William R. Jarnagin

Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade.

Objective To assess the nature of changes in the field of hepatic resectional surgery and their impact on perioperative outcome.

Staging, Resectability, and Outcome in 225 Patients With Hilar Cholangiocarcinoma

ObjectiveTo 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 DataIn 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. MethodsDemographics, 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. ResultsFrom 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. ConclusionBy 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.

Tumour exosome integrins determine organotropic metastasis.

Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

An Analysis of 412 Cases of Hepatocellular Carcinoma at a Western Center

OBJECTIVE Using a large single-institution experience at a Western referral center, the authors examine partial hepatectomy as treatment of hepatocellular carcinoma and relate treatment outcomes to clinical parameters, including the etiology of underlying cirrhosis. METHODS Four hundred and twelve patients seen between December 1991 and January 1998 were identified in a prospective database. Data about the surgical procedure, perioperative complications, and long-term outcome were examined. RESULTS One hundred twenty-six patients did not have underlying cirrhosis. Of the 286 patients with cirrhosis, 119 were the result of hepatitis B, 39 hepatitis C, 36 both B and C, 43 ethanol abuse, and the remainder other causes. Two hundred forty-three patients underwent surgical exploration, and 154 patients underwent hepatic resection. Seven (4.5%) died from the surgery. One hundred forty-three patients were treated by ablative methods. Patients with cirrhosis had smaller tumors but nevertheless had a lower resectability rate. Neither the presence of cirrhosis nor the etiology of the cirrhosis altered the perioperative morbidity or mortality rate. The greatest determinant of long-term outcome was resectability. The size of the lesion, an alpha-fetoprotein level >2000 ng/ml, and vascular invasion were also determinants of poor outcome. The presence of cirrhosis was a detrimental factor when analysis was stratified for size of tumor. The cause of cirrhosis did not influence the long-term outcome. The 5-year survival rate was 57% for patients with resected lesions <5 cm and 32% for patients with tumors >10 cm. CONCLUSION Partial hepatectomy is safe, effective, and potentially curative therapy for hepatocellular carcinoma. The presence of cirrhosis did not affect the surgical mortality rate but did affect the long-term survival rate. The cause of cirrhosis did not influence outcome. As treatment for small hepatocellular carcinomas, partial hepatectomy produces results similar to those of transplantation. For patients with large tumors who are poor candidates for transplantation, resection results in long-term survival in one third of patients.

Actual 10-Year Survival After Resection of Colorectal Liver Metastases Defines Cure

PURPOSE Resection of colorectal liver metastases (CLM) in selected patients has evolved as the standard of care during the last 20 years. In the absence of prospective randomized clinical trials, a survival benefit has been deduced relative to historical controls based on actuarial data. There is now sufficient follow-up on a significant number of patients to address the curative intent of resecting CLM. METHODS Retrospective review of a prospectively maintained database was performed on patients who underwent resection of CLM from 1985 to 1994. Postoperative deaths were excluded. Disease-specific survival (DSS) was calculated from the time of hepatectomy using the Kaplan-Meier method. RESULTS There were 612 consecutive patients identified with 10-year follow-up. Median DSS was 44 months. There were 102 actual 10-year survivors. Ninety-nine (97%) of the 102 were disease free at last follow-up. Only one patient experienced a disease-specific death after 10 years of survival. In contrast, 34% of the 5-year survivors suffered a cancer-related death. Previously identified poor prognostic factors found among the 102 actual 10-year survivors included 7% synchronous disease, 36% disease-free interval less than 12 months, 25% bilobar metastases, 50% node-positive primary, 39% more than one metastasis, and 35% tumor size more than 5 cm. CONCLUSION Patients who survive 10 years appear to be cured of their disease, whereas approximately one third of actual 5-year survivors succumb to a cancer-related death. In well-selected patients, there is at least a one in six chance of cure after hepatectomy for CLM. The presence of poor prognostic factors does not preclude the possibility of long-term survival and cure.

Hepatic neuroendocrine metastases: does intervention alter outcomes?

