Jason J. Schwartz

Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers.

BACKGROUND & AIMS Excellent single-center outcomes of neoadjuvant chemoradiation and liver transplantation for unresectable perihilar cholangiocarcinoma caused the United Network of Organ Sharing to offer a standardized model of end-stage liver disease (MELD) exception for this disease. We analyzed data from multiple centers to determine the effectiveness of this treatment and the appropriateness of the MELD exception. METHODS We collected and analyzed data from 12 large-volume transplant centers in the United States. These centers met the inclusion criteria of treating 3 or more patients with perihilar cholangiocarcinoma using neoadjuvant therapy, followed by liver transplantation, from 1993 to 2010 (n = 287 total patients). Center-specific protocols and medical charts were reviewed on-site. RESULTS The patients completed external radiation (99%), brachytherapy (75%), radiosensitizing therapy (98%), and/or maintenance chemotherapy (65%). Seventy-one patients dropped out before liver transplantation (rate, 11.5% in 3 months). Intent-to-treat survival rates were 68% and 53%, 2 and 5 years after therapy, respectively; post-transplant, recurrence-free survival rates were 78% and 65%, respectively. Patients outside the United Network of Organ Sharing criteria (those with tumor mass >3 cm, transperitoneal tumor biopsy, or metastatic disease) or with a prior malignancy had significantly shorter survival times (P < .001). There were no differences in outcomes among patients based on differences in surgical staging or brachytherapy. Although most patients came from 1 center (n = 193), the other 11 centers had similar survival times after therapy. CONCLUSIONS Patients with perihilar cholangiocarcinoma who were treated with neoadjuvant therapy followed up by liver transplantation at 12 US centers had a 65% rate of recurrence-free survival after 5 years, showing this therapy to be highly effective. An 11.5% drop-out rate after 3.5 months of therapy indicates the appropriateness of the MELD exception. Rigorous selection is important for the continued success of this treatment.

Liver transplantation in septuagenarians receiving model for end-stage liver disease exception points for hepatocellular carcinoma: the national experience.

Current liver allocation policy in the United States grants liver transplant candidates with stage T2 hepatocellular carcinoma (HCC) a priority Model for End‐Stage Liver Disease (MELD) score of 22, regardless of age. Because advanced age may portend an increase in all‐cause mortality after transplantation for any diagnosis, the aim of this study was to examine overall posttransplant survival in elderly patients with HCC versus younger cohorts. Based on Organ Procurement and Transplantation Network data, Kaplan‐Meier 5‐year survival rates were compared. Recipients undergoing primary liver transplantation were stratified into cohorts based on age (<70 or ≥70 years) and the receipt of MELD exception points for HCC. Log‐rank and Wilcoxon tests were used for statistical comparisons. In 2009, 143 transplants were performed for patients who were 70 years old or older. Forty‐two percent of these patients received a MELD exception for HCC. Regardless of the diagnosis, the overall survival rate was significantly attenuated for the septuagenarians versus the younger cohort. After 5 years of follow‐up, this disparity exceeded 10% to 15% depending on the populations being compared. The 1‐, 2‐, 3‐, 4‐, and 5‐year actuarial survival rates were 88.4%, 83.2%, 79.6%, 76.1%, and 72.7%, respectively, for the patients who were younger than 70 years and 81.1%, 73.8%, 67.1%, 61.9%, and 55.2%, respectively, for the patients who were 70 years old or older. Five‐year survival was negatively affected for patients with HCC who were younger than 70 years; this disparity was not observed for patients with HCC who were 70 years old or older. In conclusion, although patients who are 70 years old or older compose a small fraction of transplant recipients in the United States, patients in this group undergoing transplantation for HCC form an even smaller subset. Overall, transplantation in this age group yields outcomes inferior to those for younger cohorts. However, unlike patients who are less than 70 years old and receive MELD exception points, overall liver transplant survival is not affected by HCC at an advanced age. Liver Transpl 18:423–433, 2012.

Liver transplantation for cholangiocarcinoma.

