Trevor W. Reichman

Paxillin is a target for somatic mutations in lung cancer: Implications for cell growth and invasion

Lung cancer is characterized by abnormal cell growth and invasion, and the actin cytoskeleton plays a major role in these processes. The focal adhesion protein paxillin is a target of a number of oncogenes involved in key signal transduction and important in cell motility and migration. In lung cancer tissues, we have found that paxillin was highly expressed (compared with normal lung), amplified (12.1%, 8 of 66) and correlated with increased MET and epidermal growth factor receptor (EGFR) gene copy numbers, or mutated (somatic mutation rate of 9.4%, 18 of 191). Paxillin mutations (19 of 21) were clustered between LD motifs 1 and 2 and the LIM domains. The most frequent point mutation (A127T) enhanced lung cancer cell growth, colony formation, focal adhesion formation, and colocalized with Bcl-2 in vitro. Gene silencing from RNA interference of mutant paxillin led to reduction of cell viability. A murine in vivo xenograft model of A127T paxillin showed an increase in tumor growth, cell proliferation, and invasion. These results establish an important role for paxillin in lung cancer.

Thrombolytic protocol minimizes ischemic‐type biliary complications in liver transplantation from donation after circulatory death donors

Liver transplantation (LT) with donation after circulatory death (DCD) donors has been associated with a high rate of ischemic‐type biliary strictures (ITBSs) and inferior graft survival. To investigate the impact of an intraoperative tissue plasminogen activator (tPA) on outcomes following DCD LT, we conducted a retrospective analysis of DCD LT at the Toronto General Hospital (TGH) and the Ochsner Medical Center (OMC). Between 2009 and 2013, 85 DCD LTs were performed with an intraoperative tPA injection (n = 30 at TGH, n = 55 at OMC), and they were compared with 33 DCD LTs without a tPA. Donor and recipient characteristics were similar in the 2 groups. There was no significant difference in the intraoperative packed red blood cell transfusion requirement (3.2 ± 3.4 versus 3.1 ± 2.3 U, P = 0.74). Overall, biliary strictures occurred less commonly in the tPA‐treated group (16.5% versus 33.3%, P = 0.07) with a much lower rate of diffuse intrahepatic strictures (3.5% versus 21.2%, P = 0.005). After 1 and 3 years, the tPA group versus the non‐tPA group had superior patient survival (97.6% versus 87.0% and 92.7% versus 79.7%, P = 0.016) and graft survival (96.4% versus 69.7% and 90.2% versus 63.6%, P < 0.001). In conclusion, a tPA injection into the hepatic artery during DCD LT reduces ITBSs and improves graft and patient survival without increasing the risk for bleeding. Liver Transpl 21:321–328, 2015.

Living donor versus deceased donor liver transplantation: a surgeon-matched comparison of recipient morbidity and outcomes.

Informed consent for living donor liver transplantation (LDLT) requires that patients are provided with accurate information on the relative benefits and risks of this procedure compared with deceased donor liver transplantation (DDLT). There is strong evidence to suggest that LDLT facilitates timely transplantation to patients; however, information on the relative morbidity and death risks after LDLT as compared with DDLT is limited. A matched cohort comparison was performed matching recipients for age, MELD, date of transplant, gender, primary diagnosis, and recipient surgeon. A total of 145 LDLT were matched with 145 DDLT. LDLT had a higher overall rate of perioperative surgical complications (P = 0.009). Most of this difference was caused by a higher rate of biliary complications. However, the complications that occurred in the DDLT group tended to be more serious (P = 0.037), and these complications were strongly associated with graft loss in multivariate analysis. The 3‐ and 5‐year graft and patient survivals were similar. In conclusion, DDLT and LDLT have different complication profiles, but comparable hospital stays and survival rates. In areas of deceased donor organ shortages, LDLT offers an excellent alternative to DDLT because it facilitates access to a liver transplant without compromising short‐ or medium‐term recipient outcomes.

