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Effective diagnosis of inflammation and cancer by molecular imaging is challenging because of interference from nonselective accumulation of the contrast agents in normal tissues. Here, we report a series of novel fluorescence imaging agents that efficiently target cyclooxygenase-2 (COX-2), which is normally absent from cells, but is found at high levels in inflammatory lesions and in many premalignant and malignant tumors. After either i.p. or i.v. injection, these reagents become highly enriched in inflamed or tumor tissue compared with normal tissue and this accumulation provides sufficient signal for in vivo fluorescence imaging. Further, we show that only the intact parent compound is found in the region of interest. COX-2–specific delivery was unambiguously confirmed using animals bearing targeted deletions of COX-2 and by blocking the COX-2 active site with high-affinity inhibitors in both in vitro and in vivo models. Because of their high specificity, contrast, and detectability, these fluorocoxibs are ideal candidates for detection of inflammatory lesions or early-stage COX-2–expressing human cancers, such as those in the esophagus, oropharynx, and colon. Cancer Res; 70(9); 3618–27. ©2010 AACR.

Supplementary Methods, Figures 1-6 from Selective Visualization of Cyclooxygenase-2 in Inflammation and Cancer by Targeted Fluorescent Imaging Agents

Epithelioid hemangioendothelioma is a very rare, low-grade vascular tumor known to arise in soft tissues and visceral organs. Clinical diagnosis of hepatic epithelioid hemangioendothelioma remains a challenge, and although it is frequently managed with a liver transplant due to its multifocal nature, recurrence is a common complication. We review recent advances in the diagnosis of hepatic epithelioid hemangioendothelioma, including major genetic breakthroughs, and discuss efforts to reduce post-liver transplant recurrence of hepatic epithelioid hemangioendothelioma.

Postoperative hemorrhage after orthotopic liver transplantation (OLT) may require early reoperative intervention. Previous studies have shown intraoperative transfusion requirement as a main determinant of reoperative intervention after OLT. The goal of this study was to develop an intraoperative hemorrhage model predicting need for reoperation after OLT. A single institution, retrospective review of adult primary OLT patients from January 2002 to 2008 was conducted. Multivariate logistical regression analysis was performed to identify predictors of reoperation due to postoperative hemorrhage. Secondary analysis was conducted on patients in the reoperation group managed with temporary open abdomen techniques. Four hundred and ten primary transplantations were performed with 59 patients (14.4%) requiring reoperation. The adjusted odds of reoperation when intraoperative blood loss (IBL) increases from 1.5 L to 10.0 L is 2.48 [95% confidence interval: (1.18, 5.31)]. IBL of 10.0 L predicts a 19.4 per cent probability of reoperation. Patients managed with open abdomen (n = 8) exhibited a significant IBL difference (16.0 L vs 6.0 L, P < 0.001) when compared with the closed abdomen cohort. Our results indicate that intraoperative blood loss is the primary predictor of reoperation after OLT and provide a hemorrhage threshold to guide postoperative management of complicated OLT patients.

The purpose of this study is to evaluate the safety and effectiveness of laparoscopic surgery by comparing laparoscopic and conventional surgery of right colonic diverticulitis (RCD). Among 124 patients who were treated for RCD from January 1997 to July 2007, we enrolled 54 patients who received resection therapy of RCD. Patients were divided into two groups: laparoscopic (LAP; n = 19) and conventional (CON; n = 35) surgery groups according to the respective surgical modality. The diverticulectomy (DIV; n = 46) and right colectomy (COL; n = 8) groups were also compared according to operative methods. There were significant differences between preoperative diagnosis and selection of the operative method and between RCD type and selection of operative method. However, there were no significant differences between preoperative diagnosis and selection of laparoscopic surgery and between RCD type and selection of laparoscopic surgery. The Kaplan-Meier estimated recurrence risk for all patients also showed no significant differences between LAP and CON and DIV and COL ( P = 0.413). The Kaplan-Meier-estimated RCD-free period after surgery was 92.7 months (limited to 100 months). Laparoscopic surgery of RCD is an effective and safety method as a result of no differences in clinical data between conventional and laparoscopic surgery.

Effective diagnosis of inflammation and cancer by molecular imaging is challenging because of interference from nonselective accumulation of the contrast agents in normal tissues. Here, we report a series of novel fluorescence imaging agents that efficiently target cyclooxygenase-2 (COX-2), which is normally absent from cells, but is found at high levels in inflammatory lesions and in many premalignant and malignant tumors. After either i.p. or i.v. injection, these reagents become highly enriched in inflamed or tumor tissue compared with normal tissue and this accumulation provides sufficient signal for in vivo fluorescence imaging. Further, we show that only the intact parent compound is found in the region of interest. COX-2–specific delivery was unambiguously confirmed using animals bearing targeted deletions of COX-2 and by blocking the COX-2 active site with high-affinity inhibitors in both in vitro and in vivo models. Because of their high specificity, contrast, and detectability, these fluorocoxibs are ideal candidates for detection of inflammatory lesions or early-stage COX-2–expressing human cancers, such as those in the esophagus, oropharynx, and colon. Cancer Res; 70(9); 3618–27. ©2010 AACR.

Small bowel obstruction after intra-abdominal surgery is a common cause of morbidity necessitating reoperation. The aim of this study was to determine the feasibility of and indications for laparoscopic surgery for acute adhesive small bowel obstruction (AASBO). We conducted a retrospective review of all patients with AASBO who underwent laparoscopic adhesiolysis at a major university medical center. Laparoscopic treatment was performed successfully in 16 patients, and conventional treatment was performed in 13 patients. The rate of conversion from laparoscopic to open was 16.7 per cent. In 15 of 16 total patients who underwent laparoscopic surgery, laparoscopic bandlysis was performed and one patient underwent laparoscopic adhesiolysis. Laparoscopic surgery was performed successfully in nine who had a single adhesive band demonstrated on an abdominal CT, and conventional surgery was performed in all 10 patients without a single adhesive band identified radiographically. Abdominal CT scans facilitate the selection of operative approach for AASBO based on preoperative identification of the obstruction site. Laparoscopic adhesiolysis is a safe and effective treatment modality for patients with AASBO with a single band or single transition zone identified by preoperative imaging.

