Search

Background: In the US, systemic chemotherapy is often administered after liver resection for hepatic colorectal metastases, even though no clinical trials data directly support this practice. The bias in America for chemotherapeutic treatment has made studies difficult. Until recently, no well accepted staging systems existed to categorize these patients with liver metastases, who have greatly varied prognoses., Study Design: All liver resections from an American and from a European tertiary care center performed between 1991 and 1998 were assembled from two prospective databases. Of 792 liver resections, the 518 patients treated with no chemotherapy (379 American, 139 European) were compared with 274 patients treated (240 American, 34 European) with 5-FU-based adjuvant chemotherapy. Patients treated by all other treatment regimens, including regional chemotherapy, were excluded, as were patients who died perioperatively. Patient survival analysis was performed by log-rank, with stratification by the clinical risk score (CRS, a staging system grading risk of recurrence by five clinical parameters: node-positive primary, short disease-free interval, large (> 5 cm) liver tumor, multiple liver tumors, and high carcinoembryonic antigen)., Results: Patients subjected to adjuvant chemotherapy had improved survival (p=0.007, log-rank test) even after stratification by clinical risk score (p=0.001, stratified log-rank test). In every clinical risk score category, patients subjected to adjuvant chemotherapy had a higher chance of survival (range 1.3 to 2.0 times). Adjuvant chemotherapy was an independent predictor of outcomes., Conclusions: This large study, with patients stratified by risk of recurrence, demonstrates that systemic adjuvant chemotherapy, such as a 5-FU-based regimen, prolongs survival after hepatic resection for colorectal metastases.

Background: The authors evaluated the impact of bland particle embolization on survival in patients with metastatic sarcoma to the liver., Methods: Twenty-four patients with liver-dominant metastases from sarcoma were treated with particle embolization from 1996 to 2002. Primary tumors included 16 gastrointestinal stromal tumors (GISTs), 7 intestinal leiomyosarcomas, and 1 liposarcoma. Thirteen patients had known extrahepatic disease. Embolization was performed by using polyvinyl alcohol or trisacryl microspheres to effect stasis in the target vessel(s). Follow-up images to assess response were obtained 4 weeks after the procedure. Decrease in the size of the target lesion by >25% or development of >50% necrosis on follow-up imaging was considered a treatment response., Results: Nineteen patients had metachronous liver metastases, and the median disease-free interval was 22 months (range 10-156 months) from resection of the primary tumor. Ten patients underwent prior liver resection for metastatic disease. Of 15 evaluable patients, 9 patients (60%) had a radiographic response. The median follow-up for all patients was 21 months. The median follow-up for surviving patients was 59 months. Overall survival from the time of initial embolization was 62% at 1 year, 41% at 2 years, and 29% at 3 years. Patients who had radiographic evidence of response survived significantly longer than patients who did not respond (63 months vs. 19 months; P < .007). Patients with GIST survived significantly longer than patients with visceral leiomyosarcoma (median, 36 months vs. 18 months; P < .03)., Conclusions: Bland embolization was efficacious in some patients with metastatic sarcoma to the liver. Radiographic evidence of response was correlated with improved survival. This regional therapy may enter the treatment algorithm for patients who have unresectable disease or disease that has failed conventional therapies., ((c) 2006 American Cancer Society.)

Objective: To define a group of patients with pancreatic cysts who do not require resection., Summary Background Data: The increased use of cross-sectional imaging has resulted in an increased identification of small, asymptomatic pancreatic cysts. Data have not been available to determine which lesions should be resected., Methods: All patients evaluated at our institution between January 1995 and January 2005 for the ICD-9 diagnosis of pancreatic cyst were reviewed. Analysis was performed to identify associations between patient and cyst characteristics, and selection of operative or nonoperative management., Results: Pancreatic cysts were evaluated in 539 patients. Initial management was operative in 170 patients (32%), and nonoperative (radiographic follow-up) in 369 patients (68%). Factors associated with initial operative management included presence of a solid component (45% vs. 6%, P < 0.001), larger size of the lesion (mean 4.8 cm vs. 2.4 cm, P = 0.001), and presence of symptoms (44% vs. 16%, P = 0.001). Malignancy was present in 18% (32 of 170) of patients initially resected. Mucinous tumors (n = 18) were the most common malignant histologic subtype. None of the invasive cancers arising from mucinous cysts was <3 cm. Median radiographic follow-up in patients initially managed nonoperatively was 24 months (range, 1-172 months). In 29 patients (8%), changes developed within the cyst that resulted in resection; malignancy was present in 11 of 39 (38%), representing 3% (11 of 369) of all patients being followed radiographically., Conclusions: Selected patients with cystic lesions <3 cm in diameter and without a solid component may be followed radiographically with a malignancy risk (3% this study) that approximates the risk of mortality from resection. Malignancy within mucinous tumors is associated with size, and small mucinous tumors are very unlikely to be malignant.

This article evaluates the available evidence for the efficacy of combined liver and lung metastasectomy. In addition, selection criteria identifying patients most likely to benefit from this approach are discussed. Surgery offers the only possibility for prolonged survival and is occasionally curative.

Background: Nontraumatic inflammatory hilar strictures are uncommon, but are known to mimic malignancy. This study examines the clinical and pathologic features of benign idiopathic strictures., Study Design: Patients without a history of trauma or earlier biliary operation treated for benign strictures were identified. Clinical information was obtained from the medical record and all resected specimens were reexamined., Results: From January 1992 to July 2003, 275 patients with proximal biliary strictures were referred. Among these, 22 patients had a final histologic diagnosis of benign stricture, despite a suspected preoperative diagnosis of malignancy. All 22 patients underwent resection of the extrahepatic biliary tree, which in 10 patients was combined with en bloc partial hepatectomy. Histologic reexamination identified five different benign processes: lymphoplasmacytic sclerosing pancreatitis and cholangitis, primary sclerosing cholangitis, granulomatous disease, nonspecific fibrosis/inflammation, and stone disease. Major postoperative morbidity occurred in 6 (26%) patients but none died. No preoperative clinical or radiographic features were identified that could reliably distinguish patients with benign strictures from those with cancer., Conclusions: "Malignant masquerade" of the proximal bile duct results from several different underlying conditions, and differentiating benign strictures from cancer remains problematic. The treatment approach should continue to be resection for presumed malignancy.

