Follistatin Gene Therapy for Sporadic Inclusion Body Myositis Improves Functional Outcomes.

Sporadic inclusion body myositis, a variant of inflammatory myopathy, has features distinct from polymyositis/dermatomyositis. The disease affects men more than women, most commonly after age 50. Clinical features include weakness of the quadriceps, finger flexors, ankle dorsiflexors, and dysphagia. The distribution of weakness is similar to Becker muscular dystrophy, where we previously reported improvement following intramuscular injection of an isoform of follistatin (FS344) by AAV1. For this clinical trial, rAAV1.CMV.huFS344, 6 × 1011 vg/kg, was delivered to the quadriceps muscles of both legs of six sporadic inclusion body myositis subjects. The primary outcome for this trial was distance traveled for the 6-min walk test. The protocol included an exercise regimen for each participant. Performance, annualized to a median 1-year change, improved +56.0 m/year for treated subjects compared to a decline of -25.8 m/year (p = 0.01) in untreated subjects (n = 8), matched for age, gender, and baseline measures. Four of the six treated subjects showed increases ranging from 58-153 m, whereas two were minimally improved (5-23 m). Treatment effects included decreased fibrosis and improved regeneration. These findings show promise for follistatin gene therapy for mild to moderately affected, ambulatory sporadic inclusion body myositis patients. More advanced disease with discernible muscle loss poses challenges.

Modeling functional decline over time in sporadic inclusion body myositis.

INTRODUCTION: The ability to individualize recommendations or expectations of disease progression based on a patient's unique characteristics has merit for use in sporadic inclusion body myositis (sIBM). METHODS: Fifty-five subjects with sIBM completed a battery of strength and functional outcomes at 2 study visits. These were used to develop mathematical models of disease progression in patients with sIBM for use in clinical and research settings. RESULTS: The 6-minute walk test (6MWT) distance declined by an average of 27.5 meters (12%) per year. Significant factors that predict 6MWT were knee extension and plantarflexion strength and body weight, whereas the ability to stand from a chair was impacted by elbow extension strength. Stepping up on a curb was influenced by the patient's age at diagnosis and by knee extension. Statistical models to predict functional decline in sIBM were developed. CONCLUSION: Statistical models help explain the complex factors that influence decreased walking ability and other functional activities in sIBM. Muscle Nerve 55: 526-531, 2017.

Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis.

Traditional approaches to evaluating antitumor agents using human tumor xenograft models have generally used cohorts of 8 to 10 mice against a limited panel of tumor models. An alternative approach is to use fewer animals per tumor line, allowing a greater number of models that capture greater molecular/genetic heterogeneity of the cancer type. We retrospectively analyzed 67 agents evaluated by the Pediatric Preclinical Testing Program to determine whether a single mouse, chosen randomly from each group of a study, predicted the median response for groups of mice using 83 xenograft models. The individual tumor response from a randomly chosen mouse was compared with the group median response using established response criteria. A total of 2,134 comparisons were made. The single tumor response accurately predicted the group median response in 1,604 comparisons (75.16%). The mean tumor response correct prediction rate for 1,000 single mouse random samples was 78.09%. Models had a range for correct prediction (60%-87.5%). Allowing for misprediction of ± one response category, the overall mean correct single mouse prediction rate was 95.28%, and predicted overall objective response rates for group data in 66 of 67 drug studies. For molecularly targeted agents, occasional exceptional responder models were identified and the activity of that agent confirmed in additional models with the same genotype. Assuming that large treatment effects are targeted, this alternate experimental design has similar predictive value as traditional approaches, allowing for far greater numbers of models to be used that more fully encompass the heterogeneity of disease types. Cancer Res; 76(19); 5798-809. ©2016 AACR.

Early Conventional MRI for Prediction of Neurodevelopmental Impairment in Extremely-Low-Birth-Weight Infants.

