External validation of Cardiac disease, Hypertension, and Logarithmic Left anterior descending coronary artery radiation dose (CHyLL) for predicting major adverse cardiac events after lung cancer radiotherapy.

Background and purpose: Major adverse cardiac events(MACE) are prevalent in patients with locally advanced-non-small cell lung cancer(LA-NSCLC) following radiotherapy(RT). The CHyLL model, incorporating coronary heart disease(CHD),Hypertension(HTN),Logarithmic LADV15 was developed and internally-validated to predict MACE among LA-NSCLC patients. We sought to externally validate CHyLL to predict MACE in an independent LA-NSCLC cohort. Patients and methods: Patients with LA-NSCLC treated with RT were included. CHyLL score was calculated:5.51CHD + 1.28HTN + 1.48ln(LADV15 + 1)-1.36CHD*ln(LADV15 + 1). CHyLL performance in predicting MACE was assessed and compared to mean heart dose(MHD) using Cox-proportional hazard(PH) analyses and Harrel's concordance(C)-indices. MACE and overall survival(OS) among low-vs high-risk groups(CHyLL < 5 vs ≥ 5) were compared. Results: In the external validation cohort(N = 102), the median age was 71 years and 55% were females. Most(n = 74,73%), had clinical Stage III disease and 35(34%) underwent surgery. CHyLL demonstrated good MACE prediction with C-index of 0.73(95% Confidence Interval(CI):0.58-0.89), while MHD did not (C-index = 0.46 (95% CI:0.30-0.62)). Per CHyLL, 32(31%) and 70(69%) patients were considered low-and high-risk for MACE, respectively. CHyLL consistently identified lower MACE rates in the low-vs high-risk group(log-rank p = 0.108):0 vs 8%(12 months),5 vs 16%(24 months),5 vs 16%(36 months),and 5 vs 19%(48 months) post-RT. In the pooled internal and external validation cohort(N = 303), MACE rates in low-vs high-risk groups were statistically significantly different(log-rank p = 0.01):1 vs 6%(12 months),3 vs 12%(24 months),6 vs 19%(36 months),and 6 vs 21%(48 months). Conclusions: CHyLL was externally validated and superior to MHD in predicting MACE. CHyLL has the potential to identify high-risk patients who may benefit from cardio-oncology optimization and to estimate personalized LADV15 constraints based on cardiac risk factors and acceptable MACE thresholds.

En Bloc Liver Kidney Transplantation Using Donor Splenic Artery as Inflow to the Kidney: Report of Two Cases.

The number of simultaneous liver-kidney transplants has been increasing. This surgery is associated with an increased risk of complications, longer duration of surgery and longer ischemia time for the renal allograft. Two patients listed for liver-kidney transplant at our center underwent en bloc combined liver-kidney transplantation using donor splenic artery as inflow. Patient 1 previously underwent cardiac catheterization that was complicated by a bleeding pseudoaneurysm of the right external iliac artery that required endovascular stenting of the external iliac artery and embolization of the inferior epigastric artery. Patient 2 was on vasopressor support and continuous renal replacement therapy at the time of transplant. In this paper, we described a novel technique of en bloc liver-kidney transplant with simultaneous reperfusion of both allografts using the donor splenic artery for renal inflow. This technique is useful for decreasing cold ischemia time and total operative time by simultaneous reperfusion of both allografts. It is a useful technical variant that can be used in patients with severe disease of the iliac arteries.

Many de novo donor-specific antibodies recognize ß2 -microglobulin-free, but not intact HLA heterodimers.

