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Importance: Serum α-fetoprotein (AFP) is a biomarker for hepatocellular carcinomas (HCCs) associated with a more aggressive tumor phenotype and inferior outcomes after a liver transplant (LT). Data on the outcomes for patients with HCCs that do not produce AFP are limited., Objective: To compare characteristics and outcomes among LT recipients with radiographically apparent HCC lesions with AFP-producing tumors or with tumors that do not produce AFP (hereafter referred to as non-AFP-producing tumors), and to identify factors influencing recurrence in LT recipients with non-AFP-producing tumors., Design, Setting, and Participants: Retrospective analysis at a university transplant center of 665 adults with HCC who underwent an LT during the period from 1989 to 2013. Of the 665 LT recipients, 457 (68.7%) had AFP-producing tumors, and 208 (31.3%) had non-AFP-producing tumors (the maximum AFP level before an LT was ≤10 ng/mL). Dates of study analysis were from August 2015 to June 2016., Intervention: Liver transplant., Main Outcomes and Measures: Recurrence-free survival and recurrence rates., Results: Patients with non-AFP-producing tumors had radiographic tumor characteristics similar to those of patients with AFP-producing tumors, but, pathologically, they had fewer lesions (25% vs 35% with >2 lesions; P = .03), smaller cumulative tumor diameters (4.2 vs 5.0 cm; P = .02), fewer microvascular (17% vs 22%) and macrovascular (2% vs 9%) invasions (P < .001), and fewer poorly differentiated tumors (15% vs 28%; P < .001). Patients with non-AFP-producing tumors also had significantly superior recurrence-free survival at 1, 3, and 5 years (88%, 74%, and 67% vs 76%, 59%, and 51%, respectively; P = .002) and lower 5-year recurrence rates (8.8% vs 22%; P < .001) than patients with AFP-producing tumors. When stratified by radiologic Milan criteria, 5-year survival was better, and recurrence lowest, among patients with non-AFP-producing tumors within the Milan criteria (71% survival and 6% recurrence), and survival was worse, and recurrence highest, for patients with AFP-producing tumors outside the Milan criteria (40% survival and 42% recurrence; P < .001). Significant predictors of recurrence among patients with non-AFP-producing tumors include radiologic (>2 tumors [HR, 4.98; 95% CI, 1.72-14.4; P = .003]; cumulative diameter [1.70 per log SD; 1.12-2.59; P < .001]; outside the Milan criteria [10.0; 3.7-33.3; P < .001) and pathologic factors (>2 tumors [4.39; 1.32-14.6; P = .02]; cumulative diameter [2.32 per log SD; 1.43-3.77; P = .001]; microvascular [3.07; 1.02-9.24; P = .05] and macrovascular invasion [8.75; 2.15-35.6; P = .002])., Conclusions and Relevance: Nearly one-third of patients with radiographically apparent HCC have non-AFP-producing tumors that have more favorable pathologic characteristics, lower posttransplant recurrence, and superior survival compared with patients with AFP-producing tumors. Posttransplant HCC recurrence for patients with non-AFP-producing tumors is predicted by important radiologic and pathologic factors, and is negligible for patients within the Milan criteria. Stratifying patients by AFP status in addition to radiological criteria may improve the selection process for and the prioritization of transplant candidates.

We report on whole-exome sequencing (WES) of 213 melanomas. Our analysis established NF1, encoding a negative regulator of RAS, as the third most frequently mutated gene in melanoma, after BRAF and NRAS. Inactivating NF1 mutations were present in 46% of melanomas expressing wild-type BRAF and RAS, occurred in older patients and showed a distinct pattern of co-mutation with other RASopathy genes, particularly RASA2. Functional studies showed that NF1 suppression led to increased RAS activation in most, but not all, melanoma cases. In addition, loss of NF1 did not predict sensitivity to MEK or ERK inhibitors. The rebound pathway, as seen by the induction of phosphorylated MEK, occurred in cells both sensitive and resistant to the studied drugs. We conclude that NF1 is a key tumor suppressor lost in melanomas, and that concurrent RASopathy gene mutations may enhance its role in melanomagenesis.

Historically, the OPTN liver allocation policies have favored candidates listed with MELD exception scores, and the use of exceptions has increased each year since the inception of the MELD era. The implementation of Share 35 and other recent changes in OPTN liver allocation policies have reduced the preference for MELD exception candidates to some extent, but the nature and degree of the impact appears to vary widely from one region to another. This report emphasizes the geographic inequities and regional variations in transplant practices, with a focus on liver transplant candidates with hepatocellular carcinoma exceptions, and highlights the need for strategies to promote equitable organ distribution across geographical regions and patient conditions., (Copyright© 2016 by the Terasaki Foundation Laboratory.)