BACKGROUND: Extremely-low-birth-weight (ELBW; ≤1,000 g) infants are at high risk for neurodevelopmental impairments. Conventional brain MRI at term-equivalent age is increasingly used for prediction of outcomes. However, optimal prediction models remain to be determined, especially for cognitive outcomes. OBJECTIVE: The aim was to evaluate the accuracy of a data-driven MRI scoring system to predict neurodevelopmental impairments. METHODS: 122 ELBW infants had a brain MRI performed at term-equivalent age. Conventional MRI findings were scored with a standardized algorithm and tested using a multivariable regression model to predict neurodevelopmental impairment, defined as one or more of the following at 18-24 months' corrected age: cerebral palsy, bilateral blindness, bilateral deafness requiring amplification, and/or cognitive/language delay. Results were compared with a commonly cited scoring system. RESULTS: In multivariable analyses, only moderate-to-severe gyral maturational delay was a significant predictor of overall neurodevelopmental impairment (OR: 12.6, 95% CI: 2.6, 62.0; p < 0.001). Moderate-to-severe gyral maturational delay also predicted cognitive delay, cognitive delay/death, and neurodevelopmental impairment/death. Diffuse cystic abnormality was a significant predictor of cerebral palsy (OR: 33.6, 95% CI: 4.9, 229.7; p < 0.001). These predictors exhibited high specificity (range: 94-99%) but low sensitivity (30-67%) for the above outcomes. White or gray matter scores, determined using a commonly cited scoring system, did not show significant association with neurodevelopmental impairment. CONCLUSIONS: In our cohort, conventional MRI at term-equivalent age exhibited high specificity in predicting neurodevelopmental outcomes. However, sensitivity was suboptimal, suggesting additional clinical factors and biomarkers are needed to enable accurate prognostication.

Patterns of Fever in Children After Primary Treatment for Kawasaki Disease.

BACKGROUND: We sought to determine if fever in the early postintravenous immunoglobulin (IVIG) time period (first 36 hours after IVIG completion) for Kawasaki disease, with or without additional infliximab, can predict IVIG resistance and coronary artery abnormalities (CAA). METHODS: Acute Kawasaki disease subjects enrolled in a clinical trial of infliximab plus IVIG (n = 96) versus placebo/IVIG (n = 94) had temperatures recorded every 6 hours after completion of IVIG infusion. Fever was defined as temperature >38.0°C; patients with persistent or recrudescent fever >36 hours after completion of IVIG were classified as IVIG resistant. Multivariable logistic regression by fever pattern was performed to predict outcomes (IVIG resistance and CAA). RESULTS: There was no difference in the time to defervescence between the infliximab/IVIG group (n = 96) versus placebo/IVIG group (n = 94). There was no fever after completion of IVIG in the majority of subjects [66% of those with no CAA (n = 139) and 76.5% of those with CAA, (n = 51)]. Although subjects with at least 1 fever 24-36 hours post-IVIG had a higher probability of IVIG resistance [odds ratio = 30.6 (95% confidence interval: 6.7-139.8); P < 0.0001], fever at 24-36 hours was not associated with higher likelihood of CAA. There were also 11% (n = 19) of IVIG responders who had fever at 24-36 hours post-IVIG. The majority of subjects with CAA (43 of 51, 84.3%) were identified by the initial echocardiogram, so the effect of fever on development of CAA could not be assessed. CONCLUSIONS: Fever in the first 36 hours after IVIG completion is not predictive of CAA. Our data support refraining from retreatment until 36 hours after completion of IVIG.

Reliability and validity of active-seated: An outcome in dystrophinopathy.

