William R. Jarnagin

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.

Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.

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.

Objective To assess the nature of changes in the field of hepatic resectional surgery and their impact on perioperative outcome. Methods Demographics, extent of resection, concomitant major procedures, operative and transfusion data, complications, and hospital stay were analyzed for 1,803 consecutive patients undergoing hepatic resection from December 1991 to September 2001 at Memorial Sloan-Kettering Cancer Center. Factors associated with morbidity and mortality and trends in operative and perioperative variables over the period of study were analyzed. Results Malignant disease was the most common diagnosis (1,642 patients, 91%); of these cases, metastatic colorectal cancer accounted for 62% (n = 1,021). Three hundred seventy-five resections (21%) were performed for primary hepatic or biliary cancers and 161 (9%) for benign disease. Anatomical resections were performed in 1,568 patients (87%) and included 544 extended hepatectomies, 483 hepatectomies, and 526 segmental resections. Sixty-two percent of patients had three or more segments resected, 42% had bilobar resections, and 37% had concomitant additional major procedures. The median blood loss was 600 mL and 49% of patients were transfused at any time during the index admission. Median hospital stay was 8 days, morbidity was 45%, and operative mortality was 3.1%. Over the study period, there was a significant increase in the use of parenchymal-sparing segmental resections and a decrease in the number of hepatic segments resected. In parallel with this, there was a significant decline in blood loss, the use of blood products, and hospital stay. Despite an increase in concomitant major procedures, operative mortality decreased from approximately 4% in the first 5 years of the study to 1.3% in the last 2 years, with 0 operative deaths in the last 184 consecutive cases. On multivariate analysis, the number of hepatic segments resected and operative blood loss were the only independent predictors of both perioperative morbidity and mortality. Conclusions Over the past decade, the use of parenchymal-sparing segmental resections has increased significantly. The number of hepatic segments resected and operative blood loss were the only predictors of both perioperative morbidity and mortality, and reductions in both are largely responsible for the decrease in perioperative mortality, which has occurred despite an increase in concomitant major procedures.

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.

The use of laparoscopy for liver surgery is increasing rapidly. The Second International Consensus Conference on Laparoscopic Liver Resections (LLR) was held in Morioka, Japan, from October 4 to 6, 2014 to evaluate the current status of laparoscopic liver surgery and to provide recommendations to aid its future development. Seventeen questions were addressed. The first 7 questions focused on outcomes that reflect the benefits and risks of LLR. These questions were addressed using the Zurich-Danish consensus conference model in which the literature and expert opinion were weighed by a 9-member jury, who evaluated LLR outcomes using GRADE and a list of comparators. The jury also graded LLRs by the Balliol Classification of IDEAL. The jury concluded that MINOR LLRs had become standard practice (IDEAL 3) and that MAJOR liver resections were still innovative procedures in the exploration phase (IDEAL 2b). Continued cautious introduction of MAJOR LLRs was recommended. All of the evidence available for scrutiny was of LOW quality by GRADE, which prompted the recommendation for higher quality evaluative studies. The last 10 questions focused on technical questions and the recommendations were based on literature review and expert panel opinion. Recommendations were made regarding preoperative evaluation, bleeding controls, transection methods, anatomic approaches, and equipment. Both experts and jury recognized the need for a formal structure of education for those interested in performing major laparoscopic LLR because of the steep learning curve.

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.

In Brief 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. Intrahepatic cholangiocarcinoma (IHC) incidence has increased dramatically in the last 16 years with resection offering the best opportunity for long-term survival. Patients with large, node-positive, or multifocal IHC seem to derive little benefit with resection. The recent increase in survival seems largely because of improved nonoperative therapy for unresectable disease and may be related to increased use of regional chemotherapy.

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 emobolization (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.

To assess the nature of changes in the field of hepatic resectional surgery and their impact on perioperative outcome.Demographics, extent of resection, concomitant major procedures, operative and transfusion data, complications, and hospital stay were analyzed for 1,803 consecutive patients undergoing hepatic resection from December 1991 to September 2001 at Memorial Sloan-Kettering Cancer Center. Factors associated with morbidity and mortality and trends in operative and perioperative variables over the period of study were analyzed.Malignant disease was the most common diagnosis (1,642 patients, 91%); of these cases, metastatic colorectal cancer accounted for 62% (n = 1,021). Three hundred seventy-five resections (21%) were performed for primary hepatic or biliary cancers and 161 (9%) for benign disease. Anatomical resections were performed in 1,568 patients (87%) and included 544 extended hepatectomies, 483 hepatectomies, and 526 segmental resections. Sixty-two percent of patients had three or more segments resected, 42% had bilobar resections, and 37% had concomitant additional major procedures. The median blood loss was 600 mL and 49% of patients were transfused at any time during the index admission. Median hospital stay was 8 days, morbidity was 45%, and operative mortality was 3.1%. Over the study period, there was a significant increase in the use of parenchymal-sparing segmental resections and a decrease in the number of hepatic segments resected. In parallel with this, there was a significant decline in blood loss, the use of blood products, and hospital stay. Despite an increase in concomitant major procedures, operative mortality decreased from approximately 4% in the first 5 years of the study to 1.3% in the last 2 years, with 0 operative deaths in the last 184 consecutive cases. On multivariate analysis, the number of hepatic segments resected and operative blood loss were the only independent predictors of both perioperative morbidity and mortality.Over the past decade, the use of parenchymal-sparing segmental resections has increased significantly. The number of hepatic segments resected and operative blood loss were the only predictors of both perioperative morbidity and mortality, and reductions in both are largely responsible for the decrease in perioperative mortality, which has occurred despite an increase in concomitant major procedures.

Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas.

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.

To test the hypothesis that routine intraperitoneal drainage is not required after pancreatic resection.The 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.After 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.One 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.This 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.

To determine if transfusion affected perioperative and long-term outcome in patients undergoing liver resection for metastatic colorectal cancer.Blood transfusion produces host immunosuppression and has been postulated to result in adverse outcome for patients undergoing surgical resection of malignancies.Blood transfusion records and clinical outcomes for 1,351 patients undergoing liver resection at a tertiary cancer referral center were analyzed.Blood 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.Perioperative 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.

To determine the resectability rate for hilar cholangiocarcinoma, to analyze reasons for unresectability, and to devise a presurgical clinical T-staging system.Ninety patients with hilar cholangiocarcinomas seen between March 1, 1991, and April 1, 1997, were evaluated. Accurate patterns of disease progression and therapy were evaluable. Disease was staged in 87 patients using extent of ductal tumor involvement, portal vein compromise, and liver atrophy.In 21 patients, disease was deemed unresectable for cure at presentation. In 39 patients, disease was found to be unresectable at laparotomy, 23 secondary to nodal (N2) or distant metastases. Unresectability was the result of metastases in 52% and of locally advanced disease in 28%. Thirty patients (33%) had resection of all gross disease, and 25 of these (83%) had negative histologic margins. Twenty-two patients underwent partial hepatectomy. The 30-day mortality rate was 7%. Projected survival is greater than 60 months in those with a negative histologic margin, with a median follow-up of 26 months. A presurgical T-staging system allows presurgical selection for therapy, predicts partial hepatectomy, and offers an index of prognosis.In half the patients, unresectability is mainly the result of intraabdominal metastases. Presurgical imaging predicts unresectability based on local extension but is poor for assessing nodal metastases. In one third of patients, disease can be resected for cure with a long median survival. Curative resection depends on negative margins, and hepatic resection is necessary to achieve this. The T-staging system correlates with resectability, the need for hepatectomy, and overall survival.

This study analyzes factors associated with differences in long-term outcomes after hepatic resection for metastatic colorectal cancer over time.Sixteen-hundred consecutive patients undergoing hepatic resection for metastatic colorectal cancer between 1985 and 2004 were analyzed retrospectively. Patients were grouped into 2 eras according to changes in availability of systemic chemotherapy: era I, 1985 to 1998; era II, 1999 to 2004.There were 1,037 patients in era I and 563 in era II. Operative mortality decreased from 2.5% in era I to 1% in era II (p = 0.04). There were no differences in age, Clinical Risk Score, or number of hepatic metastases between the 2 groups; however, more recently treated patients (era II) had more lymph node-positive primary tumors, shorter disease-free intervals, more extrahepatic disease, and smaller tumors. Median follow-up was 36 months for all patients and 63 months for survivors. Median and 5-year disease-specific survival (DSS) were better in era II (64 months and 51% versus 43 months and 37%, respectively; p < 0.001); but median and 5-year recurrence-free survival (RFS) for all patients were not different (23 months and 33% era II versus 22 months and 27% era I; p = 0.16). There was no difference in RFS or DSS for high-risk (Clinical Risk Score >2, n = 506) patients in either era. There was a marked improvement in both RFS and DSS for low risk (Clinical Risk Score < or =2, n = 1,094) patients.Despite worse clinical and pathologic characteristics, survival but not recurrence rates after hepatic resection for colorectal metastases have improved over time and might be attributable to improvements in patient selection, operative management, and chemotherapy. The improvement in survival over time is largely accounted for by low-risk patients.

Abstract BACKGROUND Current approaches to adjuvant treatment after resection of gallbladder carcinoma (GBCA) and hilar cholangiocarcinoma (HCCA) are based on an incomplete understanding of the recurrence patterns of these diseases. Through an in‐depth analysis of the sites of initial recurrence after resection of GBCA and HCCA, the current study aimed to highlight differences in the biology of these tumors and to provide further insight for adjuvant therapeutic strategies. METHODS Patients with either GBCA or HCCA who underwent a potentially curative resection were identified prospectively from a maintained database. Specific sites of initial disease recurrence were identified retrospectively and categorized as locoregional (resection margin, porta hepatis, or retroperitoneal lymph nodes) or distant (peritoneal, extraabdominal, or discontiguous liver metastases). Differences in disease recurrence patterns, time to disease recurrence, and overall and site‐specific survival were analyzed. RESULTS Between May 1990 and August 2001, 177 patients underwent potentially curative resection, 97 for GBCA and 80 for HCCA. Disease recurrence and follow‐up data were available for 156 patients (80 with GBCA and 76 with HCCA). The median time to disease recurrence was shorter for patients with GBCA compared with patients with HCCA (11.5 vs. 20.3 months; P = 0.007). Overall, 52 (68%) patients with HCCA and 53 (66%) patients with GBCA had disease recurrene at a median follow‐up of 24 months. Of those who developed disease recurrence, isolated locoregional disease as the first site of failure occurred in 15% of patients with GBCA compared with 59% of patients with HCCA ( P &lt; 0.001). By contrast, an initial GBCA recurrence involving a distant site, with or without concomitant locoregional recurrence, occurred in 85% of patients compared with 41% of patients with HCCA ( P &lt; 0.001). This pattern of disease recurrence was diagnosis specific and did not change significantly when patients were stratified by several clinicopathologic factors, including disease stage and its component variables. Using multivariate analysis, diagnosis was an independent predictor of the site of disease recurrence. Among patients who experienced disease recurrence, survival was greater among the patients with HCCA compared with patients with GBCA (29 months vs. 20.6 months, respectively; P = 0.037). For both tumors, the site of initial disease recurrence had no apparent impact on survival time. CONCLUSIONS After resection, recurrent GBCA is much more likely than recurrent HCCA to involve a distant site. GBCA is also associated with a much shorter time to recurrence and a shorter survival period after recurrence. The results demonstrated significant differences in the clinical behavior of these tumors and suggested that an adjuvant therapeutic strategy targeting locoregional disease, such as radiotherapy, is unlikely to have a significant impact in the overall management of GBCA. Conversely, there is at least some rationale for such an approach in patients with HCCA based on the pattern of initial recurrence. Cancer 2003. © 2003 American Cancer Society. DOI 10.1002/cncr.11699

We have examined the cell-specific expression of two fibronectin isoforms, EIIIA and EIIIB, during experimental hepatic fibrosis induced by ligation of the biliary duct. AT the mRNA level, EIIIA and EIIIB were undetectable in normal liver but expressed early injury, preceding fibrosis. The cellular sources of these changes were determined by fractionating the liver at various time points after bile duct ligation into its constituent cell populations and extracting RNA from the fresh isolates. EIIIA-containing fibronectin mRNA was undetectable in normal sinusoidal endothelial cells but increased rapidly within 12 h of injury. By contrast, the EIIIB form was restricted to hepatic lipocytes (Ito or fat-storing cells) and appeared only after a lag of 12-24 h: it was minimal in sinusoidal endothelial cells. Both forms were minimal in hepatocytes. At the protein level, EIIIA-containing fibronectin was markedly increased within two days of injury and exhibited a sinusoidal distribution. Secretion of this form by endothelial cells was confirmed in primary culture. Matrices deposited in situ by endothelial cells from injured liver accelerated the conversion ("activation") of normal lipocytes to myofibroblast-like cells, and pretreatment of matrices with monoclonal antibody to the EIIIA segment blocked this response. Finally, recombinant fibronectin peptide containing the EIIIA segment was stimulatory to lipocytes in culture. We conclude that expression of EIIIA fibronectin by sinusoidal endothelial cells is a critical early event in the liver's response to injury and that the EIIIA segment is biologically active, mediating the conversion of lipocytes to myofibroblasts.

Abstract Purpose: Prior molecular profiling of hepatocellular carcinoma (HCC) has identified actionable findings that may have a role in guiding therapeutic decision-making and clinical trial enrollment. We implemented prospective next-generation sequencing (NGS) in the clinic to determine whether such analyses provide predictive and/or prognostic information for HCC patients treated with contemporary systemic therapies. Experimental Design: Matched tumor/normal DNA from patients with HCC (N = 127) were analyzed using a hybridization capture–based NGS assay designed to target 341 or more cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles. Results: WNT/β-catenin pathway (45%) and TP53 (33%) alterations were frequent and represented mutually exclusive molecular subsets. In sorafenib-treated patients (n = 81), oncogenic PI3K–mTOR pathway alterations were associated with lower disease control rates (DCR, 8.3% vs. 40.2%), shorter median progression-free survival (PFS; 1.9 vs. 5.3 months), and shorter median overall survival (OS; 10.4 vs. 17.9 months). For patients treated with immune checkpoint inhibitors (n = 31), activating alteration WNT/β-catenin signaling were associated with lower DCR (0% vs. 53%), shorter median PFS (2.0 vs. 7.4 months), and shorter median OS (9.1 vs. 15.2 months). Twenty-four percent of patients harbored potentially actionable alterations including TSC1/2 (8.5%) inactivating/truncating mutations, FGF19 (6.3%) and MET (1.5%) amplifications, and IDH1 missense mutations (&amp;lt;1%). Six percent of patients treated with systemic therapy were matched to targeted therapeutics. Conclusions: Linking NGS to routine clinical care has the potential to identify those patients with HCC likely to benefit from standard systemic therapies and can be used in an investigational context to match patients to genome-directed targeted therapies. See related commentary by Pinyol et al., p. 2021

To compare patients with gallbladder cancer presenting for therapy with and without prior operation elsewhere to determine if an initial noncurative procedure alters outcome.Nihilism has traditionally surrounded treatment of gallbladder cancer, particularly since the majority of cases are discovered during exploration for presumed gallstone disease when unsuspected cancers cannot be handled definitively and tumor is often violated.Presentation, operative data, complications, and survival were examined for 410 patients presenting between July 1986 and March 2000. In particular, the 248 patients presenting for therapy after prior operation elsewhere were compared with the remainder who presented without prior operation to determine if an initial noncurative procedure alters outcome.Overall Outcome: 51 patients were inoperable, 92 were subjected to exploration and biopsy only, 135 to noncurative cholecystectomy, 30 to surgical bypass, and 102 to potentially curative resections consisting of portal lymph node dissection and liver parenchymal resections. Operative mortality was 3.9%. T-stage predicted likelihood of distant metastases and resectability. Median survival for resected patients was 26 months and 5-year survival was 38%, and for patients not resected, 5.4 months and 4% (P <.0001). Effect of Prior Operation: 22 patients subjected to potentially curative resection as the first surgical procedure were compared to 80 patients resected after prior exploration elsewhere. Mortality, complication, and long-term survival were the same. By multivariate analysis (Cox regression), resectability and stage were independent predictors (P <.001) of long-term survival, but prior surgical exploration was not.Unresected gallbladder cancer is a rapidly fatal disease. Radical resection can provide long-term survival, even for large tumors with extensive liver invasion. Long-term survival can be achieved for patients presenting after prior noncurative surgical exploration.