Introduction. Several methods for hepatic parenchymal division exist. The primary aim was to assess differences in postoperative bile leaks, operative blood loss, and margin status between three transection methods: crush/clamp (CC), stapler (SP), or dissecting sealer (DS). Methods. A single institution, retrospective cohort study was performed on data collected over a three-year period in patients undergoing elective liver resection using the CC, SP, or DS. Patients were excluded if multiple methods of transection were used or for intraoperative death. The association of bile leak with transection type was assessed. A logistic regression model was tested to assess if blood loss was associated with the covariates of transection method, use of portal inflow occlusion, extent of liver resection, and other concurrent major operations. Results. Analyses included 141 patients. The stapler method was quicker than the other methods (p=0.01). The risk of postoperative bile leak was no different between CC, SP, and DS transection methods (p=0.23). There was no difference in mean blood loss or transfusions; however, hepatectomies performed with DS were associated with an increased risk of blood loss ≥1000mL compared to CC (p=0.04). There were no differences in mean surgical margin between the three methods. Conclusion. The risk of bile leaks was not different between the three methods. While mean blood loss was similar, hepatectomy performed with the DS was associated with an increased risk of having operative blood loss ≥1000mL compared to CC. Margins were equal by all methods. The stapler method was quicker.

The in vivo assessment of mouse colorectal anatomy and function is challenging for all imaging modalities but could potentially provide new insights into disease progression and aid in the evaluation of new therapeutics for clinical use. Computed tomography (CT) colonography has shown great promise in the detection of colorectal polyps in both humans and mice and serves as an accurate high-resolution anatomical screening tool but provides no functional information relevant to the underlying tumor physiology (1,2). Conversely, optical and positron emission tomography (PET) imaging can interrogate the underlying biochemical processes of tissue function with the use of targeted contrast agents but have a limited spatial resolution (3-5). MRI has only recently been used to study the mouse colon but could potentially bridge the gap between these imaging paradigms by providing high-resolution anatomical and dynamic contrast-enhanced functional images of the colon. In contrast to conventional imaging-based colonography, which yields a morphological assessment of the colon, a “functional colonography” could provide a physiological characterization of the colon tissue. The use of dynamic contrast-enhanced (DCE) MRI methods and standard gadolinium (Gd)-based agents, such as Gd-DTPA, has the potential to measure colonic tissue contrast agent kinetic parameters that have been shown to differentiate malignant from benign tumors (6), aid in tumor staging (7), and monitor treatment response (8) in other disease states. With targeted Gd-based agents this approach could potentially report on gene activity, cell receptor expression, and/or other biochemical processes in colon tissue (9-11). Functional MRI colonography has great potential for the physiological assessment of murine models of colon cancer. One such model, the Min (multiple intestinal neoplasia) mouse, is an appropriate model for the study of earlystage colon tumor progression as a result of an APC mutation similar to the human Familial Adenomatous Polyposis Coli (FAP) syndrome that predisposes to colon cancer (12). These mice contain a truncating mutation of the Apc tumor suppressor gene and spontaneously develop adenomas in both the small and large intestine. This murine model is increasingly utilized to evaluate the efficacy of colorectal cancer treatments (13,14). Treatment of Min mice with the colitis-inducing agent dextran sodium sulfate (DSS) results in a greater number specifically of colonic as opposed to small intestinal polyps (15). Additionally, the DSS-elicited polyps are generally larger and more advanced than colonic polyps in non-DSS treated mice. The noninvasive, serial, and functional characterization of the microenvironment of these polyps could offer new insights into their progression and potentially provide a means to identify polyps that will undergo malignant transformation. In both humans and animals the detection of colon polyps using MR colonography requires clear delineation of the colon wall from bowel lumen and the capability to differentiate between polyps and artifacts of residual stool or air bubbles. With T1-weighted imaging, high contrast between the colon wall and the lumen can be achieved by enhancing either the colon lumen using Gd-doped enemas (bright lumen MRI) or the colon wall by intravenous administration of paramagnetic contrast agents and water enemas (dark lumen MRI). With bright lumen MRI, colonic polyps appear as dark filling defects within the bright colon lumen but differentiating these masses from air bubbles or residual stool is difficult and often requires multiple scans with the patient in different positions (16). To overcome this limitation while maintaining high contrast between the colon wall and lumen, dark lumen colonography was proposed and has been shown to be highly accurate for the detection of colorectal masses (17,18). Dark lumen MRI relies on minimizing the signal intensity of the intestinal lumen and its contents while enhancing the signal from the lumen wall and any masses using intravenous injections of paramagnetic contrast agents. Clinically, two dark lumen strategies have been developed to enhance the contrast between the colon wall and the lumen on T1-weighted images, including backfilling the colon with water or air following an enema (17,19,20) or alternatively adding contrast agents (typically barium sulfate) to the food that reduces the MRI signal from feces (fecal tagging) (21). Currently, two studies have adapted these methods for use in mouse models. Using the fecal tagging approach with barium sulfate, Larsson et al. (22) were able to differentiate between healthy and inflamed colon tissue in a mouse model of colitis. Hensley et al. (23) identified colon polyps in a Min mouse model as small as 1.5 mm in diameter using a 7T animal scanner by first cleansing the bowels and then inserting a polyurethane tube filled with Gd-DTPA fully into the colon, which assisted in the identification of the colon on the MRI images. Despite the success of these early studies, these methods are not optimal for functional colonography. To serially assess tumor growth and evaluate treatment response, it is important to identify lesions and changes in their size on a scale smaller than 1.5 mm. Also, given that the location and number of polyps is unknown prior to a study it would be advantageous to clearly and repeatedly delineate all portions of the colon. Without distending the colon this is a challenging problem given that mucosal folds and redundancies of the colon can be unpredictably flattened, hindering both the detection of polyps and the accurate determination of their dimensions. We propose that these issues can be minimized if the colon is fully distended using a filling agent prior to each scan, similar to the original dark lumen MRI methods that require patients to retain 2-2.5 L of enema solution during the examination (19). Furthermore, although water enemas do reduce the lumen signal intensity, we propose that the residual signal seen using water enemas can be effectively eliminated with the use of nonhydrogenous perfluorinated oil enemas. Therefore, the goals of this study were to demonstrate: 1) the potential of perfluorinated oils as colon-filling agents for dark lumen MRI mouse studies, 2) the feasibility of dark lumen MRI to serially assess polyp growth, and 3) the feasibility of dark lumen DCE-MRI to characterize the physiology of colon polyps and the colon wall.

