Diagnosis and staging of hepatobiliary malignancies: Potential incremental value of (18)F-FDG-PET/MRI compared to MRI of the liver.

OBJECTIVE: The purpose of the study was to investigate the potential added value of 18F-FDG-PET/MRI (functional information derived from PET) over standard diagnostic liver MRI (excellent soft tissue characterization) in diagnosing and staging suspected primary hepatobiliary malignancies including extrahepatic cholangiocarcinoma (ECC), intrahepatic cholangiocellular carcinoma (ICC) and gallbladder cancer (GBCA). METHODS: Twenty consecutive patients with suspected hepatobiliary malignancy were included in this retrospective study. All patients underwent combined whole-body (WB) 18F-FDG-PET/MRI including contrast-enhanced MRI of the liver, contrast-enhanced WB-MRI and WB 18F-FDG-PET. Two experienced readers staged hepatobiliary disease using TNM criteria: first based on MRI alone and then based on combined 18F-FDG-PET/MRI. Subsequently, the impact of FDG-PET/MRI on clinical management compared to MRI alone was recorded. Histopathologic proof served as the reference standard. RESULTS: Hepatobiliary neoplasms were present in 16/20 patients (ECC n = 3, ICC n = 8, GBCA n = 5), two patients revealed benign disease, two were excluded. TNM staging with 18F-FDG-PET/MRI was identical to MRI alone in 11/18 (61.1 %) patients and correctly changed the stage in 4/18 (22.2 %), resulting in a change in management for 2/4 patients (11.1 %). 18F-FDG-PET/MRI was false-positive in 3/18 cases (16.7 %). Both MRI and 18F-FDG-PET/MRI were falsely positive in 1 case without malignancy. CONCLUSIONS: A small incremental benefit of 18F-FDG-PET/MRI over standard MRI of the liver was observed. However, in some cases 18F-FDG-PET/MRI may lead to false-positive findings. Overall there is seemingly limited role of 18F-FDG-PET/MRI in patients with suspected hepatobiliary malignancy.

Pretherapy neutrophil to lymphocyte ratio and platelet to lymphocyte ratio do not predict survival in resectable pancreatic cancer.

BACKGROUND: Pretherapy serum neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have both been identified as prognostic in pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to identify the prognostic implication of pretherapy NLR and PLR in patients with resectable PDAC. METHODS: Data were collected retrospectively on patients operated at our institution between 2004 and 2014. A Cox proportional hazards model was used to investigate the relationship between clinical and pathological parameters, NLR and PLR to overall survival (OS). Survival data were analyzed using the Kaplan-Meier method. RESULTS: 217 patients were analyzed with a median overall survival (OS) of 17.5 months. Factors identified as being predictive of OS by univariate analysis included age, receipt of adjuvant therapy, margin positivity, pathologic angiolymphatic invasion, T-stage, and N-stage (P < 0.05). Factors identified as being independently predictive of OS by multivariate analysis included age and angiolymphatic invasion (P < 0.05). NLR and PLR were not predictive of OS. Survival analysis demonstrated no difference in OS in patients who had high or low NLR or PLR. DISCUSSION: Pretherapy NLR and PLR do not predict survival in patients who underwent pancreatectomy for PDAC at our institution.

Functional liver tissue engineering by an adult mouse liver-derived neuro-glia antigen 2-expressing stem/progenitor population.

Deaths due to end-stage liver diseases are increasingly registered annually in the world. Liver transplantation is the ultimate treatment for end-stage liver diseases to date, which has been hampered by a critical shortage of organs. The potential of decellularized liver scaffolds (DLS) derived from solid organs as a three-dimensional platform has been evolved as a promising approach in liver tissue engineering for translating functional liver organ replacements, but questions still exist regarding the optimal cell population for seeding in DLS and the preparation of the DLS themselves. The aim of our study was to utilize a sodium dodecyl sulfate decellularization procedure in combination with a low concentration of trypsin (0.005%)-ethylenediaminetetraacetic acid (0.002%) process to manufacture DLS from whole mouse livers and recellularized with hepatic stem/progenitors for use in liver tissue engineering and injured liver treatment. Results showed that the DLS generated with all the necessary microstructure and the extracellular components to support seeded hepatic stem/progenitor cell attachment, functional hepatic cell differentiation. Hepatic differentiation from stem/progenitor cells loaded by DLS was more efficient than that of the stem/progenitor cells in the two-dimensional cell culture model. In summary, the method of DLS loaded by hepatic stem/progenitor cells provided by this study was effective in maintaining DLS extracellular matrix to introduce seeded stem/progenitor cell differentiation, hepatic-like tissue formation and functional hepatic protein production in vitro that promoted functional recovery and survival in a mouse model of dimethylnitrosamine-induced liver cirrhosis after auxiliary heterotopic liver transplantation. Copyright © 2016 John Wiley & Sons, Ltd.