Expression of the group of cytokines known as transforming growth factor-beta (TGF-beta 1, -beta 2 and -beta 3) is increased during liver regeneration induced by a 70% partial hepatectomy. The origin of these changes was examined in purified isolates of hepatocytes, sinusoidal endothelial cells, Kupffer cells (liver macrophages), and lipocytes (Ito or stellate cells) from normal and regenerating liver. In normal liver, TGF-beta 1 and -beta 2 levels were relatively high in sinusoidal endothelial cells and Kupffer cells. After partial hepatectomy, an early peak of TGF-beta 2 and -beta 3 was present in all four cell types, followed by a sustained increase in mRNA for TGF-beta 1, -beta 2, and -beta 3 primarily in the hepatocyte population. The specificity of these changes was established by examining a mechanistically different injury model, fibrosis induced by ligation of the biliary duct. In this model, TGF beta mRNA was increased only in lipocytes and the increase was progressive over a 7-d period of observation. Secretion of TGF beta protein was examined in cell isolates placed in short-term primary culture and generally reflected the corresponding mRNA level. The TGF beta released by hepatocytes was entirely in the latent form, whereas the individual nonparenchymal cell isolates released 50-90% active TGF beta. Hepatocyte-conditioned culture medium, after treatment to activate latent TGF beta, inhibited hepatocellular DNA synthesis as did the authentic factor. The data indicate that after injury TGF beta increases selectively in the cells that are the target of the factor, i.e., in hepatocytes after partial hepatectomy and in lipocytes in inflammation and fibrosis. We conclude that the effects of TGF beta in liver regeneration and fibrogenesis are predominantly, if not exclusively, autocrine.

The incidence of gallbladder cancer (GBC) in the US is 1.2/100,000. This report examines the patterns of presentation, adjuvant treatment and survival of a large cohort of patients with GBC evaluated at MSKCC over a 10-year period.A retrospective analysis of patients referred to MSKCC with a diagnosis of GBC between January 1995 and December 2005 was performed. Patients were identified from the MSKCC cancer registry. Information extracted included, demographics, clinical and pathological stage, surgical management, pathology, adjuvant and palliative therapy, date of relapse, death or last follow-up. Date of diagnosis was defined as date of surgery or biopsy. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test.Four hundred thirty-five GBC cases were identified: 285 (65.5%) females,150 (34.5%) males. Median age 67 years (range 28-100). Pathology: 88% adenocarcinoma, 4% squamous, 3% neuroendocrine, 2% sarcoma. 36.6% presented as AJCC Stage IV. 47% were discovered incidentally at laparoscopic cholecystectomy. One hundred thirty-six of these were re-explored, of whom 100 (73.5%) had residual disease. Of those who underwent curative resections (N = 123), 8 (6.5%) received adjuvant chemotherapy, 8 (6.5%) chemoradiation alone and 8 (6.5%) both chemoradiation and systemic chemotherapy. Median overall survival for the cohort was 10.3 months (95% CI 8.8-11.8) with a median follow up of 26.6 months. The median survival for those presenting with stage Ia-III disease was 12.9 months (95% CI 11.7-15.8 months) and 5.8 months (95% CI 4.5-6.7) for those presenting with stage IV disease. Median survival was 15.7 months (95% CI 12.4-18.4) for those discovered incidentally at laparoscopic cholecystectomy. For those who underwent re-exploration, median survival was 14.6 months (95% CI 12.6-18.3) if residual disease was present, and 72 months (95% CI 34 to infinity) if no evidence of disease. The median survival for those who received adjuvant therapy was 23.4 months (95% CI 15.7-47).GBC is commonly diagnosed incidentally (47%). Re-exploration reveals a high incidence of residual disease (74%). Median survival is better for patients who have no evidence of disease on re-exploration (72 months) compared to those with residual disease detected (P < 0.0001). Overall prognosis is poor. Although we did not observe a survival benefit for those who received adjuvant therapy, the study did not have sufficient power to address this question. In addition, the number of patients who received adjuvant therapy was small with marked heterogeneity in clinical and therapeutic details, precluding any definitive conclusions being drawn. Prospective randomized trials of adjuvant therapy are needed in this disease.

Semantic segmentation of medical images aims to associate a pixel with a label in a medical image without human initialization. The success of semantic segmentation algorithms is contingent on the availability of high-quality imaging data with corresponding labels provided by experts. We sought to create a large collection of annotated medical image datasets of various clinically relevant anatomies available under open source license to facilitate the development of semantic segmentation algorithms. Such a resource would allow: 1) objective assessment of general-purpose segmentation methods through comprehensive benchmarking and 2) open and free access to medical image data for any researcher interested in the problem domain. Through a multi-institutional effort, we generated a large, curated dataset representative of several highly variable segmentation tasks that was used in a crowd-sourced challenge - the Medical Segmentation Decathlon held during the 2018 Medical Image Computing and Computer Aided Interventions Conference in Granada, Spain. Here, we describe these ten labeled image datasets so that these data may be effectively reused by the research community.

In Brief Objective: To determine if the degree of blood loss during resection of hepatocellular carcinoma (HCC) is predictive of recurrence and long-term survival. Background: Several studies have addressed the impact of blood transfusion on survival and recurrence after liver resection for HCC. However, the independent effect of intraoperative estimated blood loss (EBL) on oncologic outcome is unclear. Methods: From our prospective database, we identified 192 patients who had a partial hepatectomy for HCC from 1985 to 2002. Clinicopathologic predictors of EBL were identified using logistic regression. Overall survival (OS), disease-specific survival (DSS), and recurrence free survival (RFS) were assessed using the Kaplan-Meier and Cox regression methods. Results: The median patient age was 64 (range, 19–86) and 66% were men. All patients had histologically proven HCC. The median follow-up time was 34 months (range, 1–297). Factors associated with increased EBL on multivariate analysis were male gender, vascular invasion, extent of hepatectomy, and operative time (P < 0.01). EBL and vascular invasion were independent predictors of OS and DSS. Only EBL was significantly associated with RFS on multivariate analysis (P = 0.02). Additionally, we found a significant inverse correlation between increasing levels of EBL and length of DSS (P = 0.01). Conclusions: The magnitude of EBL during HCC resection is related to biologic characteristics of the tumor as well as the extent of surgery. Increased intraoperative blood loss during HCC resection is an independent prognostic factor for tumor recurrence and death. We studied the relationship between blood loss and long-term outcomes in 192 patients after resection of hepatocellular carcinoma. Increased intraoperative blood loss was significantly associated with an increased risk of recurrence and death independent of allogeneic transfusion or American Joint Committee on Cancer staging components after hepatocellular carcinoma resection.

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.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.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).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.

Abstract Purpose: Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be prognostic biomarkers and/or predictive of drug response. Experimental Design: Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next-generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes. Fisher exact tests were performed to identify associations between clinical characteristics and genetic alterations. Results: A total of 195 patients were studied: 78% intrahepatic and 22% extrahepatic cholangiocarcinoma. The most commonly altered genes in intrahepatic cholangiocarcinoma were IDH1 (30%), ARID1A (23%), BAP1 (20%), TP53 (20%), and FGFR2 gene fusions (14%). A tendency toward mutual exclusivity was seen between multiple genes in intrahepatic cholangiocarcinoma including TP53:IDH1, IDH1:KRAS, TP53:BAP1, and IDH1:FGFR2. Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease. Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker-directed therapy or clinical trial enrollment in 16% of patients. Conclusions: Cholangiocarcinoma is a genetically diverse cancer. Alterations in CDKN2A/B and ERBB2 are associated with negative prognostic implications in patients with advanced disease. Somatic alterations with therapeutic implications were identified in almost half of patients. These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers. Clin Cancer Res; 24(17); 4154–61. ©2018 AACR.

Postoperative pancreatic fistula is a major contributor to complications and death associated with pancreatic resection. Pasireotide, a somatostatin analogue that has a longer half-life than octreotide and a broader binding profile, decreases pancreatic exocrine secretions and may prevent postoperative pancreatic fistula.We conducted a single-center, randomized, double-blind trial of perioperative subcutaneous pasireotide in patients undergoing either pancreaticoduodenectomy or distal pancreatectomy. We randomly assigned 300 patients to receive 900 μg of subcutaneous pasireotide (152 patients) or placebo (148 patients) twice daily beginning preoperatively on the morning of the operation and continuing for 7 days (14 doses). Randomization was stratified according to the type of resection and whether the pancreatic duct was dilated at the site of transection. The primary end point was the development of pancreatic fistula, leak, or abscess of grade 3 or higher (i.e., requiring drainage).The primary end point occurred in 45 of the 300 patients (15%). The rate of grade 3 or higher postoperative pancreatic fistula, leak, or abscess was significantly lower among patients who received pasireotide than among patients who received placebo (9% vs. 21%; relative risk, 0.44; 95% confidence interval [CI], 0.24 to 0.78; P=0.006). This finding was consistent among 220 patients who underwent pancreaticoduodenectomy (10% vs. 21%; relative risk, 0.49; 95% CI, 0.25 to 0.95) and 80 patients who underwent distal pancreatectomy (7% vs. 23%; relative risk, 0.32; 95% CI, 0.10 to 0.99), as well as among 136 patients with a dilated pancreatic duct (2% vs. 15%; relative risk, 0.11; 95% CI, 0.02 to 0.60) and 164 patients with a nondilated pancreatic duct (15% vs. 27%; relative risk, 0.55; 95% CI, 0.29 to 1.01).Perioperative treatment with pasireotide decreased the rate of clinically significant postoperative pancreatic fistula, leak, or abscess. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00994110.).

An American Hepato-Pancreato-Biliary Association (AHPBA)-sponsored consensus meeting of expert panellists was convened on 15 January 2014 to review current evidence on the management of gallbladder carcinoma in order to establish practice guidelines. In summary, within high incidence areas, the assessment of routine gallbladder specimens should include the microscopic evaluation of a minimum of three sections and the cystic duct margin; specimens with dysplasia or proven cancer should be extensively sampled. Provided the patient is medically fit for surgery, data support the resection of all gallbladder polyps of >1.0 cm in diameter and those with imaging evidence of vascular stalks. The minimum staging evaluation of patients with suspected or proven gallbladder cancer includes contrasted cross-sectional imaging and diagnostic laparoscopy. Adequate lymphadenectomy includes assessment of any suspicious regional nodes, evaluation of the aortocaval nodal basin, and a goal recovery of at least six nodes. Patients with confirmed metastases to N2 nodal stations do not benefit from radical resection and should receive systemic and/or palliative treatments. Primary resection of patients with early T-stage (T1b-2) disease should include en bloc resection of adjacent liver parenchyma. Patients with T1b, T2 or T3 disease that is incidentally identified in a cholecystectomy specimen should undergo re-resection unless this is contraindicated by advanced disease or poor performance status. Re-resection should include complete portal lymphadenectomy and bile duct resection only when needed to achieve a negative margin (R0) resection. Patients with preoperatively staged T3 or T4 N1 disease should be considered for clinical trials of neoadjuvant chemotherapy. Following R0 resection of T2-4 disease in N1 gallbladder cancer, patients should be considered for adjuvant systemic chemotherapy and/or chemoradiotherapy.

International challenges have become the de facto standard for comparative assessment of image analysis algorithms given a specific task. Segmentation is so far the most widely investigated medical image processing task, but the various segmentation challenges have typically been organized in isolation, such that algorithm development was driven by the need to tackle a single specific clinical problem. We hypothesized that a method capable of performing well on multiple tasks will generalize well to a previously unseen task and potentially outperform a custom-designed solution. To investigate the hypothesis, we organized the Medical Segmentation Decathlon (MSD) - a biomedical image analysis challenge, in which algorithms compete in a multitude of both tasks and modalities. The underlying data set was designed to explore the axis of difficulties typically encountered when dealing with medical images, such as small data sets, unbalanced labels, multi-site data and small objects. The MSD challenge confirmed that algorithms with a consistent good performance on a set of tasks preserved their good average performance on a different set of previously unseen tasks. Moreover, by monitoring the MSD winner for two years, we found that this algorithm continued generalizing well to a wide range of other clinical problems, further confirming our hypothesis. Three main conclusions can be drawn from this study: (1) state-of-the-art image segmentation algorithms are mature, accurate, and generalize well when retrained on unseen tasks; (2) consistent algorithmic performance across multiple tasks is a strong surrogate of algorithmic generalizability; (3) the training of accurate AI segmentation models is now commoditized to non AI experts.

Transarterial chemoembolization is accepted therapy for hepatocellular carcinoma (HCC). No randomized trial has demonstrated superiority of chemoembolization compared with embolization, and the role of chemotherapy remains unclear. This randomized trial compares the outcome of embolization using microspheres alone with chemoembolization using doxorubicin-eluting microspheres.At a single tertiary referral center, patients with HCC were randomly assigned to embolization with microspheres alone (Bead Block [BB]) or loaded with doxorubicin 150 mg (LC Bead [LCB]). Random assignment was stratified by number of embolizations to complete treatment, and assignments were generated by permuted blocks in the institutional database. The primary end point was response according to RECIST 1.0 (Response Evaluation Criteria in Solid Tumors) using multiphase computed tomography 2 to 3 weeks post-treatment and then at quarterly intervals, with the reviewer blinded to treatment allocation. Secondary objectives included safety and tolerability, time to progression, progression-free survival, and overall survival. This trial is currently closed to accrual.Between December 2007 and April 2012, 101 patients were randomly assigned: 51 to BB and 50 to LCB. Demographics were comparable: median age, 67 years; 77% male; and 22% Barcelona Clinic Liver Cancer stage A and 78% stage B or C. Adverse events occurred with similar frequency in both groups: BB, 19 of 51 patients (38%); LCB, 20 of 50 patients (40%; P = .48), with no difference in RECIST response: BB, 5.9% versus LCB, 6.0% (difference, -0.1%; 95% CI, -9% to 9%). Median PFS was 6.2 versus 2.8 months (hazard ratio, 1.36; 95% CI, 0.91 to 2.05; P = .11), and overall survival, 19.6 versus 20.8 months (hazard ratio, 1.11; 95% CI, 0.71 to 1.76; P = .64) for BB and LCB, respectively.There was no apparent difference between the treatment arms. These results challenge the use of doxorubicin-eluting beads for chemoembolization of HCC.

To determine the survival impact of adding extensive upper abdominal surgical cytoreduction to standard surgical techniques for advanced ovarian cancer.The records of all patients with stages IIIC-IV epithelial ovarian cancer who underwent primary surgery at our institution from 1998 to 2003 were reviewed. The cohort was divided into 3 groups. Group 1 patients required extensive upper abdominal surgery, such as diaphragm peritonectomy/resection, resection of parenchymal liver or porta hepatis disease and/or splenectomy with or without distal pancreatectomy, to achieve optimal cytoreduction (residual disease<or=1 cm). Group 2 patients were optimally cytoreduced by standard surgical techniques, including hysterectomy, oophorectomy, omentectomy, and bowel resection. Group 3 patients were suboptimally cytoreduced. Primary outcome measures were response to primary chemotherapy, progression-free survival, and overall survival.The cohort of 262 patients was divided as follows: Group 1, 57 patients; Group 2, 122 patients; and Group 3, 83 patients. The median follow-up was 36 months (range, 1-94 months). Frequency of clinical complete response in Groups 1, 2, and 3 was 82%, 78%, and 57%, respectively. The median progression-free survival for Groups 1, 2, and 3 was 24, 23, and 11 months, respectively. Progression-free survival for Groups 1 and 2 were equivalent (P=0.53) and were significantly longer than for Group 3 (P<0.001). The median overall survival was 84 and 38 months for Groups 2 and 3, respectively, and had not been reached for Group 1 by 68 months. Patients in Group 1 had equivalent overall survival to patients in Group 2 (P=0.74) and improved survival over patients in Group 3 (P<0.001). Prognostic factors significant on multivariate analysis included stage, optimal status, and ascites.Patients requiring extensive upper abdominal procedures to achieve optimal cytoreduction demonstrated a similar initial response, progression-free survival, and overall survival to patients optimally cytoreduced by standard surgical techniques. The presence of bulky upper abdominal disease alone did not appear to indicate poor tumor biology. This initial maximal surgical effort was associated with improved survival in patients who would have otherwise been suboptimally cytoreduced.