INTRODUCTION: Traditional upper extremity measures typically focus on distal abilities and do not quantify the unique progression of decline in dystrophinopathy. We designed ACTIVE-seated to meet this need. Our objective was to establish the tool's validity and reliability. METHODS: ACTIVE-seated uses the Microsoft Kinect gaming interface to quantify functional reaching ability while playing a custom-designed game. A skeletal tracking algorithm was used to determine the furthest arm excursion in all planes in 61 subjects with dystrophinopathy and 16 controls. RESULTS: Total reachable area was scaled based on arm length to standardize comparisons across subjects and accommodate growth. ACTIVE-seated discriminately ranked subjects from normal controls and by Brooke level (P < 0.001). Scores were highly correlated with parent reports of daily activities and mobility (P < 0.05). Test-retest reliability of ACTIVE-seated was excellent (ICC = 0.97, P < 0.0001). CONCLUSIONS: Initial evaluation of reliability and validity suggests that ACTIVE-seated shows promise as a clinical and research outcome for individuals with dystrophinopathy.

Impact of preoperative location on outcomes in congenital heart surgery.

BACKGROUND: Little is known about the impact of preoperative location on outcomes in infants undergoing cardiac surgery for congenital heart disease. This study was designed to evaluate the morbidity and mortality among infants who were cared for in a neonatal ICU (NICU) versus dedicated cardiovascular intensive care unit (CVICU) prior to cardiac surgery in a multi-institutional population. METHODS: Data were obtained from a multicenter, administrative, national dataset, Pediatric Health Information System (PHIS). Patients 0 to 45 days undergoing surgery for congenital heart disease (with or without cardiopulmonary bypass) at a PHIS-participating hospital (2004 to 2013) were included. Propensity score matching was performed to match the NICU and the CVICU patients with similar demographic and preoperative clinical characteristics. RESULTS: A total of 5,376 patients from 20 hospitals met inclusion criteria. By propensity score matching, 2,456 patients matched 1 to 1 between the NICU and the CVICU groups. Outcomes including mortality (NICU vs CVICU, 11.9% vs 8.8%, p < 0.001), preoperative and total hospital length of stay (LOS), and total length of mechanical ventilation were significantly greater among the NICU patients compared with the CVICU patients. There was no significant difference in mortality among the patients undergoing "low" complexity operations (NICU vs CVICU, 8.4% vs 6.7%, p = 0.22), and patients undergoing treatment at high volume hospitals (NICU vs CVICU, 9.6% vs 9.5%, p = 0.95). CONCLUSIONS: This study demonstrates that preoperative location might impact outcomes in children undergoing operation for congenital heart disease. It is possible that preoperative location may be surrogate for other factors that may bias the results. Further study is warranted.

Resection of isolated local and metastatic recurrence in periampullary adenocarcinoma.

BACKGROUND: The majority of patients with periampullary cancer develop local or metastatic recurrence despite successful negative margin resection. Unfortunately, there are no established therapeutic strategies for managing these patients. The literature on the surgical resection of recurrent disease is limited. METHODS: This is a retrospective study evaluating patients who underwent reoperative resection of recurrent periampullary cancer at a single institution between 1990 and 2011. Perioperative outcomes were compared with those of the original primary resections for patients with local recurrence. Kaplan-Meier curves were used to evaluate survival. RESULTS: Twenty-two patients underwent reoperative resection following the successful primary resection of periampullary cancers. Median survival from the time of reoperation was 28.1 months. A greater survival benefit was seen in patients undergoing reoperative resection with >15 months between the primary resection and recurrence (40.6 months versus 8.2 months; P < 0.05). Complication rates were lower after reoperative resection compared with the primary resection (20% versus 70%). Perioperative characteristics including operative time, estimated blood loss and hospital stay were similar in both the primary and reoperation procedures. CONCLUSIONS: Surgical resection of periampullary cancer recurrence is feasible, safe and may offer survival benefits in comparison with alternative treatment modalities. Reoperative resection should be considered, especially in patients in whom the time to recurrence is lengthy.

A validated model for predicting outcome after liver transplantation: implications on transplanting the extremely sick.

