Peter T. W. Kim

Impact of sirolimus on the recurrence of hepatocellular carcinoma after liver transplantation

Tumor recurrence after liver transplantation for hepatocellular carcinoma is associated with a poor prognosis. Because immunosuppression is a well‐known risk factor for tumor growth, it is surprising that its possible role in the outcome of liver transplantation has been poorly evaluated. We performed a case‐control review of prospectively collected data and compared 2 groups of patients according to the type of immunosuppression after liver transplantation for hepatocellular carcinoma at a single center. One hundred six patients received tacrolimus and mycophenolate mofetil, and 121 received sirolimus. Patients in the sirolimus group had significantly higher recurrence‐free survival rates than patients in the tacrolimus group (P = 0.0003). The sirolimus group also had significantly higher patient survival rates than the tacrolimus group at 1 year (94% versus 79%), 3 years (85% versus 66%), and 5 years (80% versus 59%; P = 0.001). Sirolimus was well tolerated, and the patients in this study did not have the increase in surgical complications noted by other investigators. Leukopenia was the most common side effect, but it typically resolved with dose reduction. Dyslipidemia and mouth ulcers were common but were easily controlled. In summary, the data suggest a beneficial effect of sirolimus immunosuppression on recurrence‐free survival, which translates into patient survival benefits. Liver Transpl 15:1834–1842, 2009.

Multidisciplinary management of ruptured hepatocellular carcinoma

Spontaneous rupture of hepatocellular carcinoma (HCC) is a dramatic presentation of the disease. Most published studies are from Asian centers, and North American experience is limited. This study was under-taken to review the experience of ruptured HCC at a North American multidisciplinary unit. Thirty pa-tients presenting with ruptured HCC at a tertiary care center from 1985 to 2004 were studied retrospectively and analyzed according to the demographics, clinical presentation, tumor characteristics, treatment, and outcome in four treatment groups: emergency resection, delayed resection (resection after angiographic embolization), transcatheter arterial embolization (TAE), and conservative management. Ten, 10, 7, and 3 patients underwent emergency resection, delayed resection, TAE, and conservative treat-ment, respectively. The mean age of all patients was 57 years, and the mean Child-Turcotte-Pugh score was 7 ± 2. Cirrhosis was present in 57% of the patients. Seventy percent of tumors were greater than 5 cm in diameter, and 68% of patients had multiple tumors. There was a trend toward higher 30-day mortality in the emergency resection group than in the delayed resection group. One-year survival was significantly bet-ter in the delayed resection group. In selected patients, the multidisciplinary approach of angiographic em-bolization and delayed resection affords better short-term survival than emergency resection.

Differentiation of Mouse Embryonic Stem Cells into Endoderm without Embryoid Body Formation

Pluripotent embryonic stem cells hold a great promise as an unlimited source of tissue for treatment of chronic diseases such as Type 1 diabetes. Herein, we describe a protocol using all-trans-retinoic acid, basic fibroblast growth factor and dibutyryl cAMP (DBcAMP) in the absence of embryoid body formation, for differentiation of murine embryonic stem cells into definitive endoderm that may serve as pancreatic precursors. The produced cells were analyzed by quantitative PCR, immunohistochemistry and static insulin release assay for markers of trilaminar embryo, and pancreas. Differentiated cells displayed increased Sox17 and Foxa2 expression consistent with definitive endoderm production. There was minimal production of Sox7, an extraembryonic endoderm marker, and Oct4, a marker of pluripotency. There was minimal mesoderm or neuroectoderm formation based on expression levels of the markers brachyury and Sox1, respectively. Various assays revealed that the cell clusters generated by this protocol express markers of the pancreatic lineage including insulin I, insulin II, C-peptide, PDX-1, carboxypeptidase E, pan-cytokeratin, amylase, glucagon, PAX6, Ngn3 and Nkx6.1. This protocol using all-trans-retinoic acid, DBcAMP, in the absence of embryoid bodies, generated cells that have features of definitive endoderm that may serve as pancreatic endocrine precursors.

Long-term follow-up of liver transplantation for Budd-Chiari syndrome with antithrombotic therapy based on the etiology.