Serious complications of adrenalectomy are rare but the incidence may be underestimated if they occur outside major referral centers. We report five cases of high-grade complications after adrenalectomy that have not been previously described.The records of five cases of adrenalectomy performed at outside hospitals were reviewed. Four cases were referred for management of complications and one for medical-legal review. The nature of the adrenal lesion, operative approach, complication(s), and subsequent clinical course and complication management were assessed. Both open adrenalectomy (OA) and laparoscopic adrenalectomy (LA) cases were included.Operative indications were pheochromocytoma (N = 3), aldosteronoma (N = 1), and a nonfunctioning 6-cm hypervascular mass (N = 1). Complications of adrenalectomy included: case 1--complete transection of the porta hepatitis during right LA resulting in hepatic failure requiring emergent liver transplantation; case 2--ligation of the hepatic artery during right OA resulting in recurrent cholangitis and bile duct sclerosis requiring liver transplantation; case 3--ligation of the left ureter during LA resulting in postoperative hydronephrosis and loss of renal function; case 4--loss of left kidney function after OA, likely secondary to renal artery ligation ultimately requiring laparoscopic nephrectomy; case 5--LA of a normal adrenal gland for a 6-cm hypervascular mass thought to be arising from the adrenal gland. Three-month postoperative imaging demonstrated a persistent mass and the patient underwent hand-assisted laparoscopic nephrectomy for a left upper pole renal cell carcinoma that was missed at the time of LA.Despite the generally low morbidity of adrenalectomy, serious and potentially life-threatening complications can occur. Surgeon inexperience may be a factor in the occurrence of some of these complications which have not been previously described.

Surgical resection remains the best treatment for colorectal metastases isolated to the liver; however, 5-year survival rates following liver resection are only 40% to 50%, with liver recurrence being a significant reason for treatment failure. The ischemia-reperfusion (I/R) injury incurred during liver surgery can lead to cellular dysfunction and elevations in proinflammatory cytokines and matrix metalloproteinases (MMP). In rodents, I/R injury to the liver has been shown to accelerate the outgrowth of implanted tumors. The mechanism for increased tumor growth in the setting of liver I/R injury is unknown. To investigate the effect of I/R on tumor growth, an experimental model was used whereby small hepatic metastases form after 28 days. Mice subjected to 30 min of 70% liver ischemia at the time of tumor inoculation had significantly larger tumor number and volume, and had elevated MMP9 serum and liver tissue MMP9 as evidenced by zymography and quantitative real-time PCR. Mice treated with doxycycline, a broad-spectrum MMP inhibitor, had reduced MMP9 levels and significantly smaller tumor number and volume in the liver. MMP9-null mice were used to determine if the effects of doxycycline were due to the absence of stromal-derived MMP9. The MMP9-null mice, with or without doxycycline treatment, had reduced tumor number and volume that was equivalent to wild-type mice treated with doxycycline. These findings indicate that hepatic I/R-induced elevations in MMP9 contribute to the growth of metastatic colorectal carcinoma in the liver and that postresection MMP9 inhibition may be clinically beneficial in preventing recurrence following hepatic surgery. [Cancer Res 2007;67(6):2720–8]

Thymoglobulin® (Genzyme, Cambridge, MA) is an antithymocyte globulin preparation used for induction immunosuppression therapy in solid organ transplantation. It is being utilized with increasing frequency in orthotopic liver transplantation (OLT) in an effort to minimize or delay the use of calcineurin inhibitors due to their inherent nephrotoxicity. Experience with thymoglobulin in OLT remains limited. We report a case of serum sickness in a patient who received thymoglobulin following OLT. The patient experienced intermittent fevers, polyarthralgia, and acute renal failure 9 days after completion of thymoglobulin administration. The patient's symptoms resolved rapidly and completely with a course of intravenous steroids. We review a set of diagnostic criteria for serum sickness and emphasize the importance of early recognition of the process. Early treatment of serum sickness with steroids or plasmapheresis is highly effective and can reduce unnecessary morbidity from this unusual sequela of induction immunosuppression with antithymocyte globulin. Liver Transpl 13:647-650, 2007. © 2007 AASLD.

The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. Recognition and timely diagnosis of these different stages, particularly NASH, is important for both potential reversibility and limitation of complications. Liver biopsy remains the clinical standard for definitive diagnosis. Diagnostic tools minimizing the need for invasive procedures or that add information to histologic data are important in novel management strategies for the growing epidemic of NAFLD. We describe an "omics" approach to detecting a reproducible signature of lipid metabolites, aqueous intracellular metabolites, SNPs, and mRNA transcripts in a double-blinded study of patients with different stages of NAFLD that involves profiling liver biopsies, plasma, and urine samples. Using linear discriminant analysis, a panel of 20 plasma metabolites that includes glycerophospholipids, sphingolipids, sterols, and various aqueous small molecular weight components involved in cellular metabolic pathways, can be used to differentiate between NASH and steatosis. This identification of differential biomolecular signatures has the potential to improve clinical diagnosis and facilitate therapeutic intervention of NAFLD.

G protein-coupled receptor ligand-dependent transactivation of growth factor receptors has been implicated in human cancer cell proliferation, migration, and cell survival. For example, prostaglandin E 2 (PGE 2 )-induced transactivation of the EGF receptor (EGFR) in colorectal carcinoma cells is mediated by means of a c-Src-dependent mechanism and regulates cell proliferation and migration. Recent evidence indicates that β-arrestin 1 may act as an important mediator in G protein-coupled receptor-induced activation of c-Src. Whether β-arrestin 1 serves a functional role in these events is, however, unknown. We investigated the effects of PGE 2 on colorectal cancer cells expressing WT and mutant β-arrestin 1. Here we report that PGE 2 induces the association of a prostaglandin E receptor 4/β-arrestin 1/c-Src signaling complex resulting in the transactivation of the EGFR and downstream Akt (PKB) signaling. The interaction of β-arrestin 1 and c-Src is critical for the regulation of colorectal carcinoma cell migration in vitro as well as metastatic spread of disease to the liver in vivo . These results show that the prostaglandin E/β-arrestin 1/c-Src signaling complex is a crucial step in PGE 2 -mediated transactivation of the EGFR and may play a pivotal role in tumor metastasis. Furthermore, our data implicate a functional role for β-arrestin 1 as a mediator of cellular migration and metastasis.

Background. Graft-versus-host disease (GVHD) is a rare complication following liver transplantation and carries a poor prognosis with mortality approaching 90-95%. Diagnosis of GVHD is often delayed due to early symptoms mimicking more common, entities such as drug reactions and viral syndromes. To date, definitive diagnosis has been difficult and has relied on a constellation of clinical and histopathologic variables. We present the use of short tandem repeat DNA fingerprinting technology as a method of early, definitive diagnosis of GVHD in patients after liver transplantation. Methods. A patient status-postorthotopic cadaveric-liver transplant, with an uncomplicated immediate posttransplant course, presented 4 weeks after transplant with fever, diarrhea, and maculopapular rash on her palms, soles, and back. The patient's condition worsened despite empiric treatment for an infectious etiology. Skin and rectal biopsies were suspicious for GVHD. Results. DNA was isolated from the skin and rectal biopsies as well as from a donor lymph node. PCR amplification was done for nine highly polymorphic short tandem repeats for each specimen and a unique DNA fingerprint was obtained from each. DNA from skin and rectum demonstrated mixed chimerism with both donor and recipient alleles detected. Thorough analysis confirmed GVHD. Conclusion. Short tandem repeats for DNA fingerprinting represents an efficient and reproducible method for the definitive diagnosis of GVHD after liver transplantation. Rapid detection of GVHD using this technology, coupled with early initiation of therapy, may lead to improved survival for patients with GVHD after solid organ transplant. Graft versus host disease, Liver transplantation, DNA short tandem repeats.

