Jay A. Graham

Early Acceptance of Renal Allografts in Mice Is Dependent on Foxp3+ Cells

Mouse renal allografts have a remarkable ability to promote acceptance across full major histocompatibility complex incompatibilities in certain strain combinations without immunosuppression. The mechanism is unknown but is believed to involve immunoregulation. This study tests whether Foxp3(+) T-regulatory cells are responsible in the early phase of graft acceptance, using B6.Foxp3(DTR) mice that express diphtheria toxin receptor (DTR) in Foxp3(+) cells. The administration of DT to B6.Foxp3(DTR) recipients with accepted DBA/2 kidneys, 3 weeks to 3 months after transplantation, caused a marked depletion of Foxp3 cells and triggered acute cellular rejection, manifested by a sudden increase in blood urea nitrogen within a week. None of the controls showed an increase in blood urea nitrogen, including DT-treated B6 wild-type recipients of DBA/2 kidneys or B6.Foxp3(DTR) recipients of isografts. Accepted DBA/2 allografts showed prominent lymphoid sheaths around arteries containing numerous CD3(+)Foxp3(+) cells, CD4(+) cells, dedritic cells, and B cells, which was independent of CCR4. The lymphoid sheaths disintegrate after Foxp3 depletion, accompanied by widespread CD8 interstitial mononuclear inflammation, tubulitis, and endarteritis. The Foxp3 depletion caused an increased frequency of donor-reactive cells in the spleen by interferon (IFN) γ enzyme-linked immunosorbent spot (ELISPOT) assays and increased expression of the maturation markers, CD86 and IA(b), on dendritic cells in the spleen and kidney. We conclude that Foxp3(+) cells are needed to maintain acceptance of major histocompatibility complex-incompatible renal allografts in the first 3 months after transplantation and may act by inhibiting DC maturation.

Laparoscopic-assisted versus open pancreaticoduodenectomy: Early favorable physical quality-of-life measures

BACKGROUND We compared outcomes and postpancreatectomy quality of life (QOL) in paired cohorts of patients undergoing conventional open pancreaticoduodenectomy (OPD) or laparoscopic-assisted pancreaticoduodenectomy (LAPD). METHODS Comparative analysis of QOL was performed in a matched cohort of 53 patients after OPD or LAPD between 2010 and 2013. The Medical Outcomes Study Short Form-36 Health Survey and the Karnofsky score were used. RESULTS Physical component score, mental component score, and Karnofsky scores were calculated at multiple time points for OPD (n = 25) and LAPD (n = 28). Operative times, complications, and readmission rates were equivalent. Time to starting adjuvant therapy trended toward clinical importance in LAPD (61 vs 110 days, P = .0878). Duration of stay was less in LAPD (7.10 vs 9.44 days, P = .02). LAPD had a superior QOL centered on functional status compared with OPD (physical component score 49.09 vs 38.4, P = .04; Karnofsky 92.22 vs 66.92%, P = .003). These statistical differences were not observed beyond 6 months. CONCLUSION LAPD provided a more favorable QOL within the first 6 months and shorter length of stay compared with conventional OPD. LAPD may serve as an alternative operative therapy to potentially minimize delays in receipt of and enhance tolerability of adjuvant therapies.

Viral infection induces de novo lesions of coronary allograft vasculopathy through a natural killer cell-dependent pathway

Viral infections including those due to cytomegalovirus have been associated with accelerated cardiac allograft vasculopathy (CAV) in clinical trials and some animal models. Evidence demonstrating a direct causal relationship between such infections and de novo formation of coronary vascular lesions is lacking. Heterotopic murine cardiac transplants were performed in a parental to F1 combination in animals lacking both T‐ and B‐lymphocytes (RAG−/−). Coronary vasculopathy developed almost exclusively in the presence of recipient infection with lymphocytic choriomeningitis virus but not in uninfected controls. This process was also dependent upon the presence of natural killer (NK) cells as depletion of NK cells abrogated the process. These data show that a viral infection in its native host, and not previously implicated in the production of CAV, can contribute to the development of advanced coronary vascular lesions in cardiac allotransplants in mice. These data also suggest that virus‐induced CAV can develop via an NK‐cell‐dependent pathway in the absence of T‐ and B‐lymphocytes.

