Effect of Donor Transaminase Levels on Graft Survival Following Liver Transplant: An Analysis of the Organ Procurement and Transplantation Network Database.

OBJECTIVES: Despite data showing equivalent outcomes between grafts from marginal versus standard criteria deceased liver donors, elevated donor transaminases constitute a frequent reason to decline potential livers. We assessed the effect of donor transaminase levels and other characteristics on graft survival. MATERIALS AND METHODS: We performed a retrospective cohort analysis of adult first deceased donor liver transplant recipients with available transaminase levels registered in the Organ Procurement and Transplantation Network database (2008-2018). We used Cox proportional hazards regression to determine the effects of donor characteristics on graft survival. RESULTS: Of 53 913 liver transplants, 52 158 were allografts from donors with low transaminases (≤ 500 U/L; group A) and 1755 were from donors with elevated transaminases (> 500 U/L; group B). Group A recipients were more likely to be hospitalized (P = .01) or in intensive care (P < .001) or to have mechanical assistance (P < .001), portal vein thrombosis (P = .01), diabetes mellitus (P = .003), or dialysis the week before liver transplant (P = .004). Multivariable analysis (controlling for recipient characteristics) showed donor risk factors of graft failure included diabetes mellitus (P < .001), donation after cardiac death (P < .001), total bilirubin > 3.5 mg/dL (P < .001), serum creatinine > 1.5 mg/dL (P = .01), and cold ischemia time > 6 hours (P < .001). Regional organ sharing showed lower risk of graft failure (P = .02). Donor transaminases > 500 U/L were not associated with graft failure (relative risk, 1.02; 95% CI, 0.91-1.14; P = .74). CONCLUSIONS: Donor transaminases > 500 U/L should not preclude the use of liver grafts. Instead, donor total bilirubin > 3.5 mg/dL and serum creatinine > 1.5 mg/dL appear to be associated with higher likelihood of graft failure after liver transplant.

Living vs deceased donor liver transplantation in cholestatic liver disease: An analysis of the OPTN database.

BACKGROUND: Living donor liver transplantation (LDLT) and donation after circulatory death (DCD) can expand the donor pool for cholestatic liver disease (CLD) patients. We sought to compare the outcomes of deceased donor liver transplant (DDLT) vs LDLT in CLD patients. METHODS: Retrospective cohort analysis of adult CLD recipients registered in the OPTN database who received primary LT between 2002 and 2018. Cox proportional hazards regression models with mixed effects were used to determine the impact of graft type on patient and graft survival. RESULTS: Five thousand, nine hundred ninety-nine DDLT (5730 donation after brain death [DBD], 269 DCD) and 912 LDLT recipients were identified. Ten-year patient/graft survival rates were DBD: 73.8%/67.9%, DCD: 74.7%/60.7%, and LDLT: 82.5%/73.9%. Higher rates of biliary complications as a cause of graft failure were seen in DCD (56.8%) than LDLT (30.5%) or DBD (18.7%) recipients. On multivariable analysis, graft type was not associated with patient mortality, while DCD was independently associated with graft failure (P = .046). CONCLUSION: DBD, DCD, and LDLT were associated with comparable overall patient survival. No difference in the risk of graft failure could be observed between LDLT and DBD. DCD can be an acceptable alternative to DBD with equivalent patient survival, but inferior graft survival likely related to the high rate of biliary complications.

Adiponectin receptor agonists inhibit leptin induced pSTAT3 and in vivo pancreatic tumor growth.

Obesity is a significant risk factor for pancreatic cancer, harboring a chronic inflammatory condition characterized by dysregulation of the adipokines, leptin and adiponectin, that in turn alter oncogenic signaling pathways. We and others have shown that leptin promotes the proliferation and an invasive potential of pancreatic cancer cells through STAT3 mediated signaling. However, the role of adiponectin on the tumorigenicity of pancreatic cancer has not been elucidated. Adiponectin represents an important negative regulator of cytokines, which acts through two receptors, ADIPOR1 and ADIPOR2, to elicit pro-apoptotic, anti-inflammatory, and anti-angiogenic responses. We show that the level and expression of both adiponectin receptors are decreased in pancreatic tumors relative to normal pancreatic tissue. In vitro stimulation with adiponectin or a small molecule adiponectin receptor agonist, AdipoRon, increases apoptosis while inhibiting pancreatic cancer cell proliferation, colony formation, and anchorage independent growth. In addition, adiponectin receptor agonism inhibits leptin mediated STAT3 activation. In vivo, treatment of mice with AdipoRon inhibits orthotopic pancreatic tumor growth. These results demonstrate that adiponectin receptor activation is a key regulator of pancreatic cancer growth and AdipoRon provides a rational agent for the development of novel therapeutic strategies for pancreatic cancer.