Portal vein embolization is evolving as an important adjunctive tool in hepatic surgery. In select patients, preoperative hypertrophy of the future remnant liver via contralateral portal vein embolization decreases postoperative liver dysfunction. Hepatic steatosis is the most common liver parenchymal disorder in Western populations. Moderate and severe degrees of hepatic steatosis convey an increased risk of postoperative liver dysfunction following major hepatic resections, but no studies exist examining the role of preoperative portal vein embolization in patients with hepatic steatosis. In this manuscript, we review the indications for portal vein embolization currently supported by the literature and present a patient with moderate to severe steatosis who successfully underwent portal vein embolization and a subsequent major liver resection.

Nonalchoholic fatty liver disease (NAFLD) is a problem of increasing prevalence and clinical significance worldwide and is associated with increased risk of development of end stage liver disease and cirrhosis, and can be complicated by hepatocellular carcinoma (HCC). NAFLD is characterized by physical and molecular changes in the liver microenvironment which include an influx of inflammatory cell populations, fibrosis, changes in gene expression, and cytokine production. To better understand changes to the liver in the setting of steatosis, we used a murine model of diet induced hepatic steatosis and corroborated our results with human patient samples of NAFLD. Among the cellular changes, we identified a significant increase in hepatocellular proliferation in the setting of steatosis as compared to controls. Analysis of inflammatory cell populations revealed increased infiltration of CD11b positive myeloid and CD3 positive lymphocytic cell populations in steatotic livers compared to normal livers. Resident Kupffer cells of the liver comprise the largest percentage of these myeloid cells and appear to be responsible for important cytokine alterations impacting proliferation of cells in the liver microenvironment. Significant alterations in cytokine profiles in the plasma and liver tissue lysates from normal and steatotic mice were detected including leptin, CXCL1, CXCL2, and CXCL16 that were further shown to directly increase hepatocyte proliferation in vitro. This increased hepatocellular proliferation and turnover in the setting of steatosis may play important roles in the progression and complications of NAFLD.

Background: Pro-inflammatory processes associated with the early postoperative state are known to contribute to peritoneal metastases in patients with advanced diseases. This study aimed to determine whether the wound healing response after an abdominal incision leads to increased matrix metalloproteinase (MMP)-9 activity locally, contributing to peritoneal metastasis. Materials and methods: Metastatic tumors were initiated in C57bl/6J male mice (8 wk of age) using a peritoneal injection model with syngeneic MC38 murine colon cancer cells; appropriate control mice also were studied. Injections were performed into the peritoneum in the right lower quadrant. We then observed the occurrence and rate of peritoneal metastasis for each group. Results: By making an incision into the abdominal wall of mice, an inflammatory response was induced at the wound site. The inflammatory response initiated by the wound, in turn, increased the proliferation of mesothelial cells and increased inflammatory cell numbers locally, which contributed to an increase in parietal peritoneal metastases. In addition, the wound healing process increased the expression of pro-inflammatory cytokines and the number of inflammatory cells in the peritoneum. Moreover, MMP-9 in the modeled postoperative injury setting increased the number and severity of peritoneal metastases. Conclusions: Thus, we conclude that wound-associated inflammation enhances pro-MMP-9 expression, which plays a key role in the growth and progression of cancer cells associated with peritoneal metastases.

Background and Aims: The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and progression to cirrhosis. While differences in liver lipids between disease states have been reported, precise composition of phospholipids and diacylglycerols (DAG) at a lipid species level has not been previously described. The goal of this study was to characterize changes in lipid species through progression of human NAFLD using advanced lipidomic technology and compare this with a murine model of early and advanced NAFLD. Methods: Utilizing mass spectrometry lipidomics, over 250 phospholipid and diacylglycerol species (DAGs) were identified in normal and diseased human and murine liver extracts. Results: Significant differences between phospholipid composition of normal and diseased livers were demonstrated, notably among DAG species, consistent with previous reports that DAG transferases are involved in the progression of NAFLD and liver fibrosis. In addition, a novel phospholipid species (ether linked phosphatidylinositol) was identified in human cirrhotic liver extracts. Conclusions: Using parallel lipidomics analysis of murine and human liver tissues it was determined that mice maintained on a high-fat diet provide a reproducible model of NAFLD in regards to specificity of lipid species in the liver. These studies demonstrated that novel lipid species may serve as markers of advanced liver disease and importantly, marked increases in DAG species are a hallmark of NAFLD. Elevated DAGs may contribute to altered triglyceride, phosphatidylcholine (PC), and phosphatidylethanolamine (PE) levels characteristic of the disease and specific DAG species might be important lipid signaling molecules in the progression of NAFLD.

Postoperative hemorrhage after orthotopic liver transplantation (OLT) may require early reoperative intervention. Previous studies have shown intraoperative transfusion requirement as a main determinant of reoperative intervention after OLT. The goal of this study was to develop an intraoperative hemorrhage model predicting need for reoperation after OLT. A single institution, retrospective review of adult primary OLT patients from January 2002 to 2008 was conducted. Multivariate logistical regression analysis was performed to identify predictors of reoperation due to postoperative hemorrhage. Secondary analysis was conducted on patients in the reoperation group managed with temporary open abdomen techniques. Four hundred and ten primary transplantations were performed with 59 patients (14.4%) requiring reoperation. The adjusted odds of reoperation when intraoperative blood loss (IBL) increases from 1.5 L to 10.0 L is 2.48 [95% confidence interval: (1.18, 5.31)]. IBL of 10.0 L predicts a 19.4 per cent probability of reoperation. Patients managed with open abdomen (n = 8) exhibited a significant IBL difference (16.0 L vs. 6.0 L, P0.001) when compared with the closed abdomen cohort. Our results indicate that intraoperative blood loss is the primary predictor of reoperation after OLT and provide a hemorrhage threshold to guide postoperative management of complicated OLT patients.

