Charles H. Scudamore

Radiofrequency ablation of porcine liver in vivo: effects of blood flow and treatment time on lesion size.

OBJECTIVE To determine, in vivo, the effect of radiofrequency ablation (RFA) treatment time and tissue blood flow on the size and shape of the resulting necrotic lesion in porcine liver. SUMMARY BACKGROUND DATA Radiofrequency ablation is an electrosurgical technique that uses a high frequency alternating current to heat tissues to the point of desiccation (thermal coagulation). Radiofrequency ablation is well established as the treatment of choice for many symptomatic cardiac arrhythmias because of its ability to create localized necrotic lesions in the cardiac conducting system. Until recently, a major limitation of RFA was the small lesion size created by this technique. Development of bipolar and multiple-electrode RFA probes has enabled the creation of larger lesions and therefore has expanded the potential clinical applications of RFA, which includes the treatment of liver tumors. A basic understanding of factors that influence RFA lesion size in vivo is critical to the success of this treatment modality. The optimal RFA technique, which maximizes liver lesion size, has yet to be determined. Theoretically, lesion size varies directly with time of application of the RF current, and inversely with blood flow, but these relationships have not been previously studied in the liver. METHODS Six animals underwent hepatic RFA (460 kHz), for 5, 7.5, 10, 12.5, 15, and 20 minutes. Identical, predetermined anatomic areas of the liver were ablated in each animal. Two additional animals underwent 12 RFA treatments -- 6 with vascular inflow occlusion (Pringle maneuver) and 6 with uninterrupted hepatic blood flow. Animals were euthanized and the livers were removed for gross pathologic examination. All lesions were measured in three dimensions and photographed. Tissues were examined by routine histology and by histochemistry to determine viability. RESULTS Increasing duration of RFA application from 5 through 20 minutes did not create lesions of larger diameter, but this time increase did predict deeper lesion production (beta = 0.34, p = 0.04). A range of lesion shapes were created from four separate ovals (corresponding to each electrode), to larger ovals intersecting to form a cross, to spheroid lesions. The number of blood vessels in close proximity to the probe tip (within a 1-cm radius from the center of the lesion) strongly predicted minimum lesion diameter (beta = -0.61, p = 0.0001) and lesion volume (beta = -0.56, p = 0.0004). This negative effect of blood flow on lesion size was confirmed experimentally. Radiofrequency ablation lesions created during a Pringle maneuver were significantly larger in all three dimensions than lesions created without a Pringle maneuver: minimum diameter was 3.0 cm (with Pringle) versus 1.2 cm (p = 0.002), maximum diameter was 4.5 cm (with Pringle) versus 3.1 cm (p = 0.002), depth was 4.8 cm (with Pringle) versus 3.1 cm (p < 0.001), and lesion volume was 35.0 cm3 (with Pringle) versus 6.5 cm3 (p < 0.001). CONCLUSIONS Blood flow is a strong predictor of all RFA lesion dimensions in porcine liver in vivo, whereas a change of treatment time from 5 to 20 minutes is predictive only of lesion depth, but not diameter or volume.

Indocyanine green clearance as a predictor of successful hepatic resection in cirrhotic patients.

Twenty-two cirrhotic patients who underwent hepatic resection from July 1989 to March 1991 at Vancouver General Hospital were analyzed prospectively in order to determine whether there was any preoperative evaluation of liver function that would help identify those patients who would not survive hepatic resection. Patients were analyzed on the basis of age, type of resection, and a variety of so-called standard liver function tests. In addition, all patients were evaluated preoperatively with an indocyanine green (ICG) clearance test, a relatively new test that we attempted to evaluate in terms of its role in hepatic resection in cirrhotic patients. Parametric statistical evaluation used included Students t-test and multivariate regression, as well as discriminate analysis. The nonparametric evaluation used was the Wilcoxon rank sum test. Overall, the 30-day mortality rate was 18%, with those patients who did not survive resection having a significantly lower ICG clearance than those who underwent successful resection (p less than 0.0001). No other liver function test was useful in determining the outcome of resection. Similarly, neither age nor type of resection appeared to influence outcome. Use of discriminate analysis (p = 0.0029) allowed the identification of a cutoff point for ICG clearance below which hepatic resection should not be attempted.