Purpose: To determine the maximum-tolerated dose (MTD) of concurrent systemic oxaliplatin (Oxal) combinations plus hepatic arterial infusion (HAI) in patients with unresectable hepatic metastases from colorectal cancer., Patients and Methods: Thirty-six patients (89% previously treated) with unresectable liver metastases were treated with concurrent HAI and systemic Oxal plus irinotecan (CPT-11; group A) or Oxal, fluorouracil (FU), and leucovorin (LV; group B). Systemic chemotherapy was administered every 2 weeks concurrent with 2 weeks of HAI floxuridine (FUDR) and dexamethasone (Dex) every 28 days., Results: The MTD for patients in group A was Oxal 100 mg/m(2), CPT-11 150 mg/m(2), and FUDR 0.12 mg/kg x 30 mL divided by pump flow rate. The MTD for group B was Oxal 100 mg/m(2), LV 400 mg/m(2), and FU 1,400 mg/m(2) by continuous infusion over 48 hours, with the same FUDR dose as in group A. Grade 3 or 4 toxicities in groups A and B included diarrhea (24% and 20%), neutropenia (10% and 7%), neurotoxicity (24% and 20%), and bilirubin more than 3 mg/mL (5% and 7%, respectively). The complete and partial response rate totaled 90% for group A and 87% for group B. Median survival time was 36 and 22 months for groups A and B, respectively. Seven patients in group A were ultimately able to undergo liver resection., Conclusion: Combination therapy with HAI FUDR and Dex plus systemic Oxal combinations may be safely administered to patients with colorectal cancer. The high response rate (88%) and the possibility of conversion to resectability, despite disease progression on prior systemic regimens, suggest that these combinations should be evaluated in larger studies as first- or second-line therapy in patients with hepatic metastases from colorectal cancer.

Purpose: The vast majority of hepatocellular carcinomas (HCC) occur in patients with underlying liver dysfunction, making surgical resection available to only a subset of patients with adequate hepatic reserve. This study analyzes the authors' results with bland arterial embolization combined with radiofrequency ablation (RFA) or percutaneous ethanol injection (PEIT) compared with surgical resection for the treatment of solitary HCC up to 7 cm in size., Materials and Methods: A retrospective review of all patients undergoing either surgical resection or bland embolization combined with local ablation for solitary HCC between January 1996 and August 2002 was performed. Progression-free survival rate and overall survival rate were calculated by the Kaplan-Meier method., Results: There were 40 patients who underwent surgical resection and 33 patients who underwent embolization and ablation. Age, gender, and size of the treated lesion were not significantly different between the groups. The embolization/ablation group had more patients classified as Okuda stage II (P<.001). The surgical group had a longer median recurrence-free survival rate (53.1 vs 25.1 months). With a median follow-up of 23 months, the 1-, 3- and 5-year actuarial overall survival rates were 97%, 77%, and 56% for the embolization/ablation group and 81%, 70%, and 58% for the surgical group, respectively. There was no statistical difference in overall survival rates (P=.20)., Conclusions: Bland arterial embolization in combination with ablation is effective in treating solitary HCC lesions up to 7 cm and achieves similar overall survival rates to surgical resection in selected patients.

Objective: To determine the impact of the incorporation of extensive upper abdominal debulking procedures on the rates of optimal primary cytoreduction and complications in stages IIIC and IV epithelial ovarian, fallopian tube, and primary peritoneal carcinomas., Methods: Two groups of patients were identified for comparison. Group 1, the control group, consisted of 70 consecutive patients who underwent "standard" primary cytoreductive surgery before May 2000. Group 2, the study group, was composed of 70 consecutive patients who underwent surgery after January 2001, during which time, a more comprehensive debulking of upper abdominal disease was used, including diaphragm stripping/resection, splenectomy, distal pancreatectomy, liver resection, resection of porta hepatis tumor, and cholecystectomy., Results: The median age of the entire cohort was 60 years (range, 36-88 years). The majority had stage IIIC disease (86%) and serous histology (76%). Optimal cytoreduction (residual disease

Segment-oriented liver resection is a distinct surgical approach and represents the virtuosity of hepatic surgery. It is unique in the finesse of its execution and in its oncologic efficacy and safety. The varied combinations of segmentectomy allow greater flexibility and opportunity for liver surgeons to extirpate the equally diverse nature and location of intrahepatic pathologic conditions. The technique promotes tumor clearance while con-serving uninvolved parenchyma.

Background: Patients with hepatocellular carcinoma (HCC) are frequently found to be inoperable at surgical exploration. Laparoscopy may reduce the rate of unnecessary laparotomy in these patients. However, there are no criteria for selective use of laparoscopy., Methods: Sixty patients with potentially operable HCC underwent laparoscopy prior to planned partial hepatectomy. Intraoperative findings and postoperative course were analyzed, and factors for the selective use of laparoscopy were identified., Results: Fourteen of 19 inoperable patients (74%) were identified by means of laparoscopy, which increased the resectability rate from 68% to 89%. Compared with patients undergoing exploratory laparotomy only, patients determined to be inoperable on laparoscopy had significantly less intraoperative blood loss, a shorter operating room time, and a briefer hospital stay. In a multivariate analysis, clinically apparent liver cirrhosis and radiologic evidence of major vascular invasion or bilobar tumors predicted the likelihood of finding inoperable disease at laparoscopy. The initial use of laparoscopy avoided unnecessary laparotomy in almost 30% of patients with-but only 5% of patients without-these features., Conclusions: If high-risk patients with HCC are selectively targeted, the yield of laparoscopy is increased and unnecessary laparotomy may be avoided. In patients without cirrhosis, major vascular invasion, or bilobar tumors, the yield of laparoscopy is low and is therefore not generally recommended.

Background: The optimal surgical strategy for the treatment of synchronous resectable colorectal liver metastasis has not been defined. The aims of this study were to review our experience with synchronous colorectal metastasis and to define the safety of simultaneous versus staged resection of the colon and liver., Study Design: From September 1984 through November 2001, 240 patients were treated surgically for primary adenocarcinoma of the large bowel and synchronous hepatic metastasis. Clinicopathologic, operative, and perioperative data were reviewed to evaluate selection criteria, operative methods, and perioperative outcomes., Results: One hundred thirty-four patients underwent simultaneous resection of a colorectal primary and hepatic metastasis in a single operation (Group I), and 106 patients underwent staged operations (Group II). Simultaneous resections tend to be performed for right colon primaries (p < 0.001), smaller (p < 0.01) and fewer (p < 0.001) liver metastases, and less extensive liver resection (p < 0.001). Complications were less common in the simultaneous resection group, with 65 patients (49%) sustaining 142 complications, compared with 71 patients (67%) sustaining 197 complications for both hospitalizations in the staged resection group (p < 0.003). Patients having simultaneous resection required fewer days in the hospital (median 10 days versus 18 days, p = 0.001). Perioperative mortality was similar (simultaneous, n = 3; staged, n = 3)., Conclusions: Simultaneous colon and liver resection is safe and efficient in the treatment of patients with colorectal cancer and synchronous liver metastasis. By avoiding a second laparotomy, the overall complication rate is reduced, with no change in operative mortality. Given its reduced morbidity, shorter treatment time, and similar cancer outcomes, simultaneous resection should be considered a safe option in patients with resectable synchronous colorectal metastasis.

Objective: This study was designed to determine the effectiveness of magnetic resonance cholangiopancreatography (MRCP) using a breath-hold single-shot fast spin echo (SSFSE) technique in imaging patients with malignant biliary and/or pancreatic duct obstruction., Methods: One hundred thirty-one breath-hold MRCP studies in patients with malignant pancreatic and/or biliary obstruction were evaluated. Pathologic diagnoses included pancreatic cancer, biliary malignancy, gallbladder carcinoma, hepatic neoplasms, malignant lymphadenopathy, and ampullary carcinoma. Two observers independently reviewed the images in a blinded fashion to assess the level of obstruction and the site of underlying tumor., Results: The level of obstruction was correctly identified in 104 of 131 cases (79%) by observer 1 and in 107 of 131 cases (82%) by observer 2. The site of underlying tumor was correctly identified in 113 of 131 cases (86%) by observer 1 and in 110 of 131 cases (84%) by observer 2., Conclusion: Magnetic resonance cholangiopancreatography utilizing the SSFSE technique can accurately assess the level of obstruction and the site of underlying tumor in patients with malignant pancreaticobiliary obstruction, without the risks of cholangiography. This MRCP technique allows for visualization of intra- and extraductal anatomy and pathology.