Liver transplantation for cholangiocarcinoma (CCA) remains a controversial subject. More than 15 years after, a novel protocol combining neoadjuvant chemoradiation and orthotopic liver transplantation was first used in patients with unresectable hilar CCAs, these methods have yet to reach broad application. Results have confirmed that this approach leads to significantly lower recurrence rates and higher long-term survival rates than other existing treatment modalities. Despite this, protocols to treat patients with CCA are not widespread, and are available at only a handful of transplant programs. At these centers, treatment success may ultimately hinge on regional model for end-stage liver disease scores and waiting time for transplant. While acknowledging these factors as well as a severe organ shortage, it is important that the transplant community not overlook a potentially effective form of therapy for a previously untreatable disease.

ENCODE Tiling Array Analysis Identifies Differentially Expressed Annotated and Novel 5′ Capped RNAs in Hepatitis C Infected Liver

Microarray studies of chronic hepatitis C infection have provided valuable information regarding the host response to viral infection. However, recent studies of the human transcriptome indicate pervasive transcription in previously unannotated regions of the genome and that many RNA transcripts have short or lack 3′ poly(A) ends. We hypothesized that using ENCODE tiling arrays (1% of the genome) in combination with affinity purifying Pol II RNAs by their unique 5′ m7GpppN cap would identify previously undescribed annotated and unannotated genes that are differentially expressed in liver during hepatitis C virus (HCV) infection. Both 5′-capped and poly(A)+ populations of RNA were analyzed using ENCODE tiling arrays. Sixty-four annotated genes were significantly increased in HCV cirrhotic as compared to control liver; twenty-seven (42%) of these genes were identified only by analyzing 5′ capped RNA. Thirty-one annotated genes were significantly decreased; sixteen (50%) of these were identified only by analyzing 5′ capped RNA. Bioinformatic analysis showed that capped RNA produced more consistent results, provided a more extensive expression profile of intronic regions and identified upregulated Pol II transcriptionally active regions in unannotated areas of the genome in HCV cirrhotic liver. Two of these regions were verified by PCR and RACE analysis. qPCR analysis of liver biopsy specimens demonstrated that these unannotated transcripts, as well as IRF1, TRIM22 and MET, were also upregulated in hepatitis C with mild inflammation and no fibrosis. The analysis of 5′ capped RNA in combination with ENCODE tiling arrays provides additional gene expression information and identifies novel upregulated Pol II transcripts not previously described in HCV infected liver. This approach, particularly when combined with new RNA sequencing technologies, should also be useful in further defining Pol II transcripts differentially regulated in specific disease states and in studying RNAs regulated by changes in pre-mRNA splicing or 3′ polyadenylation status.

Cholangiocarcinoma in a 17-year-old boy with primary sclerosing cholangitis and inflammatory bowel disease.

JPGN Volume 52, N C holangiocarcinoma (CCA) is a known complication of primary sclerosing cholangitis (PSC) in adults. We describe a young patient who developed CCA 3 years after diagnosis of inflammatory bowel disease (IBD) and PSC. We describe the use of molecular marker techniques for diagnosis, and neoadjuvant cytoreductive therapy and orthotopic liver transplantation for therapy. The patient first presented at age 14 with 2 days of jaundice, fever, dyspnea, and chest and abdominal pain. He also complained of several months of nonbloody, watery diarrhea up to 9 times per day and fecal urgency both day and night, often waking him from sleep. This was unrelieved by daily loperamide and a prescribed course of empiric metronidazole. Medical and family histories were unremarkable. He was febrile, tachycardic, tachypneic, and mildly hypoxemic. Physical examination demonstrated jaundice with scleral icterus. He had a soft but tender abdomen with prominent splenomegaly. Breathing was labored with retractions, but the lungs were clear to auscultation. Initial laboratory studies revealed cholestasis, elevated transaminases, low albumin, leukocytosis, and a normal coagulation profile (Table 1). C-reactive protein and erythrocyte sedimentation rate were elevated and stool was positive for occult blood. Magnetic resonance cholangiopancreatography demonstrated an irregular and narrowed common hepatic duct, without biliary dilatation, cystic lesions, and intrahepatic mass. Liver biopsy revealed bile duct proliferation and periductular fibrosis consistent with PSC and without findings of overlap (Fig. 1). Anti-nuclear antibody and smooth muscle antibody were negative. Anti-nuclear cytoplasmic antibody was present in a 1:512 titer with peripheral staining pattern. Endoscopic retrograde cholangiopancreatography (ERCP) was not obtained at this time because clinical, radiographic, and histological findings were consistent with PSC and there was no biliary ductal dilatation on magnetic resonance imaging. Stool culture and Clostridium difficile cytotoxins were negative. Colonoscopy revealed regionally distributed inflammation and friable mucosa throughout the colon, with rectal sparing. A biopsy showed transmucosal chronic inflammatory cells, moderate crypt