Solid-phase single antigen bead (SAB) assays are standard of care for detection and identification of donor-specific antibody (DSA) in patients who receive solid organ transplantation (SOT). While several studies have documented the reproducibility and sensitivity of SAB testing for DSA, there are little data available concerning its specificity. This study describes the identification of antibodies to ß(2) -microglobulin-free human leukocyte antigen (ß(2) -m-fHLA) heavy chains on SAB arrays and provides a reassessment of the clinical relevance of DSA testing by this platform. Post-transplant sera from 55 patients who were positive for de novo donor-specific antibodies on a SAB solid-phase immunoassay were tested under denaturing conditions in order to identify antibodies reactive with ß(2) -m-fHLA or native HLA (nHLA). Antibodies to ß(2) -m-fHLA were present in nearly half of patients being monitored in the post-transplant period. The frequency of antibodies to ß(2) -m-fHLA was similar among DSA and HLA antigens that were irrelevant to the transplant (non-DSA). Among the seven patients with clinical or pathologic antibody-mediated rejection (AMR), none had antibodies to ß(2) -m-fHLA exclusively; thus, the clinical relevance of ß(2) -m-fHLA is unclear. Our data suggests that SAB testing produces false positive reactions due to the presence of ß(2) -m-fHLA and these can lead to inappropriate assignment of unacceptable antigens during transplant listing and possibly inaccurate identification of DSA in the post-transplant period.

Colorectal and anal neoplasms following liver transplantation.

OBJECTIVE: Liver transplantation (LT) is the treatment of choice for end-stage liver disease. The required immunosuppression increases the risk for developing malignancies. Some viruses play a crucial role. Data on neoplasms of the colon, rectum and anus in LT are limited. METHOD: A retrospective evaluation of the incidence and clinical course of colorectal and anal malignancies and colonic polyps in a series of 467 consecutive LTs in 402 individuals between 1998 and 2001 was performed. Standard immunosuppression included Tacrolimus, Mycophenolic acid and steroids. RESULTS: During a median follow up of 5.2 years, three colon adenocarcinomas, one EBV associated cecal posttransplant lymphoproliferative tumour and two HPV associated anal tumours were identified. Pre-LT colonoscopy was performed in 161 patients (40%), and of 153 evaluable individuals, 53 (34.9%) had polyps. Colonoscopy was performed in 186 patients (46.3%) median 14.8 (range 0.2-77.8) months post-LT and 55 (29.3%) had polyps. Post-LT adenomatous polyps were detected in 47.3% of patients with pre-LT polyps vs 6.7% of patients without pre-LT polyps (P < 0.001). Patients with alcoholic liver disease had a significantly higher rate of adenoma formation (50.0% vs 11.1%, P < 0.001). No patient died from colorectal/anal malignancy. CONCLUSION: The incidence of metachronous and new polyp formation in our study is similar to people who are not immunocompromised, but subgroups are at increased risk. Viral-associated malignancies, including post-transplant lymphoproliferative disorders and anal cancer, are important entities in the LT population suggesting that complete screening of the colon, rectum and anus including pre-LT and post-LT colonoscopy should be utilized.

Clinicopathological review of 18 cases of liver allografts lost due to bile duct necrosis.

Clinical, radiographic, and pathological features of 18 patients with biliary necrosis in their explanted liver allografts were reviewed. Twelve patients were men and ages ranged from 27 to 72 years. Indications for initial liver transplant (LT) were viral hepatitis (n = 7), steatohepatitic cirrhosis (n = 3), cryptogenic cirrhosis (n = 3), secondary sclerosing cholangitis (n = 2), primary sclerosing cholangitis (n = 1), biliary atresia (n = 1), and nodular regenerative hyperplasia (n = 1). Donor age ranged from 16 to 75 years. Duct-to-duct biliary anastomoses were fashioned in 13 cases; warm and cold ischemia times were not significantly different from general LT population. Seventeen allograft biopsies after recirculation had no significant findings. Post-LT, clinical and radiographic evaluation indicated biliary strictures (n = 7), bile leak (n = 7), intrahepatic abscess (n = 1), and duodenal perforation (n = 1). Radiographic vascular studies suggested hepatic arterial thrombosis or stenosis in 11 cases. Biopsies prior to retransplantation were performed on 17 patients and showed acute rejection (n = 10), biliary outflow impairment (n = 4), normal histology (n = 2), and centrilobular necrosis (n = 1). Retransplantation was performed 14 to 334 days after initial LT. Pathological examination of explants revealed perihilar duct necrosis in all cases, with bacterial colonies (n = 10) and fungal organisms (n = 2). Arterial thrombi were seen in 10 cases, and two had prominent arteriosclerosis. Infarction and centrilobular necrosis were seen in 9 and 13 cases, respectively. Four explants showed features of biliary outflow impairment. Twelve patients were alive 6 to 18 months following retransplantation. We conclude that post-LT biliary necrosis is associated with ischemia, and such a complication is rarely evident in allograft biopsies. Biliary and vascular imaging studies are essential in evaluating patients for this complication.