Pyogenic liver abscesses: a contemporary analysis of management strategies at a tertiary institution.

BACKGROUND: Despite equivocal evidence, non-surgical management for pyogenic liver abscess (PLA) has become the standard of care at most institutions with surgery relegated to salvage therapy for those who fail less invasive means. The aim of this study was to describe the outcomes of a step-up approach to PLA management. METHODS: A retrospective chart review was conducted at a single institution for patients diagnosed with PLA over a 10-year period. Demographic, radiologic, microbiological, treatment, and outcomes data were collected and analyzed. RESULTS: 64 patients with PLA were identified. Initial treatment included antibiotics alone (n = 9), percutaneous drainage (PD) (n = 54), and surgery (n = 1). Surgery was ultimately required in 8 patients while 50 were cured with PD and 4 with antibiotics alone. Two (3%) patients died. Overall, PD carried an 85% success rate. CONCLUSION: PLA patients should be initially treated non-operatively, barring indications for emergent surgery or inaccessibility for PD. Surgery can be reserved for failure of PD.

Extended Perioperative Antibiotic Coverage in Conjunction with Intraoperative Bile Cultures Decreases Infectious Complications after Pancreaticoduodenectomy.

Background. Bile contamination from the digestive tract is a well-known risk factor for postoperative complications. Despite the literature concerning prevalence of bacterobilia and fungobilia in patients with biliary pathologies, there are no specific recommendations for perioperative antimicrobial coverage for biliary/pancreatic procedures. We evaluated the effect of at least 72 hours of perioperative broad spectrum antibiotic coverage on outcomes of pancreaticoduodenectomy (PD). Materials and Methods. A retrospective review of all patients at Case Medical Center of Case Western Reserve University undergoing PD procedure, from 2006 to 2011, was performed (n = 122). Perioperative data including demographics, comorbidities, biliary instrumentation, antibiotic coverage, culture results, and postoperative outcomes were analyzed. Propensity score matching method was used to match the patients according to duration of antibiotic coverage into two groups: 72 hours (A72) and 24 hours (A24). Results. Longer broad spectrum antibiotic coverage in group A72 resulted in significantly less surgical site infections after PD, compared to routine 24 hours of perioperative antibiotics in group A24. This study did not reveal a statistically significant decrease in postoperative fungal infections in patients receiving preoperative antifungals. Conclusion. Prolonged perioperative antibiotic therapy in conjunction with intraoperative bile cultures decreases the short-term infectious complications of PD, with no significant increase in Clostridium difficile colitis incidence.

Repair of liver mediated by adult mouse liver neuro-glia antigen 2-positive progenitor cell transplantation in a mouse model of cirrhosis.

NG2-expressing cells are a population of periportal vascular stem/progenitors (MLpvNG2(+) cells) that were isolated from healthy adult mouse liver by using a "Percoll-Plate-Wait" procedure. We demonstrated that isolated cells are able to restore liver function after transplantation into a cirrhotic liver, and co-localized with the pericyte marker (immunohistochemistry: PDGFR-ß) and CK19. Cells were positive for: stem cell (Sca-1, CD133, Dlk) and liver stem cell markers (EpCAM, CD14, CD24, CD49f); and negative for: hematopoietic (CD34, CD45) and endothelial markers (CD31, vWf, von Willebrand factor). Cells were transplanted (1 × 10(6) cells) in mice with diethylnitrosamine-induced cirrhosis at week 6. Cells showed increased hepatic associated gene expression of alpha-fetoprotein (AFP), Albumin (Alb), Glucose-6-phosphatase (G6Pc), SRY (sex determining region Y)-box 9 (Sox9), hepatic nuclear factors (HNF1a, HNF1ß, HNF3ß, HNF4α, HNF6, Epithelial cell adhesion molecule (EpCAM), Leucine-rich repeated-containing G-protein coupled receptor 5-positive (Lgr5) and Tyrosine aminotransferase (TAT). Cells showed decreased fibrogenesis, hepatic stellate cell infiltration, Kupffer cells and inflammatory cytokines. Liver function markers improved. In a cirrhotic liver environment, cells could differentiate into hepatic lineages. In addition, grafted MLpvNG2(+) cells could mobilize endogenous stem/progenitors to participate in liver repair. These results suggest that MLpvNG2(+) cells may be novel adult liver progenitors that participate in liver regeneration.

