Michael I. D’Angelica

CD133 expression is not restricted to stem cells, and both CD133+ and CD133– metastatic colon cancer cells initiate tumors

Colon cancer stem cells are believed to originate from a rare population of putative CD133+ intestinal stem cells. Recent publications suggest that a small subset of colon cancer cells expresses CD133, and that only these CD133+ cancer cells are capable of tumor initiation. However, the precise contribution of CD133+ tumor-initiating cells in mediating colon cancer metastasis remains unknown. Therefore, to temporally and spatially track the expression of CD133 in adult mice and during tumorigenesis, we generated a knockin lacZ reporter mouse (CD133lacZ/+), in which the expression of lacZ is driven by the endogenous CD133 promoters. Using this model and immunostaining, we discovered that CD133 expression in colon is not restricted to stem cells; on the contrary, CD133 is ubiquitously expressed on differentiated colonic epithelium in both adult mice and humans. Using Il10-/-CD133lacZ mice, in which chronic inflammation in colon leads to adenocarcinomas, we demonstrated that CD133 is expressed on a full gamut of colonic tumor cells, which express epithelial cell adhesion molecule (EpCAM). Similarly, CD133 is widely expressed by human primary colon cancer epithelial cells, whereas the CD133- population is composed mostly of stromal and inflammatory cells. Conversely, CD133 expression does not identify the entire population of epithelial and tumor-initiating cells in human metastatic colon cancer. Indeed, both CD133+ and CD133- metastatic tumor subpopulations formed colonospheres in in vitro cultures and were capable of long-term tumorigenesis in a NOD/SCID serial xenotransplantation model. Moreover, metastatic CD133- cells form more aggressive tumors and express typical phenotypic markers of cancer-initiating cells, including CD44 (CD44+CD24-), whereas the CD133+ fraction is composed of CD44lowCD24+ cells. Collectively, our data suggest that CD133 expression is not restricted to intestinal stem or cancer-initiating cells, and during the metastatic transition, CD133+ tumor cells might give rise to the more aggressive CD133(- )subset, which is also capable of tumor initiation in NOD/SCID mice.

Lack of Evidence for Increased Operative Morbidity After Hepatectomy with Perioperative Use of Bevacizumab: A Matched Case-Control Study

BackgroundBevacizumab (bev) is a humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF). Perioperative bev is now commonly used in patients undergoing hepatic resection. Little is known, however, about the safety of perioperative bev use in the setting of hepatic resection.MethodsComputerized pharmacy records were used to identify all patients who received bev between January 2004 and June 2005. Patients who underwent hepatectomy for colorectal metastases and received bev within 12 weeks of surgery were identified and compared with a group of matched historical controls.ResultsThirty-two patients underwent hepatic resection of colorectal cancer metastases and received bev within the specified perioperative period. Sixteen patients received bev before surgery and 24 received bev after surgery. A subset of eight patients received bev both before and after surgery. The median time between bev administration and surgery was 6.9 weeks before (range, 3–15 weeks) and 7.4 weeks after (range, 5–15 weeks). Perioperative complications occurred in 13 patients (40.6%), two of which were considered major complications. There was no statistically significant difference in perioperative morbidity and severity of complications when compared with a set of matched controls.ConclusionsClinical experience thus far does not indicate a statistically significantly increased risk of perioperative complications with the incorporation of bev into pre- and/or postoperative treatment paradigms. Given the long half-life of bev and the potential for anti-VEGF therapy to impede wound healing and/or liver regeneration, we continue to favor a window of 6 to 8 weeks between bev administration and surgery.