Suppressive Treg cell activity is potentiated by glycogen synthase kinase 3β inhibition

The mechanism by which regulatory T (Treg) cells suppress the immune response is not well defined. A recent study has shown that β-catenin prolongs Treg cell survival. Because β-catenin is regulated by glycogen synthase kinase 3β (GSK-3β)-directed phosphorylation, we focused on GSK-3β and the role it plays in Treg cell function. Inhibition of GSK-3β led to increased suppression activity by Treg cells. Inhibitor-treated Treg cells exhibited prolonged FoxP3 expression and increased levels of β-catenin and of the antiapoptotic protein Bcl-xL. Systemic administration of GSK-3β inhibitor resulted in prolonged islet survival in an allotransplant mouse model. Our data suggest that GSK-3β could be a useful target in developing strategies designed to increase the stability and function of Treg cells for inducing allotransplant tolerance or treating autoimmune conditions.

How does laparoscopic-assisted hepatic resection compare with the conventional open surgical approach?

BACKGROUND Laparoscopic-assisted hepatic resection (LAHR) has been described as a safe and reliable means of liver resection for tumors or live-donor hepatectomy. Here we compare the outcomes in paired cohorts between patients undergoing open hepatic resection (OHR) and LAHR. STUDY DESIGN Two hundred and twelve patients who underwent either OHR or LAHR from March 2004 to July 2011 were analyzed to assess outcomes. During this time period, 124 patients underwent OHR and 88 underwent LAHR. Demographic and outcomes data were assessed. RESULTS In the total patient cohort, mean age found in both surgical arms was similar, as was the mean BMI. In addition, there was no difference in the cohort between those who underwent either minor or major hepatic resections (p = 0.52). Operatively, in the OHR arm the mean duration of the operation was 234 minutes and comparable with LAHR at 238 minutes (p = 0.75). There was also no difference in the mean lesion size in the OHR (5.72 cm) and LAHR (5.37 cm) groups (p = 0.55). Notably, there was no difference in the complication incidence rates, which were 10.5% (OHR) and 6.8% (LAHR) (p = 0.59). However, when analyzing for length of stay, there was a significant difference between the 2 arms; patients in OHR arm had longer stays than those in the LAHR arm (7.59 days vs 6.30 days, respectively; mean difference 1.29 days; 95% CI, 0.08-2.5; p = 0.036). CONCLUSIONS Although reduced surgical pain, improved cosmesis, and shortened hospital stays have been shown to correlate with laparoscopic abdominal procedures, our study indicates these marked advantages are also conferred to those undergoing LAHR. In addition, these findings demonstrate the use of LAHR and highlight the need for the addition of this technique to the liver surgeons skill set.

A prospective study of prophylactic long-acting octreotide in high-risk patients undergoing pancreaticoduodenectomy

BACKGROUND Postoperative pancreatic fistula (postoperative pancreatic fistula [POPF]) is the most common complication after pancreaticoduodenectomy. Despite some studies showing little effect of octreotide in unselected patients, we hypothesized that in high-risk patients depot octreotide may reduce the risk of POPF. METHODS Sixty-eight patients were prospectively evaluated for inclusion in the current study. Two groups were identified: pancreatic ducts ≤3 mm (high risk) and those with ducts >3 mm (low risk). Thirty-two patients were low risk, whereas 36 patients were high risk. High-risk patients were treated preoperatively with depot octreotide and begun on an intravenous drip for 24 hours. Low-risk patients underwent pancreaticoduodenectomy without pharmacologic intervention. In contrast, the control cohort represents 106 retrospectively analyzed patients who underwent a pancreaticoduodenectomy without depot octreotide injection without regard to low- or high-risk status. RESULTS Overall, POPF was 11 of 68 (16%). Nine of 36 high risk patients treated with depot octreotide developed POPF (25%), and 2 of 32 low risk patients developed POPF (6%). In the control cohort of high-risk patients, 9 of 44 (20%) and 3 of 62 (5%) low-risk patients developed POPF (P = .628 when comparing the development of POPF in high-risk patients with or without pharmacologic intervention). CONCLUSIONS Prophylactic use of depot octreotide in high-risk patients does not result in reduced incidence of POPF. Duct size has a significant impact on the occurrence of POPF.