Dendritic cells initiate the immune response by presenting antigen in the context of varying levels of costimulation. The maturation state of the dendritic cell determines the quantity and quality (Th1, Th2) of the subsequent T cell response. Members of the NF-kappaB family of transcription factors have previously been implicated in dendritic cell development. Here, we used a mouse with a homozygous c-Rel deletion to investigate the role of c-Rel in the function of bone marrow derived dendritic cells. When direct presentation was evaluated, we found c-Rel(-/-) dendritic cells induce less allogeneic T cell stimulation than c-Rel(+/+) dendritic cells. In addition, T cell encounters with c-Rel(-/-) dendritic cells generate less IFN-gamma and IL-4 when compared to those with c-Rel(+/+) DCs. A similar degree of functional compromise was observed in antigen-specific T cells that were stimulated by c-Rel(-/-) dendritic cells. Functional deficits were not linked to differences in the ability to undergo maturation per se, as LPS exposure induced similar morphologic and cell surface changes in both c-Rel(+/+) and cRel(-/-) DCs. Although LPS induced a compensatory increase in the nuclear activity of fellow NF-kappaB family members, RelB and p65, LPS exposure was unable to negate the deficiencies in autologous T cell proliferation and cytokine production associated with the loss of c-Rel in dendritic cells. Taken together, our study supports a unique and non-redundant role for c-Rel in dendritic cell costimulatory capacity.

Background: Patients with potentially resectable hepatobiliary malignancy are frequently found to have unresectable tumors at laparotomy. We prospectively evaluated staging laparoscopy in patients with resectable disease on preoperative imaging., Methods: Staging laparoscopy was performed on 410 patients with potentially resectable hepatobiliary malignancy. The preoperative likelihood of resectability was recorded. Data on preoperative imaging, operative findings, and hospital course were analyzed., Results: Laparoscopic inspection was complete in 291 (73%) patients. In total, 153 patients (38%) had unresectable disease, 84 of whom were identified laparoscopically, increasing resectability from 62% to 78%. On multivariate analysis, a complete examination, preoperative likelihood of resection, and primary diagnosis were significant predictors of identifying unresectable disease at laparoscopy. The highest yield was for biliary cancers, and the lowest was for metastatic colorectal cancer. In patients with unresectable disease identified at laparoscopy, the mean hospital stay was 3 days, and postoperative morbidity was 9%, compared with 8 days and 27%, respectively, in patients found to have unresectable disease at laparotomy., Conclusions: Laparoscopy spared one in five patients a laparotomy while reducing hospital stay and morbidity. Targeting laparoscopy to patients at high risk for unresectable disease requires consideration of disease-specific factors; however, the surgeons' preoperative impression of resectability is also important.

The purpose of this study was to compare the treatment and outcome in patients referred for staged resection of synchronous colorectal liver metastases. The records of patients who had undergone colon or rectal resection and were then referred for evaluation of clinically resectable synchronous liver metastases between January 1995 and January 2000 were reviewed. Comparisons were made between patients who did not receive neoadjuvant chemotherapy and had exploratory operations after recovery from colon resection and patients who did receive chemotherapy before liver resection. A total of 106 patients were treated during the 5-year period. Neoadjuvant chemotherapy was given to 52 of the patients; in 29 of them the disease did not progress, but in 17 patients the disease progressed while they were receiving treatment. Median follow-up was 30 months. Patient- and tumor-related variables were similar between groups. Five-year survival was statistically similar between patients who did and those who did not receive neoadjuvant chemotherapy (43% vs. 35%, P = 0.49). Patients within the neoadjuvant group whose disease did not progress while they were receiving chemotherapy experienced significantly improved survival as compared to patients who did not receive chemotherapy (85% vs. 35%, P = 0.03). In the setting of synchronous colorectal liver metastases, the response to neoadjuvant chemotherapy may be a prognostic indicator of survival and may assist in the selection of patients for conventional or experimental adjuvant therapies., (Copyright 2003 The Society for Surgery of the Alimentary Tract, Inc.)

Background: It was hypothesized that routine operative drainage is unnecessary for elective hepatic resection., Methods: A review was made of the clinical records of patients undergoing liver resection at a tertiary referral hepatobiliary surgery center since the conclusion in April of 1994 of our previous randomized drainage trial. The main outcome measures were operative drainage versus no operative drainage assessed for possible association with diagnoses, extent of hepatectomy, hospital course, and postoperative radiologic percutaneous drainage procedures., Results: Of 1,165 patients, 184 were operatively drained with closed drains according to specific practice criteria and 981 were not subject to operative drainage. Patients who were not operatively drained had length of stay (10.1 days), mortality (2%), and complication rate (34%) comparable with the nondrained patients in the previous randomized trial. Ten percent of these patients required postoperative percutaneous drainage. Patients who were operatively drained were a group who were at higher risk for biliary leakage or infections and consequently had a significantly longer hospital stay, greater mortality, higher complication rate, and required a greater number of percutaneous abdominal drainages., Conclusions: The 84% of patients not operatively drained had no greater adverse outcome. After hepatic resection, routine drainage of the abdomen is unnecessary.

Objective: To determine the value of repeat liver resection for recurrent colorectal metastases to the liver., Summary Background Data: Liver resection represents the best and a potentially curative treatment for metastatic colorectal cancer to the liver. After resection, however, most patients develop recurrent disease, often isolated to the liver., Methods: This study reports the combined experience of repeat liver resection for recurrent liver metastases at an American and a European surgical oncology center. Patients were identified from prospective databases and records were retrospectively reviewed. A total of 126 patients (American n = 96, 1986-2001; European n = 30, 1985-1999) underwent repeat liver resection. Patient characteristics were similar in the two institutions. Median follow-up from first liver resection was 88 and 105 months, respectively., Results: Operations performed included 90 minor resections and 36 resections of a lobe or more. The 1-, 3-, and 5-year survival rates were 86%, 51%, and 34%. There were 19 actual 5-year survivors to date. By multivariate regression analysis (proportional hazard model), more than one lesion and tumor size larger than 5 cm were independent prognostic indicators of reduced survival. The interval between the first and second liver resection was not predictive of outcome., Conclusions: Repeat liver resection for colorectal liver metastases is safe. Patients with a low tumor load are the best candidates for a repeat resection. In well-selected patients, further resection of the liver can provide prolonged survival after recurrence of colorectal liver metastases.