Given the organ shortage, there is a need to optimize outcome after liver transplantation (LT). We defined posttransplant hospital length of stay > 60 days (LOS > 60) as a surrogate of suboptimal outcome. In the first phase of the study, a 'Study cohort' (SC) of 643 patients was used to identify risk factors and construct a mathematical model to identify recipients with anticipated inferior results. In the second phase, a cohort of 417 patients was used for validation of the model ['Validation Cohort' (VC)]. In the SC, 65 patients (10.1%) had LOS > 60 days. One- and 3-year patient/graft survival rates were 81.9%/76.1% and 73.4%/67.4%, respectively. Patient and graft survival rates of those with LOS > 60 days were inferior (P < 0.0001), while transplant cost was greater [3.42 relative units (RU) vs. 1 RU, P < 0.0001]. In a multivariable analysis, pretransplant dialysis (P < 0.001), mechanical ventilation (P < 0.015), MELD (P < 0.003), and age (P < 0.009) were predictors of LOS > 60 days [ROC curve - 0.75 (95% CI 0.70, 0.81)]. In the VC, 53 patients (12.7%) were expected to have adverse outcome by the model. These patients had longer LOS (P < 0.0001), higher cost (<0.0001), and inferior patient and graft survival (P < 0.007).

Parental ranking of terms describing nonepileptic events.

Paroxysmal nonepileptic events of psychogenic etiology in children and adolescents are common. Patients and their parents are often confused by the terminology used to describe these events. This can lead to frustration and may result in the failure to obtain the necessary nonpharmacologic treatment. Various terms are used to describe such events, some of which might be considered offensive to some individuals. Surveys from 146 parents or guardians of patients identified from a general pediatric clinic, a general neurology clinic, and a pediatric epilepsy monitoring unit were completed with the aim of determining which words and phrases were least offensive. It was determined that nonepileptic events, functional seizures, and nonepileptic attack disorder were the least offensive labels; whereas "it is all in his or her head," hysterical seizures, and psychogenic seizures were the most offensive terms. This is the only study of its type in the pediatric population. Although each child and family requires individualized communication, we hope that this article will provide useful information to guide the practicing pediatric neurologist in informing families that their children are having events of nonepileptic etiology.

A randomized, double-blind trial of lisinopril and losartan for the treatment of cardiomyopathy in duchenne muscular dystrophy.

OBJECTIVES: This study sought to compare the effectiveness and safety of an angiotensin converting enzyme inhibitor (ACE-I) (lisinopril) vs. an angiotensin receptor blocker (ARB) (losartan) for the treatment of cardiomyopathy (CM) in boys with Duchenne muscular dystrophy (DMD). BACKGROUND: Development of CM is universal in boys with DMD. ACE-I and ARB have both been suggested as effective treatment options. ARBs have been associated with skeletal muscle regeneration in a mouse model of DMD. The question of which, if either, is more effective for CM treatment in DMD remains. The purpose of this multicenter double-blind prospective study was to compare efficacy and safety of lisinopril versus losartan in the treatment of newly diagnosed CM in boys with DMD. METHODS: Echocardiographic technician inter- and intraobserver variability were tested on 2 separate days on 2 different boys with DMD CM. Results were compared with paired t-testing. Twenty-two boys with newly diagnosed DMD CM (echocardiographic ejection fraction (EF) 10% EF drop. Three boys in the aCE-I group had 3 visits, due to study funding termination. Two were withdrawn because of low EF. All their data are included in the analysis for as long as they remained in the study. Mean EF's were similar at baseline (47.5%- ACE-I, 48.4%- ARB). After 1 year each group significantly improved to 54.6% and 55.2% respectively (p=.02). There was no difference between the 2 treatment groups at 1 year. CONCLUSIONS: Inter-observer and intra-observer reliability studies showed no differences between echocardiographers on serial examinations. EF improved equally in the two groups. There is no therapeutic difference in EF improvement between lisinopril and losartan over the one-year duration for treatment of boys with DMD-related CM. TRIAL REGISTRATION: ClinicalTrials.gov NCT01982695.

Is juvenile dermatomyositis a different disease in children up to three years of age at onset than in children above three years at onset? A retrospective review of 23 years of a single center's experience.