Review of 31 cases of morphologic hepatitis in liver transplant patients not related to disease recurrence.

AIMS: We examined the clinical and pathologic features of morphologic hepatitis occurring after liver transplantation (LT) that is unrelated to disease recurrence. METHODS: Between February 1998 and December 2003, 704 primary LTs were performed at our center. Patients transplanted for diagnoses with low risk of disease recurrence were considered for our study (n = 282). Those with hepatitis C (HCV), hepatitis B (HBV), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) were excluded. Those with morphologic hepatitis comprised our case series and had medical records reviewed for clinical associations, duration, and outcome. RESULTS: Thirty-one cases were identified. They were transplanted for cryptogenic cirrhosis (n = 13), steatohepatitis (n = 12), alpha-1-antitrypsin deficiency (n = 3), tumor (n = 2), and acetaminophen toxicity (n = 1); 22 cases (67%) presented within the first 8 months post-LT (range, 0.5-72 months). Histological activity was mild in 19 and moderate in 12. Associated conditions were identified in 19 patients (57%) with 3 categories being identified: probable drug toxicity (n = 7), systemic infection (n = 4), and mechanical or hemodynamic abnormalities (n = 8). Of the 25 cases that underwent follow-up biopsy 2 to 32 months (mean, 15.5 months) after the index biopsy, 10 cases had resolution and 15 cases had persistence of the infiltrate. One patient had evidence of de novo HBV infection. CONCLUSIONS: Morphologic hepatitis occurred in 11% of patients at low risk for disease recurrence. Associated conditions could be grouped into three categories: drug toxicity, systemic infection, and mechanical or hemodynamic factors. Most cases did not appear to progress or improved over time, with no allograft loss occurring as a result of chronic hepatitis.

Liver transplantation for massive hepatic haemangiomatosis causing restrictive lung disease.

A 34-yr-old man with hepatic haemangiomatosis presented for orthotopic liver transplantation. His massively distended abdomen caused thoracic compression and severe restrictive lung disease. Respiratory failure was the principal indication for transplantation. Increased airway pressures, pulmonary hypertension, systemic hypotension caused by aorto-caval compression, and blood loss, complicated the intra-operative anaesthetic management. Weaning from mechanical ventilation was impaired by acute and chronic metabolic alkalosis, and diaphragmatic laxity.

Hepatic localization of endothelin-1 in patients with idiopathic portal hypertension and cirrhosis of the liver.

Endothelin-1 (ET-1) may mediate increased resistance to hepatic sinusoidal blood flow. We evaluated the hepatic distribution of ET-1 in patients with idiopathic portal hypertension (IPH), in which liver architecture may be normal, and in patients with cirrhosis, in which distortion of hepatic sinusoidal architecture is prominent. Immunohistochemistry and in situ hybridization were used to localize ET-1 in hepatic tissue of patients with IPH and cirrhosis. ET-1 was measured in plasma from a peripheral vein, the hepatic vein, and the portal vein of patients with cirrhosis of the liver and controls. On immunohistochemistry and in situ hybridization, ET-1 was localized to periportal hepatocytes and sinusoidal cells in patients with IPH and cirrhosis. Minimal positive staining for ET-1 was observed in control livers. Plasma ET-1 levels were significantly greater in patients with cirrhosis than in controls. In patients with cirrhosis, ET-1 was greater in the hepatic vein compared with the portal vein. However, the level of plasma ET-1 in patients with cirrhosis did not correlate with either the presence of ascites or portacaval pressure gradient. We conclude that in IPH, ET-1 is localized to sites in which it can modulate intrahepatic resistance. In late stages of cirrhosis, ET-1 may not modulate resistance. We speculate that vascular resistance in late stages of cirrhosis probably results from distortion of hepatic architecture.

Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma.

Orthotopic liver transplantation (OLT) alone for unresectable cholangiocarcinoma is often associated with early disease relapse and limited survival. Because of these discouraging results, most programs have abandoned OLT for cholangiocarcinoma. However, a small percentage of patients have achieved prolonged survival after OLT, suggesting that adjuvant approaches could perhaps improve the survival outcome. Based on these concepts, a protocol was developed at the Mayo Clinic using preoperative irradiation and chemotherapy for patients with cholangiocarcinoma. We report our initial results with this pilot experience. Patients with unresectable cholangiocarcinoma above the cystic duct without intrahepatic or extrahepatic metastases were eligible. Patients initially received external-beam irradiation plus bolus fluorouracil (5-FU), followed by brachytherapy with iridium and concomitant protracted venous infusion of 5-FU. 5-FU was then administered continuously through an ambulatory infusion pump until OLT. After irradiation, patients underwent an exploratory laparotomy to exclude metastatic disease. To date, 19 patients have been enrolled onto the study and have been treated with irradiation. Eight patients did not go on to OLT because of the presence of metastasis at the time of exploratory laparotomy (n = 6), subsequent development of malignant ascites (n = 1), or death from intrahepatic biliary sepsis (n = 1). Eleven patients completed the protocol with successful OLT. Except for 1 patient, all had early-stage disease (stages I and II) in the explanted liver. All patients who underwent OLT are alive, 3 patients are at risk at 12 months or less, and the remaining 8 patients have a median follow-up of 44 months (range, 17 to 83 months; 7 of 9 patients > 36 months). Only 1 patient developed tumor relapse. OLT in combination with preoperative irradiation and chemotherapy is associated with prolonged disease-free and overall survival in highly selected patients with early-stage cholangiocarcinoma.

A case of bilateral optic neuropathy in a patient on tacrolimus (FK506) therapy after liver transplantation.

PURPOSE: To report a case of bilateral optic neuropathy in a patient receiving tacrolimus (FK 506, Prograf; Fujisawa USA, Inc, Deerfield, Illinois) for immunosuppression after orthotropic liver transplantation. METHOD: Case report. In a 58-year-old man receiving tacrolimus after orthotropic liver transplantation, serial neuro-ophthalmologic examinations and laboratory studies were performed. RESULTS: The patient had episodic deterioration of vision in both eyes, with clinical features resembling ischemic optic neuropathies. Deterioration of vision occurred despite discontinuation of the tacrolimus. CONCLUSION: Tacrolimus and other immunosuppressive agents may be associated with optic nerve toxicity.

Success with intestinal failure: from adaptation to transplantation.

Intestinal failure can result from large resections of small intestine (short bowel syndrome) and from failure of normal intestinal motility. The medical management of short bowel syndrome centers around appropriate diet and use of specific medications including experimental trophic factors. Enteral tubes and prokinetic medications can be successfully used to treat patients with intestinal failure as a result of abnormal intestinal motility. Small bowel transplantation may be a treatment option in certain patients with intestinal failure. This article reviews the management of intestinal failure with a recent update on small bowel transplantation.

Late recurrence and rapid evolution of severe hepatopulmonary syndrome after liver transplantation.

Recurrence of hepatopulmonary syndrome (HPS) after orthotopic liver transplantation (OLT) in an adult has never been reported. We describe a 23-year-old woman who initially underwent OLT because of debilitating and severe HPS associated with nonalcoholic steatohepatitis (NASH). Although the clinical resolution of HPS was well documented day 117 post-OLT, the reappearance of NASH was documented by liver biopsy. Severe hypoxemia because of recurrent HPS rapidly evolved beginning approximately day 700 post-OLT. Retransplantation was attempted, but the patient died post-OLT of sepsis and/or multiorgan failure.

Preoperative hepatic artery chemoembolization followed by orthotopic liver transplantation for hepatocellular carcinoma.