BACKGROUND In most instances, advanced neuroendocrine tumors follow an indolent course. Hepatic metastases are common, and although they can cause significant pain, incapacitating endocrinopathy, and even death, they are usually asymptomatic. The appropriate timing and efficacy of interventions, such as hepatic artery embolization (HAE) and operation, remain controversial. STUDY DESIGN The records of 85 selected patients referred for treatment of hepatic neuroendocrine tumor metastases between 1992 and 1998 were reviewed from a prospective database. A multidisciplinary group of surgeons, radiologists, and oncologists managed all patients. Overall survival among this cohort is reported and prognostic variables, which may be predictive of survival, are analyzed. RESULTS There were 37 men and 48 women, with a median age of 52 years. There were 41 carcinoid tumors, 26 nonfunctional islet cell tumors, and 18 functional islet cell tumors. Thirty-eight patients had extrahepatic metastases, and in 84% of patients, the liver metastases were bilobar. Eighteen patients were treated with medical therapy or best supportive care, 33 patients underwent HAE, and 34 patients underwent hepatic resection. Both the HAE-related mortality and the 30-day operative mortality rates were 6%. By univariate analysis, earlier resection of the primary tumor, curative intent of treatment, and initial surgical treatment were associated with prolonged survival (p < 0.05). On multivariate analysis, only curative intent to treat remained significant (p < 0.04). Patients with bilobar or more than 75% liver involvement by tumor were least likely to benefit from surgical resection. One-, 3-, and 5-year survival rates for the entire group were 83%, 61%, and 53%, respectively. The 1-, 3-, and 5-year survivals for patients treated with medical therapy, HAE, and operation were 76%, 39%, and not available; 94%, 83%, and 50%; and 94%, 83%, and 76%, respectively. CONCLUSIONS Hepatic metastases from neuroendocrine tumors are best managed with a multidisciplinary approach. Both HAE and surgical resection provide excellent palliation of hormonal and pain symptoms. In select patients, surgical resection of hepatic metastases may prolong survival, but is rarely curative.

Perioperative outcomes of major hepatic resections under low central venous pressure anesthesia : Blood loss, blood transfusion, and the risk of postoperative renal dysfunction

BACKGROUND We have previously demonstrated that maintenance of a low central venous pressure (LCVP) combined with extrahepatic control of venous outflow reduced the overall blood loss during major hepatic resections. This study examined the overall outcomes and, in particular, renal morbidity associated with a large series of consecutive major liver resections performed with this approach. In addition, the rationale for the anesthetic management to maintain LCVP was carefully reviewed. STUDY DESIGN All major hepatectomies performed between December 1991 and April 1997 were reviewed. The prospective Hepatobiliary Surgical Service database was merged with the Memorial Hospital Laboratory and Blood Bank databases to yield the nature of the operation, blood loss, blood product transfusions, outcomes, and levels of preoperative, postoperative, and discharge serum creatinine and blood urea nitrogen. RESULTS A total of 496 LCVP-assisted major liver resections were performed, with no intraoperative deaths and an in-hospital mortality rate of 3.8%. The median blood loss was 645 mL. Sixty-seven percent of the patients did not require perioperative blood transfusion during surgery and the immediate 12 hours after surgery. The median number of blood transfusions was 2. Only 3% of the patients experienced a persistent and clinically significant increase in serum creatinine possibly attributable to the anesthetic technique. Renal failure directly attributable to the anesthetic technique did not occur. CONCLUSIONS Major resection with LCVP allowed easy control of the hepatic veins before and during parenchymal transection. The anesthetic technique, designed to maintain LCVP during the critical stages of hepatic resection, not only helped to minimize blood loss and mortality but also preserved renal function.

Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases

ObjectiveTo determine if transfusion affected perioperative and long-term outcome in patients undergoing liver resection for metastatic colorectal cancer. Summary Background DataBlood transfusion produces host immunosuppression and has been postulated to result in adverse outcome for patients undergoing surgical resection of malignancies. MethodsBlood transfusion records and clinical outcomes for 1,351 patients undergoing liver resection at a tertiary cancer referral center were analyzed. ResultsBlood transfusion was associated with adverse outcome after liver resection. The greatest effect was in the perioperative course, where transfusion was an independent predictor of operative mortality, complications, major complications, and length of hospital stay. This effect was dose-related. Patients receiving one or two units or more than two units had an operative mortality of 2.5% and 11.1%, respectively, compared to 1.2% for patients not requiring transfusions. Transfusion was also associated with adverse long-term survival by univariate analysis, but this factor was not significant on multivariate analysis. Even patients receiving only one or two units had a more adverse outcome. ConclusionsPerioperative blood transfusion is a risk factor for poor outcome after liver resection. Blood conservation methods should be used to avoid transfusion, especially in patents currently requiring limited amounts of transfused blood products.