BACKGROUND: We tested the hypothesis that the course and outcome of juvenile dermatomyositis (JDM) in children seen at one center with the JDM disease onset at or below three years of age is different from that in the children with disease onset at greater than three years of age. METHODS: Institutional Review Board approval was obtained to retrospectively review the charts of 78 patients from age 0-18 years with JDM seen in the pediatric rheumatology clinic at Nationwide Children's Hospital in Columbus, Ohio over the past 23 years from January 1988. The diagnosis was made by the treating pediatric rheumatologist. Not all the patients met the Bohan and Peter criteria, as muscle biopsy and EMG were not always performed and we utilized a modified JDM criteria. The data regarding disease course and outcome were collected as of the last clinic follow-up or to July 1, 2010. We used the Wilcoxon Two-Sample test to compare numerical variables between two age groups, and used logistic regression to compare categorical variables between two age groups in SAS 9.1.3. Minitab-16 was used to calculate various mean, median, modes, standard deviations and range. For survival analysis, we used Kaplan-Meier method with log-rank test. RESULTS: The mean age of onset in the two groups at Nationwide Children's Hospital was 27 months and 91 months. The mean times between onset of symptoms to diagnosis in the younger and older age groups was 5.6 months and 4.5 months, respectively, not a statistically significant difference. The younger onset group had more females (p=0.05) and their disease onset occurred less frequently during the typical winter-spring seasons (p=0.031). The younger onset group was more likely to have a preceding fever (p=0.029) and family history of autoimmune diseases (p=0.012). The younger onset group was less likely to have heliotrope rash (p=0.04), Gottron's sign (p=0.049), capillary loop abnormalities (p=0.010), or elevations in creatine kinase (CK, p=0.022), aspartate aminotransferase (AST, p=0.021) or aldolase (p=0.035). The younger onset group was treated less often with pulse methylprednisolone at diagnosis (p=0.043) and less often with hydroxychloroquine (p=0.035). There were no differences between the two groups regarding initial oral steroid dose (p=0.8017), number of patients who received methotrexate at diagnosis (p=0.709), and the number who ever received other immunosuppressants (p=0.323). The mean and maximum duration (mean duration 24.3 months vs. 35.2 months, maximum duration 51 vs. 124 months in younger and older onset group respectively) of methotrexate therapy, and the mean and maximum duration of oral steroid therapy (Mean duration 16.8 months vs. 33.3 months, maximum duration 50 vs. 151 months in younger and older onset group respectively), was shorter in the younger group. The younger onset patients were less likely to have active disease at 5 years (9% vs. 35.7%, p=0.015) and 10 years post-diagnosis (9% vs. 45.1%, p=0.011, Table 7). The younger patients were less likely to have osteonecrosis (p=0.023). Two disease-related deaths occurred in the younger group, none in the older group. The results of the survival analysis showed that the difference between the age groups was statistically significant (p < 0.012). The sex and race were not significant (p> 0.26 and p>0.95, respectively). CONCLUSIONS: There were significant differences between JDM patients with disease onset at or below age three years at our center, compared to their older counterparts. Younger patients in our cohort had fewer typical findings at diagnosis and a milder disease course without needing as long a duration of corticosteroids and immunosuppression. Patients with a younger onset had a higher mortality rate but mortalities were unusual and numbers small. The younger group had a similar complication rate compared to the older onset patients, except for osteonecrosis which was higher in the older onset group. These findings differ from the previous reports that a younger age of onset in JDM is often associated with a more severe disease, as results at our center suggest that children with younger onset JDM appear to be atypical but may do well compared to the older JDM patients.

Posttraumatic seizures in children with severe traumatic brain injury.

