CD44 regulates pancreatic cancer invasion through MT1-MMP.

UNLABELLED: Pancreatic cancer is one of the deadliest human malignancies due to its early metastatic spread and resistance to therapy. The mechanisms regulating pancreatic cancer metastasis are so far poorly understood. Here, using both in vitro and in vivo approaches, it is demonstrated that CD44, a transmembrane glycoprotein expressed on a subset of pancreatic cancer cells, is required for the induction of epithelial-mesenchymal transition (EMT) and the activation of an invasive program in pancreatic cancer. Mechanistically, the transcription factor Snail1 (SNAI1), a regulator of the EMT program, is a downstream target of CD44 in primary pancreatic cancer cells and regulates membrane bound metalloproteinase (MMP14/MT1-MMP) expression. In turn, MT1-MMP expression is required for pancreatic cancer invasion. Thus, these data establish the CD44-Snail-MMP axis as a key regulator of the EMT program and of invasion in pancreatic cancer. IMPLICATIONS: This study sets the stage for CD44 and MT1-MMP as therapeutic targets in pancreatic cancer, for which small molecule or biologic inhibitors are available. Visual Overview: http://mcr.aacrjournals.org/content/early/2014/09/10/1541-7786.MCR-14-0076/F1.large.jpg.

Technical aspects of robotic-assisted pancreaticoduodenectomy (RAPD).

Minimally invasive pancreaticoduodenctomy (MIPD) is a technically challenging procedure. Current laparoscopic equipment with its limited range of motion, poor surgeon ergonomics, and lack of 3D view has limited the addition of MIPD. The robotic platform is able to overcome these limitations, allowing the recreation of time-honored open surgical principles of this procedure through a minimally invasive approach. We present here the technical aspects of the University of Pittsburgh robotic-assisted pancreaticoduodenctomy.

Cirrhosis is not a contraindication to laparoscopic cholecystectomy: results and practical recommendations.

BACKGROUND: Gallstones appear more frequently in patients with cirrhosis and open cholecystectomy in this patient population is associated with higher morbidity and mortality. The aim of the present study was to evaluate experience with laparoscopic cholecystectomy in patients with cirrhosis and to provide recommendations for management. METHODS: Retrospective review of laparoscopic cholecystectomy in patients with cirrhosis from March 1999 to May 2008 was performed. Peri-operative characteristics and subgroup analysis were performed in patients with Child-Pugh's classes A, B and C cirrhosis. RESULTS: A total of 68 patients were reviewed in this study. In all, 69% of the patients were Child's class A. The most common indication for cholecystectomy was chronic/symptomatic cholelithiasis (68%). Compared with patients with Child's class B and C, laparoscopic cholecystectomy in patients with Child's class A was associated with significantly decreased operative time (P= 0.01), blood loss (P= 0.001), conversion to open cholecystectomy (P= 0.001) and length of hospital stay (P= 0.001). CONCLUSIONS: Laparoscopic cholecystectomy in patients with cirrhosis is feasible with no mortality and low morbidity, especially in patients with Child's class A cirrhosis.

Comparative benefits of laparoscopic vs open hepatic resection: a critical appraisal.

OBJECTIVES: To perform a literature review examining the comparative benefits of laparoscopic vs open hepatic resection and to define the benefits and outcomes of laparoscopic liver resection in our own series of 314 patients. DATA SOURCES: Cited English-language publications from PubMed. In addition, between 2001 to 2010, hepatic resections were performed in our institution in 1294 patients, of whom 314 patients (24.3%) underwent laparoscopic liver resection for benign or malignant liver lesions. STUDY SELECTION: Search phrases were "laparoscopic liver resection," "open liver resection," "versus," "compared with," and "advantages." DATA EXTRACTION: Thirty-one studies were reviewed that directly compared laparoscopic with open hepatic resection in 2473 patients. DATA SYNTHESIS: In case-cohort matched studies, and our institutional series, laparoscopic liver resection was associated with less blood loss, quicker resumption of oral diet, less pain medication requirement, and shorter length of stay, with no difference in complication rates. In those patients undergoing laparoscopic hepatic resection for malignancy, there was no difference in 3- or 5-year overall survival when compared with well-matched open hepatic resection cases. Financially, the total hospital costs of laparoscopic liver resection were either offset or improved because of a shorter length of stay. CONCLUSIONS: Based on review of the literature and our institutional series, minimally invasive hepatic resection for benign and malignant liver lesions is safe and feasible with significant benefits for patients consisting of less blood loss, less narcotic requirements, and shorter length of hospital stay. There are no economic disadvantages to the laparoscopic approach, and case-cohort matched studies show no difference in oncologic outcomes between the laparoscopic and open groups.