Background: Carefully selected patients with noncolorectal, nonneuroendocrine (NCNN) liver metastases may benefit from hepatic resection. The incidence of occult unresectable disease and the possible benefits of staging laparoscopy in these patients are not known., Methods: From December 1997 to July 2000, staging laparoscopy was performed in 30 consecutive patients with NCNN metastases before planned open exploration and resection. Demographics, extent of preoperative imaging, operative and postoperative findings, and factors associated with laparoscopic identification of unresectable disease were analyzed., Results: Twenty-four patients (80%) had a complete laparoscopic examination, and 23 had laparoscopic ultrasonography. All patients underwent preoperative computed tomography or magnetic resonance imaging, and 21 (70%) patients had 2 or more preoperative radiological studies. Overall, nine patients had unresectable disease, six of whom were identified by laparoscopy. Of the remaining 24 patients believed to have resectable disease at laparoscopy, 21 went on to a potentially curative procedure. Laparoscopy did not identify irresectability because of vascular involvement in three patients. Laparoscopy added a median of 30 minutes of operative time to those patients going on to laparotomy., Conclusions: Laparoscopy identified the majority of patients with occult unresectable disease, improved resectability, and should be routine in patients being considered for potentially curative hepatic resection.

Background: Evaluation of peritoneal cytology provides valuable staging information in patients with gastric and pancreatic adenocarcinoma, but its usefulness in patients with extrahepatic cholangiocarcinoma is unclear. The aim of this study was to evaluate the predictive value of peritoneal cytology in patients with potentially resectable hilar cholangiocarcinoma. This study evaluated a possible association between positive peritoneal cytology and percutaneous transhepatic biliary drainage, which is commonly used in these patients and may result in peritoneal biliary leakage and peritoneal seeding., Study Design: From October 1997 through June 2000 26 patients with hilar cholangiocarcinoma underwent staging laparoscopy immediately before planned open exploration and resection. Peritoneal washings were obtained during laparoscopic examination before any biopsies were taken. Cytologic analysis was performed using the Papanicolau technique., Results: There were 18 men and 8 women, with a median age of 69 years (range 42 to 81 years). The most common presenting symptom was jaundice (n = 19). Previous biliary drainage was performed in 23 patients: 9 percutaneous and 14 endoscopic. Metastatic disease was suspected preoperatively in six patients, three to the liver, two to the peritoneum, and one to regional lymph nodes, all of which were confirmed at laparoscopy. Laparoscopy identified five additional patients with metastatic disease. Peritoneal cytology was positive for malignant cells in two patients, both of whom had gross peritoneal metastases. Nine other patients had metastatic disease to distant sites within the abdomen, but none had positive cytology. Overall, six patients had metastatic disease to the peritoneal cavity, only one of whom had undergone earlier percutaneous biliary drainage., Conclusions: Peritoneal cytology was not predictive of occult metastatic disease. Laparoscopic staging identified some patients with unresectable hilar cholangiocarcinoma, but analysis of peritoneal cytology provided no additional information. There was no association between percutaneous transhepatic biliary drainage and peritoneal tumor seeding.

Intrahepatic recurrence is common after major resection for colorectal cancer (CRC) metastases to the liver. In this review, the available data on different adjuvant therapies from systemic chemotherapy to regional approaches by direct perfusion of chemotherapeutic agents via the hepatic artery and portal vein will be discussed. Intraperitoneal administration of chemotherapy is another form of regional therapy. Novel approaches with immunotherapy and trials of neoadjuvant therapy in association with resection of CRC hepatic metastases have also been reported. The purpose of this review is to outline these various strategies and their role in combination with resection of CRC liver metastases. Although improved hepatic disease-free survival has been demonstrated with some strategies, overall survival is minimally affected and recurrence of metastatic disease at distant sites is still a major problem. Therefore, future directions should incorporate the use of new systemic agents effective against CRC metastases. Identification of subgroups through clinical features, molecular markers, proteins, or specific tumor properties may also help to individualize treatment.

Objective: To evaluate the outcome of patients with liver metastases from sarcoma who underwent hepatic resection at a single institution and were followed up prospectively., Summary Background Data: The value of hepatic resection for metastatic sarcoma is unknown., Methods: There were 331 patients with liver metastases from sarcoma who were admitted to Memorial Hospital from 1982 to 2000, and 56 of them underwent resection of all gross hepatic disease. Patient, tumor, and treatment variables were analyzed to assess outcome., Results: Of the 56 patients who underwent complete resection, 34 (61%) had gastrointestinal stromal tumors or gastrointestinal leiomyosarcomas. Half of the patients required an hepatic lobectomy or extended lobectomy. There were no perioperative deaths in the completely resected group, although 3 of the 75 patients who underwent exploration (4%) died. The postoperative 1-, 3-, and 5-year actuarial survival rates were 88%, 50%, and 30%, respectively, with a median of 39 months. In contrast, the 5-year survival rate of patients who did not undergo complete resection was 4%. On multivariate analysis, a time interval from the primary tumor to the development of liver metastasis greater than 2 years was a significant predictor of survival after hepatectomy., Conclusions: Complete resection of liver metastases from sarcoma in selected patients is associated with prolonged survival. Hepatectomy should be considered when complete gross resection is possible, especially when the time to the development of liver metastasis exceeds 2 years.

Objective: To analyze resectability and survival in patients with hilar cholangiocarcinoma according to a proposed preoperative staging scheme that fully integrates local, tumor-related factors., Summary Background Data: In patients with hilar cholangiocarcinoma, long-term survival depends critically on complete tumor resection. The current staging systems ignore factors related to local tumor extent, preclude accurate preoperative disease assessment, and correlate poorly with resectability and survival., Methods: Demographics, results of imaging studies, surgical findings, pathology, and survival were analyzed prospectively in consecutive patients. Using data from imaging studies, all patients were placed into one of three stages based on the extent of ductal involvement by tumor, the presence or absence of portal vein compromise, and the presence or absence of hepatic lobar atrophy., Results: From March 1991 through December 2000, 225 patients were evaluated, 77% of whom were seen and treated within the last 6 years. Sixty-five patients had unresectable disease; 160 patients underwent exploration with curative intent. Eighty patients underwent resection: 62 (78%) had a concomitant hepatic resection and 62 (78%) had an R0 resection (negative histologic margins). Negative histologic margins, concomitant partial hepatectomy, and well-differentiated tumor histology were associated with improved outcome after all resections. However, in patients who underwent an R0 resection, concomitant partial hepatectomy was the only independent predictor of long-term survival. Of the 9 actual 5-year survivors (of 30 at risk), all had a concomitant hepatic resection and none had tumor-involved margins; 3 of these 9 patients remained free of disease at a median follow-up of 88 months. The rates of complications and death after resection were 64% and 10%, respectively. In the 219 patients whose disease could be staged, the proposed system predicted resectability and the likelihood of an R0 resection and correlated with metastatic disease and survival., Conclusion: By taking full account of local tumor extent, the proposed staging system for hilar cholangiocarcinoma accurately predicts resectability, the likelihood of metastatic disease, and survival. Complete resection remains the only therapy that offers the possibility of long-term survival, and hepatic resection is a critical component of the surgical approach.