PURPOSE: Traumatic brain injury (TBI) remains a leading cause of childhood death and disability worldwide. Seizures are a common complication of TBI and they are particularly common in pediatric populations. The proper management of children sustaining severe TBI is still controversial. Our study aims to share our experience contributing to build evidence for better care. METHODS: Retrospective chart review was performed on individuals ages 0 to <18 who presented to a level 1 trauma center during a 10-year period with the diagnosis of severe TBI. Data analyzed included patient's demographics, event information, clinical and radiological presentation, management, and midterm follow-up. Presence of seizures was tracked through EEG monitoring, staff witnessing, or guardian referral. RESULTS: The incidence of early posttraumatic seizures (EPTS) observed in our population (19 %) exceeds those previously reported. Such findings likely reflect the importance of close monitoring including EEG. An association between the presence of EPTS and the development of late posttraumatic seizures (LPTS) was evidenced (p=0.001; 95 % CI 2.2, 16.5), while this association should not be assumed as a measure of causality, it should be considered for the management of patients presenting EPTS. Non-accidental trauma and young age were identified as independent predictors for the development of seizures. CONCLUSIONS: Seizures are a common complication of severe TBI among children aged 0-3 years. Given the detrimental effects that seizures produce on the injured brain, close observation and appropriate monitoring with EEG are essential for the management of children sustaining severe TBI.

Outcomes of renal transplantation in recipients with peak panel reactive antibody >30% under tacrolimus-based immunosuppression.

BACKGROUND: Renal transplant recipients with high panel reactive antibodies (PRA) have worse outcomes than those with lower PRA. High PRA re-transplant recipients are thought to have worse outcomes than high PRA first transplant recipients. In this study, we examined outcomes of renal transplantation recipients with a peak PRA >30% and compared the outcomes of first and re-transplanted recipients. MATERIAL/METHODS: Survival outcomes between recipients of first transplants (n=68) and re-transplants (n=155) operated between June 1990 and August 2000 were compared. Sub-group analysis was done based on patient's gender, race and first/re-transplant. All patients received tacrolimus-based immunosuppression. RESULTS: No difference in graft survival was noted between first and re-transplanted patients. Ten-year patient survival was better in the re-transplanted group (p<0.004). Factors affecting patient survival on univariate analysis were age >55 years (p=0.015), deceased donor transplant (p=0.009), first transplant patient (p=0.004) and diabetes mellitus (DM) as the cause of End Stage Renal Disease (ESRD) (p=0.005). On multivariable analysis, factors affecting patient survival were number of the transplant (re-transplant versus first transplant, Relative risk [RR]=0.54, p=0.009) and cause of ESRD (DM versus no DM, RR=1.91, p=0.012).Diabetes as a cause for ESRD was the only factor affecting graft survival on univariate(p=0.015) and multivariable analysis (DM versus no DM, RR=1.63, p=0.017). CONCLUSIONS: High PRA recipients of first transplants had poorer patient survival than high PRA re-transplants. On multivariable analysis, diabetes etiology of ESRD and first transplantation were found to be independent risk factors for poorer patient survival.

Use of positron emission tomography in the evaluation of diffuse intrinsic brainstem gliomas in children.

BACKGROUND: Diffuse intrinsic brainstem gliomas (DIBSGs) in children remain difficult tumors to treat and have a very poor prognosis. Intensifying both chemotherapy and radiation programs have been attempted without success. Positron emission tomography (PET) has been used to differentiate benign from malignant tumors and may predict outcome. OBJECTIVES: To determine whether PET can characterize a specific metabolic pattern of DIBSGs and correlate this with patient survival. METHODS: We conducted a retrospective review of patients with DIBSGs and PET scans at diagnosis. Data for ¹8[F] fluorodeoxyglucose (FDG) and ¹¹C-methionine (CMET) PET scans were collected. Treatment and survival were reviewed. RESULTS: We identified 30 patients with DIBSGs, 25 of whom had FDG and/or CMET PET scans. Scans showed both focal and generalized metabolic activity, and the patterns showed no correlation with survival. Patients with both FDG and CMET positive scans had a mean survival of 380 days, whereas those negative for both isotopes had a mean survival of 446 days. CONCLUSIONS: There was no specific PET pattern identified in this DIBSG cohort but a trend toward improved survival was noted with absence of FDG and CMET metabolism. Metabolically active areas may suggest potential sites for biopsy. We believe that biopsy is essential for improving therapy for this patient population.