Rescue ALPPS: Intraoperative Conversion to ALPPS during Synchronous Resection of Rectal Cancer and Liver Metastasis.

Future liver remnant (FLR) is the most important deciding factor in planning for liver resection. Portal vein embolization (PVE) was first introduced in the 1980s to induce liver hypertrophy, enabling removal of multiple/bilobar tumors. PVE was later combined with sequential hepatectomies with the aim of allowing the liver remnant to hypertrophy (15-20%) between procedures. However, the interval between the two procedures (3-8 weeks) put patients at risk for disease progression. With portal vein ligation alone or when combined with sequential hepatectomy, there is also a risk for inadequate liver hypertrophy because of intrahepatic portal collaterals leading to a high (19-30%) dropout rate. The ALPPS procedure (associating liver partition and portal vein ligation for staged hepatectomy) was recently developed as a feasible means to perform extensive/bilobar liver resections. It produces rapid, enormous hypertrophy of the remnant, making previously unresectable lesions resectable. Indications for ALPPS include any extensive liver resection with inadequate FLR. Here we present a novel indication for ALPPS as a rescue when inadequate FLR was faced intraoperatively, during a simultaneous resection of rectal primary and liver metastasis.

Negative regulation of the interferon response by an interferon-induced long non-coding RNA.

Long non-coding RNAs (lncRNAs) play critical roles in diverse cellular processes; however, their involvement in many critical aspects of the immune response including the interferon (IFN) response remains poorly understood. To address this gap, we compared the global gene expression pattern of primary human hepatocytes before and at three time points after treatment with IFN-α. Among ∼ 200 IFN-induced lncRNAs, one transcript showed ∼ 100-fold induction. This RNA, which we named lncRNA-CMPK2, was a spliced, polyadenylated nuclear transcript that was induced by IFN in diverse cell types from human and mouse. Similar to protein-coding IFN-stimulated genes (ISGs), its induction was dependent on JAK-STAT signaling. Intriguingly, knockdown of lncRNA-CMPK2 resulted in a marked reduction in HCV replication in IFN-stimulated hepatocytes, suggesting that it could affect the antiviral role of IFN. We could show that lncRNA-CMPK2 knockdown resulted in upregulation of several protein-coding antiviral ISGs. The observed upregulation was caused by an increase in both basal and IFN-stimulated transcription, consistent with loss of transcriptional inhibition in knockdown cells. These results indicate that the IFN response involves a lncRNA-mediated negative regulatory mechanism. lncRNA-CMPK2 was strongly upregulated in a subset of HCV-infected human livers, suggesting a role in modulation of the IFN response in vivo.

The impact of resection margin status and postoperative CA19-9 levels on survival and patterns of recurrence after postoperative high-dose radiotherapy with 5-FU-based concurrent chemotherapy for resectable pancreatic cancer.