Binding of anti-HLA class I antibody to endothelial cells produce an inflammatory cytokine secretory pattern.

Current methods are inadequate for the diagnosis of early chronic allograft rejection. The goal of this study was to determine whether ligation of anti‐HLA antibodies to endothelial cells is associated with a distinctive cytokine secretory pattern. Human iliac artery endothelial cells (HIAEC) cultured in vitro were incubated with w6/32, an anti‐HLA class I mAb. Culture supernatants collected daily for up to 4 days were tested for secretion of 13 cytokines using a multiplexed fluorescent microsphere immunoassay. Culture of HIAEC with medium containing mAb w6/32 supported the growth of HIAEC during the 4‐day study period. Levels of the pro‐inflammatory cytokines IL‐1β, IL‐6, IL‐8, and TNF‐α became significantly increased in supernatants of HIAEC incubated with the mAb w6/32. We conclude that ligation of anti‐HLA class I antibodies to HLA class I antigens in endothelial cells initiates an acute inflammatory process and detecting an inflammatory cytokine secretory pattern might be useful to diagnose sub‐clinical chronic allograft rejection. J. Clin. Lab. Anal. 23:157–160, 2009.

Decreased incidence of acute rejection in adolescent kidney transplant recipients using antithymocyte induction and triple immunosuppression

Background. Acute rejection is a frequent event in pediatric renal transplantation; it can diminish allograft function and affect long-term outcome. Recent data from the North American Pediatric Renal Transplant Cooperative Study indicates that the rate of acute rejection remains high despite current immunosuppressive regimens. Methods. In this retrospective series, we examined 37 pediatric renal transplant recipients who received induction doses of antithymocyte globulin combined with maintenance immunotherapy using tacrolimus, mycophenolate mofetil, and prednisone. The postoperative course was reviewed for initial and total hospital stay, number of rehospitalizations, evidence of posttransplant complications, graft fibrosis, and overall patient and graft survival. Results. Three episodes of acute rejection (8.1%) were recorded in the first year posttransplant. The median initial hospital stay for patients receiving a kidney transplant was 8 days. Patient and graft survival were 100% and 91.9% at 1 year, respectively. The incidence of viral infection (cytomegalovirus, BK virus, and Epstein-Barr virus) and posttransplant lymphoproliferative disease remained low. Urinary tract infection and fluid and electrolyte complications were the main causes of posttransplant hospitalization. Conclusions. We conclude that induction with antithymocyte globulin and maintenance immunosuppression with tacrolimus, mycophenolate, and prednisone should be considered a valuable tool in the management of children undergoing renal transplantation.

Plasmapheresis and Intravenous Immune Globulin Improve Neurologic Outcome of Central Pontine Myelinolysis Occurring Post Orthotopic Liver Transplant