Intrahepatic cholangiocarcinoma (IHC) is a rare primary hepatic tumor of bile duct origin for which resection is the most effective treatment. But resectability, outcomes after resection, and recurrence patterns have not been well described. Patients with IHC were identified from a prospective database. Demographic data, tumor characteristics, and outcomes were analyzed. From March 1992 to September 2000, 53 patients with hepatic tumors underwent exploration and were found to have pure IHC on pathologic analysis. Patients with mixed hepatocellular and cholangiocarcinoma tumors were excluded. At exploration, 20 patients were unresectable for an overall resectability rate of 62% (33 of 53). Median survival for patients submitted to resection was 37.4 months versus 11.6 months for patients undergoing biopsy only (p = 0.006; median followup for surviving patients, 15.6 months). Actuarial 3-year survival was 55% versus 21%, respectively. Factors predictive of poor survival after resection included vascular invasion (p = 0.0007), histologically positive margin (p = 0.009), or multiple tumors (p = 0.003). After resection, 20 of 33 patients (61%) recurred at a median of 12.4 months. Sites of recurrence included the liver (14), retroperitoneal or hilar nodes (4), lung (4), and bone (2). The median disease-free survival was 19.4 months, with a 3-year disease-free survival rate of 22%. Factors predictive of recurrence were multiple tumors (p = 0.0002), tumor size (p = 0.001), and vascular invasion (p = 0.01). About two-thirds of patients who appeared resectable on preoperative imaging were amenable to curative resection at the time of operation. Although complete resection improved survival, recurrence was common. The majority of recurrences were local or regional, which may help guide future adjuvant therapy strategies.

Background: Previous studies have shown that intraoperative ultrasonography (IOUS) during hepatic resection for malignancy changes the operative plan or identifies occult unresectable disease in a large proportion of patients. This study was undertaken to reassess the yield of IOUS in light of recent improvements in preoperative staging., Study Design: Patients with potentially resectable primary or metastatic hepatic malignancies subjected to exploration, bimanual palpation of the liver, and IOUS were evaluated prospectively. Intraoperative findings were recorded, and preoperative imaging studies were reanalyzed by radiologists blinded to the intraoperative findings. The extent of disease based on preoperative imaging was compared with the intraoperative findings., Results: From October 1997 until November 1998, 111 patients were evaluated. At exploration, a total of 77 new findings or findings different than suggested on the imaging studies were identified in 61 patients (55%), the most common of which was additional hepatic tumors (n = 37). Thirty-five of 77 (45%) new findings were identified by IOUS alone and 10 (13%) by palpation alone; the remainder were identified by both palpation and IOUS. Forty-seven of 61 patients (77%) underwent a complete resection despite new intraoperative findings, with a modification (n = 28) or no change (n = 19) in the planned operation. Twenty-one patients (19%) had new findings identified only on IOUS. Thirteen of these patients underwent resection with no change in the operative plan, six underwent a modified resection and two were considered to have unresectable disease based solely on the findings of IOUS., Conclusions: In patients with hepatic malignancies submitted to a potentially curative resection, new intraoperative findings or findings different than suggested on preoperative imaging studies are common. But resection with no change in the operative plan or a modified resection is still possible in the majority of patients despite such findings. The findings on IOUS alone rarely lead to a change in the operative plan.

Introduction: The present study was undertaken to define the clinical differences between leiomyosarcomas (LMS) occurring within the abdomen and retroperitoneum and gastrointestinal stromal tumors (GIST)., Methods: It was a retrospective, single-institution review of patients treated for intra-abdominal and retroperitoneal GIST and LMS from July 1, 1982 through August 1, 1999., Results: A total of 561 patients, 239 with GIST and 322 with LMS, were identified. Patients with GIST were older, with a median age of 58 years versus 54 years in the LMS group (P < .01). The majority of patients with GIST were male (58%), whereas 68% of LMS patients (excluding gender-specific sites) were female (P < .01). The 5-year disease-specific survival for GIST and LMS were 28% and 29%, respectively. The presentation status and ability to achieve a complete surgical resection were the main independent predictors of outcome for both GIST and LMS. Local and distant recurrence was common in both. The pattern of distant recurrence differed: 50% of all first-site GIST recurrences involved the liver, whereas 30% of all LMS first-site recurrences involved the lungs., Conclusions: Although the two patient populations appear to be distinct, their clinical courses are similar. The pattern of distant spread follows the known patterns of hematogenous dissemination. Complete surgical resection is the cornerstone of treatment for primary GIST and LMS and in selected patients with local and distant recurrence.

Replication-competent, attenuated herpes simplex viruses (HSV) have been demonstrated to be effective oncolytic agents in a variety of malignant tumors. Cytokine gene transfer has also been used as immunomodulatory therapy for cancer. To test the utility of combining these two approaches, two oncolytic HSV vectors (NV1034 and NV1042) were designed to express the murine GM-CSF and murine IL-12 genes, respectively. These cytokine-carrying variants were compared with the analogous non-cytokine-carrying control virus (NV1023) in the treatment of murine SCC VII squamous cell carcinoma. All three viruses demonstrated similar infection efficiency, viral replication, and cytotoxicity in vitro. SCC VII cells infected by NV1034 and NV1042 effectively produced GM-CSF and IL-12, respectively. In an SCC VII subcutaneous flank tumor model in immunocompetent C3H/HeJ mice, intratumoral injection with each virus caused a significant reduction in tumor volume compared with saline injections. The NV1042-treated tumors showed a striking reduction in tumor volume compared with the NV1023- and NV1034-treated tumors. On subsequent rechallenge in the contralateral flank with SCC VII cells, 57% of animals treated with NV1042 failed to develop tumors, in comparison with 14% of animals treated with NV1023 or NV1034, and 0% of naive animals. The increased antitumor efficacy seen with NV1042 in comparison with NV1023 and NV1034 was abrogated by CD4(+) and CD8(+) lymphocyte depletion. NV1042 is a novel, attenuated, oncolytic herpesvirus that effectively expresses IL-12 and elicits a T lymphocyte-mediated antitumor immune response against murine squamous cell carcinoma. Such combined oncolytic and immunomodulatory strategies hold promise in the treatment of cancer.

Background: Extended hepatic resection (more than four liver segments) is a major operative procedure that is associated with significant risk. The purpose of this study was to assess the impact of perioperative variables on in-hospital mortality after extended hepatectomy., Study Design: Consecutive patients who underwent extended hepatic resection were studied. The prognostic value of 29 perioperative variables was evaluated using in-hospital mortality as the endpoint. For each variable, the odds ratio (95% confidence interval) for in-hospital mortality was calculated. Those variables with a lower confidence limit > 1 were considered important risk factors. The population was stratified into categories of patients having the same number of risk factors, and mortality was estimated for each group. These data were used to develop a risk assessment algorithm., Results: There were 14 deaths (6%) in 226 patients. Three preoperative variables (cholangitis, creatinine > 1.3 mg/dL, and total bilirubin > 6 mg/dL) and two operative variables (blood loss > 3 L and vena caval resection) appear to be important factors for in-hospital mortality. The mortality associated with the presence of any two of the five factors was 100% (5 of 5), and the mortality associated with the absence of these factors was 3% (6 of 191)., Conclusions: Perioperative evaluation of patients undergoing extended hepatic resection should include the quantitation of mortality risk factors. The combination of any two factors among preoperative cholangitis, elevated serum creatinine, elevated serum bilirubin, high operative blood loss, and vena cava resection may carry a high mortality risk. These results require prospective validation.