Probability prediction of a postoperative pancreatic fistula after a pancreaticoduodenectomy allows for more transparency with patients and can facilitate management of expectations

Dear Editor, Here, we present an analytic instrument that through its simplicity of design, ease of use and interpretation make it an important part of our practice in assessing the likelihood of developing a post‐operative pancreatic fistula (POPF) after a pancreaticoduodenectomy (PD). More importantly, this clinical tool allows us to have a more forthright conversation with our patients about their risks of significant morbidity as it pertains to a POPF. It is well known that a PD is one of the most technically demanding abdominal oncological operations. Originally, described by Dr. Alessandro Codivilla in 1898 and later refined by Dr. Allen Oldfather Whipple, the removal of the pancreatic head and duodenum as it wraps around the route of the mesentery can pose some significant surgical challenges [1]. As such, the surgery carries a significant morbidity that can range from 30% to 50% in the early post‐operative period [2,3]. This morbidity is mainly buoyed by leakage from the pancreaticoenteric anastomosis and has been termed a POPF. The incidence of a POPF after a PD is quite variable and dependent on the institution, but is reported to occur between 10% and 40% of the time after surgery. Remarkably, this heightened prevalence has been steadfast despite the various surgical techniques and medical management strategies employed to alleviate this problem [4–6]. In the face of this overwhelming morbidity that can lead to prolonged hospital stays, initiation of parental nutrition and delay in adjuvant therapy, we recognized that we needed to be more transparent with our patients regarding the risk of a POPF after a PD. As such, we looked for easily measurable variables that could assist us in predicting the occurrence of a POPF in a particular patient. While other studies have independently verified that duct size, texture of pancreatic parenchyma, body mass index (BMI), nutritional status, and etiology of disease are important in influencing the rates of a POPF, we sought to create a clinical tool that combined many of the discrete aforementioned variables to increase the accuracy of prediction [7]. Notably, at our institution we take a more conservative approach to POPF management after a PD, which includes 6 weeks of drainage and parental nutrition. Understandably, we recognize that this regimen can be unnerving and disruptive to the patient. Therefore, using this clinical tool, through the easy input of four factors, we are able to disclose to the patient the POPF probability and thereby manage expectations with regard to hospital length‐of‐stay and start of adjuvant therapy should it be needed. A retrospective analysis of 146 patients who underwent a PD during September 2007 through June 2012 by one surgeon (L.B.J.) yielded a 34% rate of POPF. Of note, during every PD a JP drain was placed near the pancreaticoenteric anastomosis. Importantly, a POPF was defined as JP drain fluid amylase greater than three times normal serum amylase on or after post‐operative day (POD) 4 as was similarly defined by the International Study Group for Pancreatic Fistula [8]. Binary logistic regression was performed to assess the predictability of a POPF based on the quantitative variables age, BMI, pancreatic duct size, and POD 2 JP amylase levels (IU/L; SPSS, IBM®). Of note, the age and BMI were ascertained pre‐operatively while the pancreatic duct size was measured intra‐operatively with lacrimal probs. Age, BMI and day 2 JP amylase levels were assessed as interval variables while the pancreatic duct size was considered a nominal variable with a cut‐off< 3mm. The standard logit(P)1⁄4 aþ bX equation for these variables was used to establish probability. A likelihood ratio test was employed to examine the overall strength of the predictor values and the Homer and Lemeshow Test to evaluate the goodness of fit of our model. Significant variables in predicting the probability of a POPF included; age (odds ratio1⁄4 1.035, P1⁄4 0.037), BMI (odds ratio1⁄4 1.108, P1⁄4 0.02), POD 2 JP amylase level (odds ratio1⁄4 1.000155, P1⁄4 0.002), and pancreatic duct size (odds ratio1⁄4 2.536, P1⁄4 0.025). Overall this model, which is based on beta coefficients from these predictive covariates, is statistically significant (likelihood ratio: chi‐ square 41.696; df 4; P< 0.001) and had a goodness of fit (Homer and Lemeshow Test: chi square 7.815; df 8; P1⁄4 0.452). Using a classification table we demonstrated that a probability cut‐off value of 36% offers an optimal balance of 72% sensitivity and 81.3% specificity. Lastly, to facilitate clinical use at our institution this probability equation was placed online and can be accessed with any device with a web browser. (http://georgetowncriteria.tumblr.com/). The following is the exact formula: ln(1 P/P)1⁄4 aþb0(age)þb1(BMI)þb2(JP Amy d2)þb3(duct size).

