William C. Chapman

Research from JAMA Surgery — Effective Control of Hepatic Bleeding With a Novel Collagen-Based Composite Combined With Autologous Plasma — Results of a Randomized Controlled Trial

To compare the effects of 35% hepatic cryoablation with a similar degree of radiofrequency ablation (RFA) on lung inflammation, nuclear factor κB (NF-κB) activation, and production of NF-κB dependent cytokines. Multisystem injury, including acute lung injury, is a severe complication associated with hepatic cryoablation of 30% to 35% or more of liver parenchyma, but this complication has not been reported with RFA. Sprague-Dawley rats underwent 35% hepatic cryoablation or RFA and were killed at 1, 2, and 6 hours. Liver and lung tissue were freeze-clamped for measurement of NF-κB activation, which was detected by electrophoretic mobility shift assay. Serum concentrations of tumor necrosis factor α and macrophage inflammatory protein 2 were measured by enzyme-linked immunosorbent assay. Histologic studies of pulmonary tissue and electron microscopy of ablated liver tissue were compared among treatment groups. Histologic lung sections after cryoablation showed multiple foci of perivenular inflammation, with activated lymphocytes, foamy macrophages, and neutrophils. In animals undergoing RFA, inflammatory foci were not present. NF-κB activation was detected at 1 hour in both liver and lung tissue samples of animals undergoing cryoablation but not after RFA, and serum cytokine levels were significantly elevated in cryoablation versus RFA animals. Electron microscopy of cryoablation-treated liver tissue demonstrated disruption of the hepatocyte plasma membrane with extension of intact hepatocyte organelles into the space of Disse; RFA-treated liver tissue demonstrated coagulative destruction of hepatocyte organelles within an intact plasma membrane. To determine the stimulus for systemic inflammation, rats treated with cryoablation had either immediate resection of the ablated segment or delayed resection after a 15-minute thawing interval. Immediate resection of the cryoablated liver tissue prevented NF-κB activation and lung injury; however, pulmonary inflammatory changes were present when as little as a 15-minute thaw interval preceded hepatic resection. Hepatic cryoablation, but not RFA, induces NF-κB activation in the nonablated liver and lung and is associated with acute lung injury. Lung inflammation is associated with the thawing phase of cryoablation and may be related to soluble mediator(s) released from the cryoablated tissue. These findings correlate the clinical observation of an increased incidence of multisystem injury, including adult respiratory distress syndrome (ARDS), after cryoablation but not RFA.

This study had two purposes: to optimize the semiquantitative interpretation of 18F-fluorodeoxyglucose (FDG) PET scans in the diagnosis of pancreatic carcinoma by analyzing different cutoff levels for the standardized uptake value (SUV), with and without correction for serum glucose level (SUV(gluc)); and to evaluate the usefulness of FDG PET when used in addition to CT for the staging and management of patients with pancreatic cancer. Sixty-five patients who presented with suspected pancreatic carcinoma underwent whole-body FDG PET in addition to CT imaging. The PET images were analyzed visually and semiquantitatively using the SUV and SUV(gluc). The final diagnosis was obtained by pathologic (n = 56) or clinical and radiologic follow-up (n = 9). The performance of CT and PET at different cutoff levels of SUV was determined, and the impact of FDG PET in addition to CT on patient management was reviewed retrospectively. Fifty-two patients had proven pancreatic carcinoma, whereas 13 had benign lesions, including chronic pancreatitis (n = 10), benign biliary stricture (n = 1), pancreatic complex cyst (n = 1) and no pancreatic pathology (n = 1). Areas under receiver operating characteristic curves were not significantly different for SUV and SUV(gluc). Using a cutoff level of 3.0 for the SUV, FDG PET had higher sensitivity and specificity than CT in correctly diagnosing pancreatic carcinoma (92% and 85% versus 65% and 61%). There were 2 false-positive PET (chronic pancreatitis, also false-positive with CT) and 4 false-negative PET (all with true-positive CT, abnormal but nondiagnostic) examinations. There were 5 false-positive CT (4 chronic pancreatitis and 1 pancreatic cyst) and 18 false-negative CT (all with true-positive FDG PET scans) examinations. FDG PET clarified indeterminate hepatic lesions or identified additional distant metastases (or both) in 7 patients compared with CT. Overall, FDG PET altered the management of 28 of 65 patients (43%). FDG PET is more accurate than CT in the detection of primary tumors and in the clarification and identification of hepatic and distant metastases. The optimal cutoff value of FDG uptake to differentiate benign from malignant pancreatic lesions was 2.0. Correction for serum glucose did not significantly improve the accuracy of FDG PET. Although FDG PET cannot replace CT in defining local tumor extension, the application of FDG PET in addition to CT alters the management in up to 43% of patients with suspected pancreatic cancer.