Background: Hepatic resection is potentially curative in selected patients with colorectal metastases. It is a widely held practice that multiple colorectal hepatic metastases are not resected, although outcome after removal of four or more metastases is not well defined., Methods: Patients with four or more colorectal hepatic metastases who submitted to resection were identified from a prospective database. Number of metastases was determined by serial sectioning of the gross specimen at the time of resection. Demographic data, tumor characteristics, complications, and survival were analyzed., Results: From August 1985 to September 1998, 155 patients with four or more metastatic tumors (range 4-20) underwent potentially curative resection by extended hepatectomy (39%), lobectomy (42%), or multiple segmental resections (19%). Operative morbidity and mortality were 26% and 1%, respectively. Actuarial 5-year survival was 23% for the entire group (median = 32 months) and there were 12 actual 5-year survivors. On multivariate analysis, only number of hepatic tumors (P = .005) and the presence of a positive margin (P = .003) were independent predictors of poor survival., Conclusions: Hepatic resection in patients with four or more colorectal metastases can achieve long-term survival although the results are less favorable as the number of tumors increases. Number of hepatic metastases alone should not be used as a sole contraindication to resection, but it is clear that the majority of patients will not be cured after resection of multiple lesions.

Hepatic surgery has emerged over the last three decades and has proven to be a safe and effective treatment for primary and secondary malignancies, as well as for benign diseases of the liver. During the past 10 years, several major advances have been made in 1) surgical technique with the advent of portal pedicle ligation maneuvers and the implementation of mechanical staplers, 2) intraoperative management with the development of low central venous pressure anesthesia, and 3) surgical technology with the innovation of laparoscopy for staging of patients with cancer and performing minimally invasive liver resection. We present a summary of our experience with these advances.

Hepatobiliary neoplasms comprise a significant portion of the worldwide cancer burden. Advances in basic science research have led to rapid progress in our understanding of the molecular events responsible for these dreaded diseases. The genetic changes associated with hepatocellular carcinoma (HCC) have received the most attention. Aflatoxin B1 exposure leads to mutations in the p53 tumor suppressor gene, most commonly a transversion in codon 249 that leads to a substitution of serine for arginine in the p53 protein. Numerous other tumor suppressor genes, oncogenes, and tumor gene pathways are altered in HCC. Hepatitis B virus (HBV) infection is strongly associated with HCC. HBV may cause HCC either directly via the HBV X protein, or indirectly by causing liver inflammation and cirrhosis. Hepatitis C virus (HCV) infection is also associated with HCC. Recent evidence suggests that the HCV core protein may play a role in hepatocarcinogenesis. Several inherited metabolic diseases are associated with HCC. It is likely that these diseases cause HCC indirectly by causing cirrhosis. The molecular pathogenesis of cholangiocarcinoma and gallbladder cancer has not been well defined. However, multiple tumor suppressor genes and oncogenes, including p53 and K-ras, are altered in these tumors. Further molecular characterization of hepatobiliary tumors may lead to earlier diagnosis, better staging, improved treatment planning, and the development of more effective therapies.

Background: Recent innovations in laparoscopic instrumentation make routine resection of solid organs a clinical possibility., Hypothesis: Hand-assisted laparoscopic liver resection is a safe and feasible procedure for solitary cancers requiring removal of 2 segments of liver or less., Design and Patients: Eleven patients with liver tumors deemed technically resectable by laparoscopic techniques were subjected to laparoscopic evaluation and attempted hand-assisted laparoscopic resection between July 1998 and July 1999. During the same period, 230 patients underwent open liver resection., Setting: Tertiary care referral center for liver cancer., Main Outcome Measures: Success of laparoscopic resection, reasons for conversion to open liver resection, blood loss, tumor clearance margin, complications, and length of hospital stay., Results: Five patients underwent successful resection by the hand-assisted laparoscopic technique. Data from the 5 successful cases and the 6 aborted cases are presented to outline the issues and the lessons learned., Conclusions: In selected patients, hand-assisted laparoscopic liver resection can be safely performed and might have potential advantages over traditional liver resection if the tumor is limited to the left lateral segment or is at the margins of the liver.

Hepatic wedge resection for colorectal liver metastasis has been reported to have a high incidence of positive surgical margins. Anatomic segmental resection is now widely practiced, although there are few data comparing segmental and wedge resection in terms of tumor clearance or long-term outcome. There were 267 patients who underwent liver resection for metastatic colorectal cancer between July 1985 and October 1998 at our institution who had either a wedge (n = 119) or segmental (n = 148) resection. Patient, tumor, and treatment data were compared, actuarial survival was determined, and prognostic factors were analyzed. Anatomic segmental resection was associated with similar blood loss, operative time, and complications as wedge resection. Segmental resection had a significantly lower rate of positive margins (2% vs. 16%) compared to wedge hepatectomy (P <0.001). On univariate analysis, segmentectomy resulted in longer survival with a median of 53 months vs. 38 months for wedge hepatectomy (P = 0.015). Preoperative carcinoembryonic antigen level, positive margin of resection, and the presence of extrahepatic disease independently predicted survival on multivariate analysis. Anatomic segmental resection is a safe procedure and is superior to wedge resection as an oncologic operation for colorectal liver metastasis because it results in better tumor clearance and improved survival.

Objective: To analyze the outcome of 200 patients with gastrointestinal stromal tumor (GIST) who were treated at a single institution and followed up prospectively., Summary Background Data: A GIST is a visceral sarcoma that arises from the gastrointestinal tract. Surgical resection is the mainstay of treatment because adjuvant therapy is unproven., Methods: Two hundred patients with malignant GIST were admitted and treated at Memorial Hospital during the past 16 years. Patient, tumor, and treatment variables were analyzed to identify patterns of tumor recurrence and factors that predict survival., Results: Of the 200 patients, 46% had primary disease without metastasis, 47% had metastasis, and 7% had isolated local recurrence. In patients with primary disease who underwent complete resection of gross disease (n = 80), the 5-year actuarial survival rate was 54%, and survival was predicted by tumor size but not microscopic margins of resection. Recurrence of disease after resection was predominantly intraabdominal and involved the original tumor site, peritoneum, and liver., Conclusions: GISTs are uncommon sarcomas. Tumor size predicts disease-specific survival in patients with primary disease who undergo complete gross resection. Tumor recurrence tends to be intraabdominal. Investigational protocols are indicated to reduce the rate of recurrence after resection and to improve the outcome for patients with GIST.

Surgical resection is the mainstay of treatment for malignant liver tumours and offers the only chance of cure. Advances in radiological imaging, surgical technique and peri-operative management have enabled liver resection to be performed safely. Partial hepatectomy is indicated for the treatment of hepatocellular carcinoma and hepatic metastases from colorectal cancer. In addition, it may be utilized for selected patients with liver metastases from other primary tumours. Total hepatectomy with transplantation may be of benefit in some patients with unresectable neuroendocrine metastases or small hepatocellular carcinomas. The role of cryosurgery has not been precisely defined, and it needs to be compared with other palliative therapies such as ethanol injection and hepatic artery embolization.