To identify predictors of oncologic outcomes after percutaneous radiofrequency ablation (RFA) of colorectal cancer liver metastases (CLMs) and to describe and evaluate a modified clinical risk score (CRS) adapted for ablation as a patient stratification and prognostic tool.This study consisted of a HIPAA-compliant institutional review board-approved retrospective review of data in 162 patients with 233 CLMs treated with percutaneous RFA between December 2002 and December 2012. Contrast material-enhanced CT was used to assess technique effectiveness 4-8 weeks after RFA. Patients were followed up with contrast-enhanced CT every 2-4 months. Overall survival (OS) and local tumor progression-free survival (LTPFS) were calculated from the time of RFA by using the Kaplan-Meier method. Log-rank tests and Cox regression models were used for univariate and multivariate analysis to identify predictors of outcomes.Technique effectiveness was 94% (218 of 233). Median LTPFS was 26 months. At univariate analysis, predictors of shorter LTPFS were tumor size greater than 3 cm (P < .001), ablation margin size of 5 mm or less (P < .001), high modified CRS (P = .009), male sex (P = .03), and no history of prior hepatectomy (P = .04) or hepatic arterial infusion chemotherapy (P = .01). At multivariate analysis, only tumor size greater than 3 cm (P = .01) and margin size of 5 mm or less (P < .001) were independent predictors of shorter LTPFS. Median and 5-year OS were 36 months and 31%. At univariate analysis, predictors of shorter OS were tumor size larger than 3 cm (P = .005), carcinoembryonic antigen level greater than 30 ng/mL (P = .003), high modified CRS (P = .02), and extrahepatic disease (EHD) (P < .001). At multivariate analysis, tumor size greater than 3 cm (P = .006) and more than one site of EHD (P < .001) were independent predictors of shorter OS.Tumor size of less than 3 cm and ablation margins greater than 5 mm are essential for satisfactory local tumor control. Tumor size of more than 3 cm and the presence of more than one site of EHD are associated with shorter OS.

PURPOSE To determine the conversion to resectability in patients with unresectable liver metastases from colorectal cancer treated with hepatic arterial infusion (HAI) plus systemic oxaliplatin and irinotecan (CPT-11). PATIENTS AND METHODS Forty-nine patients with unresectable liver metastases (53% previously treated with chemotherapy) were enrolled onto a phase I protocol with HAI floxuridine and dexamethasone plus systemic chemotherapy with oxaliplatin and irinotecan. Results Ninety-two percent of the 49 patients had complete (8%) or partial (84%) response, and 23 (47%) of the 49 patients were able to undergo resection in a group of patients with extensive disease (73% with > five liver lesions, 98% with bilobar disease, 86% with > or = six segments involved). For chemotherapy-naïve and previously treated patients, the median survival from the start of HAI therapy was 50.8 and 35 months, respectively. The only baseline variable significantly associated with a higher resection rate was female sex. Variables reflecting extensive anatomic disease, such as number of lesions or number of vessels involved, were not significantly associated with the probability of resection. CONCLUSION The combination of regional HAI floxuridine/dexamethasone and systemic oxaliplatin and irinotecan is an effective regimen for the treatment of patients with unresectable liver metastases from colorectal cancer, demonstrating a 47% conversion to resection (57% in chemotherapy-naïve patients). Future randomized trials should compare HAI plus systemic chemotherapy with systemic therapy alone to assess the additional value of HAI therapy in converting patients with hepatic metastases to resectability.

Although (18)F-fluorodeoxyglucose positron emission tomography (PET) has widespread clinical use, its role in cancers of the biliary tract is ill-defined. The aim of this study was to determine if preoperative PET provided additional staging information in patients with biliary tract cancer, beyond that obtained through conventional anatomic imaging. The role of PET in detecting disease recurrence after resection was also examined.Between March 2001 and October 2003, 126 patients with biopsy-proved or presumed biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma and gallbladder carcinoma) underwent PET in addition to standard imaging evaluation. Histologic confirmation of the diagnosis was used as the reference standard with which PET results were compared. Patient followup information and serial imaging were reviewed for progression of lesions detected by PET.Of the 126 study patients, 93 (74%) underwent preoperative staging PET scans, the results of which changed the stage and treatment in 22 patients (24%): 15 of 62 (24%) with cholangiocarcinoma and 7 of 31 (23%) with gallbladder carcinoma. When used to assess for cancer recurrence (n=33), PET identified disease in 86% of patients but altered treatment in only 9%. So, of the entire study group, the findings of PET influenced management in 20% of patients (24% preoperative staging and 9% cancer recurrence). The sensitivity of PET for identifying the primary tumor was 80% overall: 78% for cholangiocarcinoma, 86% for gallbladder carcinoma.Most biliary tract cancers are (18)F-fluorodeoxyglucose avid tumors. In patients with potentially resectable tumors based on conventional imaging, PET identified occult metastatic disease and changed management in nearly one-fourth of all patients. PET also helped confirm recurrent cancer after resection.

Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression.

BACKGROUND: Ablation is increasingly used to treat primary and secondary liver cancer. Ablation near portal pedicles and hepatic veins is challenging. Irreversible electroporation (IRE) is a new ablation technique that does not rely on heat and, in animals, appears to be safe and effective when applied near hepatic veins and portal pedicles. This study evaluated the safety and short-term outcomes of IRE to ablate perivascular malignant liver tumors. STUDY DESIGN: A retrospective review of patients treated with IRE between January 1, 2011 and November 2, 2011 was performed. Patients were selected for IRE when resection or thermal ablation was not indicated due to tumor location. Treatment outcomes were classified by local, regional, and systemic recurrence and complications. Local failure was defined as abnormal enhancement at the periphery of an ablation defect on post-procedure contrast imaging. RESULTS: Twenty-eight patients had 65 tumors treated. Twenty-two patients (79%) were treated via an open approach and 6 (21%) were treated percutaneously. Median tumor size was 1 cm (range 0.5 to 5 cm). Twenty-five tumors were <1 cm from a major hepatic vein; 16 were <1 cm from a major portal pedicle. Complications included 1 intraoperative arrhythmia and 1 postoperative portal vein thrombosis. Overall morbidity was 3%. There were no treatment-associated mortalities. At median follow-up of 6 months, there was 1 tumor with persistent disease (1.9%) and 3 tumors recurred locally (5.7%). CONCLUSIONS: This early analysis of IRE treatment of perivascular malignant hepatic tumors demonstrates safety for treating liver malignancies. Larger studies and longer follow-up are necessary to determine long-term efficacy.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients 1 , yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3 . Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA–lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8 + T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.