OBJECTIVE To report 2 cases of central pontine myelinolysis (CPM) post liver transplantation in which treatment with plasmapheresis and intravenous immune globulin improved expected neurologic outcome. CASE SUMMARY Two patients who underwent orthotopic liver transplant developed CPM early in their postoperative course. Magnetic resonance imaging of the brain demonstrated severe demyelination of either the pons or the midbrain, respectively. Both patients developed significant neurologic abnormalities, including acute mental status changes, severe muscle weakness, spasticity, and/or prolonged paralysis. Pretransplant laboratory results indicated serum sodium levels fluctuating between 115 mEq/L and 152 mEq/L. Both patients received 6 days of plasmapheresis (PP) followed by 5 consecutive days of intravenous immune globulin (IVIG). Significant neurologic improvement was experienced at 2 and 4 weeks, respectively, after therapy was initiated. Complete resolution of neurologic symptoms was evident at 1 year follow-up. DISCUSSION Currently, specific guidelines or recommendations for the treatment of CPM are practically nonexistent. CPM remains a neurologic complication that is difficult to treat and may result in permanent significant neurologic sequelae. The etiology and pathogenesis of this disease are unclear, although aggressive osmolar correction, particularly in the setting of hyponatremia, is the main risk factor. While patients may eventually show some improvement with supportive care, progress is often protracted, and complete resolution of symptoms is exceedingly rare. The severity of the midbrain lesions juxtaposed against the rapidity of symptom resolution in these 2 patients alludes to a potential therapeutic benefit after initiation of therapy with PP and IVIG. CONCLUSIONS These cases suggest that prompt recognition of CPM and initiation of PP and IVIG may help modulate its progress and improve long-term neurologic outcome.

Perceived Benefits of a Transplant Surgery Experience to General Surgery Residency Training

OBJECTIVES The benefit of a solid-organ transplant experience during general surgical training has been questioned recently. In 2008, in response to an American Board of Surgery (ABS) directive, a survey was conducted by the Association of Program Directors in Surgery (APDS) in coordination with the American Society of Transplant Surgeons (ASTS) to determine the perceived value of a transplant surgery rotation to program directors and residents. With the aim of providing additional insight, we conducted a separate study, independent of the ABS and ASTS, to ascertain resident perceptions regarding the specific skill sets that they acquire during their transplant surgery rotations and their applicability to other surgical subspecialties. METHODS A preliminary, 51-item, web-based questionnaire was completed by 69.6% of residents in nationally accredited general surgery programs who accessed the survey. The results were examined using appropriate statistical methods to determine associations between answers. RESULTS Although only 16.6% of participants responded that they were considering a career in transplantation, 63.4% answered that the skill sets acquired during this rotation would assist them in their surgical careers regardless of their chosen specialty. Most (65.5%) respondents answered that the techniques learned were directly applicable to other specialties, such as vascular, urologic, trauma, and hepatobiliary surgery. Free response questions indicated that the most common criticisms of this rotation were the limited amount of operative participation, lack of teaching by attendings, and lifestyle limitations. CONCLUSIONS The results of this study indicate that surgery residents are conflicted regarding their transplant surgery experience but regard it as a beneficial addition to their training. Most respondents indicated also that these skills were transferable directly to other surgical specialties.

Adult post-transplant lymphoproliferative disease in the liver graft in patients with recurrent hepatitis C

Aim The aim of this study is to clarify the association between hepatitis C virus (HCV) infection and post-transplant lymphoproliferative disease (PTLD) in the liver allograft. Methods Of the 933 adults who underwent liver transplantation (LT) between 1990 and 2005, 10 patients developed PTLD. Seven of the 10 patients that were HCV(+) (group 1) were compared with three HCV-negative recipients (group 2). Results The mean time between LT and PTLD was 24.5 months. There were no differences between in Epstein–Barr virus antibody status or tumor lymphocyte subsets. In five of the seven HCV-positive recipients who developed PTLD, PTLD recurred preferentially in the liver allograft, whereas none of the three HCV-negative patients who developed PTLD did so in the liver (71.4 vs. 0%, respectively, P=0.038). In all five patients with graft PTLD, HCV recurred within 12 months followed by PTLD. There were significant differences between groups 1 and 2 in mean lymphocyte infiltrate scores (6.0±2.1 vs. 2.0±0.7, P=0.037), fibrosis stage (2.4±0.5 vs. 0.7±0.5, P=0.029), and frequency of lymphoid follicles in portal areas (33.6±14.8% vs. 1.1±2.3%, P=0.0002). Conclusion When PTLD occurs in patients with HCV recurrence after LT, it does so preferentially in the liver allograft.