To examine the interplay between tumor cells and the microenvironment during early breast cancer metastasis, we developed a technique for ex vivo imaging of murine tissue explants using two-photon microscopy. Cancer cells in the liver and the lung were compared by imaging both organs at specific time points after the injection of the same polyomavirus middle T-initiated murine mammary tumor cell line. Extravasation was greatly reduced in the lung compared with the liver, with 56% of tumor cells in the liver having extravasated by 24 hours, compared with only 22% of tumor cells in the lung that have extravasated. In the liver, imaged cells continually transitioned from an intravascular location to an extravascular site, whereas in the lung, extravasation rates slowed after 6 hours. Within the liver microenvironment, the average size of the imaged micrometastatic lesions increased 4-fold between days 5 and 12. Histologic analysis of these lesions determined that by day 12, the micrometastases were heterogeneous, consisting of both tumor cells and von Willebrand factor–positive endothelial cells. Further analysis with intravenously administered lectin indicated that vessels within the micrometastatic tumor foci were patent by day 12. These data present the use of two-photon microscopy to directly compare extravasation times in metastatic sites using the same tumor cell line and highlight the differences in early events and metastatic patterns between two important secondary sites of breast cancer progression with implications for future therapy. Mol Cancer Res; 8(10); 1319–27. ©2010 AACR.

Small bowel obstruction after intra-abdominal surgery is a common cause of morbidity necessitating reoperation. The aim of this study was to determine the feasibility of and indications for laparoscopic surgery for acute adhesive small bowel obstruction (AASBO). We conducted a retrospective review of all patients with AASBO who underwent laparoscopic adhesiolysis at a major university medical center. Laparoscopic treatment was performed successfully in 16 patients, and conventional treatment was performed in 13 patients. The rate of conversion from laparoscopic to open was 16.7 per cent. In 15 of 16 total patients who underwent laparoscopic surgery, laparoscopic bandlysis was performed and one patient underwent laparoscopic adhesiolysis. Laparoscopic surgery was performed successfully in nine who had a single adhesive band demonstrated on an abdominal CT, and conventional surgery was performed in all 10 patients without a single adhesive band identified radiographically. Abdominal CT scans facilitate the selection of operative approach for AASBO based on preoperative identification of the obstruction site. Laparoscopic adhesiolysis is a safe and effective treatment modality for patients with AASBO with a single band or single transition zone identified by preoperative imaging.

Early diagnosis and management of peritoneal metastases from colorectal cancer patients are difficult clinical challenges. The aims of this study were to evaluate the clinical significance of tumor markers and cytology in peritoneal effusions (PE) and peritoneal irrigation fluid (PI) and to determine their value as prognostic indicators in this disease. Two hundred thirty-four consecutive patients who underwent abdominal surgery for colorectal cancer from January 2006 to December 2007 were included, and tumor markers and cytology in PE and PI were analyzed prospectively. The incidence of free cancer cells retrieved from peritoneal samples was 7.9%. Cytology was positive in 40.0% by Papanicolaou and Giemsa staining, 73.3% by hematoxylin and eosin staining of cell blocks, and 66.7% by carcinoembryonic antigen (CEA) and calretinin immunohistochemistry. Multivariate analysis revealed that peritoneal CEA and cancer antigen (CA) 19–9 in PI were correlated with peritoneal metastasis and cytology. Level of peritoneal fluid CEA was statistically significantly correlated with recurrence and peritoneal metastatic recurrence in patients with negative peritoneal cytology. Cytology, peritoneal CEA, and peritoneal CA 19-9 showed correlations with cancer-free survival and overall survival. These correlations demonstrate the importance of continuous follow-up of peritoneal metastasis if there is positive cytology or an increase in CEA and CA 19-9 in peritoneal fluid.

In this study, we evaluate prospective diagnostic criteria and propose a clinical scoring system for the evaluation of patients suspected to have right colonic diverticulitis (RCD) prospectively. One hundred adult patients, who were clinically suspected to have appendicitis or RCD, and in whom we were not able to preoperatively rule out appendicitis, were examined prospectively. Patients were scored upon clinical presentation based on major diagnostic criteria included (1) no migration pain to the right lower quadrant; (2) a leukocyte count

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It represents the fifth most common cancer worldwide, and one whose incidence is on the rise. Liver cancer is the third most common cause of cancer mortality globally and thus a major health concern worldwide. Therapeutic options for this tumor include surgical resection, local ablative therapies, and systemic treatment. Liver transplantation has emerged as a highly effective treatment for patients with HCC, particularly in the setting of significant underlying liver disease. Current protocols in transplantation for this tumor utilize strict size criteria and staging (TNM classification) to select patients for this therapy. Selection criteria for liver transplantation for HCC that are accepted in the U.S. include: 1 tumor < 5cm, no greater than three tumor nodules, each less than 3cm in diameter 3) no macroscopic invasion of blood vessels or lymph nodes, and no extra-hepatic spread of tumor. Eligibility criteria and immunosuppression strategies are continuing to evolve in this field. Nonetheless, in appropriately selected patients, liver transplantation may provide a cure for HCC with survival rates equal to that of liver transplantation for end-stage liver disease (ESLD) from other causes. Liver transplantation has been established as one of the principal treatment modalities for this difficult disease.

Colorectal cancer, the second leading cause of cancer deaths in the United States, has a high probability of metastasizing to the liver. Matrix metalloproteinases (MMPs) are a family of zinc dependent endopeptidases that are implicated in cancer metastasis and many aspects of tumor progression. Using a splenic injection experimental metastasis model, mice that are genetically deficient in MMP-9 demonstrated a nearly 2-fold decrease in liver weight compared with wild type (WT) mice following injection with MC38 syngeneic colorectal cancer cells. Bioluminesence imaging data demonstrates an early negative effect on tumor growth in MMP-9 null mice when compared with WT controls. Reconstitution of the bone marrow in MMP-9-/- mice with cells competent to produce MMP-9 did not recapitulate the WT phenotype of overwhelming burden of metastatic disease in the liver. In situ hybridization revealed the presence of MMP-9 mRNA in both MC38 tumor cells and in surrounding stromal cells, and immunostaining with anti MMP-9 was consistent with MMP-9 expression by resident liver Kupffer cells. Stromal-derived MMP-9 contributes to the establishment and growth of colorectal metastases in the liver. Stromal MMP-9 was derived from resident cells, most likely Kupffer cells, as opposed to infiltrating bone marrow-derived cells and the effect of stromal MMP-9 was independent of expression of MMP-9 by tumor cells. Stromal-derived MMP-9 may represent an important target for selective inhibition in the treatment of metastases. (c) 2007 Wiley-Liss, Inc.