Living donor hepatectomy: The importance of the residual liver volume

Living liver donation is a successful treatment for patients with end‐stage liver disease. Most adults are provided with a right lobe graft to ensure a generous recipient liver volume. Some centers are re‐exploring the use of smaller left lobe grafts to potentially reduce the donor risk. However, the evidence showing that the donor risk is lower with left lobe donation is inconsistent, and most previous studies have been limited by potential learning curve effects, small sample sizes, or poorly matched comparison groups. To address these deficiencies, we conducted a case‐control study. Forty‐five consecutive patients who underwent left hepatectomy (LH; n = 4) or left lateral segmentectomy (LLS; n = 41) were compared with matched controls who underwent right hepatectomy (RH) or extended right hepatectomy (ERH). The overall complication rates of the 3 groups were similar (31%‐37%). There were no grade 4 or 5 complications. There were more grade 3 complications for the RH patients (13.3%) and the ERH patients (15.6%) versus the LH/LLS patients (2.2%). The extent of the liver resection significantly correlated with the peak international normalized ratio (INR), the days to INR normalization, and the peak bilirubin level. A univariate analysis demonstrated that hepatectomy, the spared volume percentage, and the peak bilirubin level were strongly associated with grade 3 complications. A higher peak bilirubin level, which correlated with a lower residual liver volume, was associated with grade 3 complications in a multivariate analysis (P = 0.005). RH and grade 3 complications were associated with an increased length of stay (>7 days) in a multivariate analysis. In conclusion, this analysis demonstrates a significant correlation between the residual liver volume and liver dysfunction, serious adverse postoperative events, and longer hospital stays. Donor safety should be the first priority of all living liver donor programs. We propose that the surgical procedure removing the smallest amount of the liver required to provide adequate recipient graft function should become the standard of care for living liver donation. Liver Transpl, 2011.

Anonymous Living Liver Donation: Donor Profiles and Outcomes

There are no published series of the assessment process, profiles and outcomes of anonymous, directed or nondirected live liver donation. The outcomes of 29 consecutive potential anonymous liver donors at our center were assessed. We used our standard live liver assessment process, augmented with the following additional acceptance criteria: a logical rationale for donation, a history of social altruism, strong social supports and a willingness to maintain confidentiality of patient information. Seventeen potential donors were rejected and 12 donors were ultimately accepted (six male, six female). All donors were strongly motivated by a desire and sense of responsibility to help others. Four donations were directed toward recipients who undertook media appeals. The donor operations included five left lateral segmentectomies and seven right hepatectomies. The overall donor morbidity was 40% with one patient having a transient Clavien level 3 complication (a pneumothorax). All donors are currently well. None expressed regret about their decision to donate, and all volunteered the opinion that donation had improved their lives. The standard live liver donor assessment process plus our additional requirements appears to provide a robust assessment process for the selection of anonymous live liver donors. Acceptance of anonymous donors enlarges the donor liver pool.

Acute humoral rejection in an ABO compatible combined liver-kidney transplant--the kidney is not always protected.

Combined liver–kidney transplantation has become a common practice for the treatment of patients with concurrent end‐stage renal disease and end‐stage liver disease. Liver transplantation in the setting of multiorgan transplantation is thought to have a protective effect against humoral rejection even when a positive crossmatch is obtained prior to surgery. In most centers, a pre liver–kidney transplant crossmatch is rarely performed because of the known immunoprotective effect of the liver allograft. In this report, a case of acute humoral rejection in the kidney allograft after a combined liver–kidney transplant is described. Although humoral rejection was treated using plasmapheresis, intravenous immunoglobulin and rituximab, the kidney required 3 months to recover function and finally progressed to chronic allograft nephropathy. A heightened index of suspicion for acute humoral rejection of the renal allograft is necessary when performing combined liver–kidney transplants to highly sensitized patients due to previous organ transplants.

Liver transplantation in hepatitis B core–negative recipients using livers from hepatitis B core–positive donors: A 13‐year experience