Outcome After Hepatectomy for Multiple (Four or More) Colorectal Metastases in the Era of Effective Chemotherapy

BackgroundHepatic resection is generally accepted as the only potential for long-term survival in patients with colorectal metastases confined to the liver. Despite an unknown benefit, hepatic resection is playing an increasing role in patients with extensive disease.MethodsA retrospective review of a prospectively maintained hepatobiliary surgical database was carried out. Outcome after hepatectomy for four or more colorectal hepatic metastases was reviewed.ResultsBetween 1998 and 2002, out of a total of 584 patients, 98 (17%) with four or more colorectal hepatic metastases were resected. Actuarial 5-year survival was 33% for the entire group, with seven actual 5-year survivors. There were no perioperative deaths, and the perioperative morbidity was 28%. Positive margins and extrahepatic disease resection were independently associated with poor outcome. The median disease-free survival was 12 months, with no actuarial disease-free survivors at 5 years. Recurrence pattern, response to neoadjuvant chemotherapy, time to recurrence, and resection of recurrent disease were also associated with outcome.ConclusionsLong-term survival can be achieved after resection of multiple colorectal metastases; however, because most patients will experience recurrence of disease, effective adjuvant therapy and close follow-up is necessary.

The Role of Staging Laparoscopy in Hepatobiliary Malignancy: Prospective Analysis of 401 Cases

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

Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions

BackgroundColorectal cancer is the second leading cause of cancer death in the United States, with over 50,000 deaths estimated in 2014. Molecular profiling for somatic mutations that predict absence of response to anti-EGFR therapy has become standard practice in the treatment of metastatic colorectal cancer; however, the quantity and type of tissue available for testing is frequently limited. Further, the degree to which the primary tumor is a faithful representation of metastatic disease has been questioned. As next-generation sequencing technology becomes more widely available for clinical use and additional molecularly targeted agents are considered as treatment options in colorectal cancer, it is important to characterize the extent of tumor heterogeneity between primary and metastatic tumors.ResultsWe performed deep coverage, targeted next-generation sequencing of 230 key cancer-associated genes for 69 matched primary and metastatic tumors and normal tissue. Mutation profiles were 100% concordant for KRAS, NRAS, and BRAF, and were highly concordant for recurrent alterations in colorectal cancer. Additionally, whole genome sequencing of four patient trios did not reveal any additional site-specific targetable alterations.ConclusionsColorectal cancer primary tumors and metastases exhibit high genomic concordance. As current clinical practices in colorectal cancer revolve around KRAS, NRAS, and BRAF mutation status, diagnostic sequencing of either primary or metastatic tissue as available is acceptable for most patients. Additionally, consistency between targeted sequencing and whole genome sequencing results suggests that targeted sequencing may be a suitable strategy for clinical diagnostic applications.

Laparoscopic versus Open Liver Resection: A Matched-Pair Case Control Study

BackgroundLaparoscopic liver resection (LLR) has become an increasingly popular operation; however, its theoretical benefits remain unproven. The aim of this study was to conduct a comparative outcome study between LLR and matched-pair open liver resections (OLR).MethodsSixty five patients underwent attempted LLR from 1998 through 2008; 52 of which were completed laparoscopically. Patients who underwent OLR prior to 1998 were matched to laparoscopic cases for demographics, comorbidities, diagnosis, tumor characteristics, procedure, and background liver. Perioperative and oncologic outcomes were compared between the two groups. Analyses were performed excluding and including conversion cases.ResultsCharacteristics were comparable between both groups. LLR was associated with significant reductions in estimated blood loss, frequency of transfusion, frequency of Pringle maneuver, postoperative morbidity, time to recovery, length of hospital stay, and incidence of incisional hernia. For patients with malignant tumors, there were no positive surgical margins or local recurrence in either group and the overall pattern of recurrence was similar.ConclusionFor well-selected patients, LLR is a feasible operation that does not compromise operative or oncologic outcomes. While LLR was associated with some benefits, these can only be definitively proven in a randomized controlled trial.

Ninety-Six Five-Year Survivors After Liver Resection for Metastatic Colorectal Cancer

BACKGROUND Studies have consistently confirmed the benefit of liver resection for metastatic colorectal cancer. Few reports, however, have a long enough followup or sufficient 5-year survivors to study the clinical course of patients beyond 5 years. STUDY DESIGN From July 1985 through December 1991, 456 patients underwent liver resection for colorectal metastases. Ninety-six actual 5-year survivors (21%) were identified and their clinical course retrospectively reviewed. RESULTS Five-year survivors (n = 96) were more likely to have a Dukes B primary colorectal carcinoma, fewer than four metastatic lesions, unilobar disease, and a negative histologic margin when compared with patients not surviving 5 years (n = 298). Forty-four (46%) of the 96 five-year survivors had a recurrence after hepatectomy. Of these 44, 19 (43%) were rendered disease free after further treatment. Overall, 71 of the 96 five-year survivors were free of disease at last followup. The actuarial 10-year survival of this group was 78%. CONCLUSIONS Patients that are disease free 5 years after liver resection are likely to have been cured by liver resection. Patients should be aggressively followed for recurrence because of the potential for further treatment and longterm survival.