Biliary complications following orthotopic liver transplantation have been reported in 10% to 30% of patients. Most surgeons perform an end-to-end choledochocholedochostomy with interrupted sutures for biliary reconstruction. The goal of this study was to compare biliary complications between interrupted suture (IS) and continuous suture (CS) techniques during liver transplantation in which an end-to-end choledochocholedochostomy over an internal biliary stent was performed. A retrospective cohort study of 100 consecutive liver transplants occurring between December 2003 and July 2005 was conducted. An end-to-end choledochocholedochostomy over an internal biliary stent was performed during liver transplantation. Data were analyzed using Kaplan-Meier methods, t tests, and chi-square tests of proportions. IS and CS techniques were used in 59 and 41 patients, respectively, for biliary reconstruction during liver transplantation. Mean follow-up time for the CS group was 17 ± 8 months and 15 ± 7 months for the IS group (P = .21). The overall biliary complication rate was 15%. There was no difference in the proportion of leaks (CS = 7.3%, IS = 8.5%; P = .83) or strictures (CS = 9.8%, IS = 5.1%; P = .37) between groups. Kaplan-Meier event rates show no difference in leaks (P = .79), strictures (P = .41), graft survival (P = .52), and patient survival (P = .32) by anastomosis type. In conclusion, there was no difference in biliary complications, graft survival, or patient survival between the 2 groups. CS and IS techniques for biliary reconstruction during liver transplantation yield comparable outcomes. Liver Transpl 13:234–238, 2007. © 2007 AASLD.

Background . Biliary complications occur following approximately 25% of liver transplantations. Efforts to decrease biliary complications include methods designed to diminish tissue ischemia. Previously, we reported excellent short‐term results and decreased biliary anastomosis time in a porcine liver transplant model using non‐penetrating, tissue everting clips (NTEC), specifically VCS® clips. Methods . We examined the incidence of biliary anastomotic complications in a group of patients in whom orthotopic liver transplantation was performed with biliary reconstruction using NTEC and compared that group to a matched group treated with biliary reconstruction via conventional end‐to‐end sewn choledochocholedochostomy. Patients were matched in a 1:2 fashion by age at transplantation, disease etiology, Child‐Turcot‐Pugh scores, MELD score or UNOS status (prior to 1998), cold and warm ischemia times, organ donor age, and date of transplantation. Results . Seventeen patients had clipped anastomosis and 34 comparison patients had conventional sewn anastomosis. There were no differences between groups in terms of baseline clinical or demographic data. The median time from completion of the hepatic artery anastomosis to completion of clipped versus conventional sewn biliary anastomosis was 45 (interquartile range = 20 min) versus 47 min (interquartile range = 23 min), respectively ( p =0.12). Patients were followed for a mean of 29 months. Biliary anastomotic complications, including leak or anastomotic stricture, were observed in 18% of the clipped group and 24% of the conventional sewn group. Conclusions . Biliary reconstruction can be performed clinically using NTEC as an alternative to conventional sewn biliary anastomoses with good results.

The role of specific stromal-derived matrix metalloproteinases (MMPs) was analyzed in experimental metastasis assays in wild-type and either MMP-9, MMP-7, or MMP-2 null mice. MMP-9 null mice showed an 81% reduction in Lewis lung carcinoma tumor number, whereas MMP-7 null mice showed a 42% increase in tumor number, and there was no difference in tumor number in MMP-2 null mice compared with wild-type controls. Similarly, in an orthotopic model of lung cancer, 50% fewer MMP-9 null mice were able to establish tumors in the lung compared with control mice, although the size of the tumors was not different. The effect of MMP-9 on lung tumor colonization was dependent on the expression of MMP-9 from bone marrow–derived cells and is most likely contributed by neutrophils. To examine temporal effects of stromal MMP-9, bioluminescence imaging from luciferase-expressing human lung cancer–derived A549 cells revealed that there were fewer tumor cells in the lungs of MMP-9 null mice as early as 19 hours after injection compared with control mice, with no difference in subsequent growth rates. Six hours after injection of tumor cells, MMP-9 null mice showed a 4-fold increase in the percent of tumor cells undergoing apoptosis compared with control mice. We conclude that MMP-9 from the bone marrow contributes to the early survival and establishment of tumors in the lung and has no effect on subsequent growth. These results provide insights into the failure of MMP inhibitors in clinical trials in patients with late-stage lung cancer. (Cancer Res 2006; 66(1): 259-66)

Objective: Evaluate experience over 15 years with treatment of this lesion. Background Data: Biliary cystadenoma, a benign hepatic tumor arising from Von Meyenberg complexes, usually present as septated intrahepatic cystic lesions. Methods: Data were collected concurrently and retrospectively on patients identified from hospital medical records reviewed for pertinent International Classification of Diseases, Ninth Revision, Clinical Modification and CPT codes, pathology logs, and from operative case logs. Pathology specimens were rereviewed to confirm the diagnosis of biliary cystadenoma or biliary cystadenocarcinoma by 2 GI pathologists. Results: From October 1989 to April 2004 at our institution, 19 (18F:1M) patients had pathologically confirmed biliary cystadenomas, including one with a biliary cystadenocarcinoma. The mean age was 48 ± 15 years at initial evaluation. Complaints included abdominal pain in 74%, abdominal distension in 26%, and nausea/ vomiting in 11%. Only 1 patient presented with an incidental finding. Symptoms had been present for 3 ± 5 years, with 1 to 4 different surgeons and many other physicians involved in the diagnosis or treatment prior to definitive ablation. Eight patients had undergone 20 previous treatments, including multiple percutaneous aspirations in 4 and 11 operative procedures. CT or US was diagnostic in 95%, with internal septations present in the hepatic cysts. Definitive operative intervention consisted of hepatic resection in 12 patients, enucleation in 6 patients, and fenestration and complete fulguration in 1 patient. There were no perioperative deaths. No recurrences were observed after definitive therapy, with follow-up of 4 ± 4 years. Conclusions: Biliary cystadenoma must be recognized and treated differently than most hepatic cysts. There remains a need for education about the imaging findings for biliary cystadenoma to reduce the demonstrated delay in appropriate treatment. Traditional treatment of simple cysts such as aspiration, drainage, and marsupialization results in near universal recurrence and occasional malignant degeneration. This experience demonstrates effective options include total ablation by standard hepatic resection and cyst enucleation.

