Kevin P. Charpentier

Irreversible electroporation of the liver and liver hilum in swine

BACKGROUND Irreversible electroporation (IRE) is a novel, non-thermal form of ablation. We studied the safety and efficacy of IRE for the ablation of liver tissue around the liver hilum. We also studied the ability of triphenyltetrazolium chloride staining (TTC) to predict the zone of ablation after IRE. METHODS Eight swine underwent 20 ablations of the liver and liver hilum. Two monopolar probes were positioned 2 cm apart. IRE was performed using 90 pulses of 2500-3000 V/cm. IRE treatments were performed from 15 min to 14 days (n= 4) before sacrifice. RESULTS All animals survived. No major complications were encountered. Ablation width ranged from 2.27 to 4.45 cm and ablation height ranged from 1.5 to 1.8 cm. TTC staining demonstrated the zone of ablation in all animals. Hepatocyte necrosis occurs immediately adjacent to large central veins without evidence of heat sink. Bile ducts, portal veins and hepatic arteries appear to be more resistant to the effects of IRE. CONCLUSIONS IRE appears to be safe and effective for liver tissue ablation in the liver hilum. The portal structures appear more resistant to the effects of IRE. TTC staining can predict the zone of IRE ablation as early as 15 min after treatment.

Irreversible electroporation of the pancreas in swine: a pilot study.

BACKGROUND Irreversible electroporation (IRE) is a novel, non-thermal method of tissue ablation using short pulses of high-voltage DC current to ablate tissue. METHODS Irreversible electroporation of the pancreas was performed in four domestic female swine using two monopolar probes spaced 9-15 mm apart. Ninety pulses of 1500 V/cm were delivered for each ablation. RESULTS All animals survived for their designated times of 2 h (n = 1), 2 days (n = 1) and 14 days (n = 2), respectively. No procedure-related complications occurred. Three animals in which probes had been spaced at intervals of 10 ± 1 mm showed evidence of irreversible ablation, with ablation height ranging from < 10 mm to 21 mm and ablation width ranging from < 10 mm to 16 mm by gross appearance and triphenyltetrazolium chloride (TTC) staining. The only animal in which probes had been spaced at intervals of 15 mm did not show evidence of irreversible ablation at 2 weeks. This may be secondary to the wider probe spacing and relatively low voltage, which results in a mostly reversible form of electroporation without cell death. CONCLUSIONS Irreversible electroporation appears to be a safe method for pancreas tissue ablation. Staining with TTC can predict the zone of IRE ablation within 2 h of treatment.

Irreversible Electroporation for the Ablation of Liver Tumors: Are We There Yet?

OBJECTIVE To explore irreversible electroporation (IRE) as a novel, nonthermal form of tissue ablation using high-voltage electrical current to induce pores in the lipid bilayer of cells, resulting in cell death. DATA SOURCES PubMed searches were performed using the keywords electroporation, IRE, and ablation. The abstracts for the 2012 meetings of both the American Hepato-Pancreato-Biliary Association and the Society for Interventional Radiology were also searched. All articles and abstracts with any reference to electroporation were identified and reviewed. STUDY SELECTION All studies and abstracts pertaining to electroporation. DATA EXTRACTION All data pertaining to the safety and efficacy of IRE were extracted from preclinical and clinical studies. Preclinical data detailing the theory and design of IRE systems were also extracted. DATA SYNTHESIS Preclinical studies have suggested that IRE may have advantages over conventional forms of thermal tumor ablation including no heat sink effect and preservation of the acellular elements of tissue, resulting in less unwanted collateral damage. The early clinical experience with IRE demonstrates safety for the ablation of human liver tumors. Short-term data regarding oncologic outcome is now emerging and appears encouraging. CONCLUSION Irreversible electroporation is likely to fill a niche void for the ablation of small liver tumors abutting a major vascular structure and for ablation of tumors abutting a major portal pedicle where heat sink and collateral damage must be avoided for maximum efficacy and safety. Studies are still needed to define the short-term and long-term oncologic efficacy of IRE.

