined intervals before and after treatment until evidence of recurrence was seen, administration of additional antitumor treatment was performed, or a total of 3 years had elapsed. RESULTS DLT criteria were met at 60 mg/m(2), and the MTD was defined as 50 mg/m(2). RF ablation was performed during the peak of the plasma concentration-time curve in an effort to yield maximal drug deposition. LTLD produced reversible, dose-dependent neutropenia and leukopenia. CONCLUSIONS LTLD can be safely administered systemically at the MTD (50 mg/m(2)) in combination with RF ablation, with limited and manageable toxicity. Further evaluation of this agent combined with RF ablation is warranted to determine its role in the management of liver tumors.

Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies

PURPOSE We conducted a phase I study of a 30-minute hepatic artery infusion of melphalan via a percutaneously placed catheter and hepatic venous hemofiltration using a double balloon catheter positioned in the retrohepatic inferior vena cava to shunt hepatic venous effluent through an activated charcoal filter and then to the systemic circulation. The purpose of the study was to demonstrate feasibility in an initial cohort and subsequently determine the maximum tolerated dose and dose-limiting toxicity of melphalan. PATIENTS AND METHODS The initial cohort (n = 12) was treated with 2.0 mg/kg of melphalan before dose escalation to 3.5 mg/kg (n = 16). Total hepatic drug delivery, systemic levels, and percent filter efficiency were determined. Patients were assessed for hepatic and systemic toxicity and response. RESULTS A total of 74 treatments were administered to 28 patients. Twelve patients with primary and metastatic hepatic tumors received 30 treatments (mean, 2.5 per patient) at an initial melphalan dose of 2.0 mg/kg. At 3.5 mg/kg, a dose-limiting toxicity (neutropenia and/or thrombocytopenia) was observed in two of six patients. Transient grade 3/4 hepatic and systemic toxicity was seen after 19% and 66% of treatments, respectively. An overall radiographic response rate of 30% was observed in treated patients. In the 10 patients with ocular melanoma, a 50% overall response rate was observed, including two complete responses. CONCLUSION Delivery of melphalan via this system is feasible, with limited, manageable toxicity and evidence of substantial antitumor activity; 3 mg/kg is the maximum safe tolerated dose of melphalan administered via this technique.

Radiofrequency Ablation of Cancer

Radiofrequency ablation (RFA) has been used for over 18 years for treatment of nerve-related chronic pain and cardiac arrhythmias. In the last 10 years, technical developments have increased ablation volumes in a controllable, versatile, and relatively inexpensive manner. The host of clinical applications for RFA have similarly expanded. Current RFA equipment, techniques, applications, results, complications, and research avenues for local tumor ablation are summarized.

Closed-loop control in fused MR-TRUS image-guided prostate biopsy

Multi-modality fusion imaging for targeted prostate biopsy is difficult because of prostate motion during the biopsy procedure. A closed-loop control mechanism is proposed to improve the efficacy and safety of the biopsy procedure, which uses real-time ultrasound and spatial tracking as feedback to adjust the registration between a preoperative 3D image (e.g. MRI) and real-time ultrasound images. The spatial tracking data is used to initialize the image-based registration between intraoperative ultrasound images and a preoperative ultrasound volume. The preoperative ultrasound volume is obtained using a 2D sweep and manually registered to the MRI dataset before the biopsy procedure. The accuracy of the system is 2.3 +/- 0.9 mm in phantom studies. The results of twelve patient studies show that prostate motion can be effectively compensated using closed-loop control.

Thermal protection with 5% dextrose solution blanket during radiofrequency ablation.

A serious complication for any thermal radiofrequency ablation is thermal injury to adjacent structures, particularly the bowel, which can result in additional major surgery or death. Several methods using air, gas, fluid, or thermometry to protect adjacent structures from thermal injury have been reported. In the cases presented in this report, 5% dextrose water (D5W) was instilled to prevent injury to the bowel and diaphragm during radiofrequency ablation. Creating an Insulating envelope or moving organs with D5W might reduce risk for complications such as bowel perforation.

CT fluoroscopy shielding: decreases in scattered radiation for the patient and operator.

PURPOSE High-radiation exposure occurs during computed tomographic (CT) fluoroscopy. Patient and operator doses during thoracic and abdominal interventional procedures were studied in the present experiment, and a novel shielding device to reduce exposure to the patient and operator was evaluated. MATERIALS AND METHODS With a 16-slice CT scanner in CT fluoroscopy mode (120 kVp, 30 mA), surface dosimetry was performed on adult and pediatric phantoms. The shielding was composed of tungsten antimony in the form of a lightweight polymer sheet. Doses to the patient were measured with and without shielding for thoracic and abdominal procedures. Doses to the operator were recorded with and without phantom, gantry, and table shielding in place. Double-layer lead-free gloves were used by the operator during the procedures. RESULTS Tungsten antimony shielding adjacent to the scan plane resulted in a maximum dose reduction of 92.3% to the patient. Maximum 85.6%, 93.3%, and 85.1% dose reductions were observed for the operators torso, gonads, and hands, respectively. The use of double-layer lead-free gloves resulted in a maximum radiation dose reduction of 97%. CONCLUSIONS Methods to reduce exposure during CT fluoroscopy are effective and should be searched for. Significant reduction in radiation doses to the patient and operator can be accomplished with tungsten antimony shielding.