Donor, technical, and recipient risk factors cumulatively impact survival and health-related quality of life after liver transplantation.Retrospective study.Tertiary care center.A total of 483 adults undergoing primary orthotopic liver transplantation between January 1, 1991, and July 31, 2003.Graft and patient survival, Karnofsky functional performance scores, Medical Outcomes Study Short Form 36 Health Survey scores, and Psychosocial Adjustment to Illness Scale scores as influenced by potential risk factors including donor age, weight, warm ischemia time, cold ischemia time (CIT), sex, United Network for Organ Sharing (UNOS) status (1 or 2A vs 2B or 3), recipient age and disease, bilirubin level, and creatinine level.Five-year graft survival was 72% for recipients of donors younger than 60 years and 35% for recipients of donors 60 years and older (P.001). A CIT of 12 hours or more was associated with shorter 5-year graft survival (71% vs 58%; P = .004). Five-year graft survival for UNOS status 2B or 3 was 71% vs 60% for status 1 or 2A (P = .02). A comparable pattern was seen for patient survival in relation to donor age (P = .003), CIT (P = .005), and urgency status (P = .03). Urgent UNOS status, advanced donor age, and prolonged CIT were independently associated with shorter graft and patient survival (P.05). Functional performance and health-related quality of life were not affected by donor, recipient, or technical characteristics.Combining advanced donor age, urgent status, and prolonged CIT adversely affects graft and patient survival, and the cumulative effects of these risk factors can be modeled to predict posttransplant survival.

Retrospective studies suggest that resection improves 5-year survival for patients with hepatic carcinoid metastasis (HCM). The purpose of our study was to describe clinical outcomes following resection for HCM, including survival and longitudinal functional quality of life (QOL). We reviewed the records of patients undergoing resection for HCM from 1980 to 2001 at our institution. Outcome measures included tumor symptoms, biochemical tumor markers, functional QOL through Karnofsky functional scores, and survival. Thirteen patients underwent a total of 17 resections. Overall 5-year survival was 85%. Eleven patients were symptomatic, including eight with classic carcinoid syndrome. Nine experienced complete relief of symptoms and two had incomplete relief for 30 +/- 12 months. Eight patients had elevated tumor markers, and 50% of these had postoperative normalization of all tumor markers that persisted to the close of the study. For the 10 patients with longitudinal follow-up available to 54 months, significant improvement in functional QOL was observed at all follow-up time points compared to preresection functional QOL (P0.05). Resection of/=90% tumor volume was significantly associated with more favorable survival and tumor marker normalization compared to resection of90% tumor volume (P0.01 and P0.05, respectively), but trajectory of functional QOL improvement did not differ between these two groups (P=0.24). We conclude that resection for HCM is associated with significantly improved and sustained functional QOL and prolonged survival. Resection of/=90% tumor volume is significantly associated with extended survival and normalization of tumor markers, but is not required for symptomatic or functional QOL improvement.

Background: We sought to determine if disparities in survival and health-related quality of life (HRQOL) occurred after solid organ transplantation at our institution. Methods: Data were extracted from a database including information regarding transplants that took place from 1990 to 2002. The HRQOL was assessed in patients by using the Karnofsky functional performance (FP) index and the Medical Outcomes Study Short Form 36 (SF-36) questionnaire. Results: Data were collected on recipients of liver (n = 413), heart (n = 299), kidney (n = 892), and lung (n = 156). Blacks represented a minority of recipients: liver 7%, heart 8%, kidney 23%, and lung 6%. There were no statistically significant differences in patient survival between blacks and whites. Graft survival differed in kidney only with a 5-year survival: 72% for blacks versus 79% for whites (P

Long-term quality of life (QOL) in patients undergoing laparoscopic cholecystectomy (LC) incurring bile duct injury (BDI) and repair is comparable to that of patients undergoing uncomplicated LC.Case comparison study.Secondary and tertiary care centers.Eighty-six patients incurring BDI during LC between January 1, 1991, and July 31, 2003, were surveyed. Comparison subjects underwent uncomplicated LC during the same period.Health-related QOL as assessed by the Karnofsky Performance Scale, Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), and Psychosocial Adjustment to Illness Scale.Fifty patients with BDI (39 [78%] female; mean +/- SEM age, 55 +/- 2 years) and 74 patients with uncomplicated LC (51 [69%] female, mean +/- SEM age, 52 +/- 2 years) responded. Of the 50 BDI patients, 48 (96%) had no stricture and normal liver function at QOL assessment. The mean +/- SEM follow-up period to QOL assessment for the BDI and uncomplicated LC groups was 62 +/- 6 and 47 +/- 3 months, respectively. The mean +/- SD Karnofsky Performance Scale scores were 77 +/- 9 vs 93 +/- 8 for the 2 groups, respectively (P.001). The mean +/- SD SF-36 physical component scale scores after BDI vs uncomplicated LC were 36 +/- 11 vs 47 +/- 12, respectively (P.001), compared with 50 +/- 10 for the normal population (P.001). The mean +/- SD SF-36 mental component scale scores were 43 +/- 14 vs 49 +/- 11 for the 2 groups, respectively (P =.02), compared with 50 +/- 10 for the normal population (P =.01). Patients with BDI scored poorer on the Psychosocial Adjustment to Illness Scale health care orientation and domestic environment scales (P=.01).After BDI and repair, there are long-term detrimental effects of BDI on health-related QOL.

Background Some previous studies suggested that transplantation performed in Department of Veterans Affairs (VA) patients was associated with a higher rate of complications and poorer outcomes. We examined more than a decade of experience with solid organ transplantation at a single center and compared VA patients with nonveteran patients to assess long-term patient and graft survival and health-related quality of life (HRQOL). Methods Demographic, clinical, and survival data were extracted from a database that included all transplants from January 1990 through December 2002 at Vanderbilt University Medical Center (non-VA) and the Nashville VA Medical Center (VA). The HRQOL was assessed in a subset of patients using the Karnofsky functional performance (FP) index and the Short-Form-36 self-report questionnaire. Data were analyzed by Kaplan-Meier survival and analysis of variance methods. Results One thousand eight hundred nine adult patients receiving solid organ transplants (1,896 grafts) between 1990 and 2002 were reviewed: 380 VA patients (141 liver, 54 heart, 183 kidney, 2 lung) and 1429 non-VA patients (280 liver, 246 heart, 749 kidney, 154 lung). Mean follow-up time was 46 ± 1 months. Five-year graft survival for VA and non-VA patients, respectively, was liver 65% ± 5% versus 69% ± 3% (P = 0.97); heart 73% ± 8% versus 73% ± 3% (P = 0.67); and kidney 76% ± 5% versus 77% ± 2% (P = 0.84). Five-year patient survival was liver 75% ± 5% versus 78% ± 3% (P = 0.94); heart 73% ± 8% versus 74% ± 3% (P = 0.75); and kidney 84% ± 4% versus 87% ± 2% (P = 0.21) for VA and non-VA, respectively. In the first 3 years after transplant, the FP scores for VA versus non-VA patients were 85 ± 2 versus 87 ± 1 (P = 0.50). The SF-36 mental component scales were 47 ± 3 versus 49 ± 1 (P = 0.39); and the SF-36 physical component scales were 37 ± 2 versus 38 ± 1 (P = 0.59), respectively. Longer-term (through year 7) HRQOL scores for VA versus non-VA patients were FP 85 ± 1 versus 88 ± 1 (P = 0.17); mental component scales 47 ± 2 versus 49 ± 1 (P = 0.29); and physical component scales 35 ± 2 versus 39 ± 1 (P = 0.05), respectively. Conclusions The veteran patients have similar graft and patient survival as the nonveteran patients. Overall quality of life is similar between veterans and nonveterans during the first three years after transplantation. A trend toward a later decline in the veterans' perception of their physical functioning may stem from the increased prevalence of hepatitis C virus among VA liver transplant recipients, a known factor reducing late HRQOL.