HepatologyVolume 56, Issue 4 p. 1352-1360 Hepatobiliary MalignanciesFree Access Intraductal papillary neoplasm of the bile duct: A biliary equivalent to intraductal papillary mucinous neoplasm of the pancreas?† Flavio G. Rocha, Flavio G. Rocha Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorHwajeong Lee, Hwajeong Lee Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorNora Katabi, Nora Katabi Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorRonald P. DeMatteo, Ronald P. DeMatteo Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorYuman Fong, Yuman Fong Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorMichael I. D'Angelica, Michael I. D'Angelica Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorPeter J. Allen, Peter J. Allen Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorDavid S. Klimstra, David S. Klimstra Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorWilliam R. Jarnagin, Corresponding Author William R. Jarnagin [email protected] Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NYHepatopancreatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065===Search for more papers by this author Flavio G. Rocha, Flavio G. Rocha Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorHwajeong Lee, Hwajeong Lee Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorNora Katabi, Nora Katabi Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorRonald P. DeMatteo, Ronald P. DeMatteo Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorYuman Fong, Yuman Fong Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorMichael I. D'Angelica, Michael I. D'Angelica Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorPeter J. Allen, Peter J. Allen Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorDavid S. Klimstra, David S. Klimstra Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NYSearch for more papers by this authorWilliam R. Jarnagin, Corresponding Author William R. Jarnagin [email protected] Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NYHepatopancreatobiliary Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065===Search for more papers by this author First published: 13 April 2012 https://doi.org/10.1002/hep.25786Citations: 187 † Potential conflict of interest: Nothing to report. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Intraductal papillary neoplasm of the bile duct (IPNB) is a variant of bile duct carcinoma characterized by intraductal growth and better outcome compared with the more common nodular-sclerosing type. IPNB is a recognized precursor of invasive carcinoma, but its pathogenesis and natural history are ill-defined. This study examines the clinicopathologic features and outcomes of IPNB. A consecutive cohort of patients with bile duct cancer (hilar, intrahepatic, or distal) was reviewed, and those with papillary histologic features identified. Histopathologic findings and immunohistochemical staining for tumor markers and for cytokeratin and mucin proteins were used to classify IPNB into subtypes. Survival data were analyzed and correlated with clinical and pathologic parameters. Thirty-nine IPNBs were identified in hilar (23/144), intrahepatic (4/86), and distal (12/113) bile duct specimens between 1991 and 2010. Histopathologic examination revealed 27 pancreatobiliary, four gastric, two intestinal, and six oncocytic subtypes; results of cytokeratin and mucin staining were similar to those of intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Invasive carcinoma was seen in 29/39 (74%) IPNBs. Overall median survival was 62 months and was not different between IPNB locations or subtypes. Factors associated with a worse median survival included presence and depth of tumor invasion, margin-positive resection, and expression of MUC1 and CEA. Conclusion: IPNBs are an uncommon variant of bile duct cancer, representing approximately 10% of all resectable cases. They occur throughout the biliary tract, share some histologic and clinical features with IPMNs of the pancreas, and may represent a carcinogenesis pathway different from that of conventional bile duct carcinomas arising from flat dysplasia. Given their significant risk of harboring invasive carcinoma, they should be treated with complete resection. (HEPATOLOGY 2012) Cancer of the bile duct (cholangiocarcinoma or adenocarcinoma of the extrahepatic bile ducts) can occur anywhere along the biliary tree. In the United States, approximately 2000 to 3000 cases are diagnosed each year, representing 3% of all gastrointestinal malignancies.1 Historically, tumors arising from the biliary confluence or hilar cholangiocarcinoma have been the most common, but recent epidemiologic data suggest a rising incidence of intrahepatic cholangiocarcinoma.2 Papillary cholangiocarcinoma is a rare variant of this disease compared with the more common mass-forming or periductal infiltrating phenotypes in the intrahepatic biliary tree or the nodular-sclerosing phenotype of extrahepatic biliary tumors. Due to the exophytic nature of the lesions and intraductal growth pattern, papillary cholangiocarcinomas appear to have a more favorable prognosis. We have previously demonstrated, in a cohort of patients with hilar cholangiocarcinoma, that the papillary phenotype was associated with improved survival.3 Several reports from Asia have suggested that the progression of papillary biliary neoplasia from benign lesions to invasive cancers may represent an analogous pathway to that of intraductal papillary mucinous neoplasm of the pancreas.4-7 Because both the bile ducts and the pancreas develop from the ventral endoderm of the foregut, some authors have suggested that these may develop malignancies along similar genetic and molecular oncologic pathways.8 However, although intrahepatic stones and liver fluke infestation have been associated with papillary lesions of the bile duct in the Far East, the etiology and malignant potential of this tumor have not been examined in detail.9 In addition, unlike their pancreatic counterparts, very little is known about the molecular pathways and prognostic variables in papillary bile duct tumors. It was only recently that the World Health Organization recognized intraductal papillary neoplasm of the bile duct (IPNB) as a distinct pathologic entity.10 The purpose of this study was to define the natural history of this lesion in a Western patient cohort and to examine its putative tumor markers. Abbreviations BilIN, biliary intraepithelial neoplasia; IPMN, intraductal papillary mucinous neoplasm; IPNB, intraductal papillary neoplasm of the bile duct. Patients and Methods This study was approved by the Institutional Review Board at Memorial Sloan-Kettering Cancer Center. All cases of resected intrahepatic, hilar, and extrahepatic bile duct tumors with gross and microscopic features of intraductal growth were retrieved from the surgical pathology files (1981-2010) using SNOMED II (Systematized Nomenclature of Medicine). Search criteria included the terms “biliary,” “intraductal,” “cholangiocarcinoma,” “adenocarcinoma,” and “papillary.” In addition, a prospectively maintained database of bile duct tumors from the Hepatopancreatobiliary Service since 1991 was queried, and all papillary bile duct tumors were selected for histologic review. Pancreatic intraductal papillary mucinous neoplasms, ampullary and periampullary tumors of uncertain origin, and cases with intraductal epithelial dysplasia/neoplasia without compelling evidence of intraductal mass formation (biliary intraepithelial neoplasia) were excluded. Individual and departmental consult cases, biopsy cases, and cases with insufficient tissue for analysis were excluded from the study. Patients with bile duct tumors containing intraductal growth between 1993 and 2010 were identified. Available slides from the retrieved cases (5-61 hematoxylin and eosin slides per case) were reviewed, and slides containing tumors (1-33 hematoxylin and eosin slides per case) were examined. Tumors were evaluated for overall architecture (papillary, tubular, solid), epithelial subtype (pancreatobiliary, intestinal, oncocytic, gastric), grade of dysplasia, presence of extraductal invasion, depth of extraductal invasive component, percentage of intraductal invasion in relation to intraductal tumor volume, growth pattern of invasive components, lymphovascular invasion, perineural invasion, lymph node metastasis, and resection margin status. Information on gross tumor size and any associated cyst formation was obtained from surgical pathology reports. Anatomic location of the tumors was confirmed by pathologic, radiographic, and operative findings. Choledocholithiasis, history of parasite exposure, underlying liver disease including viral infection, and autoimmune liver disease were noted. Formalin-fixed and paraffin-embedded tissue blocks were available in 32 cases, and one to two representative blocks from each case were subjected to immunohistochemical staining. In one case, six stained slides from a tissue block were available for review without the original block. In another case, immunohistochemical staining was performed on a tissue block from a locally recurrent tumor. Staining by hematoxylin and eosin as well as 16 immunostains was performed on 4-μm-thick tissue sections from the representative tissue blocks (Table 1). The staining patterns were separately documented for the invasive and noninvasive components, when both components were present, on selected tissue blocks. A binary system (positive or negative) was employed for the evaluation of staining. The cutoff for positive staining was 10% for CDX2, mesothelin, CEA, B72.3, HepPar1, MUC1, MUC2, MUC5AC, and MUC6 and was 25% for CK7, CK20, and p53. The cutoff of positivity for CA125 and Ki67 was 50%. Table 1. Antibodies for Immunohistochemistry Antigen Manufacturer Dilution Clone Pretreatment Method CK7 Dako 1:1000 OV-TL Ventana CK20 Dako 1:1000 Ks20.8 Ventana CEA-m Dako 1:500 11-7 Citrate buffer Manual CDX2 Cell Marque 1:90 EPR2764Y Ventana MUC1 Vector 1:100 Ma695 Ventana MUC2 Vector 1:200 Ccp58 Citrate buffer Manual MUC5AC NovaCastro 1:400 CLH2 Citrate buffer Manual MUC6 BD Pharmingen 1:100 CLH5 Ventana B72.3 BioGenics 1:400 B72.3 Ventana CA125 Ventana Prediluted OC125 Ventana Mesothelin Vector 1:50 5B2 Ventana Ki67 Dako 1:200 Mib1 Ventana p53 Dako 1:500 DO7 Ventana SMAD4 Santa Cruz Biotechnology 1:800 B-8 Citrate buffer Manual HepPar1 Dako 1:500 OCH1E5 Citrate buffer Manual β-Catenin BD Transduction 1:2000 14 Ventana Clinical data were obtained from the electronic medical record or outside medical reports. Demographic, preoperative evaluation, operative therapy, postoperative course, long-term outcome, and recurrence patterns were included. Survival (in months) was measured from the date of operation, to date of death or date of last follow-up. Statistical analysis was performed using Stata 7.0. Continuous variables were compared using the Student t test, and categorical variables were compared using a chi-square test. Survival probability was estimated using the Kaplan-Meier method, and comparison between groups was performed using a log-rank test. A P value of < 0.05 was considered statistically significant. Results Demographics. Thirty-nine (11%) cases of intraductal papillary neoplasm were identified from a total of 343 bile duct tumors resected from 1991 to 2010. The mean age was 67 years, and men (67%) were more commonly affected. The most common presenting symptom was abdominal pain (39%), followed by jaundice (36%) and elevations in liver function tests (15%); less common was cholangitis (5%); 5% of patients were asymptomatic (Table 2). The symptoms did not differ significantly between invasive and noninvasive lesions. Table 2. Clinicopathologic Features of IPNB Feature Value Patients, n 39 Mean age, years 67 Sex, n Men 26 Women 13 Mean tumor size, cm 4.5 Presence of cyst/mucin/stones, n 5/3/1 Presenting symptoms, n (%) Abdominal pain 15 (39) Jaundice 14 (36) Elevated liver enzymes 6 (15) Cholangitis 2 (5) Asymptomatic 2 (5) Location, n (%) Hilar 3/144 (16) Intrahepatic 4/86 (5) Distal 12/113 (11) Total 39/343 (11) Operation, n Left hepatectomy 14 Right hepatectomy 2 Extended right 6 Extended left 2 Pancreatico-duodenectomy 12 Bile duct excision 3 Invasive component, n (%) 29/39 (74) Lymph node metastasis, n (%) 1/33 (3) Overall median survival, months 62 5-Year survival, % 50 Recurrence, n Locoregional 7 Distant 7 Combined 6 Treatment. Five tumors had cystic dilatations of the bile ducts but only three contained gross mucin, and one tumor occurred in conjunction with intrahepatic stones. The majority of tumors were located at the biliary confluence (59%), followed by the distal common bile duct (31%); tumors were least common within the liver (10%). However, the highest frequency of invasive lesions was found in the distal bile duct (93%) followed by the hilus (65%) and liver (25%). The most commonly performed procedure was a left hepatectomy, in 16 patients, compared with a right hepatectomy, in eight patients, and 12 patients required a pancreaticoduodenectomy for tumor clearance. Three patients underwent a bile duct excision alone. Two patients received adjuvant chemotherapy, and another two patients received adjuvant chemoradiation therapy. Pathology. Papillary architecture was noted in 31/39 IPNBs, whereas the remaining eight cases expressed tubular architecture, including one carcinosarcoma with rare tubules. All tumors were classified according to epithelial subtypes of the intraductal component (Fig. 1). The most common epithelial subtype was pancreatobiliary (n = 27 [69%]), followed by oncocytic (n = 6, [15%]), gastric (n = 4, [10%]), and intestinal (n = 2 [5%]). More than one epithelial type was recognized in the same tumor in 14 cases, including one case with squamous type epithelium, but the subtype was designated based on the dominant pattern. Figure 1Open in figure viewerPowerPoint Histologic appearance of epithelial subtypes of IPNB (magnification ×200). (A) Gastric-type epithelium resembling pyloric glands. (B) Intestinal-type epithelium resembling colonic adenocarcinoma with elongated, stratified, and hyperchromatic nuclei. (C) Oncocytic-type epithelium consisting of relatively uniform cells with abundant eosinophilic cytoplasm and centrally located nuclei with prominent nucleoli was associated with occasional intraepithelial mucin-containing lumen formation. (D) Pancreatobiliary-type epithelium resembling monolayered malignant biliary epithelium with marked nuclear pleomorphism and high nuclear-to-cytoplasmic ratio. An invasive component was found in 29/39 cases, and whereas 6/10 noninvasive cases exhibited high-grade dysplasia, all invasive cases had high-grade dysplasia in the intraductal components. Twenty-seven out of 29 IPNBs with invasive components exhibited tubular carcinomas, three of which included anaplastic, squamous, or papillary features within the invasive tumor without mucin. Of the remaining two cases, one case showed invasive colloid carcinoma, and the other showed mucinous features with a minimal invasive component precluding the histologic typing of the invasive carcinoma. The latter two carcinomas with mucin were associated with an oncocytic type IPNB. In one case, invasive tumor was tubular with pancreatobiliary subtype, while the intraductal counterpart was pure intestinal subtype. Of the 10 cases without microscopic evidence of invasion, five cases showed gastric type epithelium in the intraductal tumor as either predominant epithelial type, or minor type mixed with another predominant type. Of the 29 invasive carcinomas, 16 had <5 mm of extraductal invasion, whereas 13 had ≥5 mm. Lymphovascular invasion was noted in 6 patients and perineural invasion was noted in nine patients. Of 33 patients submitted to a concomitant porta hepatis lymphadenectomy, only one had nodal metastases (1/22 lymph nodes involved with cancer). The majority of invasive carcinomas (20/29) were moderately differentiated, with only one well-differentiated and eight poorly differentiated. Immunohistochemical staining (Table 3) revealed that the majority of pancreatobiliary subtypes expressed MUC1 (19/23) and CK7 (22/23), whereas very few expressed MUC2 (3/23) or CDX2 (4/23). Similarly, the gastric subtypes all expressed MUC1 (3/3) and CK7 (3/3), but none expressed MUC2 or CDX 2. In contrast, intestinal-type tumors were MUC2+ (1/2), MUC1− (0/2), and both CK7 and CK20 were positive (2/2). Oncocytic tumors were MUC5AC+ (5/5) and MUC6+ (4/5). Invasive carcinoma components were noted in 100% of the intestinal tumors, 80% of pancreatobiliary tumors, 60% of oncocytic tumors, and 25% of gastric tumors. Table 3. Immunohistochemical Profiles of IPNB Subtype MUC1 MUC2 MUC5AC MUC6 CDX2 CK7 CK20 CEA Gastric/Pyloric (n = 3) 3 0 2 3 0 3 0 2 Intestinal (n = 2) 0 1 0 0 2 2 2 2 Oncocytic (n = 5) 3 2 5 4 0 3 0 1 Pancreatobiliary (n = 23) 19 3 10 13 4 22 3 11 Outcome. There was one operative mortality (3%) due to overwhelming multiorgan failure after extended right hepatectomy. There were 21 complications in 15 patients with an overall morbidity rate of 38%. Intra-abdominal abscess requiring drainage accounted for 29% (6/21) of the complications, whereas gastrointestinal complications of delayed gastric emptying, ascites, and anastomotic leak occurred in two patients each. One patient developed respiratory failure; two patients developed postoperative hemorrhage; one patient developed a deep venous thrombosis. Margin-negative resection was achieved in 30 (77%) patients, and nine (23%) patients had an R1 resection. Overall median survival was 62 months for the entire cohort and 49 months for the cases with an invasive component at a median follow-up of 86 months. Of the 20 documented recurrences, seven were locoregional, seven were distant, and six were both. In patients with R1 resections, 7/9 recurred compared with 11/30 in patients with R0 resections. Of the 10 patients with noninvasive tumors, all had R0 resections and two had a recurrence with an invasive component (one local, one distant), both at 5 years after resection. On univariate analysis, neither age nor sex was associated with survival. In addition, there was no difference in survival based on location of the primary tumor (hilar, distal, or intrahepatic) or epithelial subtypes. R0 resection was associated with an improved median survival of 82 months, compared with 36 months in the R1 resection group (P < 0.04). Both presence and depth of an invasive component correlated with survival. Depth of invasion, graded as ≥5 mm, <5 mm, and none, was associated with a survival of 39 months, 128 months, and 144 months, respectively (P < 0.007) (Fig. 2). In addition, percentage of invasive carcinoma components, graded as ≥10%, <10%, and none, was associated with a survival of 42 months, 128 months, and 144 months, respectively (P < 0.03). Patients with poorly differentiated carcinomas as well as those with lymphovascular invasion also suffered a worse outcome (Table 4). However, margin status did not affect survival in the cases with an invasive component. Figure 2Open in figure viewerPowerPoint Kaplan-Meier survival estimates of overall survival (A) and disease-specific survival (B) according to depth of extraductal invasion (none, <5 mm, and ≥5 mm) and resection type (R0 versus R1). P < 0.05 was considered significant. Table 4. Univariate Analysis of Clinicaopathologic Features Feature n Median Survival (Months) P Value Clinical features Age, years 0.42 ≥70 21 59 <70 18 82 Sex 0.89 Men 26 62 Women 13 83 Subtype 0.69 Gastric/Pyloric 4 58 Intestinal 2 NR Oncocytic 6 82 Pancreatobiliary 27 53 Location 0.31 Hilar 23 82 Intrahepatic 4 33 Distal 12 49 Resection type 0.04 R0 30 82 R1 9 36 Pathologic features Depth of invasion 0.007 None 10 10 <5 mm 16 16 ≥5 mm 13 13 Extraductal invasion 0.03 None 10 10 <10% 13 13 ≥10% 16 16 Grade of invasion 0.04 Well 1 NR Moderate 20 62 Poor 8 32 Perineural invasion 0.10 Absent 20 53 Present 9 39 Lymphovascular invasion 0.04 Absent 23 53 Present 6 28 Abbreviation: NR, not reached. Of the immunohistochemical stains used in this study, only MUC1 and CEA were associated with a poorer prognosis. Patients whose tumors expressed MUC1 had a median survival of 58 months versus144 months in patients whose tumors lacked MUC1 expression (P < 0.009). The median survival of patients with CEA+ tumors was 42 months versus 128 months in patients with CEA− tumors (P < 0.01). When considering only the cases with an invasive component, MUC1 expression remained a statistically significant predictor of survival, whereas CEA lost significance. None of the other MUC proteins (CA 125, mesothelin, Ki67, p53, B72.3, or HepPar-1) was associated with survival (Table 5). Table 5. Univariate Analysis of Tumor Markers Tumor Marker n Median Survival (in Months) P Value MUC1 0.009 Positive 22 58 Negative 12 144 MUC2 0.82 Positive 6 82 Negative 28 62 MUC5AC 0.85 Positive 17 82 Negative 17 62 MUC6 0.77 Positive 19 59 Negative 14 128 CDX2 0.14 Positive 6 42 Negative 27 82 CA125 0.33 Positive 5 33 Negative 28 128 CEA 0.01 Positive 16 42 Negative 17 128 Mesothelin 0.38 Positive 20 82 Negative 13 53 Ki67 0.66 Positive 14 59 Negative 19 82 p53 0.66 Positive 15 NR Negative 18 59 B72.3 0.17 Positive 21 128 Negative 13 53 HepPar1 0.56 Positive 14 82 Negative 20 62 Abbreviation: NR, not reached. Discussion Bile duct carcinoma usually develops through a multistep process involving one of two separate precursor pathways. The initial lesion is flat biliary dysplasia (biliary intraepithelial neoplasia [BilIN]) found in both the intra- and extrahepatic biliary tree and graded in severity as 1 (mild dysplasia), 2 (moderate dysplasia), or 3 (severe dysplasia/carcinoma in situ). This sequence resembles the progression of pancreatic intraepithelial neoplasia in pancreatic ductal adenocarcinoma. A less common variant is the intraductal papillary neoplasm characterized by exophytic proliferation of biliary epithelium on fibrovascular stalks within the bile duct lumen, sometimes associated with mucin hypersecretion and cystic dilatation of the affected bile ducts.11 These tumors can be entirely intraductal or they can have an associated invasive carcinoma component, and although many different terms have been used for this spectrum of neoplasms, recently they have been collectively termed IPNB. IPNBs can be separated from mucinous cystic neoplasms of the liver by their origin and connection to the biliary system. In addition, the latter lesion is characterized by an ovarian-type stroma resembling pancreatic mucinous cystic neoplasms.12 In the present study, 12% of resected bile duct carcinomas met the pathologic definition of IPNB.10 Previous reports found the incidence of IPNBs among all bile duct carcinomas to range from 7% to 38%.13, 14 However, unlike prior studies, mainly from Asia, there was a lack of association with hepatolithiasis or liver flukes in this cohort, as only one patient was found to have an intrahepatic stone and no infestations were noted. In addition, gross mucin production was present in only three cases. In two recent reports from Asia, tumors that secreted mucin were associated with decreased invasion and better survival,15, 16 but the protective role of mucin-producing tumors could not be assessed in the current study. The majority of lesions were found in the hilum and left-sided biliary ductal system. However, despite its variable location, the primary site did not affect the course of the disease or its prognosis, as there was no difference in survival according to anatomic site of origin. This finding was not surprising, because our previous analysis of extrahepatic bile duct carcinomas failed to demonstrate a difference in surgical outcomes or disease-specific survival between proximal and distal tumors after R0 resection.17 Another study of patients with IPNB did not find any clinical or pathologic differences based on primary tumor location.18 The immunohistochemical profiles of IPNBs in the present study were very similar to those published in cholangiocarcinoma as well as in pancreatic intraductal papillary mucinous neoplasm (IPMN). Zen et al.9 initially reported a series of 110 cases of biliary neoplasm associated with hepatolithiasis, separating cases of BilIN and IPNB by cytokeratin and mucin staining. Cholangiocarcinomas arising in association with BilIN progressed to tubular adenocarcinomas, while IPNB-associated tumors progressed to either tubular or colloid carcinomas in that study of Asian patients. A follow-up report comparing benign papillomatosis, noninvasive and invasive papillary cholangiocarcinomas, nonpapillary bile duct carcinomas, and IPMNs of the pancreas demonstrated that the pancreatobiliary subtype was present in 50% of papillary bile duct lesions and 100% of nonpapillary bile duct carcinomas. In contrast, most pancreatic IPMNs were of the gastric or intestinal subtype.4 MUC1 expression was found in all nonpapillary cholangiocarcinomas, compared with only 40% of IPNBs and 29% of IPMNs. Several studies have confirmed that the expression of MUC1 in cholangiocarcinoma is associated with poorer survival, suggesting that this phenotype is associated with more aggressive behavior.19, 20 The survival of patients with biliary papillary tumors also depended on the presence and histologic type of invasive carcinoma. Those with tubular adenocarcinomas had a prognosis similar to patients with nonpapillary tumors, whereas those with mucinous or colloid adenocarcinomas had a better prognosis, comparable to that of colloid carcinoma of the pancreas arising in association with an IPMN. In our cohort of IPNB, the majority of tumors (27/39) were pancreatobiliary subtype and MUC1+, which was associated with worse survival. A similar pattern of expression was seen in a smaller study where 7/9 IPNBs with pancreatobiliary subtype were MUC1+, with one being MUC2+, whereas 6/8 IPNBs with intestinal subtype were MUC2+ and none were stained for MUC1.21 We could only identify two cases of intestinal subtype, and although they were both MUC1+ and invasive, only one was associated with a mucinous carcinoma, whereas the other consisted of a tubular carcinoma. A larger study of 97 patients from Korea demonstrated a statistically significant increase of invasive tubular carcinoma in IPNBs with a pancreatobiliary subtype compared with other subtypes and was also associated with a poorer prognosis.22 When we compared the immunohistochemical profile of IPNBs to that of a series of 43 resected IPMNs of the pancreas,23 we noted several important similarities and differences. First, the majority of pancreatic tumors were gastric (56%) or intestinal (30%) subtypes, whereas only 9% were pancreatobiliary. Second, only 21% of IPMNs had an invasive component compared with 72% of IPNBs. So although both shared similar phenotypes and marker expression, the pattern shifted to the more aggressive MUC1-expressing pancreatobiliary subtype in IPNB, compared with the more indolent MUC2-expressing intestinal subtype in IPMN of the pancreas. A recent study from Europe directly comparing 20 IPNBs and 29 IPMNs supported the findings of the pres

Background Cystic lesions of the pancreas are being identified more frequently, and a selective approach to resection is now recommended. The aim of this study was to assess the change in presentation and management of pancreatic cystic lesions evaluated at a single institution over 15 years. Study Design A prospectively maintained registry of patients evaluated between 1995 and 2010 for the ICD-9 diagnosis of pancreatic cyst was reviewed. The 539 patients managed from 1995 to 2005 were compared with the 885 patients managed from 2005 to 2010. Results A total of 1,424 patients were evaluated, including 1,141 with follow-up >6 months. Initial management (within 6 months of first assessment) was operative in 422 patients (37%) and nonoperative in 719 patients (63%). Operative mortality in patients initially submitted to resection was 0.7% (n = 3). Median radiographic follow-up in patients initially managed nonoperatively was 28 months (range 6 to 175 months). Patients followed radiographically were more likely to have cysts that were asymptomatic (72% versus 49%, p < 0.001), smaller (1.5 versus 3 cm, p < 0.001), without solid component (94% versus 68%, p < 0.001), and without main pancreatic duct dilation (88% versus 61%, p < 0.001). Changes prompting subsequent operative treatment occurred in 47 patients (6.5%), with adenocarcinoma identified in 8 (17%) and pancreatic endocrine neoplasm in 4 (8.5%). Thus, of the 719 patients initially managed nonoperatively, invasive malignancy was identified in 12 (1.7%), with adenocarcinoma seen in 1.1%. Conclusion Cystic lesions of the pancreas are being identified more frequently, yet are less likely to present with concerning features of malignancy. Carefully selected patients managed nonoperatively had a risk of malignancy that was equivalent to the risk of operative mortality in those patients who initially underwent resection.