A new indication for pancreas transplantation: high grade pancreatic dysplasia

Abstract:  A 42‐yr‐old male presented with a family history of pancreatic carcinoma inherited an autosomal dominant pattern. The development of endocrine and exocrine pancreatic insufficiency served as early markers for neoplastic transformation. Screening endoscopic ultrasound and ERCP showed abnormalities suggestive of pancreatic dysplasia. Total pancreatectomy was performed and pathology confirmed carcinoma in situ, also known as high‐grade pancreatic ductal dysplasia or Pan IN‐3. The patients post‐operative course was complicated by life threatening, brittle diabetes. Pancreas transplantation was successfully performed. One year following transplantation, the patient has excellent pancreas graft function. He remains insulin free and has no signs of malignancy. Total pancreatectomy followed by pancreas transplantation is a viable therapeutic option for patients in the dysplastic but still pre‐malignant phase of familial pancreatic adenocarcinoma who develop hypoglycemic unawareness following total pancreatectomy.

Lapatinib and gemcitabine for metastatic pancreatic cancer. A phase II study.

Purpose: To determine the overall survival for patients with metastatic pancreatic cancer treated with lapatinib and gemcitabine. Materials and Methods: Patients with metastatic pancreatic cancer received lapatinib, 1,500 mg/d, and Gemcitabine, 1 g/m2/wk for 3 weeks followed by 1 week off, until disease progression. This multicenter phase II study was planned to enter 125 patients to evaluate whether the treatment regimen could achieve a 1-year survival of 30% and a median survival of 7 months. An additional subset of 20 patients were to receive 2 months of single agent lapatinib followed by lapatinib and gemcitabine. Results: At a planned 6 month analysis, the Brown University Oncology Group Data Safety Monitoring Board terminated accrual after 29 patients because of futility analysis. The median survival was 4 months (95% confidence interval, 3.0–5.0 months). Three of the 29 (10%) patients had a partial response. The 4 patients who received single agent lapatinib all progressed at 1 month. Conclusion: Lapatinib is not effective in pancreatic cancer. Evaluation of HER2 inhibitors in pancreatic cancer is not warranted.

Unexpected surgical difficulties leading to hemorrhage and gas embolus during laparoscopic donor nephrectomy: a case report

PurposeTo report the case of a laparoscopic donor nephrectomy in which the preoperative evaluation of the patient gave no indication of the surgical difficulties that were encountered intraoperatively, resulting in substantial bleeding, a suspected gas embolism, and emergency conversion of the procedure from laparoscopic to open donor nephrectomy.Clinical featuresA 59-yr-old man - height: 175 cm, weight: 85.5 kg, American Society of Anesthesiologists physical status I - presented as kidney donor for laparoscopic donor nephrectomy. He was healthy, on no medication, and had no previous abdominal surgery or diseases of the urinary tract. The preoperative computed tomography (CT) scan evaluation of his kidneys confirmed this by reporting a normal bilateral renal and renal vascular anatomy. In contradiction to the preoperative CT scan findings, the surgeon discovered abnormalities in the operative field. This included extensive scarring surrounding the left kidney, adenopathy near the right hilum, and a large branch lumbar vein entering the renal vein. The large branch lumbar vein was clipped but the clips dislodged, causing significant blood loss, and a suspected gas embolus. The procedure was converted to an emergency open donor nephrectomy. Postoperatively the patient made a full recovery.ConclusionLaparoscopic donor nephrectomies, though usually performed on healthy individuals, have their pitfalls, and complications during this procedure can be sudden and serious. As shown in this case, although CT scan results are regarded as reliable, they can be misleading. As an anesthetic precaution for possible gas emboli during laparoscopic procedures, nitrous oxide should be avoided and the patient be ventilated with 100% oxygen.RésuméObjectifPrésenter le cas d’une néphrectomie laparoscopique chez un donneur, Lévaluation préopératoire du patient n’avait donné aucune indication des difficultés chirurgicales peropératoires rencontrées qui ont causé un important saignement, une embolie gazeuse probable et la conversion d’urgence de la technique laparoscopique en néphrectomie ouverte.Éléments cliniquesUn homme de 59 ans, 175 cm, 85,5 kg et d’état physique ASA I, s’est présenté comme donneur de rein pour une néphrectomie laparoscopique. Il était en bonne santé, ne prenait aucun médicament et n’avait pas d’antécédent chirurgical abdominal ou de maladies des voies urinaires. L’évaluation préopératoire par tomodensitométrie des reins a confirmé la situation en montrant une anatomie rénale et vasculaire rénale normale bilatérale. Pourtant, le chirurgien a découvert des anomalies au niveau du site opératoire. Elles comprenaient une cicatrisation importante autour du rein gauche, des adénopathies près du hile droit et un grand rameau de la veine lombaire pénétrant dans la veine rénale. Ce rameau a été clippé, mais les clips se sont détachés, ce qui a provoqué une perte de sang significative et une embolie gazeuse probable. La laparoscopie a été convertie en néphrectomie ouverte d’urgence. Le patient s’est complètement rétabli par la suite.ConclusionLes néphrectomies laparoscopiques chez les donneurs d’organes, quoique réalisées habituellement chez des personnes en bonne santé, ont aussi leurs pièges. Les complications qui peuvent survenir sont parfois soudaines et critiques. Comme ce cas le montre, même les résultats de la tomodensitométrie, considérés comme fables, peuvent être trompeurs. Le protoxyde d’azote devrait être évité et le patient ventilé avec de l’oxygène à 100% afin de prévenir une possible embolie gazeuse pendant les interventions chirurgicales laparoscopiques.