OBJECTIVES: To analyze the impact of surgical margins and other clinicopathological data on treatment outcomes on 75 patients treated from 1999 to 2006 by initial potentially curative surgery (+/- intraoperative radiotherapy), followed by high-dose 3-dimensional conformal radiation therapy and concomitant fluoropyrimidine-based chemoradiotherapy. MATERIALS AND METHODS: All clinical and pathologic data on this patient cohort were analyzed by actuarial Kaplan-Meier survival methodology and by univariate and multivariate Cox proportional hazards methods to measure effects on survival and patterns of failure. RESULTS: With a median follow-up of 28 months, the median, 2-year and 5-year overall survival (OS) rates were 18.1 month, 41% and 23.6%, respectively. Disease-free survival (DFS) rates were of 11.4 months, 35% and 20%, respectively. Only 2 clinicopathological features, positive (< or =1 mm) surgical margins (P < 0.05) and a 2-fold (>70 U/mL) elevation of the postoperative serum CA19-9 (P < 0.001) impacted OS and disease-free survival. In patients with negative (>1 mm) surgical margins and a low (< or =70 U/mL) postoperative CA19-9, the projected 2- and 5-year OS were 80% and 65%, respectively, compared with 40% and 10% with positive surgical margins and a low CA19-9 and to 10% and 0% with positive or negative surgical margins and a high (>70 U/mL) CA19-9. Positive surgical margins (P < 0.001) and an elevated postoperative CA19-9 (P < 0.001) also predicted early development of distant metastases, whereas isolated loco-regional failure was less common and not affected by these or other clinicopathological features. CONCLUSIONS: Using this fluoropyrimidine-based chemoradiotherapy regimen after surgical resection (+/- intraoperative radiotherapy), positive surgical margins and an elevated (2-fold) postoperative serum CA19-9 level predicted for reduced survival and early development of distant metastatic disease.

Comparative lesion sequencing provides insights into tumor evolution.

We show that the times separating the birth of benign, invasive, and metastatic tumor cells can be determined by analysis of the mutations they have in common. When combined with prior clinical observations, these analyses suggest the following general conclusions about colorectal tumorigenesis: (i) It takes approximately 17 years for a large benign tumor to evolve into an advanced cancer but <2 years for cells within that cancer to acquire the ability to metastasize; (ii) it requires few, if any, selective events to transform a highly invasive cancer cell into one with the capacity to metastasize; (iii) the process of cell culture ex vivo does not introduce new clonal mutations into colorectal tumor cell populations; and (iv) the rates at which point mutations develop in advanced cancers are similar to those of normal cells. These results have important implications for understanding human tumor pathogenesis, particularly those associated with metastasis.

Early experience with intraoperative radiotherapy in patients with resected pancreatic adenocarcinoma.

BACKGROUND: The use of intraoperative radiotherapy (IORT) in patients with resected pancreatic adenocarcinoma has not been clearly defined. METHODS: The medical records of our first 22 patients receiving IORT for resected pancreatic adenocarcinoma (2001 to 2006) were reviewed and compared with the records of 27 consecutive patients not receiving IORT for resected pancreatic adenocarcinoma (2004 to 2006). RESULTS: There were no 30-day mortalities in either group, and complication rates were similar. Local recurrence occurred in 18% in the IORT group (median 14 months) and 12% in the no-IORT group (median 7 months). Distant recurrence occurred in 47% in the IORT group (median 11 months) and 32% in the no-IORT group (median 6.5 months). Median overall, stage-specific, and location-specific survival did not differ between the groups. CONCLUSIONS: Although limited in size and follow-up, our experience showed that complications, recurrence, and survival were not affected by IORT, but time to recurrence may be longer with IORT.

Long-term graft outcomes after steroid withdrawal in African American kidney transplant recipients receiving sirolimus and tacrolimus.

BACKGROUND: We previously reported excellent short-term outcomes in African American kidney transplant patients receiving tacrolimus/sirolimus and withdrawn from corticosteroid therapy three months after transplantation. We now report the long-term outcomes of patients subjected to this protocol. METHODS: In all, 47 African American kidney transplant recipients were enrolled in an uncontrolled trial in which they were initially treated with sirolimus, tacrolimus, and corticosteroids, without antibody induction therapy. Eligible patients were withdrawn from prednisone between three and five months posttransplant, and followed for acute rejection and changes in renal function. Outcomes (group 1, n=32) were compared to those of patients deemed not to be candidates for steroid withdrawal (group 2, n=15). RESULTS: After a mean follow-up of 48.5 months, 13 of 32 patients (41%) in group 1 developed acute rejection; only 13 patients (41%) remain steroid-free. Nine of 13 rejection episodes were associated with noncompliance. Graft loss occurred in 8 of 32 patients (25%) in group 1 and in 5 of 15 patients (33%) in group 2 (P=NS). Serum creatinine rose from 1.4+/-0.41 to 2.45+/-1.7 mg/dL in group 1 (P=0.004) and from 2.1+/-0.45 to 2.62+/-1.2 mg/dL (P=NS) in group 2. Among 13 patients in group 1 who remain steroid-free, creatinine concentration has risen from 1.28+/-.0.37 prior to steroid withdrawal to 1.64+0.54 at last follow-up (P=0.027). CONCLUSIONS: Late noncompliance and/or rejection in African Americans withdrawn from steroids have a negative impact on long-term graft function and survival. Steroid withdrawal may be associated with long-term deterioration of renal function, even in the absence of overt acute rejection.