BACKGROUND: Complete resection of hilar cholangiocarcinoma (HCCA) is a critical determinant of long-term survival. This study validates a previously reported preoperative clinical T staging system for determining resectability of HCCA. STUDY DESIGN: Consecutive patients with confirmed HCCA treated over an 18-year period were included. Patient demographics, preoperative imaging studies, resection type, margin status, lymph node status, histopathologic findings, morbidity, and outcomes were entered prospectively and analyzed retrospectively; changes in these variables over time were assessed. All patients were placed into 1 of 3 stages based on the extent of ductal involvement by tumor, portal vein compromise, or lobar atrophy. RESULTS: From March 1991 through December 2008, 380 patients were evaluated. Eighty-five patients had unresectable disease; 295 patients underwent exploration with curative intent. One hundred fifty-seven patients underwent resection: 129 (82.2%) had a concomitant hepatic resection and 120 (76.4%) had an R0 resection. Of the 32 actual 5-year survivors (120 at risk), 30 patients (93.8%) had a concomitant hepatic resection. In patients who underwent an R0 resection, concomitant partial hepatectomy, well-differentiated histology, and negative lymph nodes were independent predictors of long-term survival. In the 376 patients whose disease could be staged, the preoperative clinical T staging system predicted resectability (p < 0.001), metastatic disease (p < 0.001), and R0 resection (p = 0.007). CONCLUSIONS: The preoperative clinical T staging system of Blumgart, defined by the radial and longitudinal tumor extent, accurately predicts resectability of HCCA. The full outcomes benefit of resection is realized only if a concomitant partial hepatectomy is performed.

The indications for minimally invasive (MIS) pancreatectomy have slowly increased as experience, techniques, and technology have improved and evolved to manage malignant lesions in selected patients without compromising safety and oncologic principles. There are sparse data comparing laparoscopic, robotic, and open distal pancreatectomy (DP).All patients undergoing DP at Memorial Sloan Kettering Cancer Center between 2000 and 2013 were analyzed from a prospective database. Clinicopathologic and survival data were analyzed to compare perioperative and oncologic outcomes in patients who underwent DP via open, laparoscopic, and robotic approaches.Eight hundred five DP were performed during the study period, comprising 37 robotic distal pancreatectomies (RDP), 131 laparoscopic distal pancreatectomies (LDP), and 637 open distal pancreatectomies (ODP). The 3 groups were similar with respect to American Society of Anesthesiologists (ASA) score, sex ratio, body mass index, pancreatic fistula rate, and 90-day morbidity and mortality. Patients in the ODP group were generally older (p = 0.001), had significantly higher intraoperative blood loss (p < 0.001), and had a trend toward a longer hospital stay (p = 0.05). Of the significant preoperative variables, visceral fat was predictive of conversion on multivariate analysis (p = 0.003). Oncologic outcomes in the adenocarcinoma cases were similar for the 3 groups, with high rates of R0 resection (88% to 100%). The ODP group had a higher lymph node yield than the LDP and RDP groups (15.4, [SD 8.7] vs 10.4 [SD 8.0] vs 12[SD 7.2], p = 0.04).The RDP and LDP were comparable with respect to most perioperative outcomes, with no clear advantage of one approach over the other. Both of these MIS techniques may have advantages over ODP in well-selected patients. All approaches achieved a similarly high rate of R0 resection for patients with adenocarcinoma.

Liver surgery for perihilar cholangiocarcinoma (PHC) is associated with postoperative mortality ranging from 5% to 18%. The aim of this study was to develop a preoperative risk score for postoperative mortality after liver resection for PHC, and to assess the effect of biliary drainage of the future liver remnant (FLR).A consecutive series of 287 patients submitted to major liver resection for presumed PHC between 1997 and 2014 at 2 Western centers was analyzed; 228 patients (79%) underwent preoperative drainage for jaundice. Future liver remnant volumes were calculated with CT volumetry and completeness of FLR drainage was assessed on imaging. Logistic regression was used to develop a mortality risk score.Postoperative mortality at 90 days was 14% and was independently predicted by age (odds ratio [OR] per 10 years = 2.1), preoperative cholangitis (OR = 4.1), FLR volume <30% (OR = 2.9), portal vein reconstruction (OR = 2.3), and incomplete FLR drainage in patients with FLR volume <50% (OR = 2.8). The risk score showed good discrimination (area under the curve = 0.75 after bootstrap validation) and ranking patients in tertiles identified 3 (ie low, intermediate, and high) risk subgroups with predicted mortalities of 2%, 11%, and 37%. No postoperative mortality was observed in 33 undrained patients with FLR volumes >50%, including 10 jaundiced patients (median bilirubin level 11 mg/dL).The mortality risk score for patients with resectable PHC can be used for patient counseling and identification of modifiable risk factors, which include FLR volume, FLR drainage status, and preoperative cholangitis. We found no evidence to support preoperative biliary drainage in patients with an FLR volume >50%.

Purpose: Molecular profiling in cancer has identified potential actionable drug targets that have prompted attempts to discover clinically validated biomarkers to guide therapeutic decision-making and enrollment to clinical trials. We evaluated whether comprehensive genetic analysis of patients with pancreatic adenocarcinoma is feasible within a clinically relevant timeframe and whether such analyses provide predictive and/or prognostic information along with identification of potential targets for therapy.Experimental Design: Archival or prospectively acquired FFPE samples and matched normal DNA from N = 336 patients with pancreatic cancer were analyzed using a hybridization capture-based, next-generation sequencing assay designed to perform targeted deep sequencing of all exons and selected introns of 410 key cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles.Results: The median time from protocol consent to reporting of the genomic results was 45 days with a median time from tissue delivery of 20 days. All genetic alterations identified were stratified based upon prior evidence that the mutation is a predictive biomarker of drug response using the MSKCC OncoKB classification. Three of 225 patients (1%) received a matched therapy based upon the sequencing results.Conclusions: The practical application of molecular results to guide individual patient treatment is currently limited in patients with pancreatic adenocarcinoma. Future prospective molecular profiling efforts should seek to incorporate routine germline genetic analysis and the identification of DNA profiles that predict for clinical benefit from agents that target DNA damage repair and or immunotherapy. Clin Cancer Res; 23(20); 6094-100. ©2017 AACR.

In Brief Objectives: The impact of margin width on overall survival (OS) in the context of other prognostic factors after resection for colorectal liver metastases is unclear. We evaluated the relationship between resection margin and OS utilizing high-resolution histologic distance measurements. Methods: A single-institution prospectively maintained database was queried for all patients who underwent an initial complete resection of colorectal liver metastases between 1992 and 2012. R1 resection was defined as tumor cells at the resection margin (0 mm). R0 resection was further divided into 3 groups: 0.1 to 0.9 mm, 1 to 9 mm, and 10 mm or greater. Results: A total of 4915 liver resections were performed at Memorial Sloan Kettering Cancer Center between 1992 and 2012, from which 2368 patients were included in the current study. Half of the patients presented with synchronous disease, 43% had solitary metastasis, and the median tumor size was 3.4 cm. With a median follow-up for survivors of 55 months, the median OS of the R1, 0.1 to 0.9 mm, 1 to 9 mm, and 10 mm or more groups was 32, 40, 53, and 56 months, respectively (P < 0.001). Compared with R1 resection, all margin widths, including submillimeter margins correlated with prolonged OS (P < 0.05). The association between the margin width and OS remained significant when adjusted for all other clinicopathologic prognostic factors. Conclusions: Resection margin width is independently associated with OS. Wide margins should be attempted whenever possible. However, resection should not be precluded if narrow margins are anticipated, as submillimeter margin clearance is associated with improved survival. The prolonged OS observed with submillimeter margins is likely a microscopic surrogate for the biologic behavior of a tumor rather than the result of surgical technique. This study evaluated the impact of margin status in 2368 patients undergoing hepatic resection for colorectal liver metastases. Prolonged survival is independently associated with margin clearance down to submillimeter width. These findings suggest that margin clearance is important and that submillimeter margin clearance is likely a microscopic surrogate for the biologic behavior of a tumor.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMN) are being increasingly recognized as important precursors to pancreatic adenocarcinoma. Elucidation of the genetic changes underlying IPMN carcinogenesis may improve the diagnosis and management of IPMN. We sought to determine whether different histologic subtypes of IPMN would exhibit different frequencies of specific genetic mutations. STUDY DESIGN: Patients with resected IPMN-associated invasive carcinoma (IPMN-INV) between 1997 and 2012 were reviewed. Areas of carcinoma, high-grade dysplasia, and low-grade dysplasia were micro-dissected from each pathologic specimen. Targeted, massively parallel sequencing was then performed on a panel of 275 genes (including KRAS, GNAS, and RNF43). RESULTS: Thirty-eight patients with resected IPMN-INV and sufficient tissue for micro-dissection were identified. Median follow-up was 2.6 years. Mutations in GNAS were more prevalent in colloid-type IPMN-INV than tubular-type IPMN-INV (89% vs 32% respectively; p = 0.0003). Conversely, KRAS mutations were more prevalent in tubular-type than colloid-type IPMN-INV (89% vs 52%, respectively; p = 0.01). For noninvasive IPMN subtypes, GNAS mutations were more prevalent in intestinal (74%) compared with pancreatobiliary (31%) and gastric (50%) subtypes (p = 0.02). The presence of these mutations did not vary according to the degree of dysplasia (GNAS: invasive 61%, high-grade 59%, low-grade 53%; KRAS: invasive 71%, high-grade 62%, low-grade 74%), suggesting that mutations in these genes occur early in IPMN carcinogenesis. CONCLUSIONS: Colloid carcinoma associated with IPMN and its intestinal-type preinvasive precursor are associated with high frequencies of GNAS mutations. The mutation profile of tubular carcinoma resembles that of conventional pancreatic adenocarcinoma. Preoperative determination of mutational status may assist with clinical treatment decisions.

To analyze the natural history of small asymptomatic pancreatic neuroendocrine tumors (PanNET) and to present a matched comparison between groups who underwent either initial observation or resection. Management approach for small PanNET is uncertain.Incidentally discovered, sporadic, small (<3 cm), stage I-II PanNET were analyzed retrospectively between 1993 and 2013. Diagnosis was determined either by pathology or imaging characteristics. Intention-to-treat analysis was applied.A total of 464 patients were reviewed. Observation was recommended for 104 patients (observation group), and these patients were matched to 77 patients in the resection group based on tumor size at initial imaging. The observation group was significantly older (median 63 vs. 59 years, p = 0.04) and tended towards shorter follow-up (44 vs. 57 months, p = 0.06). Within the observation group, 26 of the 104 patients (25 %) underwent subsequent tumor resection after a median observation interval of 30 months (range 7-135). At the time of last follow-up of the observation group, the median tumor size had not changed (1.2 cm, p = 0.7), and no patient had developed evidence of metastases. Within the resection group, low-grade (G1) pathology was recorded in 72 (95 %) tumors and 5 (6 %) developed a recurrence, which occurred after a median of 5.1 (range 2.9-8.1) years. No patient in either group died from disease. Death from other causes occurred in 11 of 181 (6 %) patients.In this study, no patient who was initially observed developed metastases or died from disease after a median follow-up of 44 months. Observation for stable, small, incidentally discovered PanNET is reasonable in selected patients.

Background Hepatic resection of colorectal liver metastases is associated with long-term survival. This study analyzes actual 10-year survivors after resection of colorectal liver metastases, reports the observed rate of cure, and identifies factors that preclude cure. Methods A single-institution, prospectively maintained database was queried for all initial resections for colorectal liver metastases for the years 1992–2004. Observed cure was defined as actual 10-year survival with either no recurrence or resected recurrence with at least 3 years of disease-free follow-up. Clinical risk score was dichotomized into low (0–2) and high (3–5). Semiparametric proportional hazards mixture cure model was utilized to estimate probability of cure. Results We included 1,211 patients with a median follow-up for survivors of 11 years. Median disease-specific survival was 4.9 years (95% CI: 4.4–5.3). 295 patients (24.4%) were actual 10-year survivors. The observed cure rate was 20.6% (n = 250). Among 250 cured patients, 192 (76.8%) had no recurrence and 58 (23.2%) had a resected recurrence with at least 3 years of disease-free follow-up. Extrahepatic disease (n = 88), carcinoembryonic antigen >200 ng/mL (n = 119), positive margin (n = 109), and >10 tumors (n = 31) had observed cure rates less than 10%. In cure model analysis, patients with both extrahepatic disease and high clinical risk score (n = 31) had an estimated probability of cure of 3.5%. Conclusion Actual 10-year survival after resection of colorectal liver metastases is 24% with an observed 20% cure rate. Patients with both high clinical risk score and extrahepatic disease have an estimated probability of cure less than 5%. When such factors are identified, strong consideration may be given to preoperative strategies, such as neoadjuvant chemotherapy, to help select patients for surgical therapy.

Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients.To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC.A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded.Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin.The primary outcome was progression-free survival (PFS) of 80% at 6 months.For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4).Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.

Background and Aim Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well characterized, but their impact on outcome and prognosis remains unknown. Approach and Results This bi‐institutional study of patients with confirmed iCCA (n = 412) used targeted next‐generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were isocitrate dehydrogenase 1 ( IDH1 ; 20%), AT‐rich interactive domain–containing protein 1A (20%), tumor protein P53 ( TP53 ; 17%), cyclin‐dependent kinase inhibitor 2A ( CDKN2A ; 15%), breast cancer 1–associated protein 1 (15%), FGFR2 (15%), polybromo 1 (12%), and KRAS (10%). IDH1/2 mutations ( mut ) were mutually exclusive with FGFR2 fusions, but neither was associated with outcome. For all patients, TP53 ( P &lt; 0.0001), KRAS ( P = 0.0001), and CDKN2A ( P &lt; 0.0001) alterations predicted worse overall survival (OS). These high‐risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n = 209), TP53mut (HR, 1.82; 95% CI, 1.08‐3.06; P = 0.03) and CDKN2A deletions ( del ; HR, 3.40; 95% CI, 1.95‐5.94; P &lt; 0.001) independently predicted shorter OS, as did high‐risk clinical variables (multifocal liver disease [ P &lt; 0.001]; regional lymph node metastases [ P &lt; 0.001]), whereas KRASmut (HR, 1.69; 95% CI, 0.97‐2.93; P = 0.06) trended toward statistical significance. The presence of both or neither high‐risk clinical or genetic factors represented outcome extremes (median OS, 18.3 vs. 74.2 months; P &lt; 0.001), with high‐risk genetic alterations alone (median OS, 38.6 months; 95% CI, 28.8‐73.5) or high‐risk clinical variables alone (median OS, 37.0 months; 95% CI, 27.6‐not available) associated with intermediate outcome. TP53mut , KRASmut , and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high‐risk clinical features were notable for limited survival and no benefit of resection over chemotherapy. Conclusions TP53 , KRAS , and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Because genetic profiling can be integrated into pretreatment therapeutic decision‐making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.

Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.

BACKGROUND: 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. STUDY DESIGN: Patients with IHC were identified from a prospective database. Demographic data, tumor characteristics, and outcomes were analyzed. RESULTS: 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). CONCLUSIONS: 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.

Tumors with combined hepatocellular and cholangiocellular features are well known histopathologically but their clinical behavior is poorly understood. The objectives of the current study were to define the demographic profile of the patients in whom these uncommon tumors occur and to evaluate treatment outcome in comparison with that in patients with either hepatocellular carcinoma (HCC) or peripheral cholangiocarcinoma (CC) alone.Twenty-seven patients with combined tumors were identified from a prospective database. Pathologic specimens were analyzed to confirm the diagnosis. Demographics, clinical data, and survival were analyzed. Outcome after resection was compared with that of patients with CC and with a matched group of patients with HCC.The gender distribution of the combined tumors (52% men and 48% women) was intermediate between HCC (67% men and 33% women) and CC (30% men and 70% women) (P = 0.03). The incidence of positive hepatitis B or C serology and cirrhosis was similar in patients with combined tumors and those with CC (15% and 0% vs. 13% and 4%, respectively); similarly, patients of Asian heritage constituted 7% and 9%, respectively, of the patients with these tumors. By contrast, cirrhosis (41%) and positive hepatitis serology (56%) were far more common in patients with HCC, and 19% of these patients were of Asian heritage. Twenty-one of 27 patients with combined tumors (78%) underwent resection. All 6 patients with combined tumors that were not amenable to resection died of disease within 18 months. After resection, the 5-year survival was lowest in patients with combined tumors (24%) but was not significantly different from that in patients with CC (33%) or HCC (37%). The liver was the most common site of recurrence in all three groups.The demographic and clinical features of patients with combined tumors were most similar to those of patients with CC. Most important, combined tumors were not found to be associated with chronic liver disease; consequently, the resectability rate was higher for these tumors than typically is reported for HCC. Resection was associated with long-term survival in some patients, but recurrent hepatic disease was common. The presence of cholangiocellular differentiation appeared to worsen the prognosis when compared with pure HCC, although this difference did not reach statistical significance.

To determine the value of repeat liver resection for recurrent colorectal metastases to the liver.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.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.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.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.

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.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.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 </=1 cm) rates were 50% for group 1 and 76% for group 2 (P < 0.01). Patients in group 2 were more likely to have undergone extensive procedure(s) (27% versus 3%; P < 0.001). Operative time and estimated blood loss were greater in group 2 than group 1 (264 versus 174 min, 880 versus 460 cc, respectively; P < 0.001 for both). Complication rates and length of hospitalization were not significantly different between the two groups.The use of extensive upper abdominal surgical procedures significantly increased the rate of optimal primary cytoreduction. Although operative time and estimated blood loss were increased, the rate of major complications and length of hospitalization remained the same.