Modulation of the leptin receptor mediates tumor growth and migration of pancreatic cancer cells.

Obesity has been implicated as a significant risk factor for development of pancreatic cancer. In the setting of obesity, a systemic chronic inflammatory response is characterized by alterations in the production and secretion of a wide variety of growth factors. Leptin is a hormone whose level increases drastically in the serum of obese patients. High fat diet induced obesity in mice leads to an overall increased body weight, pancreatic weight, serum leptin, and pancreatic tissue leptin levels. Here we report the contribution of obesity and leptin to pancreatic cancer growth utilizing an in vivo orthotopic murine pancreatic cancer model, which resulted in increased tumor proliferation with concomitant increased tumor burden in the diet induced obese mice compared to lean mice. Human and murine pancreatic cancer cell lines were found to express the short as well as the long form of the leptin receptor and functionally responded to leptin induced activation through an increased phosphorylation of AKT473. In vitro, leptin stimulation increased cellular migration which was blocked by addition of a PI3K inhibitor. In vivo, depletion of the leptin receptor through shRNA knockdown partially abrogated increased orthotopic tumor growth in obese mice. These findings suggest that leptin contributes to pancreatic tumor growth through activation of the PI3K/AKT pathway, which promotes pancreatic tumor cell migration.

Presurgical planning for hepatobiliary malignancies: clinical and imaging considerations.

There are many considerations in the evaluation of liver malignancy before planned surgical treatment. This article focuses on interpretation of MR imaging of the liver for surgical treatment planning of hepatocellular carcinoma, colorectal cancer metastases, and hilar cholangiocarcinoma. Clinical status, anatomic variants, future liver remnant, and underlying liver disease are all important factors in the decision to proceed with liver resection. The primary objective of preoperative imaging is to correctly identify patients who are candidates for curative intervention and to accurately stage their disease. Treatment planning for these complex patients is best done with a multidisciplinary team approach.

Is conservative treatment with antibiotics the correct strategy for management of right colonic diverticulitis?: a prospective study.

PURPOSE: The goals of this study were to identify whether conservative treatment with antibiotics in right colonic diverticulitis (RCD) patients, our empirical method used until now, is adequate and to determine how the natural history of RCD is affected by conservative treatment. METHODS: This study was designed as a case-control study. Group I was comprised of 12 patients who were managed conservatively, and clinical data were retrospectively collected. In group II, a total of 49 patients, diagnosed by using diagnostic criteria for RCD and managed conservatively, were prospectively included. RESULTS: The period of fasting was 2.7 days, and the hospital stay was 4.6 days in all patients. The intravenous and the oral antibiotic periods were 3.8 days and 9.8 days, respectively. There were no statistically significant differences in treatment results between the two groups except the duration of fasting and the hospitalization, and there were no complications under conservative treatment. Eight patients (13.1%) had recurrent diverticulitis during the follow-up period. The recurrence risk showed no significant difference between the groups. The RCD-free period after management was 60.1 months, and patients with recurrent RCD were treated by conservative treatment or laparoscopic surgery. CONCLUSION: Conservative treatment with antibiotics is the optimal treatment of choice for RCD and shows no increase in complications.

Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): safety, efficacy and improved secondary surgical resectability.

BACKGROUND: Circadian rhythm disruption was linked to high serum levels of Transforming Growth Factor Receptor α, an Epidermal Growth Factor Receptor (EGFR) ligand and poor survival in patients with metastatic colorectal cancer (mCRC). We hypothesized that EGFR blockade with cetuximab would enhance the activity of chronotherapy as a result of improved circadian coordination. METHODS: All the patients with mCRC referred to our unit for progression on prior chemotherapy over a 30-month-period received weekly cetuximab and fortnightly chronotherapy. RESULTS: Fifty-six patients were treated with a median of six courses of fluoropyrimidine-based chemotherapy and irinotecan (61%), oxaliplatin (25%) or both (14%) after a median of three prior regimens. We found no EFGR amplification by FISH in the tumor of 27 consecutive patients. Acneiform rash and diarrhea were the most common toxicities. Objective response rate was 32.1% and positively correlated with rash grade (p = 0.025). None of the responders had K-Ras mutation in their tumor. Median progression-free and overall survival were 4.6 and 13.7 months, respectively. Complete macroscopic resections of metastases in liver, lung or other abdominopelvic sites were performed following tumor downstaging by the treatment regimen in 11 patients (21%), 8 of whom being alive at 3 years. These figures are twice as high as those reported for first-line combination of cetuximab with conventional chemotherapy or for third line chronotherapy. CONCLUSIONS: The addition of cetuximab to chronotherapy allowed safe and effective therapeutic control of metastases, including their complete resection, despite previous failure of several treatment regimens.