Kidney after nonrenal transplantation-the impact of alemtuzumab induction.

BACKGROUND: Calcineurin inhibitor nephrotoxicity in nonrenal allograft recipients can lead to end-stage renal disease and the need for kidney transplantation. We sought to evaluate the role of alemtuzumab induction in this population. PATIENTS AND METHODS: We evaluated 144 patients undergoing kidney transplantation after nonrenal transplantation between May 18, 1998, and October 8, 2007. Seventy-two patients transplanted between January 15, 2003, and October 8, 2007, received alemtuzumab induction and continued their pretransplant immunosuppression. Seventy-two patients transplanted between May 18, 1998, and July 21, 2007, did not receive alemtuzumab induction, but received additional steroids and maintenance immunosuppression. Donor and recipient demographics were comparable. RESULTS: Overall, 1- and 3-year patient survival and renal function were comparable between the two groups. One- and 3-year graft survival was 93.0% and 75.3% in the alemtuzumab group and 83.3% and 68.7% in the no alemtuzumab group, respectively (P=0.051). The incidence of acute rejection was lower in the alemtuzumab group, 15.3%, than in the no alemtuzumab group, 41.7% (P=0.0001). The incidence of delayed graft function was lower in the alemtuzumab group, 9.7%, than in the no alemtuzumab group, 25.0% (P=0.003). The incidence of viral complications was comparable. CONCLUSION: Alemtuzumab induction with simple resumption of baseline immunosuppression in patients undergoing kidney transplantation after nonrenal transplantation represents a reasonable immunosuppressive strategy.

Lymphoproliferative disorders and de novo malignancies in intestinal and multivisceral recipients: improved outcomes with new outlooks.

BACKGROUND: Early experience with intestinal and multivisceral transplantation was plagued with high risk of rejection and posttransplant lymphoproliferative disorders (PTLD). To improve outcome, innovative management and immunosuppressant strategies were sequentially evolved. METHODS: With initiation of the program in 1990, serial monitoring of Epstein-Barr-Viral load was introduced in 1994 with adoption of preemptive antiviral therapy. In 1995, cyclophosphamide or daclizumab induction was added to the tacrolimus-steroid-based multiple drug immunosuppressions. Such a conventional approach was replaced in 2001 with a novel immunosuppressive protocol consisting of recipient pretreatment with a single dose of rabbit antithymocyte globulin or alemtuzumab and posttransplant tacrolimus monotherapy. RESULTS: With a total of 395 consecutive primary recipients, de novo malignancy(s) developed in 61 (15%) patients, with PTLD in 52 (13%), and nonlymphoid cancer (NLC) in 13 (3.2%). Malignancy was donor driven in 3 (4.6%) recipients and associated with graft-versus-host disease in 7 (11.4%). Children were at a significantly higher risk (P<0.001) of PTLD, and adults were more vulnerable (P=0.01) to NLC. With multivariate analyses, type of immunosuppression, recipient age, splenectomy, and treatment of rejection were significant PTLD risk factors. CONCLUSIONS: Despite pretransplant lymphoid depletion, preemptive antiviral therapy and minimization of posttransplant immunosuppression significantly reduced PTLD morbidity (P=0.0001) and mortality (P=0.001) with no impact on NLC. Patient survival was also improved (P=0.0001) with 91% at 1 year and 75% at 5 years.

Pyridoxal-5'-phosphate deficiency after intestinal and multivisceral transplantation.