Food protein sensitivity with partial villous atrophy after pediatric liver transplantation with tacrolimus immunosuppression.

We report three pediatric liver transplant recipients receiving tacrolimus immunosuppression presented with vomiting, heme-positive stools and failure to thrive, who had subtotal villous atrophy in their histology because of food protein sensitivity. Case findings and current literature of the casual relationship between tacrolimus and food allergies briefly reviewed.

Comparative effects of sirolimus and mycophenolate mofetil on erythropoiesis in kidney transplant patients.

Anemia and erythrocytosis (PTE) are common after kidney transplantation. We sought to determine the influence of sirolimus compared to mycophenolate mofetil (MMF) on post-transplant erythropoiesis. A total of 214 patients with recent kidney or kidney-pancreas transplants were treated with either sirolimus-based (n = 87) or MMF-based (n = 127) therapy. At 12 months, the prevalence of anemia was 31% with MMF and 57% with sirolimus (p < 0.001). Linear regression was used to examine the independent influence of sirolimus on hemoglobin at 12 months, controlling for multiple factors including gender and renal function. Sirolimus remained a significant correlate of lower hemoglobin in all patients (slope =-1.060, 95% CI: -1.76 to -0.362, p = 0.003), and in patients without PTE (slope =-0.671, 95% CI: -1.32 to -0.028, p = 0.041). PTE, defined as a persistent hematocrit above 51%, occurred in 19% with MMF and 7% with sirolimus (p = 0.013). PTE was examined using logistic regression analysis. Sirolimus use correlated negatively with PTE (odds ratio with sirolimus = 0.33, 95% CI: 0.12 to 0.89, p = 0.028). Our results indicate that, compared to treatment with MMF, treatment of kidney or kidney-pancreas recipients with sirolimus is associated with a higher prevalence of anemia, lower hemoglobin levels and lower incidence of PTE.

Thrombotic events and markers of oxidation and inflammation in hemodialysis.

The goal of this study was to determine whether antioxidant therapy with vitamin E would alter the rate of vascular access complications or other macrovascular complications in hemodialysis (HD) patients. A secondary goal of the study was to explore the relationship between baseline pretreatment markers of oxidative stress (the advanced glycation end product pentosidine and basal levels of vitamin Ealpha and gamma) and the subsequent development of access failure. Thirty-five stable patients treated by HD were recruited for the study. Patients were provided with vitamin E (800 IU) or placebo capsules to be taken daily. Clinical variables, vascular access function (flow meter access flow measurements), and circulating blood markers were obtained initially and every 3 months throughout the study. Vitamin Ealpha levels rose in treated patients from 12.7 +/- 4.4 to 25.1 +/- 15.1 microg/mL at 3 months and 28.6 +/- 14.8 microg/mL at 6 months. Vitamin Egamma levels fell in treated patients from 3.9 +/- 1.7 to 2.3 +/- 1.5 microg/mL at 3 months and 1.7 microg/mL at 6 months. Patients who subsequently developed repeated thrombotic vascular access events were characterized by higher baseline pentosidine content of circulating proteins. Patients who developed a myocardial infarction had higher pentosidine, lower vitamin Ealpha, and much lower vitamin Egamma than patients who did not develop thrombotic events. These findings lead to the speculation that the anti-inflammatory effects of vitamin Egamma may play a more important role in thrombotic vascular events than the antioxidant effects of vitamin Ealpha. Additional studies of these interactions are in progress.

Withdrawal of steroid therapy in African American kidney transplant recipients receiving sirolimus and tacrolimus.