In our experience, the primary obstacle precluding the widespread use of orthotopic liver transplantation (OLT) for definitive therapy of hepatocellular carcinoma (HCC), even for early-stage disease, is preventing tumor recurrence. Chemoembolization is an attractive strategy to minimize tumor progression before OLT because of its shown antitumor effect, ability to be repeated, and minimal systemic toxicity. Thus, this pilot study was undertaken to determine the tolerability and treatment outcomes of pretransplantation chemoembolization of HCC followed by OLT. Between 1992 and 1997, 27 patients with HCC who had cirrhosis, no extrahepatic metastasis, less than three tumor nodules of less than 5 cm each, and no evidence of vascular invasion on preoperative imaging studies were enrolled onto the protocol. Chemoembolization was performed using Ivalon particles with mitomycin, doxorubicin, and cisplatin. Twenty-four patients completed the protocol with chemoembolization and a liver transplant. The mean United Network of Organ Sharing waiting time was 167 days. Chemoembolization was well tolerated. On examination of the explanted liver, the majority of patients had a single lesion, mean tumor size was 3.66 cm (range, 1.5 to 6 cm), and the majority of patients had stage II disease. None of the transplant recipients has developed recurrent HCC (mean follow-up, 29.2 months; range, 9 to 55 months). The 1- and 2-year disease-free survival rates are 91% and 84%, respectively. In conclusion, chemoembolization followed by OLT is well tolerated and associated with excellent outcomes in selected patients with HCC.

No evidence of hepatitis G virus in fulminant hepatic failure in children.

BACKGROUND: The cause of fulminant hepatic failure in children remains unknown, but a viral origin has been suspected in most cases. The recently discovered blood-borne virus, hepatitis G, has been suggested as a possible causative agent. METHOD: Six consecutive children who underwent liver transplantation for fulminant hepatic failure were studied. The children were tested for hepatitis G virus antibodies and hepatitis G virus RNA by polymerase chain reaction after excluding other causes of fulminant hepatic failure. RESULTS: No evidence of hepatitis G virus infection was found in these patients. CONCLUSION: Hepatitis G virus is unlikely to be a common cause of fulminant hepatic failure in pediatric patients from the upper midwestern United States.

Recurrence of primary sclerosing cholangitis following liver transplantation.

Recurrence of primary sclerosing cholangitis (PSC) following liver transplantation has been suggested; however, it has not been fully defined because of numerous complicating factors and the lack of diagnostic criteria. In the present study, we investigated the recurrence of PSC by developing strict criteria and applying them to a large cohort of PSC patients who underwent liver transplantation. Between March 1985 and June 1996, 150 PSC patients underwent liver transplantation at the Mayo Clinic; mean follow up was 55 months. The incidence of nonanastomotic biliary strictures and hepatic histologic findings suggestive of PSC were compared between patients transplanted for PSC and a non-PSC transplant control group. Our definition of recurrent PSC was based on characteristic cholangiographic and histologic findings that occur in nontransplant PSC patients. By using strict criteria, 30 patients with other known causes of posttransplant nonanastomotic biliary strictures were excluded leaving 120 patients for analysis of recurrence of PSC. We found evidence of PSC recurrence after liver transplantation in 24 patients (20%). Of these, 22 out of 24 patients showed characteristic features of PSC on cholangiography and 11 out of 24 had compatible hepatic histologic abnormalities with a mean time to diagnosis of 360 and 1,350 days, respectively. Both cholangiographic and hepatic histologic findings suggestive of PSC recurrence were seen in nine patients. The higher incidence and later onset of nonanastomotic biliary strictures in patients with PSC compared with a non-PSC control group is supportive of the fact that PSC does recur following liver transplantation. We were unable to identify specific clinical risk factors for recurrent PSC, and the overall patient and graft survival in patients with recurrent PSC was similar to those without evidence of recurrence. Our observations provide convincing evidence that PSC frequently recurs in the hepatic allograft using strict inclusion and exclusion criteria.

Neoral compared to Sandimmune is associated with a decrease in histologic severity of rejection in patients undergoing primary liver transplantation.