Background. Because myeloproliferative disorders (MPDs) are a frequent cause of Budd-Chiari syndrome (BCS), treatment directed toward altering platelet production and function may be more rational and effective than anticoagulation after liver transplantation. Methods. We reviewed data on 25 patients who received liver transplantation for BCS at our institution from 1987 to 2007. Posttransplant antithrombotic treatment was based on the cause of BCS: 17 patients with MPDs received hydroxyurea/aspirin; 5 received warfarin; and 3 (2 whose hypercoagulable disorder was corrected and 1 with sarcoidosis) received no therapy. Results. Both graft survival (88% at 5 years) and patient survival (92% at 5 years) were superior in the BCS group compared with the 2609 patients who received liver transplants for other indications. Vascular complications included three instances of hepatic artery stenosis (NS compared with non-BCS liver recipients), one of portal vein thrombosis (nonsignificant [NS]), and one of portal vein stenosis (NS). All 25 patients underwent multiple liver biopsies with no bleeding complications. Conclusions. Using hydroxyurea and aspirin to treat patients with BCS caused by an MPD seems to be safe and effective and avoids the risks of anticoagulation with warfarin.

Prevention and treatment of liver allograft antibody-mediated rejection and the role of the 'two-hit hypothesis'.

Purpose of reviewThe review outlines the diagnosis, prevention strategies, and possible treatment options for acute and chronic antibody-mediated rejection (AMR). Recent findingsAlthough rare, severe acute AMR (aAMR) usually occurs in patients with high mean fluorescence intensity despite serial dilutions or high-titer preformed class I donor-specific alloantibodies (DSA). The diagnosis is suspected when allograft dysfunction occurs with DSA, diffuse C4d staining, and a microvascular injury, and may be aided by the aAMR score. However, the incidence of and treatment approach to combined T-cell-mediated rejection (TCMR) with DSA present and some but not all features of AMR is yet to be determined. Chronic liver allograft AMR is characterized by low-grade chronic inflammation and progressive fibrosis with DSA, the chronic AMR (cAMR) score may facilitate diagnosis. The ‘two-hit’ hypothesis, whereby a coexistent insult upregulates human leukocyte antigen class II target antigens on the microvascular endothelium, may explain why suboptimal donors with lower sensitization levels might suffer from acute AMR and those with chronic complications (e.g., recurrent original disease) might be more susceptible to chronic AMR. Although treatment algorithms are needed, prevention is preferable and at a minimum includes transfusion minimization, and medication adherence. SummarySevere acute AMR is rare but diagnosable, and there is need to determine the incidence of and optimal therapy for less severe combined AMR and TCMR. Chronic AMR is likely more common and of significant relevance to long-term allograft survival improvement. The two-hit hypothesis may help to explain the rarity of both findings and shed insight onto future prevention and treatment strategies.

Ophthalmic complications of otitis media in children

PURPOSE To evaluate the outcome of ophthalmic complications in children with otitis media. METHODS The records of children with ophthalmic complications arising from otitis media who presented to the British Columbia Childrens Hospital between August 2006 and March 2008 were reviewed retrospectively. RESULTS Of 1,400 patients presenting to the emergency department for otitis media during the study period, 7 with ophthalmic complications were identified (age range, 1-11 years). All patients had abducens nerve palsy on presentation. Other notable ophthalmic complications included papilledema, Horner syndrome, and proptosis. Extracranial and intracranial complications included mastoiditis, petrositis, parapharyngeal abscess, hydrocephalus, epidural abscess, and cerebral venous thrombosis, including cavernous sinus thrombosis in 2. Of the 7 patients, 6 were treated with surgery, including myringotomy and tube placement (6 patients) and mastoidectomy (3 patients). All patients were initially anticoagulated and received intravenous antibiotics. Satisfactory final visual outcomes and stereopsis ranging from 40 to 100 seconds were achieved in all patients. CONCLUSIONS Ophthalmic complications of otitis media in children are likely to include abducens palsy. All patients in our series required anticoagulation and intravenous antibiotics. Most required otolaryngologic surgery, but none required strabismus surgery, and all patients had satisfactory visual and ocular motility outcomes.