THE ANATOMICAL location of hepatic tumors is usually determined preoperatively using tomographic imaging (computed tomography [CT] or magnetic resonance imaging [MRI]). This allows critical assessment of tumor resectability and assists in operative planning. However, this preoperative information at present cannot be actively used during surgery to guide resections and probe placements for ablative therapies (eg, cryoablation or radiofrequency ablation). Intraoperative ultrasonography (IOUS) can provide intraoperative imaging information regarding tumor location and surrounding vascular anatomy,¹ but it requires special expertise to perform and to interpret properly. In addition, there are the following inherent technical limitations regarding its use for operative guidance in hepatic procedures: it is 2-dimensional in its present format; there can be significant interuser variation in results; and image obliteration occurs after resection or ablative therapy is initiated.

Hepatocellular carcinoma (HCC) in Western populations historically has been associated with poor survival. In this study, we conducted a 7-year retrospective analysis of patients evaluated at our institution with HCC to determine the effects of newer treatment strategies on outcome. During the period of study, 117 patients [86 (74%) male; mean age, 59 years (range, 16-85)] were evaluated with treatment as follows: surgical resection in 22 (19%), chemoembolization with or without systemic chemotherapy in 40 (35%), systemic treatment alone in 16 (13%), orthotopic liver transplantation in 8 (7%), and supportive care only in 31 (26%). Sixty-nine patients (59%) had documented cirrhosis, with hepatitis C being the most common cause in 27 of 69 (39%). In patients receiving no treatment, median survival was just under 3 months, with only two 1-year survivors. Patients with orthotopic liver transplantation had 1-, 2-, and 3-year survival rates of 87, 87, and 58 per cent compared with 69, 52, and 43 per cent in surgically resected patients. Survival after chemoembolization was 35, 20, and 11 per cent at 1, 2, and 3 years, whereas survival after systemic chemotherapy was 30 and 15 per cent at 1 and 2 years, respectively. One-year survival was improved in noncirrhotic patients compared with cirrhotics (47% vs 29%; P < 0.05) but was no different in patients younger than 55 years compared with older patients (38% vs 38%). When possible, surgical treatment strategies offer superior survival.

Bronchobiliary fistula is an uncommon but remarkable complication after hepatic resection. The case reported illustrates the clinical presentation and preferred initial management of these fistulae. A 61-year-old white male underwent two wedge resections for colorectal metastases to the liver with removal of a portion of the right diaphragm. Four years later, he developed obstructive jaundice secondary to tumor recurrence in the porta hepatis, which required endoscopic stent placement, radiation, and chemotherapy. Almost 2 years later, he developed frank biliptysis. Percutaneous transhepatic cholangiography (PTC) revealed occlusion of the common hepatic duct stent and a bronchobiliary fistula. With adequate reestablishment of common duct drainage, the patient rapidly improved and was discharged free of symptoms. Bronchobiliary fistulae are rare complications of hepatic resection that can present from days to years after operation. Endoscopic retrograde cholangiopancreatography and PTC are the diagnostic studies of choice and offer the possibility of therapeutic intervention. Although large series in the literature emphasize the surgical management of bronchobiliary fistulae, the reoperative procedures tend to be complicated, with a significant morbidity and mortality. Nonsurgical interventions via endoscopic retrograde cholangiopancreatography or PTC are more recently notably successful when resolution of a distal biliary obstruction is accomplished. Only after aggressive attempts at nonoperative, interventional techniques have failed should operative approaches be entertained.