BACKGROUND: Withdrawal of corticosteroids from the immunosuppressive regimens of kidney transplant recipients has been associated with an increased risk of acute and chronic allograft rejection. Previous studies indicate that the risk of rejection is particularly high in African Americans. METHODS: We prospectively enrolled 44 African American kidney transplant recipients to participate in an uncontrolled trial in which they were initially treated with sirolimus, tacrolimus, and corticosteroids. No patient received antibody induction therapy. Prednisone was withdrawn from eligible patients free of acute rejection beginning as early as 3 months posttransplant, and followed for a minimum of 9 months posttransplant. Patients were followed for acute rejection and for changes in blood pressure, body weight, and serum creatinine concentrations before and after withdrawal of steroids. RESULTS: Thirty of 44 patients (68%) were weaned off of prednisone. Follow-up after withdrawal of prednisone ranged from 3 to 26 months (mean, 14.3+/-7.7 months). Two of 30 patients (6.7%) developed acute rejection. At last follow-up, 27 of 30 patients (90%) remain steroid-free. Steroid withdrawal was associated with significant reductions in blood pressure. CONCLUSIONS: Use of sirolimus and tacrolimus, without the use of induction antibody therapy, allows withdrawal of prednisone as early as 3 months posttransplant with low rates of subsequent acute rejection in African American kidney transplant recipients. Withdrawal of prednisone was associated with lower blood pressures and the need for fewer antihypertensive medications.

Comparison of sirolimus vs. mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation.

Mycophenolate mofetil (MMF) and sirolimus impair wound healing. We compared sirolimus vs. MMF to determine the relative impact on surgical complications and wound healing in adult kidney transplant recipients. This retrospective, single center study of 235 adult kidney transplants performed between 1 January 2000 and 31 January 2002 identified 158 adult, kidney-only recipients treated with tacrolimus and prednisone, from which two groups were defined: group 1 (n = 84) received MMF, group 2 (n = 74) received sirolimus. The incidence of fluid collections, wound problems, dehiscence, and urine leak were compared. A multivariate stepwise logistical regression analysis was performed to identify risk factors. The overall incidence of complications was 21.5%, with rates significantly lower in group 1 (2.4%) vs. group 2 (43.2%, p < 0.0001). Regression analysis showed only sirolimus (p < 0.001) and hypo-albuminemia (p = 0.006) to independently correlate with complication occurrence. In subanalyses, lymphoceles correlated only with sirolimus (p = 0.003), while other wound problems also correlated with higher body mass index (p = 0.067). The use of sirolimus, tacrolimus and prednisone was associated with a greater incidence of lymphoceles, non-lymphocele perinephric fluid collections and other consequences of poor wound healing, as compared to contemporary patients treated with MMF, tacrolimus and prednisone.

Outcomes of African American kidney transplant recipients treated with sirolimus, tacrolimus, and corticosteroids.

BACKGROUND: African American kidney transplant recipients generally exhibit poor long-term graft survival compared with other ethnic groups. The combination of sirolimus, tacrolimus, and corticosteroids has proven to be effective in reducing rejection episodes in high-risk organ and islet cell transplant recipients but has not yet been tested in a large number of African American patients. METHODS: The outcomes of 56 African American adult, primary kidney transplant recipients treated with corticosteroids, sirolimus, and tacrolimus targeted to relatively low trough blood levels were compared with those of a concurrent group of 65 white patients treated with steroids, mycophenolate mofetil, and tacrolimus targeted to relatively high blood levels. Induction antibody therapy was not routinely used in either group. RESULTS: The incidence of acute rejection in the first 3 posttransplantation months was 7.1% in African Americans and 16.9% in whites (P=NS). Actuarial 2-year patient, graft, and rejection-free graft survival rates were equivalent in the two groups. Posttransplantation diabetes mellitus occurred in 36% of the African American patients, despite similar doses of corticosteroids and lower trough levels of tacrolimus, compared with 15% of white patients (P=0.024). CONCLUSIONS: The combination of corticosteroids, sirolimus, and relatively low doses of tacrolimus results in acute rejection, graft survival, and patient survival rates equivalent to those achieved in white patients receiving steroids, mycophenolate mofetil, and relatively high doses of tacrolimus, even without the routine use of induction antibody therapy. Posttransplantation diabetes mellitus remains a problem for African Americans receiving this combination of immunosuppressants, despite relatively low tacrolimus blood levels.