Christopher J. Sonnenday

Sarcopenia and Mortality after Liver Transplantation

BACKGROUND Surgeons frequently struggle to determine patient suitability for liver transplantation. Objective and comprehensive measures of overall burden of disease, such as sarcopenia, could inform clinicians and help avoid futile transplantations. STUDY DESIGN The cross-sectional area of the psoas muscle was measured on CT scans of 163 liver transplant recipients. After controlling for donor and recipient characteristics using Cox regression models, we described the relationship between psoas area and post-transplantation mortality. RESULTS Psoas area correlated poorly with Model for End-Stage Liver Disease score and serum albumin. Cox regression revealed a strong association between psoas area and post-transplantation mortality (hazard ratio = 3.7/1,000 mm(2) decrease in psoas area; p < 0.0001). When stratified into quartiles based on psoas area (holding donor and recipient characteristics constant), 1-year survival ranged from 49.7% for the quartile with the smallest psoas area to 87.0% for the quartile with the largest. Survival at 3 years among these groups was 26.4% and 77.2%, respectively. The impact of psoas area on survival exceeded that of all other covariates in these models. CONCLUSIONS Central sarcopenia strongly correlates with mortality after liver transplantation. Such objective measures of patient frailty, such as sarcopenia, can inform clinical decision making and, potentially, allocation policy. Additional work is needed develop valid and clinically relevant measures of sarcopenia and frailty in liver transplantation.

Plasmapheresis, CMV hyperimmune globulin, and anti-CD20 allow ABO-incompatible renal transplantation without splenectomy

The majority of preconditioning protocols developed to allow ABO‐incompatible (ABOi) renal transplantation include concurrent splenectomy as a prerequisite to successful engraftment. Our center has developed a preconditioning protocol that includes plasmapheresis (PP), low‐dose CMV hyperimmune globulin (CMVIg), and anti‐CD20 monoclonal antibody (rituximab) to allow ABOi renal transplantation without splenectomy. Our initial experience has included treatment of six recipients and successful transplantation from blood group A1, A2, and group B living donors. Mean (± SD) serum creatinine was 1.3 ± 0.1 mg/dL among the six recipients and no episodes of antibody‐mediated rejection (AMR) occurred at a median follow‐up of 12 months. ABO antibody titers have remained below pretreatment levels. The absence of AMR and stable allograft function in this series show the potential of this preconditioning protocol to increase ABOi renal transplantation. The use of rituximab, allowing avoidance of splenectomy, may further remove one of the significant disincentives to ABOi transplantation, and eliminate the risk of post‐splenectomy infections.

Does pancreatic duct stenting decrease the rate of pancreatic fistula following pancreaticoduodenectomy? Results of a prospective randomized trial.

Pancreatic duct stenting remains an attractive strategy to reduce the incidence of pancreatic fistulas following pancreaticoduodenectomy (PD) with encouraging results in both retrospective and prospective studies. We performed a prospective randomized trial to test the hypothesis that internal pancreatic duct stenting reduces the development of pancreatic fistulas following PD. Two hundred thirty-eight patients were randomized to either receive a pancreatic stent (S) or no stent (NS), and stratified according to the texture of the pancreatic remnant (soft/normal versus hard). Four patients were excluded from the study; in three instances due to a pancreatic duct that was too small to cannulate and in the other instance because a total pancreatectomy was performed. Patients who randomized to the S group had a 6-cm-long segment of a plastic pediatric feeding tube used to stent the pancreaticojejunostomy anastomosis. In patients with a soft pancreas, 57 randomized to the S group and 56 randomized to the NS group. In patients with a hard pancreas, 58 randomized to the S group and 63 randomized to the NS group. The S and NS groups for the entire study population, as well as for the subgroup of high-risk patients with soft pancreata, were similar as regard to demographics, past medical history, preoperative symptoms, preoperative procedures, and intraoperative data. The pancreatic fistula rate for the entire study population was 9.4%. The fistula rates in the S and NS subgroups with hard pancreata were similar, at 1.7% and 4.8% (P=0.4), respectively. The fistula rates in the S and NS subgroups with soft pancreata were also similar, at 21.1% and 10.7% (P=0.1), respectively. A nonstatistically significant increase in the pancreatic fistula rate in the S group persisted after adjusting for the operating surgeon and technical details of the operation (e.g., anastomotic technique, anastomotic orientation, pancreatic duct size, and number of intra-abdominal drains placed). In patients with soft pancreata, 63% percent of the pancreatic fistulas in stented patients required adjustment to the clinical pathway (including two deaths), compared to 47% of the pancreatic fistulas in patients in the NS group (P=0.3). Internal pancreatic duct stenting does not decrease the frequency or the severity of postoperative pancreatic fistulas.