BACKGROUND: In a randomized, controlled study we investigated the clinical efficacy of the microemulsion formulation of cyclosporine (Neoral) in comparison with Sandimmune (SIM) in the treatment of patients who underwent primary orthotopic liver transplantation (OLT). METHODS: In total, 33 patients were randomized in a double-blind fashion before undergoing primary OLT to receive either Neoral or SIM. All 33 patients initially received intravenous cyclosporine, but as soon as it was tolerated, the oral study drug was initiated (median time, 3.6 days) and 17 patients received Neoral and 16 SIM (for both drugs, 10 mg/kg/day). Both groups were comparable with regard to age, sex, etiology of chronic liver disease, and hepatic biochemical profile. Episodes of rejection were diagnosed histologically and characterized as mild, moderate, or severe using criteria from the National Institute of Diabetes and Digestive and Kidney Diseases. RESULTS: Patients were followed for 1 year. Four patients in each group were discontinued prematurely. The reason for discontinuation of cyclosporine was drug-related complications in two of the NEO patients and in three of the SIM group; the other three were non-drug-related. Rejection episodes occurred in 9 of 17 patients (52.90%) in the Neoral group and in 9 of 16 patients (56.3%) in the SIM group. The total number of rejection episodes in each group was 14. However, in evaluating the severity of rejection histologically, nine episodes of rejection were characterized as moderate/ severe in the SIM group compared with only three in the Neoral group (P=0.027). Five of the nine moderate/severe rejection episodes in the SIM group occurred within the first 2 weeks after transplant. In contrast, moderate/severe rejection did not occur in the Neoral group in this early period. Two patients in the SIM group and no patients in the Neoral group required treatment with OKT3 for steroid-resistant rejection. There were no differences in mean doses or trough levels when comparing the two study groups. The incidence of adverse effects was similar in the two groups. CONCLUSIONS: Neoral is a safe and efficacious drug in the treatment of primary OLT patients. Given comparable doses of cyclosporine in each group over 1 year, there was no significant difference in the total number of rejection episodes between study groups. However, patients treated with Neoral had a lower incidence of moderate/severe histologic rejection and were free of steroid-resistant rejection when compared with SIM-treated patients.

Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer?

BACKGROUND/AIMS: The risk of cholangiocarcinoma in primary sclerosing cholangitis is widely recognized to be 8-30%, whereas the risk of acquiring hepatocellular carcinoma in primary sclerosing cholangitis is unknown. As in other chronic liver diseases, the presence of hepatocellular carcinoma in a patient with primary sclerosing cholangitis undergoing evaluation for orthotopic liver transplantation would clearly impact on the candidacy, diagnostic evaluation, and alternative treatment options. Thus, the aim of our study was to determine the prevalence of hepatocellular carcinoma in patients undergoing liver transplantation for primary sclerosing cholangitis. METHODS: The records of the 520 patients undergoing orthotopic liver transplantation at our institution between 1985 and May 1995 were reviewed. Of the 134 patients with primary sclerosing cholangitis, three (2%) had hepatocellular carcinoma. In the 386 patients without primary sclerosing cholangitis undergoing orthotopic liver transplantation, 22 (6%) had hepatocellular carcinoma. RESULTS: Neither the duration of primary sclerosing cholangitis (range 7-23 years) nor the presence of ulcerative colitis (two of three patients) distinguished those patients with primary sclerosing cholangitis plus hepatocellular carcinoma from those with primary sclerosing cholangitis alone. None of the three patients with primary sclerosing cholangitis plus hepatocellular carcinoma had evidence for hepatitis B or C, alpha-1-antitrypsin deficiency, or hemochromatosis. None of the tumors was of the fibrolamellar variety of hepatocellular carcinoma. CONCLUSIONS: The prevalence of hepatocellular carcinoma in patients with primary sclerosing cholangitis undergoing orthotopic liver transplantation is 2%. These data suggest that patients with advanced cirrhotic-stage primary sclerosing cholangitis are at increased risk for developing hepatocellular carcinoma and should be screened for hepatocellular carcinoma as well as for cholangiocarcinoma prior to orthotopic liver transplantation.