Pathophysiology of apolipoprotein E deficiency in mice: relevance to apo E-related disorders in humans

Apolipoprotein E (apo E) deficiency (or its abnormalities in humans) is associated with a series of pathological conditions including dyslipidemia, atherosclerosis, Alzheimers disease, and shorter life span. The purpose of this study was to characterize these conditions in apo E‐deficient C57BL/6J mice and relate them to human disorders. Deletion of apo E gene in mice is associated with changes in lipoprotein metabolism [plasma total cholesterol (TC) (>+400%), HDL cholesterol (‐80%), HDL/TC, and HDL/LDL ratios (‐93% and ‐96%, respectively), esterification rate in apo B‐depleted plasma (+ 100%), plasma triglyceride (+200%), hepatic HMG‐CoA reductase activity (‐50%), hepatic cholesterol content (+30%)], decreased plasma homocyst(e)ine and glucose levels, and severe atherosclerosis and cutaneous xanthomatosis. Hepatic and lipoprotein lipase activities, hepatic LDL receptor function, and organ antioxidant capacity remain unchanged. Several histological/immunohistological stainings failed to detect potential markers for neurodegenerative disease in the brain of 37‐wk‐old male apo E‐KO mice. Apo E‐KO mice may have normal growth and development, but advanced atherosclerosis and xanthomatosis may indirectly reduce their life span. Apo E plays a crucial role in regulation of lipid metabolism and atherogene‐sis without affecting lipase activities, endogenous anti‐oxidant capacity, or appearance of neurodegenerative markers in 37‐wk‐old male mice.—Moghadasian M. H., McManus B. M., Nguyen, L. B., Shefer, S., Nadji M., Godin D. V., Green, T. J., Hill, J., Yang, Y., Scud‐amore C. H., Frohlich J. J. Pathophysiology of apoli‐poprotein E deficiency in mice: relevance to apo E‐related disorders in humans. FASEB J. 15, 2623–2630 (2001)

Evaluation of renal function in liver transplant recipients receiving daclizumab (Zenapax), mycophenolate mofetil, and a delayed, low-dose tacrolimus regimen vs. a standard-dose tacrolimus and mycophenolate mofetil regimen: A multicenter randomized clinical trial

Posttransplant chronic renal failure, secondary to calcineurin inhibitor agents, is emerging as a major problem in liver transplantation. We report a randomized clinical trial comparing daclizumab, delayed low‐dose tacrolimus (target trough level 4‐8 ng/mL, starting day 4‐6), Investigational Arm (n = 72), to standard tacrolimus induction/maintenance dosing, Standard Arm (n = 76), with mycophenolate mofetil and tapering corticosteroids in both study arms. The end‐points were renal function indicated by the Modification of Diet in Renal Disease (MDRD). There was no significant difference in patient survival (86.6% Investigational Arm vs. 92.9% Standard Arm; P = 0.21) or acute rejection (23.2% vs. 27.7%, respectively; P = 0.68). Statistically significant differences in median glomerular filtration rate (GFR) were found in favor of the Investigational Arm. With the CG equation, the GFR at the end of the first week was 110.7 vs. 89.6 mL/min (P = 0.019) without significant differences thereafter. With the MDRD, statistically significant differences extended to the first posttransplant month (86.8 vs. 70.1 mL/min/1.73 m2; P < 0.001) with and was seen at month 6 (75.4 vs. 69.5 mL/min/1.73 m2; P = 0.038). In conclusion, delayed low‐dose tacrolimus, in combination with daclizumab and mycophenolate mofetil, preserves early renal function post–liver transplantation without the cost of increased acute rejection. (Liver Transpl 2005;11:1064–1072.)

Typhlitis: Selective surgical management

Typhlitis is a neutropenic enterocolitis of varying severity. Its incidence is increasing, particularly in patients with acute myelogenous leukemia undergoing high dose cytosine arabinoside chemotherapy. The onset is heralded by prodromal fever, watery or bloody diarrhea, abdominal distension, and nausea during the phase of severe neutropenia. The symptoms may then localize to the right lower quadrant with an associated increase in systemic toxicity. The diagnosis can be confirmed in these and other less specific cases by serial reexamination and abdominal radiographs, ultrasonography, computerized tomograms, or radionucleotide scans. The mainstay of management is complete bowel rest with nasogastric suction and total parenteral nutrition. Broad-spectrum combination antibiotics are essential, as is the avoidance of laxatives or antidiarrheal agents. Granulocyte support may be helpful. Patients with a history of nonspecific gastrointestinal complaints or of true typhlitis, successfully managed nonoperatively, should have prophylactic bowel rest and total parenteral nutrition instituted at the beginning of further chemotherapy. Patients with ongoing severe systemic sepsis who do not respond to chemotherapy and those with overt perforation, obstruction, massive hemorrhage, or abscess formation require surgical intervention. All necrotic material must be resected, usually by a right hemicolectomy, ileostomy, and mucous fistula. Divided ileostomy for less severe cases may be useful. Failure to remove the necrotic focus in these severely immunocompromised patients is fatal. With adequate recognition of typhlitis and its precipitating factors, the incidence of complications can be reduced through prevention and timely surgical intervention. Although typhlitis developed in a quarter of our acute myeloblastic leukemia patients, use of this combined approach was successful in all cases.

Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) overexpression in pancreatic ductal adenocarcinoma correlates with poor survival

BackgroundPancreatic ductal adenocarcinoma is a lethal disease with a 5-year survival rate of 4% and typically presents in an advanced stage. In this setting, prognostic markers identifying the more agrressive tumors could aid in managment decisions. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3, also known as IMP3 or KOC) is an oncofetal RNA-binding protein that regulates targets such as insulin-like growth factor-2 (IGF-2) and ACTB (beta-actin).MethodsWe evaluated the expression of IGF2BP3 by immunohistochemistry using a tissue microarray of 127 pancreatic ductal adenocarcinomas with tumor grade 1, 2 and 3 according to WHO criteria, and the prognostic value of IGF2BP3 expression.ResultsIGF2BP3 was found to be selectively overexpressed in pancreatic ductal adenocarcinoma tissues but not in benign pancreatic tissues. Nine (38%) patient samples of tumor grade 1 (n = 24) and 27 (44%) of tumor grade 2 (n = 61) showed expression of IGF2BP3. The highest rate of expression was seen in poorly differentiated specimen (grade 3, n = 42) with 26 (62%) positive samples. Overall survival was found to be significantly shorter in patients with IGF2BP3 expressing tumors (P = 0.024; RR 2.3, 95% CI 1.2-4.8).ConclusionsOur data suggest that IGF2BP3 overexpression identifies a subset of pancreatic ductal adenocarcinomas with an extremely poor outcome and supports the rationale for developing therapies to target the IGF pathway in this cancer.

Surgeons' anonymous response after bile duct injury during cholecystectomy.

BACKGROUND Bile duct injuries remain one of the most devastating injuries during laparoscopic cholecystectomy. Few studies target surgeons who have experienced bile duct injuries for their insight, their perspective, and their suggestions concerning this problem. METHODS A confidential questionnaire was sent to all practicing general surgeons under the age of 65 years in British Columbia, Canada. RESULTS Seventy-five percent of surgeons responded to the survey. Of the 114 questionnaires completed, more than 97% of respondents had completed formal training in laparoscopic cholecystectomy. One half of surgeons reported experience with laparoscopic bile duct injury. A significant difference in years in practice between surgeons with injury and surgeons without injury was noted. The majority of injuries occurred after the surgeonss first 100 cholecystectomies performed. The first thoughts of surgeons after injury uniformly concerned the patients well being. The next most common thoughts were in relation to obtaining help or a second opinion from another surgeon. Surgeons cited inflammation and short or anomalous cystic ducts as the most responsible factors contributing to injury. The majority of surgeons felt that these injuries are unavoidable and less than half felt that it was always a surgical error. Fewer than 15% thought injuries could be avoided by performing a cholangiogram. Surgeons suggested meticulous dissection and less haste to divide structures may prevent an injury. Surgeons recommend educating colleagues to remove the stigma of failure associated with conversion to laparotomy. CONCLUSIONS General surgeons in British Columbia have a one in two chance of experiencing a bile duct injury in their career. There were more injuries in surgeons who had already been in practice for 10 years at the time of introduction of laparoscopic cholecystectomy. The injuries are likely to occur despite high volumes of procedures and increased experience. The incidence of bile duct injuries does not seem to be different in surgeons who perform routine cholangiography and most surgeons feel that cholangiography would have little effect on injury incidence. Surgeons tend to have patient-centered concerns after injury and little concern for medicolegal issues. The majority of surgeons felt that these injuries could not be anticipated and as such it is an inherent risk of this procedure.