BACKGROUND: Successful intestinal transplantation is measured by the achievement of clinical nutritional autonomy (CNA). However, the ability of the graft to maintain normal micronutrient levels including vitamins has yet to be thoroughly evaluated. OBJECTIVE: After an initial clinical observation of isolated cases of pyridoxal-5'-phosphate (PLP) deficiency, this prospective study was designed to address the incidence of, risk factors for, and management of PLP deficiency in adult intestinal transplant recipients. DESIGN: Serum PLP and homocysteine concentrations were prospectively measured before and after transplantation at frequent intervals. RESULTS: PLP deficiency occurred in 10% of candidates and in 96% of recipients within a median onset of 30 d (range: 4-118 d) after transplantation. Of this group, 41% were receiving parenteral nutrition (PN), 41% were receiving enteral feeding, and the remaining 18% had already achieved CNA. The overall cumulative risk was 24% at 15 d, 59% at 30 d, 79% at 45 d, and 90% at 90 d; none of the risk factors, including homocysteine concentrations, were significant. Nonetheless, the development of PLP deficiency during PN therapy was associated with a significant (P < 0.001) delay in the achievement of CNA. Despite development of severe deficiency in most cases, none of the subjects experienced clinical manifestations of PLP deficiency because of prompt replacement therapy. CONCLUSIONS: Serial monitoring of serum PLP concentrations is recommended for PN-dependent patients with short-bowel syndrome before and after transplantation for early detection and prompt initiation of preemptive therapy. Long-term measurement at frequent intervals is also recommended, particularly for transplant recipients, to diagnose late deficiency despite achievement of CNA and to prevent toxicity from overdose.

Liver transplantation for hepatocellular carcinoma: extension of indications based on molecular markers.

BACKGROUND/AIMS: Liver transplantation usually cures hepatocellular carcinoma when the Milan selection criteria are applied, whereas there is substantial risk of posttransplant recurrence with tumors beyond these criteria. This study uses molecular data to identify a subgroup of patients who, despite having hepatocellular carcinoma beyond Milan criteria, have favorable outcomes. METHODS: Allelic imbalance of 18 microsatellites was analyzed in 70 consecutive patients (35 within Milan, 35 beyond Milan criteria) transplanted for hepatocellular carcinoma of whom 24 had recurrence and 46 survived at least 5 years recurrence-free. Fractional allelic imbalance (the fraction of significant microsatellites that demonstrated allelic imbalance) and relevant clinical/pathological variables were tested for correlation with time to recurrence. RESULTS: Allelic imbalance in 9/18 microsatellites correlated with recurrence. Fractional allelic imbalance > 0.27 and macrovascular invasion were independent predictors of recurrence in patients with tumors beyond Milan criteria; the probability of recurrence at 5 years was 85% with fractional allelic imbalance > or = 0.27 vs. 10% when < 0.27 (p=0.0002). An algorithm including Milan criteria and fractional allelic imbalance status is 89% accurate in predicting tumor recurrence after transplantation. CONCLUSION: Analysis of allelic imbalance of 9 microsatellites identifies a subgroup of patients who, despite having hepatocellular carcinoma beyond Milan criteria, have a low risk of posttransplant recurrence.

Fractional allelic imbalance could allow for the development of an equitable transplant selection policy for patients with hepatocellular carcinoma.

Liver transplantation (LT) in the presence of hepatocellular carcinoma (HCC) remains a controversial issue because the current staging systems are not sufficiently predictive of outcomes. Paraffin blocks from 183 patients that underwent LT in the presence of HCC were collected. Molecular analysis was carried out blindly on the native liver specimens in all cases with respect to recurrence outcomes. The fractional allelic imbalance (FAI) rate index was determined in each case and was used to compare the acquired mutational load between different tumors. The FAI was determined from the microdissected tissue site displaying the greatest amount of acquired allelic loss. FAI was found to be the strongest predictor of recurrence followed by vascular invasion and then by tumor number or hepatic lobar involvement. Based on these findings, 3 prognostic models were constructed for selection of candidates for LT in patients with concomitant HCC. Molecular markers of tumor progression are the strongest predictors of HCC recurrence currently available, surpassing all components of the tumor-node-metastasis classification system for staging of malignant tumors (TNM), including vascular invasion. Incorporation of these molecular markers of tumor progression could help resolve the ongoing conundrum of organ allocation for patients with HCC.