Frailty, core muscle size, and mortality in patients undergoing open abdominal aortic aneurysm repair

OBJECTIVES Determining operative risk in patients undergoing aortic surgery is a difficult process, as multiple variables converge to affect overall mortality. Patient frailty is certainly a contributing factor, but is difficult to measure, with surgeons often relying on subjective or intuitive influences. We sought to use core muscle size as an objective measure of frailty, and determine its utility as a predictor of survival after abdominal aortic aneurysm (AAA) repair. METHODS Four hundred seventy-nine patients underwent elective open AAA repair between 2000 and 2008. Two hundred sixty-two patients (54.7%) had preoperative computed tomography (CT) scans available for analysis. Cross-sectional areas of the psoas muscles at the level of the L4 vertebra were measured. The covariate-adjusted effect of psoas area on postoperative mortality was assessed using Cox regression. RESULTS Of the 262 patients, there were 55 deaths and the mean length of follow-up was 2.3 years. Cox regression revealed a significant association between psoas area and postoperative mortality (P = .003). The effect of psoas area was found to decrease significantly as follow-up time increased (P = .008). Among all covariates included in the Cox models (including predictors of mortality such as American Society of Anesthesiologists [ASA] score), the psoas area was the most significant. CONCLUSION Core muscle size, an objective measure of frailty, correlates strongly with mortality after elective AAA repair. A better understanding of the role of frailty and core muscle size may aid in risk stratification and impact timing of surgical repair, especially in more complex aortic operations.

Portal Vein Thrombosis and Survival in Patients with Cirrhosis

The effects of occlusive portal vein thrombosis (PVT) on the survival of patients with cirrhosis are unknown. This was a retrospective cohort study at a single center. The main exposure variable was the presence of occlusive PVT. The primary outcome measure was time‐dependent mortality. A total of 3295 patients were analyzed, and 148 (4.5%) had PVT. Variables independently predictive of mortality from the time of liver transplant evaluation included age [hazard ratio (HR), 1.02; 95% confidence interval (CI), 1.01‐1.03], Model for End‐Stage Liver Disease (MELD) score (HR, 1.10; 95% CI, 1.08‐1.11), hepatitis C (HR, 1.44; 95% CI, 1.24‐1.68), and PVT (HR, 2.61; 95% CI, 1.97‐3.51). Variables independently associated with the risk of mortality from the time of liver transplant listing included age (HR, 1.02; 95% CI, 1.01‐1.03), transplantation (HR, 0.65; 95% CI, 0.50‐0.81), MELD (HR, 1.08; 95% CI, 1.06‐1.10), hepatitis C (HR, 1.50; 95% CI, 1.18‐1.90), and PVT (1.99; 95% CI, 1.25‐3.16). The presence of occlusive PVT at the time of liver transplantation was associated with an increased risk of death at 30 days (odds ratio, 7.39; 95% CI, 2.39‐22.83). In conclusion, patients with cirrhosis complicated by PVT have an increased risk of death. Liver Transpl 16:83–90, 2010.

Successful Renal Transplantation across Simultaneous ABO Incompatible and Positive Crossmatch Barriers

ABO incompatibility and human leukocyte antigen (HLA) sensitization remain the two largest barriers to optimal utilization of kidneys from live donors. Here we describe the first successful transplantation of patients who were both ABO incompatible and crossmatch positive with their only available donor. A preconditioning regimen of plasmapheresis (PP) and low‐dose CMV hyperimmune globulin (CMVIg) was delivered every other day until donor‐specific antibody (DSA) titers were reduced to a safe level and isoagglutinin titers were ≤16. Each patient received quadruple sequential immunosuppression, splenectomy and three protocol post‐transplant PP/CMVIg treatments. There was no hyperacute rejection. Two of the three patients had a persistent positive cytotoxic crossmatch on the day of transplant and eliminated their DSA subsequently. Antibody‐mediated rejection (AMR) in one patient was reversed by reinitiating PP/CMVIg and anti‐CD20. The patients are more than 9 months post‐transplant with excellent graft function. Preconditioning with PP/CMVIg results in a durable suppression of DSA and permits accommodation of the allograft to a discordant blood type. The ability to cross these two barriers simultaneously is clinically important as sensitized patients have often exhausted their blood type compatible living donors during previous transplants.

Analytic morphomics, core muscle size, and surgical outcomes.