Predictors of relapse to significant alcohol drinking after liver transplantation

BACKGROUND End-stage alcoholic liver disease is common, with many of these patients referred for liver transplantation (LT). Alcohol relapse after LT can have detrimental outcomes such as graft loss and can contribute to a negative public perception of LT. OBJECTIVE To identify factors that predict the recurrence of harmful alcohol consumption after LT. METHODS A total of 80 patients who underwent LT for alcoholic cirrhosis or had significant alcohol consumption in association with another primary liver disease, from July 1992 to June 2006 in British Columbia, were retrospectively evaluated by chart review. Several demographic-, psychosocial- and addiction-related variables were studied. Univariate and multivariate logistic regression analyses were used to test possible associations among the variables studied and a return to harmful drinking after LT. RESULTS The relapse rate of harmful alcohol consumption post-liver transplant was 10%, with two patient deaths occurring directly as a result of alcohol relapse. Univariate analysis revealed relapse was significantly associated with pretransplant abstinence of less than six months (P=0.003), presence of psychiatric comorbidities (P=0.016), female sex (P=0.019) and increased personal stressors (P=0.044), while age at transplant of younger than 50 years approached significance (P=0.054). Multivariate logistic regression analysis revealed the following independent factors for relapse: pretransplant abstinence of less than six months (OR 77.07; standard error 1.743; P=0.013) and female sex (OR 18.80; standard error 1.451; P=0.043). CONCLUSION The findings of the present study strongly support a required minimum of six months of abstinence before LT because duration of abstinence was found to be the strongest predictor of recidivism. Female sex, younger age at transplant and psychiatric comorbidities were also associated with relapse to harmful drinking.

Surgical management of choledochal cysts.

Choledochal cysts are an unusual cause of biliary obstruction with up to 85% of reported cases being of the type I variety, that is, fusiform dilations of the common bile duct. Recommended management of this type I cyst is complete surgical excision; however, difficulties arise in type IVa cysts when the cystic dilation extends up into the intrahepatic biliary tree. The purpose of this study is to review the management of choledochal cysts with particular reference to the type IVa variety. Statistical analysis of outcome differences was undertaken using Fishers exact test. A total of 23 consecutive patients with choledochal cysts seen at our institution in a 5-year period were reviewed: 8 patients had type I cysts, 1 patient had a type III cyst, and 14 patients had type IVa cysts. All type I cysts underwent complete cyst excision with hepaticojejunostomy and modified Houston loop formation. Of 14 patients with type IVa cysts, 13 underwent complete excision of the extrahepatic portion of the cyst with hepatico- and cystojejunostomy and modified Hutson loop formation. One patient required hepatic lobectomy. With a mean follow-up of 33 months, 4 patients with type IVa choledochal cyst have had episodes of recurrent cholangitis, with access to the library tree being achieved via the Hutson loop in 3 of the 4 patients. Three of these cases represented anastomotic strictures that were treated nonoperatively. We concluded that recurrent cholangitis and anastomotic stricture after resection of type IVa choledochal cysts is frequent and recommend Hutson loop formation at the time of primary resection.

Choledochal cysts: analysis of disease pattern and optimal treatment in adult and paediatric patients

BACKGROUND Choledochal cysts are dilations of the biliary tree. Although commonly reported in Asian populations, the incidence outside of Asia is as low as 1:150 000. The largest series of patients with choledochal cyst disease outside of Asia is this one, studying 70 patients treated in Vancouver between 1971 and 2003. PATIENTS AND METHODS This was a retrospective chart review. RESULTS In all, 19 paediatric and 51 adult patients were evaluated; 21% of paediatric and 25% of adult patients were Asian. All paediatric patients had type I or IV cysts, whereas adult patients represented the different subtypes. Abdominal pain was the presenting symptom in 79% of children and 88% of adults, vomiting was present in 42% of children and 63% of adults and jaundice was seen in 31.5% of children and 39% of adults. Ultrasound was used in 94.7% of children, and ERCP in 80% of adults. In all, 84% of paediatric patients, 100% of adult patients with type I cysts and 85.7% of adult patients with type IV cysts received complete cyst excision and Roux-en-Y hepaticojejunostomy. Complications in both groups were low. CONCLUSIONS Although Vancouver does have a large Asian population, this does not explain how common choledochal cysts are in this city. Although some authors argue that paediatric and adult disease are caused by different aetiologies, presentation patterns in our study between the two groups were very similar. We recommend complete cyst excision and Roux-en-Y hepaticojejunostomy as the surgery of choice, and advocate early surgery after diagnosis to promote ease of surgery and prevention of future complications.