The formation of gallstones around surgical clips after cholecystectomy is a rare complication, with only seven reported cases in the English literature since its initial description in 1979. Three other cases report clip migration into the common bile duct and obstruction. We report a recent experience with "clip cholelithiasis." A 78-year-old female, 16 years following cholecystectomy, presented with a several-month history of colicky abdominal pain worsened by meals, and a 1 week history of jaundice, anorexia, nausea, and vomiting. An abdominal ultrasound demonstrated dilatation of the biliary tree without visible choledocholithiasis. Endoscopic retrograde cholangiopancreatography demonstrated a 1.5-cm radiolucent stone in the common bile duct containing a central surgical clip. She was successfully treated with endoscopic sphincterotomy and stone retrieval. The first report of clip cholelithiasis occurred in 1979. Six additional cases have been reported as well as three cases of clip migration without stone formation into the common bile duct. The incidence of clip cholelithiasis may increase in frequency with the increased use of metallic clips during laparoscopic cholecystectomy. The occurrence of cholelithiasis around inert metals is rare and may be prevented using absorbable clips; however, stone formation is also reported around absorbable materials.

There are reports that suggest cryosurgical techniques may be a useful adjunct or even a viable alternative to surgical resection for hepatobiliary malignancies. Our objective was to evaluate the clinical results following cryoablation in conjunction with surgical resection for advanced hepatic tumors. Cryosurgical techniques were used in 25 consecutive patients with advanced liver tumors (1) to achieve a > 1-cm tumor-free margin when standard surgical margins were close, (2) to manage multiple tumor nodules with or without standard surgical resection, or (3) to increase chemotherapy response rates in conjunction with hepatic arterial portocath placement. In these 25 patients cryoablation was applied to 44 of 91 lesions--independently in four patients and in combination with hepatic resection in 21 patients. Cryoablation was used in seven patients because of close surgical margins. In 18 patients cryosurgery was used for complete lesion ablation. In 14 of the 18 patients cryosurgery and resection were used for different lesions; in four cryosurgery alone was used. Transient changes in hepatic enzymes, PT, PTT, and platelets were at maximum on postoperative days 1 to 3. Surgical mortality and morbidity rates were 4% and 68% respectively. Coagulation abnormalities were common; at least 30% reduction in platelets occurred in all patients and a > 50% reduction occurred in 15 of 25 (60%). Sixteen patients had a PT > 15 sec and five of these 16 also had platelet count < 50,000. Associated complications included one wound hematoma, one GI hemorrhage, one intracranial hemorrhage, and one hepatic hemorrhage from the cryosurgical site. 96%, 66%, 49%, 35%, and 20% of patients were surviving respectively at 6, 12, 18, 24, and 36 months. This report helps define the risks and results of cryosurgical ablation in conjunction with surgical resection for very advanced hepatobiliary tumors. Management of lesions contiguous to major blood vessels can include the Pringle maneuver or total hepatic vascular isolation. Cryoablation can be applied carefully as a complement to resection to achieve total tumor ablation in selected otherwise unresectable patients.

We compared results using Neoral versus Sandimmune, each in combination with steroid and azathioprine immunosuppression, in primary liver transplantation recipients. There were 15 patients in each group with similar demographic distributions. Intravenous cyclosporine was stopped at 4.3 +/- 1.9 days in the Neoral group vs 7.8 +/- 4.9 days in the Sandimmune group. (P < 0.025). Cyclosporine levels in the first 10 days were higher (mean 306 ng/ml vs 231 ng/ml) in the Neoral group than the Sandimmune group (P < 0.05). The Neoral dose was less than the Sandimmune dose (mean 5.5 ng/kg per day vs 7.9 ng/kg per day) to achieve these levels in that time period (P < 0.05). Two patients (13%) experienced three episodes of biopsy-proven rejection in the Neoral group compared to nine patients (60%) with 12 episodes of rejection in the Sandimmune group (P < 0.025). Incidences of neurological and renal complications were similar between the groups. Infections requiring treatment were also similar. Liver function, renal function, and marrow function, evaluated at days 7, 14, 21, 28, and 2, 4, 6, and 12 months post-transplant, were not different between the groups. In summary, shorter use of intravenous cyclosporine and quicker stabilization of trough cyclosporine levels was achieved with Neoral than with Sandimmune. In the early post-transplant period, higher levels with lower doses were achieved with Neoral than with Sandimmune. In our experience, the incidence of rejection was lower with Neoral than with Sandimmune. There were similar lengths of hospitalization, mortality, adverse events, retransplantation, and similar liver, renal, and marrow function up to 1 year post-transplantation. Because of this experience, we continued to use Neoral in a total of 59 primary liver transplant recipients. We have not used intravenous cyclosporine in the last 44 patients. Follow-up was a mean of 11.4 months, ranging from 1 to 27 months. The incidence of rejection was 24% in these 59 patients compared to our historical experience of 70% using Sandimmune.