For growth and survival in metastasis, tumor colonies must develop new intratumoral vasculature for supply of nutrients and oxygen. Since angiopoietin-2 (Ang2) resulted in a burst of angiogenesis in the glioma model, we examined the effects of host Ang2 on colony growth and neo-angiogenesis during the liver colonization. Liver colonization was induced through the intrasplenic injection of MC38-GFP (murin colorectal carcinoma cells) into two genotype mice of the ang2−/− mice and the wild type mice. When colonies were established, the livers were isolated and analyzed using flow cytometry, immunoflorescent histochemistry and ELISA. In addition, the blood was collected from vena cava for measurement of MCP-1 at 14 days. Flow cytometry analyses of whole livers showed that the tumor cell population in the ang2−/− mice was approximately 2 times larger than in the wild type mice. Immunoflorescent histochemistry of the liver tissue using antibodies for CD31, CD34, CD146, VE-cadherin and NG2 showed that intratumoral vascular density and vascular maturity in the ang2−/− mice were approximately 2 times higher than the wild type mice. Intratumoral vessels were significantly positive for CD146 and CD34, markers more frequently associated with neo-angiogenesis, but much less for CD31. There was no significant difference in VEGF level which is known to mediate vascular response in combination with Ang2. CD11b positive cells and MCP-1 concentration in the livers were equivalent in two genotypes. Notably, there were approximately 10 times more Tie2+/CD11b+ cells in the ang2−/− mice than the wild type mice. CD11c+/CD45+ cell populations were slightly different in two genotypes. These results suggested that host Ang2 would inhibit tumor growth and neo-angiogenesis in the liver, and that the inhibition is correlated with the decreased recruitment of TEMs, one of myeloid cells, into the liver. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2847. doi:10.1158/1538-7445.AM2011-2847

Background & Aims Transforming growth factor (TGF)-β signaling occurs through Smads 2/3/4, which translocate to the nucleus to regulate transcription; TGF-β has tumor-suppressive effects in some tumor models and pro-metastatic effects in others. In patients with colorectal cancer (CRC), mutations or reduced levels of Smad4 have been correlated with reduced survival. However, the function of Smad signaling and the effects of TGF-β–receptor kinase inhibitors have not been analyzed during CRC metastasis. We investigated the role of TGF-β/Smad signaling in CRC progression. Methods We evaluated the role of TGF-β/Smad signaling on cell proliferation, migration, invasion, tumorigenicity, and metastasis in Smad4-null colon carcinoma cell lines (MC38 and SW620) and in those that transgenically express Smad4. We also determined the effects of a TGF-β–receptor kinase inhibitor (LY2109761) in CRC tumor progression and metastasis in mice. Results TGF-β induced migration/invasion, tumorigenicity, and metastasis of Smad4-null MC38 and SW620 cells; incubation with LY2109761 reversed these effects. In mice, LY2109761 blocked metastasis of CRC cells to liver, inducing cancer cell expression of E-cadherin and reducing the expression of the tumorigenic proteins matrix metalloproteinase-9, nm23, urokinase plasminogen activator, and cyclooxygenase-2. Transgenic expression of Smad4 significantly reduced the oncogenic potential of MC38 and SW620 cells; in these transgenic cells, TGF-β had tumor suppressor, rather than tumorigenic, effects. Conclusions TGF-β/Smad signaling suppresses progression and metastasis of CRC cells and tumors in mice. Loss of Smad4 might underlie the functional shift of TGF-β from a tumor suppressor to a tumor promoter; inhibitors of TGF-β signaling might be developed as CRC therapeutics.

Living donor liver transplantation (LDLT) results in improved survival compared with deceased whole and split organ transplantation in children.To evaluate the effect of LDLT on graft and patient survival in pediatric liver transplantation.Retrospective cohort.Data included all pediatric recipients (aged18 years) registered in the UNOS (United Network for Organ Sharing) database from October 1, 1987, to May 24, 2004. Covariates predictive of survival by univariate analyses were included in the Cox proportional hazards regression models in a blockwise fashion to determine predictors of survival.Kaplan-Meier graft and patient survival rates were improved in LDLT recipients compared with recipients of deceased whole and split organ transplantations (P.01). In the initial model (model P.001), prognostic factors for graft and patient survival included recipient age, race, origin of liver disease, certain pretransplantation laboratory data, medical condition, multiorgan transplantation, retransplantation, recipient-donor ABO blood compatibility, and cold and warm ischemia times. The addition of graft type to the initial covariate set did not significantly change the model (P = .21, covariate P = .09). However, most of the positive prognostic factors identified in the model were inherent characteristics of LDLT recipients and the LDLT procedure.Graft and patient survival in the pediatric population is better with LDLT than deceased organ transplantation. Factors that contribute to this difference include recipients who are less ill, who have shorter cold and warm ischemia times, and those with a decreased need for retransplantation but not the type of graft per se.

Introduction: Utilization of grafts from donors greater than 60 years old (older donors [OD]) presumably decreases wait time and improves overall survival; however, OD recipients have shortened survival, increased rejection and retransplantation. We examined the cost-effectiveness of using OD compared to donors less than 60 (younger donors [YD]) in liver transplantation. Methods: A Markov-based decision analytic model was created to simulate outcomes for liver transplantation with donors >60 versus donors Results: OD accounts for 10% of all transplants with a five-year survival of 60% versus 71% for YD (P = 0.003). After transplantation, recipients of OD averaged 4.7 QALYs (Quality Adjusted Life Years) at a cost of $69,000/QALY versus 5.7 QALYs at $56,000/QALY for YD. The wait list strategy combining OD and YD offers 5.6 QALYs at $57,000/QALY. Even assuming a 25% increase in wait list death with the elimination of OD, the YD strategy provides an average of 5.6 QALYs at $56,000/QALY to recipients. Conclusions: The current strategy combining OD and YD donors in the general donor pool offers no added benefit to overall survival and decreases the individual survival of some recipients. OD organs could be used more effectively in an alternative list for those with more controversial indications for transplantation.