Improvements in imaging have markedly improved the ability to detect hepatobiliary masses. The radiologic features of a lesion when considered in the context of the medical history, physical findings, and laboratory data can often provide a diagnosis. Investigative modalities can accurately stage hepatobiliary tumors and determine their resectability so that the patient may be offered appropriate therapeutic interventions. This article summarizes the essential imaging techniques and their application to common hepatobiliary neoplasms.

Background: Adenoviral gene therapy is a promising new approach for the treatment of neoplastic diseases. To design rational clinical trials and distinguish the effects of therapeutic transgene expression from those caused by viral infection alone, the immune response to the vector must be understood. In these experiments, we further define cellular immunity to recombinant adenovirus., Methods: The immune response to hepatic adenoviral gene transfer was studied in infected mice by depleting T cells with an anti-CD3 antibody, measuring splenocyte cytokine production, determining the impact of transgene expression on inflammation, and assessing liver MHC protein expression., Results: The cellular immune response to recombinant adenovirus is (1) averted by T lymphocyte depletion, (2) marked by a TH1 response with increased IL-2 production, (3) directed against both the transgene product and viral proteins, and (4) associated with increased hepatocyte MHC Class I expression., Conclusions: It is necessary to take into consideration the constraints imposed by the immunogenicity of recombinant adenovirus and its transient transgene expression in the clinical application of adenoviral gene transfer for the treatment of cancer.

Recombinant adenovirus accomplishes highly efficient gene transfer in vivo. Adenoviral vectors would be more attractive vehicles for gene therapy if transgene expression was inducible and restricted to the target tissue. In these studies, we hypothesized that selective transgene expression of a recombinant adenovirus could be accomplished by using a tissue-specific promoter of transcription. A replication-defective adenoviral vector was engineered to express the lacZ marker gene under control of the murine pancreatic amylase promoter. Expression of this vector occurred exclusively in the pancreas in neonatal and adult mice, while a similar vector with a constitutive promoter accomplished transgene expression in several organs. Within the adenoviral construct, the amylase promoter retained its ability to be induced by dexamethasone and insulin. This model will serve as a paradigm for selective and inducible adenoviral transgene expression., (Copyright 1997 Academic Press.)

Gene transfer technology may provide a novel approach to treatment for pancreatic diseases. Recombinant adenovirus achieves efficient gene transfer in vivo. In this study, a murine model of adenoviral-mediated pancreatic gene transfer was developed, and the factors responsible for adenoviral elimination were investigated. Three days after direct pancreatic injection of a replication-defective adenovirus containing the lacZ transgene, a high proportion (76.8 +/- 6.7%) of pancreatic cells expressed beta-galactosidase, the gene product. Gene expression was absent by 28 days posttransduction. In immunodeficient mice, beta-galactosidase expression persisted with 20.0 +/- 6.0% of pancreatic cells staining positive 60 days after viral transduction. To test whether early viral proteins are the antigenic components responsible for the potent antiviral immune response, normal mice were injected with different adenoviral vectors containing early gene deletions. Vectors containing deletions in early region 2 or 4 expressed beta-galactosidase at 28 days. Presently available adenoviral vectors engineered to avoid this response offer minimal improvements in transgene duration. Further vector modifications or alternative strategies are needed to achieve stable pancreatic adenoviral transgene expression.

Purpose: The authors sought to assess the feasibility of in vivo gene transfer to the small intestine using recombinant adenovirus in neonatal and adult mice., Methods: H5.010CMVlacZ is a replication-defective, E1-deleted human type 5 adenovirus, which contains the lacZ gene under the control of a cytomegalovirus promoter and enhancer. The lacZ gene was used as a marker because its gene product, beta-galactosidase, is readily detected by X-gal histochemistry. Sixty neonatal (3 to 5 days old) and 45 adult (6 to 8 weeks old) C57BL/6 mice were investigated. Intestinal gene transfer was attempted with H5.010CMVlacZ by intraperitoneal (i.p.), intraluminal (IL), and intramural (i.m.) injection. Based on prior studies, the optimal dose of H5.010CMVlacZ was 1 x 10(8) plaque forming units (pfu/mL). Control animals received saline injections. Gene transfer on repeat administration of adenovirus has been shown to be prevented by neutralizing antibody. To determine if neonatal inoculation induced a humoral immune response, neonates (n = 5) that received i.p. injections were rechallenged with intravenous H5.010CMV alkphos, a similar adenoviral construct containing the alkaline phosphatase marker gene. Serum samples were analyzed by Western blot to detect the presence of adenoviral-specific antibody., Results: Gene transfer to neonatal small intestine was successful by IL gastric (n = 8/10), IL jejunal (n = 9/10) and i.p. (n = 10/10) routes 2 days after injection. Macroscopic staining was present in 90% of standardized 2-cm small bowel segments. Transgene expression was identified in intestinal smooth muscle, serosa, and epithelium. Gene transfer to the adult small intestine was successful by IL jejunal (n = 4/5), i.m. (n = 5/5), and i.p. (n = 1/5) injection of adenoviruslacZ with focal staining (< 5% of 2-cm segments) in epithelium including crypts, muscle, and serosa. Three weeks after i.p. H5.010CMVlacZ in neonates, intravenous injection with H5.010CMValkphos resulted in hepatic transgene expression (n = 4/5) that was indistinguishable from a primary intravenous inoculation; persistent, lacZ expression was not detectable in the liver or intestine (n = 0/5). Western blot analysis detected adenoviral-specific antibodies after adult IM but not after neonatal i.p. injection. Furthermore, 3 weeks after neonatal i.p. injection repeat administration by the i.m. route was successful (n = 4/ 4)., Conclusion: Gene transfer to neonatal and adult small intestine is feasible using recombinant adenovirus and is more efficient in neonates as indicated by increased surface area of marker gene expression, effectiveness of intraperitoneal delivery, and the ability to readminister recombinant adenovirus.

Adenoviral gene transfer has potential use to attenuate the immunogenicity of hepatic allografts. However, the clinical application of adenoviral gene therapy is currently impeded by the potent host immune response to the virus that limits the duration of its effects. In these studies, we identify the cellular and humoral immune responses to recombinant adenovirus in the liver of mice and define the immunologic barriers to the successful application of this technology to transplantation. The immunobiology of recombinant adenovirus was studied in mouse liver using vectors containing the lacZ and alkaline phosphatase marker genes. The duration of transgene expression was studied in various immunodeficient mice to determine the mechanism of viral clearance. Adoptive transfer of serum to B lymphocyte deficient mice and neutralizing antibody assays were used to define the antiviral humoral response. Hepatic adenoviral transgene expression was prolonged in animals deficient in CD4+ or CD8+ T cells indicating their importance in viral clearance. Unexpectedly, mice lacking B lymphocytes also had delayed elimination of virus suggesting that B cells play a role in the primary immune response. Effective repeat gene transfer was blocked by adenoviral-specific neutralizing antibody. Therefore, a T lymphocyte response results in viral elimination after a primary intravenous inoculation of recombinant adenovirus and a potent humoral response inhibits effective repeat adenoviral gene transfer. The immunogenicity of the vector must be overcome for adenoviral gene therapy to have therapeutic application for hepatic transplantation.