Prospective Randomized Clinical Trial of the Value of Intraperitoneal Drainage After Pancreatic Resection

ObjectiveTo test the hypothesis that routine intraperitoneal drainage is not required after pancreatic resection. Summary Background DataThe use of surgically placed intraperitoneal drains has been considered routine after pancreatic resection. Recent studies have suggested that for other major upper abdominal resections, routine postoperative drainage is not required and may be associated with an increased complication rate. MethodsAfter informed consent, eligible patients with peripancreatic tumors were randomized during surgery either to have no drains placed or to have closed suction drainage placed in a standardized fashion after pancreatic resection. Clinical, pathologic, and surgical details were recorded. ResultsOne hundred seventy-nine patients were enrolled in the study, 90 women and 89 men. Mean age was 65.4 years (range 23–87). The pancreas was the tumor site in 142 (79%) patients, with the ampulla (n = 24), duodenum (n = 10), and distal common bile duct (n = 3) accounting for the remainder. A pancreaticoduodenectomy was performed in 139 patients and a distal pancreatectomy in 40 cases. Eighty-eight patients were randomized to have drains placed. Demographic, surgical, and pathologic details were similar between both groups. The overall 30-day death rate was 2% (n = 4). A postoperative complication occurred during the initial admission in 107 patients (59%). There was no significant difference in the number or type of complications between groups. In the drained group, 11 patients (12.5%) developed a pancreatic fistula. Patients with a drain were more likely to develop a significant intraabdominal abscess, collection, or fistula. ConclusionThis randomized prospective clinical trial failed to show a reduction in the number of deaths or complications with the addition of surgical intraperitoneal closed suction drainage after pancreatic resection. The data suggest that the presence of drains failed to reduce either the need for interventional radiologic drainage or surgical exploration for intraabdominal sepsis. Based on these results, closed suction drainage should not be considered mandatory or standard after pancreatic resection.

Intrahepatic Cholangiocarcinoma : Rising Frequency, Improved Survival, and Determinants of Outcome After Resection

Background:Despite data suggesting a rising worldwide incidence, intrahepatic cholangiocarcinoma (IHC) remains an uncommon disease. This study analyzes changes in IHC frequency, demographics, and treatment outcome in a consecutive and single institutional cohort. Methods:Consecutive patients with confirmed IHC seen and treated over a 16-year period were included. The trend in IHC frequency over the study period was compared with that of hilar cholangiocarcinoma patients (HCCA) seen during the same time. Demographics and patient disposition, histopathologic, treatment, recurrence, and survival data were analyzed; changes in these variables over time were assessed. Results:From December 1990 through July 2006, 594 patients were evaluated (IHC = 270, HCCA = 324). Over the study period, the average annual increase in new IHC patients was 14.2% (P < 0.001). Relative to HCCA, the proportional increase in IHC was nearly 3-fold, and new IHC patients have outnumbered those with HCCA by 2:1 over the last 3 years. Conditions associated with IHC were rarely seen, with only 7 patients having a history of sclerosing cholangitis and/or inflammatory bowel disease and none with hepatolithiasis or biliary parasitic disease; however, heavy tobacco use (27%) and diabetes mellitus (16.4%) were particularly prevalent. The majority of patients were not candidates for resection, most commonly because of advanced hepatic disease. After resection (n = 82), median disease-specific survival was 36 months; recurrence was observed in 62.2% of patients at a median follow-up of 26 months, with the liver remnant involved most frequently (62.7%). Multiple hepatic tumors (P < 0.001), regional nodal involvement (P = 0.012), and large tumor size (P = 0.016) independently predicted poor recurrence-free survival. Most patients (n = 115, 73.7%) with unresectable disease were treated with chemotherapy, either systemic alone (n = 75) or combined with regional hepatic arterial floxuridine (FUDR) (n = 28). Compared with the first 10 years of the study (1990–2000), the last 6 years saw an overall improvement in disease-specific survival for all patients (22 vs. 12 months, P = 0.002), which was particularly notable for patients with unresectable disease (15 vs. 6 months, P = 0.003). Conclusions:At Memorial Sloan-Kettering Cancer Center, IHC incidence has increased dramatically in the last 16 years. Resection offers the best opportunity for long-term survival but is possible in the minority, and patients with large, node-positive or multifocal IHC seem to derive little benefit. Establishing and maintaining control of the intrahepatic disease remains the biggest problem for all IHC patients. The recent increase in survival seems largely because of improved nonoperative therapy for unresectable disease.