The majority of patients with hepatocellular carcinoma (HCC) who undergo complete tumor resection subsequently develop tumor recurrence. The objectives of this study were to determine the risk factors for recurrence of HCC after hepatectomy and to examine the outcomes once tumor recurrence occurs.From February 1990 to May 2001 a total of 164 patients underwent liver resection for HCC at our institution and were prospectively followed. Time to recurrence and survival after recurrence were determined by Kaplan-Meier analysis. Patient, tumor, and treatment characteristics were tested for their prognostic significance by univariate and multivariate analysis using the logrank test and the Cox proportional hazards model, respectively.The median patient age was 64 years (range 21 to 87 years) and 106 patients (65%) were male. After a median followup of 26 months, 90 patients (55%) have developed recurrent cancer. Among them, 75 patients (83%) had tumor detectable in the liver, which was the only site of disease in 67 (74%). In all, 15 patients (20%) had extrahepatic disease (7 lung, 4 peritoneum, 2 pancreas, 1 bone, and 1 brain). The median time to recurrence was 24 months (range 1 to 274 months). Predictors of recurrence on univariate analysis were tumor size greater than 5 cm, more than one tumor, cirrhosis, vascular invasion (microscopic or macroscopic), and tumor satellites. On multivariate analysis only tumor size greater than 5 cm (p = 0.04) and vascular invasion (p = 0.01) predicted recurrence. The median survival after recurrence was 11 months (range 0 to 60 months). Of the 90 patients who developed tumor recurrence 49 (67%) were able to undergo additional ablative or surgical therapy (33 embolization, 9 ethanol injection, and 14 re-resection). On multivariate analysis vascular invasion in the original tumor predicted poor survival after recurrence (p = 0.009).The liver is the predominant site of first recurrence after resection of hepatocellular carcinoma, and once recurrence occurs survival is limited. The current study underscores the need for effective adjuvant therapy for patients with HCC treated with partial hepatectomy.

The indications for preoperative biliary stenting in patients with obstructive jaundice are controversial. We evaluated the effect of preoperative biliary stenting on bacterobilia and infectious complications following surgical treatment of proximal cholangiocarcinoma.A retrospective review was performed of all patients undergoing surgical treatment of proximal cholangiocarcinoma.A metropolitan cancer surgery service.Seventy-one patients underwent palliative biliary bypass or curative resection of proximal cholangiocarcinoma from March 1, 1991, to April 1, 1997, and were entered into a prospective database. Forty-one patients underwent preoperative biliary intubation and stent placement. We analyzed patient, nutritional, laboratory, and operating room factors. Statistical evaluation was performed using Student t test and chi2 analysis.Data were recorded for a history of cholangitis, operative time, amount of blood loss, incidence of intraoperative bacterobilia, proportion of patients with postoperative infectious and noninfectious complications, and length of hospital stay.All patients (n = 14) with a history of preoperative cholangitis had been subjected to previous endoscopic retrograde cholangiopancreatography and/or percutaneous transhepatic biliary drainage. Groups were equivalent for risk for comorbidity, proportion undergoing curative vs palliative procedures, time spent in the operating room, and amount of blood loss. Patients with stents had a significantly lower bilirubin level (P = .005). Patients with stents had a significantly increased risk for bacterobilia (P = .001) and infectious complications (P = .03). Bacterobilia was present in 11 (100%) of 11 patients undergoing endoscopic stenting and in 15 (65%) of 23 patients undergoing percutaneous stenting. There was no increased risk for noninfectious complications, length of hospital stay, or mortality in patients with stents. In 10 (59%) of 17 patients with postoperative infectious complications and positive findings of intraoperative bile culture, the organism was synonymous.Preoperative biliary stenting in proximal cholangiocarcinoma increases the incidence of contaminated bile and postoperative infectious complications. Endoscopic stents frequently do not relieve jaundice in high biliary obstruction and are rarely indicated, especially in light of their high contamination rate.

Objective To evaluate the benefit of staging laparoscopy in patients with gallbladder cancer and hilar cholangiocarcinoma. Summary Background Data In patients with extrahepatic biliary carcinoma, unresectable disease is often found at the time of exploration despite extensive preoperative evaluation, thus resulting in unnecessary laparotomy. Methods From October 1997 to May 2001, 100 patients with potentially resectable gallbladder cancer (n = 44) and hilar cholangiocarcinoma (n = 56) were prospectively evaluated. All patients underwent staging laparoscopy followed by laparotomy if the tumor appeared resectable. Surgical findings, resectability rate, length of stay, and operative time were analyzed. Results Patients underwent multiple preoperative imaging tests, including computed tomography scan, ultrasound, magnetic resonance cholangiopancreatography, and direct cholangiography. Laparoscopy identified unresectable disease in 35 of 100 patients. In the 65 patients undergoing open exploration, 34 were found to have unresectable disease. Therefore, the overall accuracy for detecting unresectable disease was 51%. There was no difference in the accuracy of laparoscopy between patients with gallbladder cancer and hilar cholangiocarcinoma. Laparoscopy detected the majority of patients with peritoneal or liver metastases but failed to detect all locally advanced tumors. In patients undergoing biopsy only, laparoscopic identification of unresectable disease significantly reduced operative time and length of stay compared with patients undergoing laparotomy. The yield of laparoscopy was 48% in patients with gallbladder cancer (56% in those who did not undergo previous cholecystectomy), but only 25% in patients with hilar cholangiocarcinoma. However, in patients with locally advanced but potentially resectable hilar cholangiocarcinoma, the yield of laparoscopy was greater, 36% (12/33, T2/T3 tumors) versus 9% (2/23, T1 tumors). Conclusions Laparoscopy identifies the majority of patients with unresectable hilar cholangiocarcinoma or gallbladder carcinoma, thereby reducing both the incidence of unnecessary laparotomy and the length of stay. The yield of laparoscopy is lower for hilar cholangiocarcinoma but can be improved by targeting patients at higher risk of occult unresectable disease. All patients with potentially resectable primary gallbladder cancer and patients with T2/T3 hilar cholangiocarcinoma should undergo staging laparoscopy before surgical exploration.

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.

This is the first report on the development and initial validation of the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire, a 45-item self-report instrument designed to measure health-related quality of life (HRQL) in patients with hepatobiliary cancers. The FACT-Hep consists of the 27-item FACT-G, which assesses generic HRQL concerns, and the newly validated 18-item Hepatobiliary Subscale (HS), which assesses disease-specific issues.The development of the HS followed a four-phase process of item generation, item reduction, scale construction, and reliability/validity testing. Two independent samples were studied: item generation (sample 1; n = 30) and reliability/validity testing (sample 2; n = 51).In sample 2, all subscales and aggregated scores showed high internal consistency at initial assessment (Cronbach's alpha range, 0.72 to 0.94) and retesting (Cronbach's alpha range, 0.81 to 0.94). Measurement stability over a 3- to 7-day period was also high for all aggregated scales (test-retest correlation range, 0.84 to 0.91; intraclass correlation coefficient range, 0.82 to 0.90). Convergent and divergent validity were demonstrated by examining relationships between FACT subscales and mood, social support, and social desirability. Finally, when performance status and treatment status were used to divide sample 2, the HS differentiated groups to a degree comparable to the Physical and Functional Well-Being subscales of the FACT-G, thereby contributing favorably to a 32-item Trial Outcome Index. In addition to the 18 validated, scored items in the HS, seven treatment-related items may be appended, if clinically indicated, as a separate subscale.The 45-item FACT-Hep can be used independently as a brief measure of disease-related symptoms and functioning. Alone or paired with the FACT-G, the HS has promise for use in assessing the disease-specific HRQL of patients with hepatobiliary cancers.

The aim of this study was to determine the results of liver resection for patients with bilateral hepatic metastases from colorectal cancer. We aimed to assess the evolution of the technical approach over time and correlations with morbidity, mortality, and oncologic outcome.Although hepatic resection for isolated colorectal metastases to the liver is thought to be beneficial when feasible, resection of bilateral liver metastases carries unique technical issues and is often associated with more aggressive tumor biology. Little has been written specifically about the results achieved in this subset of patients.Data from a prospectively maintained database of patients undergoing hepatic resection at a single institution over an 11-year time period were reviewed.Resection of bilateral liver metastases from colorectal cancer was accomplished in 443 cases (440 patients) with a 29% incidence of major complications and a 5.4% 90-day mortality. Kaplan-Meier estimated 5-year disease-specific survival was 30% and 5-year recurrence-free survival was 18%. Operative technique changed over time toward a parenchymal-sparing approach as evidenced by the greater use of multiple simultaneous liver resections, wedge resections, and ablations. Similarly, there was a decrease in the use of major hepatectomies. This correlated with decreased mortality without change in disease-specific survival or liver recurrence.Resection of bilateral colorectal liver metastases can be accomplished with acceptable morbidity, mortality, and oncologic results. Increased use of a parenchymal-sparing approach is associated with decreased mortality without compromise in cancer-related outcome.

In Brief Objective: To analyze the impact of margin width on long-term outcome after hepatic resection for colorectal metastasis. Summary Background Data: The optimal margin width and its influence on long-term outcome after hepatic resection for colorectal metastasis are unclear. Methods: All patients undergoing hepatic resection for colorectal metastasis from 1991 to 2003 were identified, and the prognostic influence of margin width and other clinicopathologic factors were analyzed. Results: A total of 1019 patients with a clear description of margin width were included. Analysis of margin width as a continuous variable suggested the following grouping: group I, involved (n = 112, 11%); group II, <1–10 mm (n = 563, 55%); and group III, >10 mm (n = 344, 33.7%). On univariate analysis, there was a statistically significant difference in median survival between all 3 groups: group II versus group I (42 vs. 30 months, P < 0.01) and group III versus group II (55 vs. 42 months, P < 0.01). Margin width >1 cm retained statistical significance (P < 0.01) on multivariate analysis after adjusting for established risk factors. After adjustment, survival in group III was significantly better than either group I or II (P < 0.01), but there was no difference between groups I and II (P = 0.31). Conclusions: This study provides evidence that margin width of >1 cm is optimal and is an independent predictor of survival after hepatic resection for colorectal metastasis. However, subcentimeter resections are also associated with favorable outcome and should not preclude patients from undergoing resection. The prognostic significance of margin width on long-term survival after hepatic resection for colorectal metastasis is unclear. The results of this study demonstrate that a >1 cm margin is an independent predictor of improved outcome when analyzed in the context of other well-known prognostic factors.

In Brief Purpose: Resection is the most effective treatment for metastatic colorectal cancer (MCRC) to the liver. However, postoperative morbidity is common and its impact on long-term oncological outcome is unclear. The objective of this study was to evaluate the impact of postoperative morbidity on the long-term outcome after liver resection for MCRC. Methods: Medical records of patients who underwent liver resection for MCRC with curative intent between 1991 and 2002 were reviewed. Patients who died of postoperative complications were excluded; operative and perioperative data, including morbidity and clinicopathological variables, were analyzed. Patients were stratified by disease extent and risk of recurrence using a clinical risk scoring system. Results: A total of 1067 patients were included in the study and the median follow-up period was 41 months. The overall morbidity rate was 42%; the 5-year disease-specific survival (DSS) and overall disease-free survival (DFS) rates of patients who had complications were 41% and 25%, respectively, compared with 48% and 33%, respectively, for patients who did not have complications (P = 0.0059 for DSS, P = 0.0053 for DFS). On multivariate analysis, morbidity was not an independent predictor of either DSS or DFS; however, in a subgroup of patients with low clinical risk scores, morbidity was associated with a significant reduction in both DSS and DFS. Conclusions: Postoperative morbidity adversely affects long-term outcome after hepatic resection for MCRC in patients at lower risk for recurrence. Efforts aimed at reducing perioperative morbidity will not only reduce usage of resources but will likely further enhance the therapeutic benefit of resection for such patients. Postoperative morbidity is common after liver resection for metastatic colorectal cancer and its impact on long-term oncological outcome is unclear. In this study, we demonstrate that postoperative morbidity adversely affects long-term outcome after hepatic resection for metastatic colorectal cancer in patients at lower risk for recurrence.

The incidence of hepatocellular carcinoma (HCC) in the United States has increased 75% in the last decade. Liver transplantation is gaining acceptance for the treatment of early HCC, even in patients with adequate liver function. The objective of this study was to determine the long-term outcome of patients with early HCC who would have been candidates for transplantation but were treated instead with partial hepatectomy.From August 1989 to November 2001, 611 patients with HCC were evaluated at our institution and entered into a prospective database. There were 180 (29%) patients who underwent partial hepatectomy, of whom 36 (20%) satisfied the currently accepted criteria for transplantation: 2 or 3 lesions each </= 3 cm in size or a solitary tumor </= 5 cm. Survival was determined by Kaplan-Meier analysis.Median tumor size was 3.5 (range, 1.8-5) cm and the median number of lesions was 1 (range, 1-3). Patients had pathologically confirmed cirrhosis of the liver in 78% (28/36) of cases, and 86% had normal liver function (Child class A). Perioperative morbidity was 25%, the median length of hospital stay was 8 (range, 4-24) days, and there was 1 (2.8%) perioperative death. At a median follow-up of 35 months for survivors, the 1-, 3-, and 5-year overall survival was 85%, 74%, and 69%, respectively, with a median survival of 71 months. The 5-year disease-free survival was 48% with a median of 52 months.Partial hepatectomy in patients with early HCC who are otherwise eligible for transplantation can be performed with minimal morbidity and can achieve comparable 5-year survival to that reported for liver transplantation. Resection should be considered the standard therapy for patients with HCC who have adequate liver reserve.

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of hepatocellular carcinoma, has distinct pathologic features, and typically occurs in young patients without underlying hepatitis or cirrhosis.Forty-one patients with the pathologic diagnosis of FL-HCC evaluated at our institution between 1986 and 2003 were identified from a prospective database.Median age of all patients was 27 years. None of these patients had underlying hepatitis or cirrhosis, and only 3 (7%) patients had an alpha-fetoprotein level > 200 ng/mL. Twenty-eight patients with primary disease underwent complete gross resection, and 13 patients were unresectable. In patients treated with resection, median tumor size was 9 cm (range, 3-17), 9 (36%) had vascular invasion, and 14 (50%) had lymph node metastases. There were no perioperative deaths. With a median follow-up of 34 months, 5-year overall survival for resected patients was 76%. However, 5-year recurrence-free survival was only 18%, and of the 9 resected patients with more than 5 years of follow-up, 7 had recurrences. Lymph node metastasis was the only significant negative prognostic factor. Seventeen (61%) patients underwent a second operation for recurrent disease. Median survival for unresected patients with FL-HCC was only 12 months, and no patient survived beyond 5 years.FL-HCC occurs in a distinctly different population of patients than common HCC, and patients with FL-HCC generally fare better after complete resection. These tumors have a relatively indolent tumor biology, and late recurrences are common. Repeat resections for recurrence should be considered given the lack of other effective treatment options.

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.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.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.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.

Hepatic hemangiomas are congenital vascular malformations and are the most common benign hepatic tumors. Because the use of cross-sectional imaging has increased, benign hepatic tumors, especially hemangiomas, are encountered more frequently, so clinicians should be familiar with the most appropriate diagnostic tests, management, and outcomes of patients with hepatic hemangioma.All patients with a primary diagnosis of hepatic hemangioma referred for surgical evaluation at our institution between January 1992 and December 2000 were identified from a prospective database. Demographics, presentation, tumor characteristics, diagnostic studies, surgical procedures, and outcomes were analyzed. RESULTS; Of 115 patients in the study, nearly half were asymptomatic. In symptomatic patients, abdominal pain or discomfort was the most common presenting symptom. At our institution, the diagnosis of hemangioma was established by ultrasonographic studies in 57% of patients tested, by CT scan in 73%, and by MRI in 84%. In patients with large tumors considered for resection, direct angiography or, more recently, CT angiography, confirmed the diagnosis in 27 of 29 patients (93%). Enucleation was performed in 31 (60%) of the 52 patients who underwent surgical resection; 63 patients were observed. Postoperative complications occurred in 13 patients (25%), and there were no perioperative deaths. Of the patients with symptoms before resection, 96% had resolution of symptoms after operation.Hepatic hemangioma can be diagnosed in most patients using noninvasive studies, particularly MRI. Hepatic hemangiomas can be removed safely if patients become symptomatic or when malignancy cannot be excluded. CT angiography can be a valuable preoperative study in patients with large tumors, and enucleation is the procedure of choice. In asymptomatic or minimally symptomatic patients, hepatic hemangiomas usually have a benign course and can be observed.