Transplantation for hepatocellular carcinoma in younger patients has an equivocal survival advantage as compared with resection.

Whereas some investigators in the surgical field advocate liver resection for the treatment of hepatocellular carcinoma (HCC), orthotopic liver transplantation (OLT) shows a significant survival advantage. Age was used to stratify survival in these groups to analyze beneficence. The Surveillance, Epidemiology, and End Results database (1998-2008) was used to identify 2355 patients who underwent either a segmentectomy, lobectomy, or extended lobectomy (resection) and 1873 patients who underwent an OLT for HCC. These patients were further stratified according to age and their relative survival was calculated. As shown in previous studies, the survival advantage is maintained in patients 40 to 59 and 60 to 79 years of age with HCC treated with OLT. However, within the 20 to 39-year-old age group, this advantage is insignificant. In this younger age group, resection patients (n = 157) have a 5-year survival rate of 50.9% whereas the OLT group (n = 40) has a 5-year survival rate of 58.9% (P = .42). Moreover, when assessing patient with lesions within the Milan criteria ages 20 to 39 years, resection shows a slight, although insignificant 4-year survival advantage: 78.2% for resection (n = 56) and 64.4% for OLT (n = 21; P = .283). This data may temper the enthusiasm for OLT in younger patients given the possibility of equivalent treatment with surgical resection.

Early Graft Dysfunction in Living Donor Liver Transplantation and the Small for Size Syndrome

Living donor liver transplantation (LDLT) has arisen as a viable means to reduce waitlist mortality. However, its widespread embrace by the liver transplant community has been met with frustration, centered on donor morbidity and small-for-size syndrome. Focusing on the latter entity, we describe the initial recognition of this early graft dysfunction, the theorized pathophysiology and solutions to remedy its emergence.

Paired Kidney Donor Exchanges and Antibody Reduction Therapy: Novel Methods to Ameliorate Disparate Access to Living Donor Kidney Transplantation in Ethnic Minorities

BACKGROUND Currently ethnic minority patients comprise 60% of patients listed for kidney transplantation in the US; however, they receive only 55% of deceased donor renal transplants and 25% of living donor renal transplants. Ethnic disparities in access to kidney transplantation result in increased morbidity and mortality for minority patients with end-stage renal disease. Because these patients remain dialysis dependent for longer durations, they are more prone to the development of HLA antibodies that further delay the possibility of receiving a successful kidney transplant. STUDY DESIGN Two to 4 pretransplant and post-transplant plasma exchanges and i.v. immunoglobulin were used to lower donor-specific antibody levels to less than 1:16 dilution; cell lytic therapy was used additionally in some cases. Match pairing by virtual cross-matching was performed to identify the maximal exchange benefit. Sixty candidates for renal transplantation were placed into 4 paired kidney exchanges and/or underwent antibody reduction therapy. RESULTS Sixty living donor renal transplants were performed by paired exchange pools and/or antibody reduction therapy in recipients whose original intended donors had ABO or HLA incompatibilities or both (24 desensitization and 36 paired kidney exchanges). Successful transplants were performed in 38 ethnic minorities, of which 33 were African American. Twenty-two recipients were white. Graft and patient survival was 100% at 6 months; graft function (mean serum creatinine 1.4 g/dL) and acute rejection rates (20%) have been comparable to traditional live donor kidney transplantation. CONCLUSIONS Paired kidney donor exchange pools with antibody reduction therapy can allow successful transplant in difficult to match recipients. This approach can address kidney transplant disparities.