Differentiation of Definitive Endoderm from Mouse Embryonic Stem Cells

Efficient production of definitive endoderm from embryonic stem (ES) cells opens doors to the possibilities of differentiation of endoderm-derived tissues such as the intestines, pancreas, and liver that could address the needs of people with chronic diseases involving these organs. The lessons learned from developmental biology have contributed significantly to in vitro differentiation of definitive endoderm. Gastrulation, a process that results in the production of all three embryonic germ cell layers, definitive endoderm, mesoderm, and ectoderm, is an important step in embryonic development. Gastrulation occurs as a result of the events that are orchestrated by the signaling pathways involving Nodal, FGF, Wnt, and BMP. Understanding these signaling pathways has led to the introduction of key ingredients such as Activin A, FGF, Wnt, and BMP to the differentiation protocols that have been able to produce definitive endoderm from ES cells. Efficient production of definitive endoderm needs to meet the specific criteria that include (a) increase in the production of markers of definitive endoderm such as Sox 17, FOXA2, GSC, and Mixl1; (b) decrease in the production of markers of primitive/visceral/parietal endoderm, Sox 7 and OCT4; and (c) decrease in the mesoderm markers (Brachyury, MEOX) and ectoderm markers (Sox1 and ZIC1).

Tumor biology and pre-transplant locoregional treatments determine outcomes in patients with T3 hepatocellular carcinoma undergoing liver transplantation

Liver transplantation is the optimal treatment for patients with hepatocellular carcinoma (HCC) and cirrhosis. This study was conducted to determine the impact of pre‐transplant locoregional therapy (LRT) on HCC and our institutions experience with expansion to United Network of Organ Sharing Region 4 T3 (R4T3) criteria. Two hundred and twenty‐five patients with HCC (176 meeting Milan and 49 meeting R4T3 criteria) underwent liver transplantation from 2002 to 2008. Compared with the Milan criteria, HCCs in R4T3 criteria displayed less favorable biological features such as higher median alpha‐fetoprotein level (21.9 vs. 8.5 ng/mL, p = 0.01), larger tumor size, larger tumor number, and higher incidence of microvascular invasion (22% vs. 5%, p = 0.002). As a result, patients meeting Milan criteria had better five‐yr survival (79% vs. 69%, p = 0.03) and a trend toward lower HCC recurrence rates (5% vs. 13%, p = 0.05). Pre‐transplant LRT did not affect post‐transplant outcomes in patients meeting Milan criteria but did result in lower three‐yr HCC recurrence (7% vs. 75%, p < 0.001) and better three‐yr survival (p = 0.02) in patients meeting R4T3 criteria. Tumor biology and pre‐transplant LRT are important factors that determine the post‐transplant outcomes in patients with HCC who meet R4T3 criteria.

Indications for combined liver and kidney transplantation: propositions after a 23‐yr experience

Ruiz R, Jennings LW, Kim P, Tomiyama K, Chinnakotla S, Fischbach BV, Goldstein RM, Levy MF, McKenna GJ, Melton LB, Onaca N, Randall HB, Sanchez EQ, Susskind BM, Klintmalm GB. Indications for combined liver and kidney transplantation: propositions after a 23‐yr experience. 
Clin Transplant 2010: 24: 807–811.

Cataract surgery in the first year of life: aphakic glaucoma and visual outcomes.

OBJECTIVE To report the incidence of aphakic glaucoma following lensectomy in infants in their first year of life and examine the impact of this diagnosis on visual outcome. DESIGN Retrospective cohort study. PARTICIPANTS All patients who had lensectomy for congenital cataract during the first year of life at British Columbia Childrens Hospital between 1995 and 2006. METHODS Retrospective review of medical records. RESULTS Seventy-five eyes of 46 patients (29 bilateral, 17 unilateral) were included. The mean age at lensectomy was 93 days (range, 2-364 days) with a mean follow-up of 77.5 months (range, 36-166 months). Patients with bilateral cataracts had a better visual outcome than those with unilateral cataracts (p < 0.032). Of the patients with measurable visual acuity (VA), 34 of 45 eyes (75.6%) with bilateral cataracts and only 3 of 16 eyes (18.8%) with unilateral cataract achieved a VA of 20/40 or better. Eighteen of 75 eyes (24%) developed aphakic glaucoma at a mean of 30 months following lensectomy. Nine patients (50%) achieved final vision of 20/40 or better. The development of aphakic glaucoma was not associated with worse visual outcomes (p < 0.315). The mean intraocular pressure (IOP) at diagnosis was 28.6±5.9 mm Hg and mean final IOP was 14.1 ± 3.0 mm Hg, a significant reduction (p < 0.0001). Fifteen of 18 eyes with aphakic glaucoma (83.3%) required surgical intervention to achieve IOP control. CONCLUSIONS Children with aphakic glaucoma may have good visual outcomes if it is recognized early and managed appropriately. A significant proportion of patients required surgical intervention to control IOP.