Microwave ablation of focal hepatic malignancies regardless of size: A 9-year retrospective study of 64 patients

PURPOSE To retrospectively evaluate the safety and efficacy of microwave ablation (MWA) as treatment for single, focal hepatic malignancies. MATERIALS AND METHODS Institutional review board approval was obtained for this HIPAA-compliant study. From December 2003 to May 2012, 64 patients were treated with MWA for a single hepatic lesion, in 64 sessions. Hepatocellular carcinoma (HCC) was treated in 25 patients (geometric mean tumor size, 3.33-cm; 95% CI, 2.65-4.18-cm; range, 1.0-12.0-cm), metastatic colorectal cancer (CRC) was treated in 27 patients (geometric mean tumor size, 2.7-cm; 95% CI, 2.20-3.40-cm; range, 0.8-6.0-cm), and other histological-types were treated in 12 patients (geometric mean tumor size, 3.79-cm; 95% CI, 2.72-5.26-cm; range, 1.7-8.0-cm). Kaplan-Meier (K-M) method was used to analyze time event data. Chi-square and correlation evaluated the relationship between tumor size and treatment parameters. RESULTS Technical success rate was 95.3% (61/64). Treatment parameters were tailored to tumor size; as size increased more antennae were used (p<0.001), treatment with multiple activations increased (p<0.028), and treatment time increased (p<0.001). There was no statistically significant relationship between time to recurrence and tumor size, number of activations, number of antennae, and treatment time. At one-year, K-M analysis predicted a likelihood of local recurrence of 39.8% in HCC patients, 45.7% in CRC metastases patients, and 70.8% in patients with other metastases. Median cancer specific survivals for patients were 38.3 months for HCC patients, 36.3 months for CRC metastases, and 13.9 months for other histological-types. Complications occurred in 23.4% (15/64) of sessions. CONCLUSION In our sample, tumor size did not appear to impact complete ablation rates or local recurrence rates for focal hepatic malignancies treated with MWA.

Lenalidomide for second-line treatment of advanced hepatocellular cancer: a Brown University oncology group phase II study.