Objective:Assess the relationship between lean core muscle size, measured on preoperative cross-sectional images, and surgical outcomes. Background:Novel measures of preoperative risk are needed. Analytic morphomic analysis of cross-sectional diagnostic images may elucidate vast amounts of patient-specific data, which are never assessed by clinicians. Methods:The study population included all patients within the Michigan Surgical Quality Collaborative database with a computerized tomography(CT) scan before major, elective general or vascular surgery (N = 1453). The lean core muscle size was calculated using analytic morphomic techniques. The primary outcome measure was survival, whereas secondary outcomes included surgical complications and costs. Covariate adjusted outcomes were assessed using Kaplan-Meier analysis, multivariate cox regression, multivariate logistic regression, and generalized estimating equation methods. Results:The mean follow-up was 2.3 years and 214 patients died during the observation period. The covariate-adjusted hazard ratio for lean core muscle area was 1.45 (P = 0.028), indicating that mortality increased by 45% per 1000 mm2 decrease in lean core muscle area. When stratified into tertiles of core muscle size, the 1-year survival was 87% versus 95% for the smallest versus largest tertile, whereas the 3-year survival was 75% versus 91%, respectively (P < 0.003 for both comparisons). The estimated average risk of complications significantly differed and was 20.9%, 15.0%, and 12.3% in the lower, middle, and upper tertiles of lean core muscle area, respectively. Covariate-adjusted cost increased significantly by an estimated

Donation after Cardiac Death Liver Transplantation: Predictors of Outcome

10,110 per 1000 mm2 decrease in core muscle size (P = 0.003). Conclusions:Core muscle size is an independent and potentially important preoperative risk factor. The techniques used to assess preoperative CT scans, namely analytic morphomics, may represent a novel approach to better understanding patient risk.

A Phase I/II Trial of Intensity Modulated Radiation (IMRT) Dose Escalation With Concurrent Fixed-dose Rate Gemcitabine (FDR-G) in Patients With Unresectable Pancreatic Cancer

We aimed to identify recipient, donor and transplant risk factors associated with graft failure and patient mortality following donation after cardiac death (DCD) liver transplantation. These estimates were derived from Scientific Registry of Transplant Recipients data from all US liver‐only DCD recipients between September 1, 2001 and April 30, 2009 (n = 1567) and Cox regression techniques. Three years post‐DCD liver transplant, 64.9% of recipients were alive with functioning grafts, 13.6% required retransplant and 21.6% died. Significant recipient factors predictive of graft failure included: age ≥ 55 years, male sex, African–American race, HCV positivity, metabolic liver disorder, transplant MELD ≥ 35, hospitalization at transplant and the need for life support at transplant (all, p ≤ 0.05). Donor characteristics included age ≥ 50 years and weight >100 kg (all, p ≤ 0.005). Each hour increase in cold ischemia time (CIT) was associated with 6% higher graft failure rate (HR 1.06, p < 0.001). Donor warm ischemia time ≥ 35 min significantly increased graft failure rates (HR 1.84, p = 0.002). Recipient predictors of mortality were age ≥ 55 years, hospitalization at transplant and retransplantation (all, p ≤ 0.006). Donor weight >100 kg and CIT also increased patient mortality (all, p ≤ 0.035). These findings are useful for transplant surgeons creating DCD liver acceptance protocols.

Frailty and delayed graft function in kidney transplant recipients

PURPOSE Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by intensity modulated radiation with fixed-dose rate gemcitabine (FDR-G), freedom from local progression (FFLP), and overall survival (OS). METHODS AND MATERIALS Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status of 0-2, absolute neutrophil count of ≥ 1,500/mm(3), platelets ≥ 100,000/mm(3), creatinine <2 mg/dL, bilirubin <3 mg/dL, and alanine aminotransferase/aspartate aminotransferase ≤ 2.5 × upper limit of normal. FDR-G (1000 mg/m(2)/100 min intravenously) was given on days -22 and -15, 1, 8, 22, and 29. Intensity modulated radiation started on day 1. Dose levels were escalated from 50-60 Gy in 25 fractions. Dose-limiting toxicity was defined as gastrointestinal toxicity grade (G) ≥ 3, neutropenic fever, or deterioration in performance status to ≥ 3 between day 1 and 126. Dose level was assigned using TITE-CRM (Time-to-Event Continual Reassessment Method) with the target dose-limiting toxicity (DLT) rate set to 0.25. RESULTS Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55 Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% confidence interval [CI]: 32-79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6-22.2) and 30% (95% CI 17-45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months. CONCLUSIONS High-dose radiation therapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local therapy.