Outcomes of laparoscopic hepatic resection for colorectal cancer metastases.

The role of laparoscopic liver resection for cancer remains controversial. This review summarizes the expanding literature on outcomes of minimally invasive hepatic resection for colorectal cancer liver metastases. Four recent studies (in more than 300 patients) show 5-year overall-survival rates of 46-64%, which are comparable to results in modern open hepatic resection series. The advantages of laparoscopic liver resection include smaller incisions, less pain, less narcotic requirements, and shorter length of stay.

Laparoscopic liver resection--current update.

An increasing number of studies are reporting the outcomes and benefits of laparoscopic liver resection. This article reviews the literature with emphasis on a recent consensus conference on laparoscopic liver resection in 2008, the learning curve for laparoscopic liver surgery, laparoscopic major hepatectomies, oncologic outcomes of laparoscopic liver resection for hepatocellular carcinoma and colorectal cancer liver metastases, and the comparative benefits of laparoscopic versus open liver resection. Current evidence suggests that minimally invasive hepatic resection is safe and feasible with short-term benefits, no economic disadvantage, and no compromise to oncologic principles.

Comparing the clinical and economic impact of laparoscopic versus open liver resection.

BACKGROUND: Laparoscopic liver resection has thus far not gained widespread acceptance among liver surgeons. Valid questions remain regarding the relative clinical superiority of the laparoscopic approach as well as whether laparoscopic hepatectomy carries any economic benefit compared with open liver surgery. OBJECTIVE: The aim of this work is to compare the clinical and economic impact of laparoscopic versus open left lateral sectionectomy (LLS). METHODS: Between May 2002 and July 2008, 44 laparoscopic LLS and 29 open LLS were included in the analysis. Deviation-based cost modeling (DBCM) was utilized to compare the combined clinical and economic impact of the open and laparoscopic approaches. RESULTS: The laparoscopic approach compared favorably with the open approach from both a clinical and economic standpoint. Not only was the median length of stay (LOS) shorter by 2 days in the laparoscopic group (3 versus 5 days, respectively, P = 0.001), but the laparoscopic cohort also benefited from a significant reduction in postoperative morbidity (P = 0.001). Because the groups differed significantly in age and ratio of benign to malignant disease, a subgroup analysis limited to patients with malignant disease was undertaken. The same reduction in LOS and postoperative morbidity was evident within the malignant subgroup undergoing laparoscopic LLS (P = 0.003). The economic impact of the laparoscopic approach was noteworthy, with the laparoscopic approach US$1,527-2,939 more cost efficient per patient compared with the open technique. CONCLUSION: Our study seems not only to corroborate the safety and clinical benefit of the laparoscopic approach but also suggests a fiscally important cost advantage for the minimally invasive approach.

Laparoscopic major hepatectomy: an evolution in standard of care.

OBJECTIVE: To analyze the results of 6 international surgical centers performing laparoscopic major liver resections. SUMMARY BACKGROUND DATA: The safety and feasibility of laparoscopy for minor liver resections has been previously demonstrated. Major anatomic liver resections, initially considered to be unsuitable for laparoscopy, are increasingly reported by several centers worldwide. METHODS: Prospective databases of 3 European, 2 U.S., and 1 Australian centers were combined. Between 1997 and 2008, 210 major liver resections were performed: 136 right and 74 left hepatectomies. Results and differences in surgical techniques between the 6 centers are outlined. RESULTS: Surgical duration was 250 minutes (range: 90-655 minutes). Operative blood loss was 300 mL (range: 20-2500 mL). Thirty patients (14.3%) received blood transfusion. Conversion to open surgery was required in 26 patients (12.4%). Portal triad clamping was performed in 24 patients (11.4%). Median tumor size was 5.4 cm (range: 1-25 cm) and surgical margin was 10.5 mm (range: 0-70 mm). Two patients died during the postoperative period from pulmonary embolism and urosepsis. Liver-specific and general complications occurred in 17 (8.1%) and 29 patients (13.8%), respectively. Hospital length of stay was 6 days (range: 1-34 days). A further analysis of early (n = 90) and late (n = 120) experience showed improved surgical and postoperative results in the latter group. CONCLUSIONS: This multicenter study demonstrates that laparoscopic major liver resections are feasible in selected patients and results improve with experience. However, proficiency in both open liver surgery and advanced laparoscopy is compulsory and surgeons must begin with minor laparoscopic resections.