BACKGROUND: Surgical resection of isolated hepatic or pulmonary colorectal metastases prolongs survival in selected patients. But the benefits of resection and appropriate selection criteria in patients who develop both hepatic and pulmonary metastases are ill defined. STUDY DESIGN: Data were prospectively collected from 131 patients with colorectal cancer who underwent resection of both hepatic and pulmonary metastases over a 20-year period. Median followup was 6.6 years from the time of resection of the primary tumor. Patient, treatment, and outcomes variables were analyzed using log-rank, Cox regression, and Kaplan-Meier methods. RESULTS: The site of first metastasis was the liver in 65% of patients, the lung in 11%, and both simultaneously in 24%. Multiple hepatic metastases were present in 51% of patients, and multiple pulmonary metastases were found in 48%. Hepatic lobectomy or trisegmentectomy was required in 61% of patients; most lung metastases (80%) were treated with wedge excisions. Median survival rates from resection of the primary disease, first site of metastasis, and second site of metastasis were 6.9, 5.0, and 3.3 years, respectively. After resection of disease at the second site of metastasis, the 1-, 3-, 5-, and 10-year disease-specific survival rates were 91%, 55%, 31%, and 19%, respectively. An analysis of prognostic factors revealed that survival was significantly longer when the disease-free interval between the development of the first and second sites of metastases exceeded 1 year, in patients with a single liver metastasis, and in patients younger than 55 years old. CONCLUSIONS: Surgical resection of both hepatic and pulmonary colorectal metastases is associated with prolonged survival in selected patients. Patients with a longer disease-free interval between metastases and those with single liver lesions had the best outcomes.

The prognostic significance of germline BRCA1 and BRCA2 mutations in Jewish patients with pancreatic adenocarcinoma (PAC) is unknown. Our objective was to define the prevalence of BRCA1 and BRCA2 in an unselected group of Jewish patients and to compare the clinical characteristics and overall survival (OS) of patients with resected BRCA mutation-associated PAC to PAC patients without mutations.Jewish patients with PAC resected between January 1986 and January 2004 were identified. DNA was extracted from the archived material, anonymized, and genotyped for founder mutations in BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT). Standard two-sided statistical tests were utilized.Of the 187 Jewish patients who underwent resection for PAC, tissue was available for 145 patients. Eight subjects (5.5%) had a BRCA founder mutation (two with BRCA1 [1.3%], six with BRCA2 [4.1%]). The BRCA2 founder mutation was identified in 4.1% of patients with pancreatic adenocarcinoma compared with only 1.1% of cancer-free Washington, DC,-area controls (4.1% v 1.1%; P = .007; odds ratio, 3.85; 95% CI, 2.1 to 10.8). Patients with and without BRCA1 or BRCA2 mutations did not differ in age (mean, 66 v 73 years; P = .6) or other clinicopathologic features. OS was not significantly different (median, 6 v 16 months; P = .35). A previous cancer was reported by 24% (35 of 145) of patients with the most common sites being breast cancer (9 of 35; 74%) and prostate cancer (8 of 35; 23%).Founder mutations for BRCA1 and BRCA2 were identified in 5.5% of Ashkenazi patients operated on for PAC. BRCA2 mutations were more prevalent than documented by population studies. Consistent with previous reports, BRCA2 mutations are associated with an increased risk of PAC.

In Brief Objective: To define perioperative and long-term outcome and prognostic factors in patients undergoing hepatectomy for liver metastases arising from noncolorectal and nonneuroendocrine (NCNN) carcinoma. Summary Background Data: Hepatic resection is a well-established therapy for patients with liver metastases from colorectal or neuroendocrine carcinoma. However, for patients with liver metastases from other carcinomas, the value of resection is incompletely defined and still debated. Methods: Between April 1981 and April 2002, 141 patients underwent hepatic resection for liver metastases from NCNN carcinoma. Patient demographics, tumor characteristics, treatment, and postoperative outcome were analyzed. Results: Thirty-day postoperative mortality was 0% and 46 of 141 (33%) patients developed postoperative complications. The median follow up was 26 months (interquartile range [IQR]) 10–49 months); the median follow up for survivors was 35 months (IQR 11–68 months). There have been 24 actual 5-year survivors so far. The actuarial 3-year relapse-free survival rate was 30% (95% confidence interval [CI], 21–39%) with a median of 17 months. The actuarial 3-year cancer-specific survival rate was 57% (95% CI, 48–67%) with a median of 42 months. Primary tumor type and length of disease-free interval from the primary tumor were significant independent prognostic factors for relapse-free and cancer-specific survival. Margin status was significant for cancer-specific survival and showed a strong trend for relapse-free survival. Conclusions: Hepatic resection for metastases from NCNN carcinoma is safe and can offer long-term survival in selected patients. Hepatic resection should be considered if all gross disease can be removed, especially in patients with metastases from reproductive tract tumors or a disease-free interval greater than 2 years. Hepatic resection for metastases from noncolorectal, nonneuroendocrine carcinoma is safe and can offer long-term survival for selected patients, especially those with reproductive tract tumors, or a long disease-free interval after treatment of the primary tumor.

In Brief Background: This study evaluates the significance of tumor involvement of the liver in early T-stage tumors and lymph node (LN) metastases on outcome after R0 resection of gallbladder cancer (GBCA). Methods: A prospectively maintained database, supplemented with review of the medical record, was used to identify patients who underwent a complete (R0) resection for GBCA. All patients underwent definitive surgical treatment at the initial operation (1 stage) or after initial noncurative cholecystectomy (incidental tumors, 2 stage), including partial hepatectomy and portal LN dissection, with or without bile duct and/or adjacent organ resection. Clinicopathological variables, including TNM stage, histologic tumor involvement of liver (residual or direct extension in the GB fossa or discontiguous disease), and the total number of regional LNs assessed were analyzed for their association with outcome. Results: One hundred twenty-two patients were identified and analyzed. The median follow up period was 23 months. Liver and nodal involvement by GBCA were observed in 61 (50%) and 41(34%) patients, respectively. Among patients with T2 tumors (n = 53), 48 (91%) were incidental. Liver involvement was present in 26%, and this factor was associated with decreased recurrence-free (RFS) and disease-specific survival (DSS) compared with patients with T2 tumors without liver involvement (median RFS, 12 months vs. not reached, P = 0.004, median DSS 25 months versus not reached, P = 0.003); T1b tumors (n = 10) were not associated with liver involvement. The median total lymph node count (TLNC) was 3 (range 0–20). For the entire cohort, survival of patients classified as N0 based on TLNC < 6 was significantly worse than that of N0 patients based on TLNC ≥ 6 (median RFS, 22 months versus not reached, P < 0.001, median DSS 41 months versus not reached, P < 0.001). Liver involvement and TLNC remained significant prognostic factors in a multivariate model that included TNM stage. Conclusion: Resection and histologic evaluation of at least 6 lymph nodes improves risk-stratification after resection of GBCA. Incidental T2 tumors are often associated with residual liver disease and should be reclassified to reflect the adverse outcome. The data suggests a need for standardized minimum requirements for adequate surgical treatment and pathological examination. Accurate staging for gallbladder cancer (GBCA) is challenging. In this study, we evaluated the impact of liver involvement in early T-stage tumors on long-term survival after R0 resection and minimal extent of lymphadenectomy for accurate risk stratification.

Hepatic lipocytes (perisinusoidal, Ito cells) are the primary matrix-producing cells in liver fibrosis. During liver injury they undergo activation, a process characterized by cell proliferation and increased fibrogenesis. We and others have established a culture model in which in vivo features of lipocyte activation can be mimicked by cells grown on plastic. Additionally, we recently showed that activation is associated with new expression of smooth muscle-specific alpha-actin both in vivo and in culture. Although interferon-gamma is known to inhibit collagen production in some systems, its action as a general modulator of lipocyte activation has not been examined; this issue forms the basis for our study. In culture-activated lipocytes, interferon-gamma (1,000 U/ml) significantly inhibited lipocyte proliferation as assessed by [3H]thymidine incorporation assay and nuclear autoradiography. In time-course studies of activation, it also markedly reduced expression of smooth muscle-specific alpha-actin and its messenger RNA. In dose-response experiments, maximal inhibitory effects on smooth muscle-specific alpha-actin mRNA gene expression were achieved with as little as 10 U interferon-gamma/ml. Inhibition of cellular activation was reversible; after interferon-gamma withdrawal, messenger RNA levels of smooth muscle-specific alpha-actin returned to untreated control levels. The effect of interferon-gamma extended to extracellular matrix gene expression, with reduction of type I collagen, type IV collagen and total fibronectin messenger RNAs to 3%, 24% and 15% of untreated control levels, respectively. In contrast to the marked effects on smooth muscle-specific alpha-actin and extracellular matrix gene expression, interferon-gamma reduced total protein synthesis by only 17.7%.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Although it is the most common cancer of the biliary tree, gallbladder carcinoma remains an uncommon disease. As a result, many clinicians rarely encounter it and there is uncertainty regarding proper management. Resection is the most effective and only potentially curative treatment. Early stage tumors are often curable with a proper resection; however, many patients present late in the course of the disease when surgical intervention is no longer effective. While other treatment modalities are used in patients with advanced disease, there is limited data on efficacy. In many cases, the diagnosis is made after a cholecystectomy has been performed and an incidental tumor is identified in the specimen. In such cases, reoperation and definitive resection is appropriate and effective for patients with invasive lesions.

In Brief Objective: The current study compares outcome after resection of papillary hilar cholangiocarcinoma to that of the more common nodular-sclerosing subtype. Methods: Clinical, radiologic, histopathologic, and survival data on all patients with hilar cholangiocarcinoma were analyzed. Resected tumors were reexamined and classified as nodular-sclerosing (no component of papillary carcinoma) or papillary (any component of papillary carcinoma); for papillary tumors, the proportion of invasive carcinoma present was determined. Differences in the clinical behavior and histopathologic features of nodular-sclerosing and papillary tumors were assessed. Results: From January 1991 to November 2003, 279 patients were evaluated, 154 men (55.2%) and 125 women (44.8%), with a mean age of 65.4 ± 0.7 years (median = 68, range 23–87 years). Of the 215 patients explored, 106 (49.5%) underwent a complete gross resection. An en bloc partial hepatectomy (n = 87) and an R0 resection (n = 82) were independent predictors of favorable outcome. Operative mortality was 7.5% but was 2.8% over the last 4 years of the study, and there were no operative deaths in the last 33 consecutive resections. Twenty-five resected tumors (23.6%) contained a papillary component: 12 were minimally or noninvasive (<10% invasive cancer) and 13 had an invasive component ranging from 10% to 95% (≥10%). Patients with papillary and nodular-sclerosing tumors had similar demographics, operative procedures, and proportion of R0 resections. By contrast, papillary tumors were significantly larger, more often well-differentiated, and earlier stage. Disease-specific survival after resection of papillary tumors (55.7 months) was greater than after resection of nodular-sclerosing lesions (33.5 months, P = 0.013). The papillary phenotype was an independent predictor of survival, although the benefit was more pronounced for less invasive tumors. Conclusions: The presence of a component of papillary carcinoma is more common than previous reports have suggested and is an important determinant of survival after resection of hilar cholangiocarcinoma. Papillary tumor morphology is an important prognostic factor in patients with hilar cholangiocarcinoma and appears to be more common than prior reports have suggested. An aggressive resectional approach to papillary tumors is warranted, given the possibility of prolonged survival and the increasing safety with which such resections can be performed.

To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of concurrent systemic irinotecan and hepatic arterial infusion (HAI) of floxuridine (FUDR) and dexamethasone in patients with unresectable hepatic metastases from colorectal cancer, to determine the safety of this combination in patients who have undergone cryosurgery, and to evaluate the pharmacokinetic effects of HAI FUDR on the metabolism of irinotecan.Forty-six previously treated patients with unresectable liver metastases and no known extrahepatic disease were treated concurrently with intravenous irinotecan weekly for 3 weeks and with HAI of FUDR and dexamethasone for 14 days (both were recycled in 28 days). Parallel cohorts of patients treated with or without cryosurgery were entered at escalating dose levels.The MTD for patients who did not undergo cryosurgery was 100 mg/m2 of irinotecan weekly for 3 weeks every 4 weeks with concurrent HAI FUDR (0.16 mg/kg/d x pump volume/flow rate) plus dexamethasone for 14 days of a 28-day cycle. The dose-limiting toxicities were diarrhea and neutropenia. The response rate (complete and partial) among all patients who did not undergo cryosurgery was 74%. All patients in the cryosurgery group responded, and seven of the eight cryosurgery patients developed normal positron emission tomography scans after chemotherapy. HAI FUDR had no effect on the metabolism of irinotecan.Combination therapy with HAI FUDR and dexamethasone plus systemic irinotecan may be safely administered to patients with unresectable hepatic metastases from colorectal cancer. The MTD has been reached for patients with unresectable disease, and we continue to investigate the MTD for patients who have undergone cryosurgery. Although the main objective of this study was to evaluate the toxicity of the combined regimen, a high response rate (74%) was observed.

BACKGROUND: The pancreas remains an organ for which routine laparoscopic resection is uncommon. STUDY DESIGN: This is a review of all distal pancreatectomies performed between January 2003 and December 2009 at Memorial Sloan-Kettering Cancer Center. Variables were compared between laparoscopic and open groups in unmatched and matched analyses. RESULTS: During the 7-year study period, 343 distal pancreatectomies were performed; 107 (31%) were attempted laparoscopically and 236 (69%) were performed open. The conversion rate was 30%. Laparoscopic patients were younger (median 60 vs 64 years, p < 0.0001), experienced less blood loss (median 150 vs 350 mL, p < 0.0001), longer operative times (median 163 vs 194 minutes, p < 0.0001), shorter hospital stay (median 5 vs 7 days, p < 0.0001), and had fewer postoperative complications (27% vs 40%, p = 0.03) than open patients. The rates of complications of grade 3 or greater (20% vs 20%, p = NS) and pancreatic leak (15% vs 13%, p = NS) were similar between laparoscopic and open groups. Patients having procedures that were converted had a higher body mass index (BMI) than patients who did not (28 vs 25, p = 0.035). Patients with converted resections experienced higher rates of complications of grade 3 or greater (36% vs 20%, p = 0.008) and pancreatic leaks (27% vs 13%, p = 0.03) than open patients. Compared with matched open patients, laparoscopic patients had longer operative times (195 minutes vs 160 minutes, p < 0.0001), less blood loss (175 mL vs 300 mL, p < 0.0001), and shorter hospital stay (5 days vs 6 days, p < 0.001). CONCLUSIONS: Patients who had laparoscopic distal pancreatectomy experienced decreased blood loss and a shorter hospital stay compared with matched patients undergoing open resection. Careful patient selection is important because patients who required conversion experienced higher rates of complications and pancreatic leak.

In Brief Objectives: The objectives of this study are 1) to determine whether the future liver remnant will grow after portal vein embolization (PVE) in patients with colon cancer on concurrent chemotherapy and 2) to determine whether recovery after extended hepatectomy is improved after PVE. Purpose: Neoadjuvant chemotherapy followed by hepatic resection is an increasingly used therapeutic strategy for curative treatment for colorectal metastases. However, such chemotherapy may result in steatosis, liver damage, and compromised liver regeneration and recovery. This study aims to determine whether PVE can be used during neoadjuvant therapy to enhance growth of future residual liver and to improve postoperative recovery. Methods: From September 1999 to September 2004, 100 patients with colorectal metastases to the liver were subjected to PVE as preparation for extended hepatic resection, 43 of whom were embolized during neoadjuvant chemotherapy. Liver growth was examined by computed tomography volumetric analysis. Clinical outcomes of the 71 patients subsequently resected were compared with 100 consecutive patients subjected to extended resection without PVE (controls). Results: After a median wait of 30 ± 2 days after PVE, patients on neoadjuvant chemotherapy experienced a median contralateral (nonembolized) liver growth of 22% ± 3% compared with 26% ± 3% for those without chemotherapy (P = NS). The number of patients with <5% growth was also similar: 4 of 43 versus 6 of 57 (P = NS). Comparison of patients resected after PVE to a simultaneous cohort of 100 consecutive patients subjected to extended resection without prior PVE demonstrated a lower fresh frozen plasma requirement (P = 0.01), a lower peak bilirubin (P = 0.002), and a shorter length of stay (P = 0.03). Mortality was similar (0% vs. 2%). Conclusions: Liver growth occurs after PVE even when cytotoxic chemotherapy is administered. No major complications occurred with PVE. Patients requiring major hepatic resection should be considered for PVE during neoadjuvant chemotherapy to improve subsequent recovery after resection. Forty-three patients with colon cancer underwent portal vein embolization (PVE) during neoadjuvant chemotherapy and were compared with the 57 who did not receive chemotherapy between PVE and resection. At 1 month, the growth in the contralateral hemiliver in the chemotherapy group was 22% ± 3% compared with 26% ± 3% (NS) for those without. Compared with a similar cohort of 100 extended liver resections at the same center, the FFP requirement, peak bilirubin, and length of stay were significantly shorter in the PVE group.