Background: The short-chain fatty acid butyrate inhibits growth of colorectal carcinoma cells in vitro. Mevalonate, a short-chain fatty acid structurally and metabolically related to butyrate, is important in signal transduction and is essential for cell growth. We investigated butyrate's effects on seeding and growth of colorectal tumor cells metastatic to the liver in vivo and hypothesized that butyrate's antiproliferative effects are associated with inhibition of mevalonate-mediated cell growth., Methods: Hepatic metastases were induced by injecting 1 x 10(5) MC-26 (N-methyl-N-nitrosourea-induced murine colorectal carcinoma) cells into the spleen of BALB/c mice. Mice were treated with a continuous intravenous infusion of butyrate (2 gm/kg/day) for 7 days starting 24 hours before tumor cells were injected. Study variables included liver weight and number of hepatic surface metastases. Proliferation studies on MC-26 cells were performed in vitro to examine the effects of butyrate alone or combined with mevalonate or mevastatin (an inhibitor of mevalonate synthesis)., Results: Butyrate reduced seeding and growth of colorectal tumor cells in vivo. Mevalonate diminished butyrate's antiproliferative action in vitro, whereas mevastatin potentiated this effect., Conclusions: These studies (1) show that butyrate inhibits seeding and growth of hepatic colorectal metastases in vivo, (2) associate butyrate's antiproliferative effects with inhibition of mevalonate-mediated cell growth, and (3) indicate that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors may have synergistic antiproliferative effects when combined with butyrate.

Gene transfer into the pancreas would be useful for the treatment of a variety of disorders, including cystic fibrosis, diabetes, cancer, and immunomodulation of pancreatic allografts. A hypothesis that various cell populations in the pancreas could be targeted by recombinant adenoviruses was developed and tested. Gene transfer into the rat ductal epithelium, acinar cells, and islets of Langerhans was accomplished with a recombinant adenovirus containing bacterial beta-galactosidase by retrograde delivery of adenovirus into the pancreaticobiliary duct. Maximal gene expression was observed at 3 days and correlated with DNA blot analysis. Histologic analysis of sections from pancreatic tissue in the adenovirus-treated rats demonstrated severe pancreatitis. Immunophenotyping of the inflammatory infiltrate with rat lymphocyte-specific markers showed CD45-, CD8-, and CD4-positive cells. Tissue injury resolved as gene expression was lost, with both features absent by 21 days. Pancreatic regeneration was documented by the presence of 5-bromo-2'-deoxyuridine-positive staining cells. Pancreatic gene transfer with first-generation recombinant adenoviruses can be accomplished by techniques applicable to clinical situations. The use of first-generation recombinant adenoviruses for pancreas-directed gene transfer is limited by the development of inflammation and transient expression.

Although first generation recombinant adenoviruses are efficient vehicles for gene transfer, their immunogenicity precludes long-term persistence. We show that adenoviral transgene expression in the liver of normal mice is prolonged from a baseline of less than 2 weeks to 7 weeks by depleting CD4+ T lymphocytes with thymectomy and a 3-day course of anti-CD4 monoclonal antibody or by nonselectively depleting T cells with a single dose of anti-thymocyte serum (ATS). Transgene expression persisted despite the development of an antiviral humoral immune response by 3 weeks after virus administration. In vitro assays of T lymphocyte function revealed an initial diminished capacity to proliferate in the presence of adenoviral antigens in animals depleted of CD4+ T cells or given anti-thymocyte serum. Eventual loss of recombinant gene expression coincided with the development of adenovirus-specific cytotoxic T lymphocyte activity in vitro. Immunosuppression provides a useful experimental tool to elucidate the immunobiology of recombinant adenoviruses and may have clinical application to adenovirus-mediated gene therapy.

Objective: The authors investigated whether adenoviral gene transfer to the thymus could be accomplished in vivo and whether immunologic unresponsiveness to recombinant adenovirus could be induced by intrathymic inoculation., Summary Background Data: A major barrier to the clinical application of adenovirus-mediated gene therapy for diseases requiring long-lasting gene expression is the immunogenicity of adenoviral vectors, which limits the duration of its effects. In other experimental models, intrathymic inoculation of foreign proteins or cells has proven to be an effective means to induce immunologic tolerance., Methods: The efficiency of gene transfer to the mouse thymus after direct inoculation of recombinant adenovirus was compared with that of several other vectors. Animals inoculated with adenovirus-infected pancreatic islets into the thymus were tested for unresponsiveness to the virus with a subsequent challenge of adenovirus administered into the liver by intravenous injection., Results: Adenovirus accomplished highly efficient gene transfer to the thymus, unlike plasmid DNA, DNA-liposome complexes, retrovirus, and adeno-associated virus. Adenoviral transgene expression was transient in the thymus of immunocompetent mice but persistent in CD8+ T-cell-deficient and severe combined immunodeficiency (SCID) mice, implicating the role of cytotoxic T lymphocytes in viral clearance. Intrathymic transplantation of syngeneic pancreatic islet cells infected with adenovirus impaired the normal antiviral cytotoxic T-lymphocyte response and prolonged hepatic transgene expression after an intravenous challenge with adenovirus., Conclusions: Recombinant adenovirus accomplishes highly efficient gene transfer to the thymus in vivo. Intrathymic inoculation of adenovirus-infected islets can be used to induce immunologic unresponsiveness to the adenoviral vector and, potentially, to other proteins that it might be engineered to encode.

Insulin-like growth factors I and II are peptides with a structural homology for proinsulin, and are involved in hepatocyte proliferation. IGF-I and IGF-II, however, have different metabolic roles, and their mechanisms of action are incompletely known. We hypothesized that IGF-I and IGF-II act by different signal transduction pathways. To test this hypothesis, hepatocytes from 200 g male Sprague-Dawley rats were isolated by a two-step collagenase perfusion technique and plated at a density of 10(5) cells/16 mm Primaria plate. Proliferation was measured by [3H]thymidine ([3H]thy) incorporation into DNA, and an autoradiographic nuclear labeling index (LI). To analyze signal transduction, cyclic AMP (cAMP) levels were measured 5 min after addition of reagents by a radioimmunoassay. Reagents (doses) used were: IGF-I (2 nM), IGF-II (2 nM), the inhibitory peptide somatostatin-14 (SS14) (10 nM), and the adenylyl cyclase antagonist dideoxyadenosine (DDA) (10 microM). A summary of the findings is as follows: (1) IGF-I stimulates [3H]thy, LI and cAMP accumulation. (2) IGF-II stimulates [3H]thy and LI but not cAMP; (3) IGF-I but not IGF-II effects are inhibited by SS14 and DDA. We conclude that the hepatotrophic effects of IGF-I and IGF-II occur by different mechanisms: IGF-I is cAMP-dependent, IGF-II is cAMP-independent.

A case of an incidental spigelian hernia discovered during a laparoscopic pelvic lymph node dissection for prostatic carcinoma is described. The proposed management of this unusual finding is reviewed.