Minimally invasive liver resection for metastatic colorectal cancer: a multi-institutional, international report of safety, feasibility, and early outcomes.

OBJECTIVE: To evaluate a multicenter, international series on minimally invasive liver resection for colorectal carcinoma (CRC) metastasis. SUMMARY BACKGROUND DATA: Multiple single series have been reported on laparoscopic liver resection for CRC metastasis. We report the first collaborative multicenter, international series to evaluate the safety, feasibility, and oncologic integrity of laparoscopic liver resection for CRC metastasis. METHODS: We retrospectively reviewed all patients who underwent minimally invasive liver resection for CRC metastasis from February 2000 to September 2008 from multiple medical centers from the United States and Europe. The multicenter series of patients were accumulated into a single database. Patient demographics, preoperative, operative, and postoperative characteristics were analyzed. Actuarial overall survival was calculated with Kaplan-Meier analysis. RESULTS: A total of 109 patients underwent minimally invasive liver resection for CRC metastasis. The median age was 63 years (range, 32-88 years) with 51% females. The most common sites of primary colon cancer were sigmoid/rectum (51%), right colon (25%), and left colon (13%). Synchronous liver lesions were present in 11% of patients. For those with metachronous lesions liver lesions, the median time interval from primary colon cancer surgery to liver metastasectomy was 12 months. Preoperative chemotherapy was administered in 68% of cases prior to liver resection. The majority of patients underwent prior abdominal operations (95%). Minimally invasive approaches included totally laparoscopic (56%) and hand-assisted laparoscopic (41%), the latter of which was employed more frequently in the US medical centers (85%) compared with European centers (13%) (P = 0.001). There were 4 conversions to open surgery (3.7%), all due to bleeding. Extents of resection include wedge/segmentectomy (34%), left lateral sectionectomy (27%), right hepatectomy (28%), left hepatectomy (9%), extended right hepatectomy (0.9%), and caudate lobectomy (0.9%). Major liver resections (> or =3 segments) were performed in 45% of patients. Median OR time was 234 minutes (range, 60-555 minutes) and blood loss was 200 mL (range, 20-2500 mL) with 10% receiving a blood transfusion. There were no reported perioperative deaths and a 12% complication rate. Median length of hospital stay for the entire series was 4 days (range, 1-22 days) with a shorter stay in medical centers in the United States (3 days) versus that seen in Europe (6 days) (P = 0.001). Negative margins were achieved in 94.4% of patients. Actuarial overall survivals at 1-, 3-, and 5-year for the entire series were 88%, 69%, and 50%, respectively. Disease-free survivals at 1-, 3-, and 5-year were 65%, 43%, and 43%, respectively. CONCLUSIONS: Minimally invasive liver resection for colorectal metastasis is safe, feasible, and oncologically comparable to open liver resection for both minor and major liver resections, even with prior intra-abdominal operations, in selected patients and when performed by experienced surgeons.

World review of laparoscopic liver resection-2,804 patients.