Remote Thermometry to Avoid Complications in Radiofrequency Ablation

Percutaneous image-guided radiofrequency ablation (RFA) of tumors has the potential risk for thermal damage to nearby normal collateral tissues. Thus, the goal of creating a sufficient area of tumor necrosis must be weighed against the risk for injury to collateral tissues. In this study, remote thermistors were used to monitor temperatures near collateral structures during tumor RFA. Four unique cases are described. When temperature-sensitive structures are near the target lesion, remote thermometry could further increase the safety of this evolving minimally invasive procedure.

Heavy Metal Pad Shielding during Fluoroscopic Interventions

Significant direct and scatter radiation doses to patient and physician may result from routine interventional radiology practice. A lead-free disposable tungsten antimony shielding pad was tested in phantom patients during simulated diagnostic angiography procedures. Although the exact risk of low doses of ionizing radiation is unknown, dramatic dose reductions can be seen with routine use of this simple, sterile pad made from lightweight tungsten antimony material.

Rabbit antithymocyte globulin induction and sirolimus monotherapy supports prolonged islet allograft function in a nonhuman primate islet transplantation model

Background. We reported that rabbit anti‐thymocyte globulin (RATG) induction followed by maintenance immunosuppression with sirolimus supports human kidney allograft survival and asked if this combination would promote islet allograft survival in our primate model. Methods. Using intra‐arterial streptozotocin infusion, we rendered four cynomolgus primates diabetic with undetectable C‐peptide levels. Animals were maintained on insulin therapy for at least 1 month, and then islets from mixed lymphocyte reaction mismatched primates were infused into the portal vein. Immediately before the islet allotransplant and for 6 additional days, primates were infused with RATG (20 mg/kg) and given a sirolimus dose to achieve a 24‐hr trough level of 8 to 14 ng/mL. Results. The regimen resulted in profound peripheral and lymph node lymphocyte depletion for up to 1 month. Repopulation was gradual thereafter. One primate remained insulin‐independent for 169 days and rejected after a sirolimus‐dose reduction. Two primates died on day 23 while insulin independent because of wound dehiscence, and a third died on day 30 with high sirolimus levels. Liver sections revealed well‐vascularized islets with no signs of inflammation. Conclusion. Using a nonhuman primate islet transplant model, RATG plus sirolimus supports islet survival as long as proper sirolimus levels are maintained, but the therapy is limited by sirolimus toxicity. Our findings suggest that RATG is not toxic for islets and thus may be considered in future clinical trails while recognizing that sirolimus monotherapy, with its difficult‐to‐achieve therapeutic dosing, may not be sufficient to maintain long‐term islet allograft function in an autoimmune environment.

Metastatic involvement of a retrieved inferior vena cava filter.

Editor: Tumor cells were found in nests within soft tissue adherent to a percutaneously retrieved Gunther Tulip inferior vena cava (IVC) filter (Cook, Bloomington, IN) in a 19-year-old man with metastatic osteosarcoma of the left lower extremity following a limb-sparing operation. The filter was in place for 14 days as prophylaxis for recurrent perioperative pulmonary emboli from a known distal superficial femoral deep vein thrombosis. Pathology favors hematogenous showering of metastatic cells during surgery, and the lack of tumor growth within the vessels suggests that direct tumor extension or bulk tumor embolism are unlikely. This unexpected finding (Figure) despite normal angiography is concerning. Preremoval imaging or angiography may not detect clinically silent small caval thromboses. The safety of IVC filters in patients with cancer with potential hematogenous spread is questionable. Filter retrieval might shower tumor emboli during manipulation, and a filter may act as a nidus for local neoplastic growth. Caval thrombosis is a known complication of permanent filters, but the incidence of tumor thrombus is unknown. Figure The tightly adherent fragmentary tissue was scraped off the filter struts, fixed in formalin, and stained with hema-toxylin and eosin. Adherent to the filter is a dense fibrosis with clusters of tumor cells in nests. The tumor cells are pleomorphic in ... Despite more than three decades of clinical use, controversy remains regarding indications for IVC filters (1). We acknowledge the existence of a consensus on several basic and sound indications (2). Although many authorities would disagree, our interpretation is that no true consensus exists among specialists regarding other indications for IVC filter placement. There are only a few randomized controlled trials assessing efficacy and safety (3). Most of the publications are retrospective studies and case reports. Study limitations include heterogeneities among patient populations, inclusion and exclusion criteria, evaluation criteria, and follow-up methodology. There are 150,000 deaths per year from venous thromboembolism, with 30,000–40,000 IVC filters inserted each year in the United States (4). Comprehensive, retrospective, multicenter statistical analysis could be facilitated by a national filter registry or a consensus conference. In the past decade, there have been multiple studies on various temporary retrievable IVC filter devices, addressing feasibility and safety of retrieval for up to 134 days (5). These emerging devices have already further broadened the nebulous inclusion criteria spectrum, and practice patterns are changing as a result. Liberal interpretation of the indications for filters could include patient populations that were traditionally excluded from filter placement. Unfortunately, filter placement has become common practice for a wide variety of unproven indications, despite the paucity of safety and efficacy data. Appropriate validation of indications for temporary retrievable IVC filters needs to be developed. Practice patterns for temporary retrievable IVC filters may represent a dangerous situation in which nonvalidated clinical practice outpaces hypothesis-driven scientific method.