Acquired KRAS mutations during progression of colorectal cancer metastases: possible implications for therapy and prognosis.

PURPOSE: Documentation of a wild-type (wt) KRAS gene in tumor has become mandatory for the prescription of anti-EGFR monoclonal antibodies in patients with colorectal cancer (CRC). Acquired KRAS mutations have seldom been reported in metastases from wt KRAS primary CRC. We report the first case of multiple KRAS mutations acquired during the metastatic phase of CRC, and retrospectively reviewed all patients with CRC, in whom KRAS was analyzed in at least two tumor samples from distinct lesions. METHODS: Genomic DNA purified from paraffin-embedded tissues was used after histological quantification of tumor tissue. The seven KRAS mutations located within codons 12 and 13 were screened using the allelic discrimination assay. RESULTS: A 35-year-old woman with CRC liver metastasis, resistant to all conventional cytotoxic agents, experienced for the first time significant tumor shrinkage while cetuximab was added, allowing hepatic resection. Further liver relapse occurred on cetuximab, but a new hepatic resection was attempted. No mutation in KRAS was detected in the primary colon tumor or in synchronous liver metastases. In contrast, in metachronous liver metastasis samples, two distinct mutations at codon 13 and 12 were detected. No acquired mutations were found in all the other 12 CRC cases with at least two serially performed KRAS analyses. CONCLUSIONS: Our findings suggest that late switch in KRAS mutational status could occur more frequently than currently recognized and account for acquired resistance to anti-EGFR therapies. Prospective studies are warranted to better estimate the incidence of change in KRAS mutational status and assess their clinical relevance.

The serum glycoprotein fetuin-A promotes Lewis lung carcinoma tumorigenesis via adhesive-dependent and adhesive-independent mechanisms.

Fetuin-A is a serum glycoprotein in the cystatin family associated with the regulation of soft tissue calcification. We tested the role of systemic fetuin in tumor cell growth and metastasis by injecting Lewis lung carcinoma (LLC) cells into fetuin-A null and their wild-type (WT) littermate control C57BL/6 mice via the tail vein, s.c., and intrasplenic routes. In the experimental metastasis assay, the lungs of the WT mice were filled with metastatic nodules, whereas the lungs of the fetuin-A null mutant mice were virtually free of colonies at the end of 2 weeks. Lung colonization responded to the levels of serum fetuin-A in a dose-dependent manner, as observed by the formation of half as many colonies in mice heterozygous for the fetuin-A locus compared with homozygous WT mice and restoration of lung colonization by the administration of purified fetuin-A to fetuin-A-null mice. Serum fetuin-A also influenced the growth of LLC cells injected s.c.: fetuin-A-null mice developed small s.c. tumors only after a substantial delay. Similarly, intrasplenic injection of LLC cells resulted in rapid colonization of the liver with metastasis to the lungs within 2 weeks in the WT but not fetuin-A null mice. To examine the mechanism by which fetuin-A influences LLC colonization and growth, we showed that LLC tumor cells adhere to fetuin-A in a Ca(2+)-dependent fashion, resulting in growth of the tumor cells. These studies support the role of fetuin-A as a major growth promoter in serum that can influence tumor establishment and growth.

Matrix metalloproteinases in colorectal cancer: is it worth talking about?

Matrix metalloproteinases (MMPs), a family of extracellular matrix degrading enzymes, are expressed in various stages of colorectal cancer (CRC) and correlate with survival and prognosis. There is considerable evidence in preclinical models that MMP inhibitors (MMPIs) are effective at multiple stages of CRC tumor progression, including reducing the number of intestinal adenomas, inhibiting the growth and establishment of primary CRC tumors, and reducing metastasis to the lung and liver. However, clinical trials with MMPIs in other tumor types have been largely unsuccessful, raising the question as to whether MMPs represent therapeutic targets in CRC. This review focuses on the expression, role, and contribution of MMP family members to various stages of CRC tumor progression. The conclusion is that there is considerable evidence to suggest that MMP inhibition may be an effective strategy if applied at either end of the tumor progression spectrum; the prevention of adenomas, or the treatment of micrometastatic disease.