OBJECTIVE: To provide a review of the world literature on laparoscopic liver resection. SUMMARY BACKGROUND DATA: Initially described for peripheral, benign tumors resected by nonanatomic wedge resections, minimally invasive liver resections are now being performed more frequently, even for larger, malignant tumors located in challenging locations. Although a few small review articles have been reported, a comprehensive review on laparoscopic liver resection has not been published. METHODS: We conducted a literature search using Pubmed, screening all English publications on laparoscopic liver resections. All data were analyzed and apparent case duplications in updated series were excluded from the total number of patients. Tumor type, operative characteristics, perioperative morbidity, and oncologic outcomes were tabulated. RESULTS: A total of 127 published articles of original series on laparoscopic liver resection were identified, and accounted for 2,804 reported minimally invasive liver resections. Fifty percent were for malignant tumors, 45% were for benign lesions, 1.7% were for live donor hepatectomies, and the rest were indeterminate. Of the resections, 75% were performed totally laparoscopically, 17% were hand-assisted, and 2% were laparoscopic-assisted open hepatic resection (hybrid) technique, with the remainder being other techniques or conversions to open hepatectomies. The most common laparoscopic liver resection was a wedge resection or segmentectomy (45%) followed by anatomic left lateral sectionectomy (20%), right hepatectomy (9%), and left hepatectomy (7%). Conversion from laparoscopy to open laparotomy and from laparoscopy to hand-assisted approach occurred in 4.1% and 0.7% of reported cases, respectively. Overall mortality was 9 of 2,804 patients (0.3%), and morbidity was 10.5%, with no intraoperative deaths reported. The most common cause of postoperative death was liver failure. Postoperative bile leak was observed in 1.5% of cases. For cancer resections, negative surgical margins were achieved in 82% to 100% of reported series. The 5-year overall and disease-free survival rates after laparoscopic liver resection for hepatocellular carcinoma were 50% to 75% and 31% to 38.2%, respectively. The 3-year overall and disease-free survival rates after laparoscopic liver resection for colorectal metastasis to the liver were 80% to 87% and 51%, respectively. CONCLUSION: In experienced hands, laparoscopic liver resections are safe with acceptable morbidity and mortality for both minor and major hepatic resections. Oncologically, 3- and 5-year survival rates reported for hepatocellular carcinoma and colorectal cancer metastases are comparable to open hepatic resection, albeit in a selected group of patients.

Initial presentation and management of hilar and peripheral cholangiocarcinoma: is a node-positive status or potential margin-positive result a contraindication to resection?

BACKGROUND: Cholangiocarcinoma (CC) frequently presents at an advanced stage and the majority of patients are unresectable at diagnosis. We sought to examine our recent experience with surgical resection for hilar and peripheral CC. METHODS: A review of all CC patients who presented to our multidisciplinary liver cancer center for evaluation of their CC between January 2000 and August 2008 was performed. Demographics, therapeutic management, pathologic characteristics, and overall survival were analyzed. RESULTS: A total of 280 patients were evaluated over the 8-year period, and 222 patients (79%) were unresectable at presentation. Fifty-eight out of 280 patients were candidates for resection, of whom, 51 patients underwent resection. Hilar CC was identified in 27 patients (53%) and peripheral CC was present in 24 patients (47%). Morbidity and 90-day mortality were 61 and 9.8%, respectively. Overall, negative margin (R0) resection was achieved in 26 patients (51%). Using multivariate Cox regression analysis, only margin status was found to be a significant predictor of survival (p = 0.009). Compared with peripheral CC, hilar CC was associated with shorter overall survival (p = 0.001) and higher rates of positive margins (p = 0.001) and perineural invasion (p = 0.02), and no difference in angiolymphatic, portal vein, and lymph node involvement. CONCLUSIONS: Survival benefits can be achieved with resection for cholangiocarcinoma. Given the lack of effective alternative therapy, when confronted with the potential risk of positive margins or isolated nodal disease, we continue to advocate aggressive surgical resection for both hilar and peripheral CC with the ultimate goal of negative margin resection.

Laparoscopic liver resection for cancer.

The field of laparoscopic liver resection surgery has rapidly evolved, with more than 1000 cases now reported. Laparoscopic hepatic resection was initially described for small, peripheral, benign lesions. Experienced teams are now performing laparoscopic anatomic resections for cancer. Operative times improved with experience. When compared with open cases, blood loss was less in most laparoscopic series, but was the main indication for conversion to an open procedure. Patients undergoing laparoscopic resection had shorter length of hospital stay and quicker recovery. Perioperative complications were comparable between the two approaches. Importantly, basic oncologic principles were maintained in the laparoscopic liver resections. The purpose of this review is to summarize the data available on outcomes for laparoscopic hepatic resection for cancer. This includes primary hepatocellular carcinoma, as well as metastatic colorectal cancer to the liver. The evidence to date suggests that laparoscopic results are comparable with the open approach in cancer patients.