Randomized Trial of Hepatic Artery Embolization for Hepatocellular Carcinoma Using Doxorubicin-Eluting Microspheres Compared With Embolization With Microspheres Alone

PURPOSE 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. MATERIALS AND METHODS 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. RESULTS 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. CONCLUSION There was no apparent difference between the treatment arms. These results challenge the use of doxorubicin-eluting beads for chemoembolization of HCC.

A Matched Case-Control Study of Preoperative Biliary Drainage in Patients with Pancreatic Adenocarcinoma: Routine Drainage Is Not Justified

BackgroundPreoperative biliary drainage (PBD) prior to pancreaticoduodenectomy (PD) continues to be routine in many centers despite retrospective and randomized data showing that PBD increases perioperative infectious complications.MethodsReview of a prospectively maintained database identified 340 consecutive patients with pancreatic adenocarcinoma who underwent PD between 2000 and 2005. From this cohort, 94 PBD and 94 nonstented (no-PBD) patients were matched for age, gender, preoperative albumin, and bilirubin levels (PBD group: prestent bilirubin; no-PBD group: preoperative bilirubin).ResultsThe majority of PBD patients (89%) underwent internal endoscopic biliary drainage. Stent-related complications occurred in 46 patients (23%) and resulted in a significant delay in time to resection. In the matched-pair comparison, there was more operative blood loss in PBD patients, but similar operative times, transfusions, and hospital stay. Bile cultures were positive in 82% of PBD patients versus 7% no PBD. There was a statistically significant increase in infectious complications including wound infections and intra-abdominal abscess in PBD patients, but equal incidence of anastomotic leak.ConclusionsIn this case-matched control study, PBD was associated with a stent-related complication rate of 23% and resulted in a twofold increase in postpancreatectomy infectious complications. The routine use of PBD remains unjustified.

Preoperative Radiographic Assessment of Hepatic Steatosis with Histologic Correlation

BACKGROUND The adverse impact of hepatic steatosis on perioperative outcomes after liver resection is gaining recognition. But the accuracy of preoperative radiologic assessment of fatty liver disease remains unclear. The objective of this study was to correlate preoperative radiologic estimation with postoperative histologic measurement of steatosis. STUDY DESIGN Patients who underwent partial hepatectomy between 1997 and 2001, with complete preoperative radiographic imaging and postoperative pathologic assessment of steatosis, were retrospectively analyzed. The presence of steatosis was assessed radiographically using noncontrast-enhanced CT (NCCT), contrast-enhanced CT (CCT), or MRI, using standard quantitative radiologic criteria. Repeat histologic analysis was used to quantify the extent of hepatic steatosis. RESULTS One hundred thirty-one patients were studied. The overall sensitivity and specificity for all imaging modalities in detecting pathologically confirmed hepatic steatosis were 56% and 82%, respectively. Sensitivity and specificity for NCCT, CCT, and MRI using standard quantitative criteria were 33% and 100%, 50% and 83%, and 88%, and 63%, respectively. Increasing body mass indices adversely affected the accuracy of NCCT (p=0.002). Preoperative chemotherapy did not notably affect radiologic accuracy. CONCLUSIONS The presence of a fatty-appearing liver on NCCT scans indicates clinically significant steatosis, but steatosis cannot be excluded based on a normal NCCT scan, particularly in obese patients. Conversely, normal MRI helps to exclude hepatic steatosis, but abnormal MRI is not a reliable indicator of fatty change. CCT is not an effective means of identifying steatosis. We conclude that, when used alone, conventional cross-sectional imaging does not consistently permit accurate identification of hepatic steatosis.