Primary hepatic sarcoma is a rare entity. The objectives of the study were to define treatment and long-term outcome and to identify prognostic factors.Between January 1981 and December 2004, 30 patients with primary sarcoma of the liver and 5 patients with primary carcinosarcoma of the liver were treated. Patient demographics, tumor characteristics, treatment, and actuarial survival were analyzed.Of the 30 patients with primary hepatic sarcoma (10 epithelioid hemangioendothelioma, 5 embryonal sarcoma, 5 angiosarcoma, 3 solitary fibrous tumor, and 7 other types), 11 underwent R0-resection and had a 5-year disease-specific survival of 64%. Of these 11 patients, 4 had low-grade sarcoma and have not developed tumor recurrence. In the group of 7 patients with high-grade sarcomas who underwent R0-resection, both patients with angiosarcoma died within 11 months, whereas the 5 patients with embryonal sarcoma had a 5-year disease-free and disease-specific survival of 80%. Six of the 10 patients with an epithelioid hemangioendothelioma were managed without surgery, as they had diffuse, slowly progressing, or stable lesions; these patients had a 5-year disease-specific survival of 67%. Of the remaining 13 patients in whom R0-resection was not performed, there were no 3-year survivors. The prognosis for patients with primary carcinosarcoma of the liver was poor, with all but 1 patient dying within a year and no 3-year survivors.The outcome of patients with primary hepatic sarcoma depends primarily on tumor histology and the ability to achieve complete tumor resection. Improvements in outcome will require the development of more effective systemic therapies.

Abstract BACKGROUND: During chemotherapy, some colorectal liver metastases (LMs) disappear on serial imaging. This disappearance may represent a complete response (CR) or a reduction in the sensitivity of imaging during chemotherapy. The objective of the current study was to determine the fate of disappearing LMs (DLMs) and the factors that predict a true CR. METHODS: Between 2000 and 2003, 435 patients who were evaluated by hepatobiliary surgeons received chemotherapy before they were considered for resection. Inclusion criteria were &lt;12 LMs before chemotherapy, at least 1 DLM on a computed tomography (CT) scan, and either surgical resection or 1 year of clinical follow‐up after the disappearance of LMs. A true CR was defined as either a pathologic CR (no tumor detected in the resection specimen) or a durable clinical CR (did not reappear on follow‐up imaging). Clinical and pathologic factors were analyzed to identify those associated with a true CR. RESULTS: During chemotherapy, 39 patients (9%) had a total of 118 DLMs on follow‐up CT scans. Sixty‐eight DLMs were resected, and 50 were followed clinically. Overall, 75 DLMs (64%) were true CRs, including 44 pathologic CRs and 31 durable clinical CRs. On multivariate analysis, the use of hepatic arterial infusion (HAI) chemotherapy (odds ratio [OR], 6.2; P = .02), the inability to observe the DLM on a magnetic resonance image (OR, 4.7; P = .005), and normalization of serum carcinoembryonic antigen levels (OR, 4.6; P = .006) were associated independently with a true CR. CONCLUSIONS: Approximately 66% of DLMs represented a true CR according to assessment by resection or radiologic follow‐up. Predictive factors may help to stratify patients who are likely to harbor residual disease. Cancer 2010. © 2010 American Cancer Society.

Purpose To determine the survival of patients with hepatocellular carcinoma (HCC) treated with a standardized method of transcatheter arterial embolization (TAE) with small embolic particles intended to impart terminal vessel blockade, and to evaluate prognostic factors that impact overall survival. Materials and Methods A total of 322 patients with HCC who underwent 766 embolizations from January 1997 to December 2004 were retrospectively reviewed. Selective embolization of vessels feeding individual tumors was performed with small (50 μm) polyvinyl alcohol or spherical embolic particles (40–120 μm) intended to cause terminal vessel blockade. Repeat embolization was performed in cases of evidence of persistent viable tumor or development of new lesions. Patient, tumor, and treatment characteristics were prospectively recorded and tested for prognostic significance by univariate and multivariate analysis. Results The median survival time was 21 months, with 1-, 2-, and 3-year overall survival rates of 66%, 46%, and 33%, respectively. In patients without extrahepatic disease or portal vein involvement by tumor, the overall 1-, 2-, and 3-year survival rates increased to 84%, 66%, and 51%, respectively. Okuda stage, extrahepatic disease, diffuse disease (≥5 tumors), and tumor size were independent predictors of survival on multivariate analysis. There were 90 complications (11.9%) in 75 patients, including eight deaths (2.5%), within 30 days of embolization. Conclusions Hepatic arterial embolization with small particles to cause terminal vessel blockade is an effective treatment method for patients with unresectable HCC. These data support our hypothesis that particles alone may be the critical component of catheter-directed embolotherapy. To determine the survival of patients with hepatocellular carcinoma (HCC) treated with a standardized method of transcatheter arterial embolization (TAE) with small embolic particles intended to impart terminal vessel blockade, and to evaluate prognostic factors that impact overall survival. A total of 322 patients with HCC who underwent 766 embolizations from January 1997 to December 2004 were retrospectively reviewed. Selective embolization of vessels feeding individual tumors was performed with small (50 μm) polyvinyl alcohol or spherical embolic particles (40–120 μm) intended to cause terminal vessel blockade. Repeat embolization was performed in cases of evidence of persistent viable tumor or development of new lesions. Patient, tumor, and treatment characteristics were prospectively recorded and tested for prognostic significance by univariate and multivariate analysis. The median survival time was 21 months, with 1-, 2-, and 3-year overall survival rates of 66%, 46%, and 33%, respectively. In patients without extrahepatic disease or portal vein involvement by tumor, the overall 1-, 2-, and 3-year survival rates increased to 84%, 66%, and 51%, respectively. Okuda stage, extrahepatic disease, diffuse disease (≥5 tumors), and tumor size were independent predictors of survival on multivariate analysis. There were 90 complications (11.9%) in 75 patients, including eight deaths (2.5%), within 30 days of embolization. Hepatic arterial embolization with small particles to cause terminal vessel blockade is an effective treatment method for patients with unresectable HCC. These data support our hypothesis that particles alone may be the critical component of catheter-directed embolotherapy.

Pancreatic adenocarcinoma is a lethal disease. Over 80% of patients are found to have metastatic disease at the time of diagnosis. Strategies to improve disease-specific outcome include identification and early detection of precursor lesions or early cancers in high-risk groups. In this study, we investigate whether screening at-risk relatives of familial pancreatic cancer (FPC) patients is safe and has significant yield.We enrolled 309 asymptomatic at-risk relatives into our Familial Pancreatic Tumor Registry (FPTR) and offered them screening with magnetic resonance cholangiopancreaticogram (MRCP) followed by endoscopic ultrasound (EUS) with fine needle aspiration if indicated. Relatives with findings were referred for surgical evaluation.As of 1 August 2009, 109 relatives had completed at least one cycle of screening. Abnormal radiographic findings were present on initial screening in 18/109 patients (16.5%), 15 of whom underwent EUS. A significant abnormality was confirmed in 9 of 15 patients, 6 of whom ultimately had surgery for an overall diagnostic yield of 8.3% (9/109). Yield was greatest in relatives >65 years old (35%, 6/17) when compared with relatives 55-65 years (3%, 1/31) and relatives <55 years (3%, 2/61).Screening at-risk relatives from FPC families has a significant diagnostic yield, particularly in relatives >65 years of age, confirming prior studies. MRCP as initial screening modality is safe and effective.

Correa-Gallego, Camilo MD; Dinkelspiel, Helen E. MD; Sulimanoff, Isabel MLS; Fisher, Sarah MD; Viñuela, Eduardo F. MD; Kingham, Peter T. MD, FACS; Fong, Yuman MD, FACS; DeMatteo, Ronald P. MD, FACS; D'Angelica, Michael I. MD; Jarnagin, William R. MD, FACS; Allen, Peter J. MD, FACS Author Information

Current regimens of systemic chemotherapy result in only modest lengthening of survival in patients with advanced stage, liver-dominant, metastatic colorectal cancer who have failed first-line chemotherapy. The objective of this study was to investigate the safety and tolerability of NV1020, a replication-competent, attenuated, genetically engineered herpes simplex virus type 1 (HSV-1), in patients with hepatic colorectal metastases refractory to first-line chemotherapy. A phase I, open-label, dose-escalating study of a single 10-min hepatic arterial infusion of NV1020 in four cohorts. Three patients in each cohort received doses of 3 × 106, 1 × 107, 3 × 107, and 1 × 108 plaque-forming units. Adverse events were either mild or moderate in severity, and self-limiting. Only three serious adverse events (one transient rise in serum γ-glutamyltransferase, one diarrhea, and one leukocytosis) experienced by three patients were considered to be possibly or probably related to NV1020. There were no deaths during the study, and there was no evidence of disseminated herpes infection. Viral presence was detected in only one saliva sample and two serum samples from one asymptomatic patient in the highest dose cohort. In the first week after viral administration only rare and minor increases were noted for tumor necrosis factor-α (six samples; three patients; peak, 40 pg/ml), interleukin (IL)-1 (two samples; two patients; peak, 28 pg/ml), and interferon-γ (four samples; two subjects; peak, 54 pg/ml). No IL-2 was detected. Mild liver enzyme elevations were self-limiting and not associated with clinical symptoms. We conclude that NV1020, a genetically engineered but replication-competent HSV-1 oncolytic virus, can be safely administered into the hepatic artery without significant effects on normal liver function.

Microwave (MWA) and radiofrequency ablation (RFA) are the most commonly used techniques for ablating colorectal-liver metastases (CRLM). The technical and oncologic differences between these modalities are unclear.We conducted a matched-cohort analysis of patients undergoing open MWA or RFA for CRLM at a tertiary-care center between 2008 and 2011; the primary endpoint was ablation-site recurrence. Tumors were matched by size, clinical-risk score, and arterial-intrahepatic or systemic chemotherapy use. Outcomes were compared using conditional logistic regression and stratified log-rank test.We matched 254 tumors (127 per group) from 134 patients. MWA and RFA groups were comparable by age, gender, median number of tumors treated, proximity to major vessels, and postoperative complication rates. Patients in the MWA group had lower ablation-site recurrence rates (6% vs. 20%; P < 0.01). Median follow-up, however, was significantly shorter in the MWA group (18 months [95% confidence interval 17-20] vs. 31 months [95% confidence interval 28-35]; P < 0.001). Kaplan-Meier estimates of ablation-site recurrence at 2 years were significantly lower for the lesions treated with MWA (7% vs. 18%, P: 0.01).Ablation-site recurrences of CRLM were lower with MWA compared with RFA in this matched cohort analysis. Longer follow-up time in the MWA may increase the recurrence rate; however, actuarial local failure estimations demonstrated better local control with MWA.

BackgroundThis study reports the results of hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (dex) in patients with unresectable intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC) and investigates dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) assessment of tumor vascularity as a biomarker of outcome.Patients and methodsThirty-four unresectable patients (26 ICC and eight HCC) were treated with HAI FUDR/dex. Radiologic dynamic and pharmacokinetic parameters related to tumor perfusion were analyzed and correlated with response and survival.ResultsPartial responses were seen in 16 patients (47.1%); time to progression and response duration were 7.4 and 11.9 months, respectively. Median follow-up and median survival were 35 and 29.5 months, respectively; 2-year survival was 67%. DCE-MRI data showed that patients with pretreatment integrated area under the concentration curve of gadolinium contrast over 180 s (AUC 180) >34.2 mM·s had a longer median survival than those with AUC 180 <34 mM·s (35.1 versus 19.1 months, P = 0.002). Decreased volume transfer exchange between the vascular space and extracellular extravascular space (-ΔKtrans) and the corresponding rate constant (-Δkep) on the first post-treatment scan both predicted survival.ConclusionsIn patients with unresectable primary liver cancer, HAI therapy can be effective and safe. Pretreatment and early post-treatment changes in tumor perfusion characteristics may predict treatment outcome.

The aim of this study was to investigate the rate and pattern of recurrence after curative intent resection of perihilar cholangiocarcinoma (PHC).Patients were included from 2 prospectively maintained databases. Recurrences were categorized by site. Time to recurrence and recurrence-free survival (RFS) were estimated using the Kaplan-Meier method. Cox proportional hazards modeling was used to identify independent poor prognostic factors.Between 1991 and 2012, 306 consecutive patients met inclusion criteria. Median overall survival was 40 months. A recurrence was diagnosed in 177 patients (58%). An initial local recurrence was found in 26% of patients: liver hilum (11%), hepaticojejunostomy (8%), liver resection margin (8%), or distal bile duct remnant (2%). An initial distant recurrence was observed in 40% of patients: retroperitoneal lymph nodes (14%), intrahepatic away from the resection margin (13%), peritoneum (12%), and lungs (8%). Only 18% of patients had an isolated initial local recurrence. The estimated overall recurrence rate was 76% at 8 years. After a recurrence-free period of 5 years, 28% of patients developed a recurrence in the next 3 years. Median RFS was 26 months. Independent prognostic factors for RFS were resection margin, lymph node status, and tumor differentiation. Only node-positive PHC precluded RFS beyond 7 years.Perihilar cholangiocarcinoma will recur in most patients (76%) after resection, emphasizing the need for better adjuvant strategies. The high recurrence rate of up to 8 years justifies prolonged surveillance. Only patients with an isolated initial local recurrence (18%) may have benefited from a more extensive resection or liver transplantation. Node-positive PHC appears incurable.

BackgroundIn patients with hilar cholangiocarcinoma, ipsilateral en bloc hepatic resection improves survival but is associated with increased morbidity. Preoperative biliary drainage of the future liver remnant (FLR) and contralateral portal vein embolization (PVE) may improve perioperative outcome, but their routine use is controversial. This study analyses the impact of FLR volume and preoperative biliary drainage on postoperative hepatic insufficiency and mortality rates.MethodsPatients who underwent hepatic resection and for whom adequate imaging data for FLR calculation were available were identified retrospectively. Patient demographic, operative and perioperative data were recorded and analysed. The volume of the FLR was calculated based on the total liver volume and the volume of the resection that was actually performed using semi-automated contouring of the liver on preoperative helical acquired scans. In patients subjected to preoperative biliary drainage, the preoperative imaging was reviewed to determine if the FLR had been decompressed. Hepatic insufficiency was defined as a postoperative rise in bilirubin of 5 mg/dl above the preoperative level that persisted for >5 days postoperatively. Operative mortality was defined as death related to the operation, whenever it occurred.ResultsSixty patients were identified who underwent hepatic resection between 1997 and 2007 and for whom imaging data were available for analysis. During this period, preoperative biliary drainage of the FLR was used selectively and PVE was used in only one patient. The mean age of the patients was 64 ± 11.6 years and 68% were male. The median length of stay was 14 days and the overall morbidity and mortality were 53% and 10%, respectively. Preoperative FLR volume was a predictor of hepatic insufficiency and death (P= 0.03). A total of 65% of patients had an FLR volume ≥30% (39/60) of the total volume. No patient in this group had hepatic insufficiency, but there were two operative deaths (5%), both occurring in patients who underwent preoperative biliary drainage. By contrast, in the group with FLR < 30% (21/60, 35%), hepatic insufficiency was seen in five patients and operative mortality in four patients, and were strongly associated with lack of preoperative biliary drainage of the FLR (P= 0.009). Patients with an FLR ≥ 30% were more likely to have radiographic evidence of ipsilateral lobar atrophy and hypertrophy of the FLR (46.2% vs. 9.5% in patients with FLR < 30%; P= 0.004).ConclusionsIn patients undergoing liver resection for hilar cholangiocarcinoma, FLR volume of < 30% of total liver volume is associated with increased risk for hepatic insufficiency and death. Preoperative biliary drainage of the FLR appears to improve outcome if the predicted volume is < 30%. However, in patients with FLR ≥ 30%, preoperative biliary drainage does not appear to improve perioperative outcome and, as many of these patients have hypertrophy of the FLR, PVE is likely to offer little benefit.