The use of livers from hepatitis B surface antigen–negative (HBsAg−)/hepatitis B core antibody–positive (HBcAb+) donors in liver transplantation (LT) for HBsAg−/HBcAb− recipients is still controversial because of a lack of standard antiviral prophylaxis and long‐term follow‐up. We present our 13‐year experience with the use of HBcAb+ donor livers in HBcAb− recipients. Patients received prophylaxis with hepatitis B immunoglobulin at the time of LT and then lamivudine daily. De novo hepatitis B virus (HBV) was defined as positive HBV DNA detection. Between January 1999 and December 2010, 1013 adult LT procedures were performed at our center. Sixty‐four HBsAg−/HBcAb− patients (6.3%) received an HBsAg−/HBcAb+ liver. All donor sera were negative for HBcAb immunoglobulin M and HBV DNA. The mean follow‐up was 48.8 ± 40.1 months (range = 1.2‐148.8). Both the patient survival rates and the graft survival rates were 92.2% and 69.2% at 1 and 5 years, respectively. No graft losses or deaths were related to de novo HBV. Nine of the 64 patients (14.1%) developed de novo HBV. The mean time from LT to de novo HBV was 21.4 ± 26.1 months (range = 10.8‐92.8 months). De novo HBV was successfully treated with adefovir or tenofovir. In conclusion, HBcAb+ allografts can be safely used in HBcAb− recipients without increased mortality or graft loss. Lifelong prophylaxis, continuous surveillance, and compliance are imperative for success. Should a de novo infection occur, our experience suggests that a variety of treatments can be employed to salvage the graft and obtain serum HBV DNA clearance. Liver Transpl 19:611–618, 2013.

Weighing the risk: Obesity and outcomes following liver transplantation.

Obesity is on the rise worldwide. As a result, unprecedented rates of patients are presenting with end stage liver disease in the setting of non-alcoholic fatty liver disease (NAFLD) and are requiring liver transplantation. There are significant concerns that the risk factors associated with obesity and the metabolic syndrome might have a detrimental effect on the long term outcomes following liver transplantation. In general, short term patient and graft outcomes for both obese and morbidly obese patients are comparable with that of non-obese patients, however, several studies report an increase in peri-operative morbidity and increased length of stay. Continued studies documenting the long-term outcomes from liver transplantation are needed to further examine the risk of recurrent disease (NAFLD) and also further define the role risk factors such cardiovascular disease might play long term. Effective weight reduction in the post liver transplant setting may mitigate the risks associated with the metabolic syndrome long-term.

Surgical revision of biliary strictures following adult live donor liver transplantation: patient selection, morbidity, and outcomes.

Biliary strictures after live donor liver transplantation (LDLT) are frequent and difficult to manage. The outcomes of surgical correction of biliary anastomotic complications remain unclear. Clinical outcomes of patients requiring surgical revision of their biliary anastomosis following LDLT were analyzed. Of 296 consecutive right lobe LDLTs, approximately 21% of patients developed biliary strictures. Of these patients, twelve required surgical revision of a biliary anastomotic stricture. For patients who had operative repair, the average time from transplantation to stricture diagnosis was 7.6 months. Mean time to surgical correction was 8.2 months from the time of stricture diagnosis. Eight of 12 (67%) patients no longer require any intervention with a mean follow‐up of 43.7 months. Two of 12 patients require intermittent medical treatment for presumed cholangitis, but have not required biliary interventions. Two patients have required chronic PTC catheter drainage. The 30‐day postoperative morbidity was 58%, with four serious (Grade 3) complications occurring in three patients. Early stricture repair (<6 months from diagnosis of stricture) and younger donor grafts were associated with better surgical outcomes. Timely surgical correction of biliary strictures is successful and durable in appropriately selected patients. However, operative repair is associated with significant postoperative morbidity.

Safety and Outcomes in 100 Consecutive Donation After Circulatory Death Liver Transplants Using a Protocol That Includes Thrombolytic Therapy

Donation after circulatory death (DCD) liver transplantation (LT) reportedly yields inferior survival and increased complication rates compared with donation after brain death (DBD). We compare 100 consecutive DCD LT using a protocol that includes thrombolytic therapy (late DCD group) to an historical DCD group (early DCD group n = 38) and a cohort of DBD LT recipients (DBD group n = 435). Late DCD LT recipients had better 1‐ and 3‐year graft survival rates than early DCD LT recipients (92% vs. 76.3%, p = 0.03 and 91.4% vs. 73.7%, p = 0.01). Late DCD graft survival rates were comparable to those of the DBD group (92% vs. 93.3%, p = 0.24 and 91.4% vs. 88.2%, p = 0.62). Re‐transplantation occurred in 18.4% versus 1% for the early and late DCD groups, respectively (p = 0.001). Patient survival was similar in all three groups. Ischemic‐type biliary lesions (ITBL) occurred in 5%, 3%, and 0.2% for early DCD, late DCD, and DBD groups, respectively, but unlike in the early DCD group, in the late DCD group ITBL was endoscopically managed and resolved in each case. Using a protocol that includes a thrombolytic therapy, DCD LT yielded patient and graft survival rates comparable to DBD LT.