Purpose:To assess the activity and toxicity of lenalidomide for patients with advanced hepatocellular cancer (HCC) previously treated with sorafenib. Materials and Methods:Patients with advanced HCC who progressed on or were intolerant to sorafenib were eligible. Patients received lenalidomide 25 mg orally for 1 to 21 days in a 28-day cycle until disease progression or unacceptable toxicities. Results:Forty patients were enrolled and were classified according to the Child-Pugh score: 19 were Child-Pugh A, 16 patients were Child-Pugh B, and 5 were Child-Pugh C. Seventeen patients had extrahepatic disease. Grade 4 neutropenia occurred in 1 of 40 patients (2.5%). Grade 3 fatigue (n=3) and rash (n=4) were the most common nonhematologic toxicities attributable to lenalidomide. Six of 40 patients (15%) had a partial response. Two patients (5%) have not progressed at 36 and 32 months. The median progression-free survival was 3.6 months and the median overall survival was 7.6 months. Conclusions:Lenalidomide can be administered to patients with advanced HCC and hepatic dysfunction. Promising, and in a small percentage of patients, durable activity has been demonstrated. Investigations are needed to explore the mechanism of action of lenalidomide in HCC.

Tumor progression-related transmembrane protein aspartate-β-hydroxylase is a target for immunotherapy of hepatocellular carcinoma

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) has a poor survival rate due to recurrent intrahepatic metastases and lack of effective adjuvant therapy. Aspartate-β-hydroxylase (ASPH) is an attractive cellular target since it is a highly conserved transmembrane protein overexpressed in both murine and human HCC tumors, and promotes a malignant phenotype as characterized by enhanced tumor cell migration and invasion. METHODS Dendritic cells (DCs), expanded and isolated from the spleen, were incubated with a cytokine cocktail to optimize IL-12 secretion and co-stimulatory molecule expression, then subsequently loaded with ASPH protein for immunization. Mice were injected with syngeneic BNL HCC tumor cells followed by subcutaneous inoculation with 5-10×10(5) ASPH loaded DCs using a prophylactic and therapeutic experimental approach. Tumor infiltrating lymphocytes (TILs) were characterized, and their role in producing anti-tumor effects determined. The immunogenicity of ASPH protein with respect to activating antigen specific CD4+ T cells derived from human peripheral blood mononuclear cells (PBMCs) was also explored. RESULTS We found that immunotherapy with ASPH-loaded DCs suppressed and delayed established HCC and tumor growth when administered prophylactically. Ex-vivo re-stimulation experiments and in vivo depletion studies demonstrated that both CD4+ and CD8+ cells contributed to anti-tumor effects. Using PBMCs derived from healthy volunteers and HCC patients, we showed that ASPH stimulation led to significant development of antigen-specific CD4+ T-cells. CONCLUSIONS Immunization with ASPH-loaded DCs has substantial anti-tumor effects which could reduce the risk of HCC recurrence.

Removing Patients from the Liver Transplant Wait List : A Survey of US Liver Transplant Programs

Guidelines are in place regarding who is a candidate for liver transplantation. Once a potential candidate is listed, there are no uniform guidelines indicating when he should be removed from the list because of a change in clinical status. A survey with 14 scenarios was sent to the medical and surgical directors of all liver transplant programs in the United States. In each scenario, clinical information was provided about a patient active on the transplant wait list. Data regarding a clinical change were provided, and responders were questioned whether they would remove the patient from the wait list. The scenarios were designed to address the issues of age, etiology of liver disease, renal dysfunction, respiratory failure, infection, failure to thrive, and social support. Two hundred four questionnaires were mailed with 47 responses (23%): 8 return to sender, 24 surgeons, and 15 hepatologists. All 11 United Network for Organ Sharing regions were represented. The responders were well distributed among university programs (n = 28), private practice programs (n = 10), and health maintenance organization programs (n = 1). Nine responses were from small‐volume programs (≤25 transplants), 12 were from medium‐volume programs (26–50 transplants), and 18 were from large‐volume programs (≥51 transplants). There was wide variability between responders regarding which patients should be removed from the transplant wait list. Patient age and etiology of liver disease led to the greatest discordance among responders. In conclusion, there is a lack of agreement and standardization among US liver transplant programs regarding who should be removed from the wait list for a change in clinical status. Liver Transpl 14:303–307, 2008.