As of September 19, 2014, 2441 cases of intestinal transplantation have been performed in 46 centers (2400 deceased, 41 living). Eight centers did more than 100 transplants. Annual case numbers peaked in 2007 (N = 198) and steadily decreased to 109 cases in 2013. Short gut syndrome (68%) and functional bowel problems (15%) are two major indications for intestinal transplantation. The 3 major types of transplants involving the intestine include: isolated intestine transplant (I); simultaneous intestine, liver, and pancreas transplant (I+L+P); and, combined intestine and liver (I+L) transplant. Graft survival has significantly improved in recent years, mainly due to improved first year graft survival. The 1-, 5-, and 10-year graft survivals were: 74%, 42%,and 26%, respectively (I); 70%, 50%, and 40%, respectively (I+L+P); and 61%, 46%, and 40%, respectively (I+L). The longest graft survivals for I, l+L+P, and l+L were 19 years, 16 years, and 23 years, respectively. Steroids, Thymoglobulin, and rituximab are 3 major induction agents used in recent years. Prograf, steroids, and Cellcept are 3 major maintenance agents. Induction recipients (68% of all patients) had a significantly lower acute rejection rate than nonrecipients before discharge (60% versus 75%, p < 0.001). Most of the patients received 2 (53%) or 3 (25%) maintenance immunosuppressants. Acute rejection episodes were usually treated with one (60%) or two agents (27%). Steroids were most commonly used (50-60%). OKT3 has been replaced with antithymocyte globulin (since 1999) and rituximab (since 2006). During 1990-2000, 94% (N = 445) of patients received ABO identical intestinal transplants, while 6% (N = 29) received ABO compatible transplants. ABO identical transplant recipients had a significantly higher 5-year graft survival rate than ABO compatible recipients (39% versus 21%, p < 0.0001). In recent years (2001- 2012), more patients received ABO compatible (N = 188, 11%) than in the early decade (p < 0.01). 5-year graft survival rates of ABO compatible transplants were lower than those of ABO identical transplants. However, the difference did not reach statistical significance (46% versus 49%, p = 0.07). The effect of ABO compatibility on graft outcome was further confirmed by Cox Analysis. ABO incompatible transplants are still rarely performed (N = 4) in intestine. In conclusion, annual case numbers of intestinal transplants have been decreasing, regardless of improved graft survival. ABO compatible intestinal transplants previously had a significantly lower graft survival rate than ABO identical transplants. However, the graft survival difference became less significant in recent years, possibly due to, or at least partly due to the use of new immunosuppressive agents.

Intestinal transplantation is a viable treatment strategy for patients with irreversible intestinal failure for whom parenteral nutrition is no longer an option. Although improvements have been made in short-term post-transplant survival outcomes, long-term allograft loss, mainly to acute or chronic rejection, remains a major obstacle to successful transplantation. In all types of solid organ transplants, there is increasing evidence that antibodies directed against human leukocyte antigens, and in particular donor-specific antibodies (DSA), contribute to acute and chronic rejection as well as allograft loss. In this single-center review of intestinal transplant recipients, we report that the presence of pretransplant circulating DSA and the de novo induction of DSA posttransplant are both associated with increased risks of allograft loss. Although the cumulative incidence of acute rejection was not significantly affected by the presence of DSA, the power of this single-center study may be limited. Prospective, multicenter studies are needed to further elucidate the role of DSA in intestinal transplant recipients. In the published literature, there is a clear link between the presence of pre-formed DSA and early injury to the mucosal vasculature of the allograft. Two groups have reported an association between pretransplant DSA and the frequency of acute rejection episodes and subsequent graft loss. Similarly, studies investigating the effects of de novo DSA have demonstrated a relationship between the presence of post-transplant circulating antibodies and the occurrence of acute rejection and the risk of allograft failure. The use of a liver-containing graft appears to facilitate the clearance of pre-formed antibodies and prevents the de novo induction of post-transplant antibodies. The most recent report stated that the de novo induction of DSA is concurrently accompanied by signs or rejection, such that the detection of circulating antibodies may signify impending graft injury, and supports the potential utility of DSA as a non-invasive biomarker for rejection in intestinal transplantation.

Advances in immunosuppression (IS) agents and strategies have resulted in reduced rejection rates and improved survival outcomes after liver transplantation. The use of induction and maintenance IS agents is both associated with reductions in acute rejection (AR) risk within the first 6 to 12 months posttransplant and with superior failure-free survival. With the lowered incidence of allograft losses attributable to rejection, the long-term sequelae of IS have become the major therapeutic challenge. The long-term use of calcineurin inhibitors and corticosteroids in maintenance immunotherapy regimens has been implicated in the development of renal dysfunction, infections, metabolic derangements, de novo and recurrent malignancies, and the propagation of hepatitis C virus reinfection. Our analysis of the United Network for Organ Sharing registry shows the use of induction and maintenance therapy is each associated with reductions in AR risk, thereby improving post-transplant survival. The administration of intensive induction regimens appears to be safe and exhibits an additive beneficial effect. Therefore, the use of intensive induction regimens may be warranted to allow for reductions in long-term maintenance IS to minimize drug toxicities while preserving graft outcomes.

Background: Renal transplant outcomes in Hispanics have been conflicting regarding acute rejection (AR) and allograft survival. Additionally, the feasibility of early corticosteroid withdrawal (ECW) regimens among Hispanics has not been adequately addressed. The purpose of this study is to report outcomes following ECW among Hispanic renal transplant recipients., Methods: We retrospectively reviewed 498 consecutive renal transplants performed at our institution between July 2005 and October 2007, including 73 Hispanic and 146 white recipients who had ECW (median follow-up 49 months). Demographics, transplant data, and outcomes of Hispanic and white recipients (WR) were analyzed., Results: Hispanics had a higher incidence of diabetes mellitus and hypertension (p = 0.007), a higher proportion of blood type O (p = 0.006), and a higher serum panel reactive antibody at the time of transplantation (p = 0.02) compared with WR. Additionally, Hispanics were on dialysis longer than WR prior to transplantation (p = 0.03). Nevertheless, the incidence of AR, patient, and graft survival rates was similar (p > 0.05) between Hispanics and WR. Ethnicity was not an independent predictor of inferior patient and graft outcomes in multivariate analyses., Conclusion: Our single-center experience indicates that ECW can be performed in Hispanic renal transplant recipients, with patient and allograft outcomes comparable with those observed in WR., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Learning and memory require orchestrated regulation of both structural and functional synaptic plasticity in the hippocampus. While a neuropeptide alpha-melanocyte-stimulating hormone, α-MSH, has been implicated in memory acquisition and retention, the functional role of its cognate receptor, melanocortin-4 receptor (MC4R), in hippocampal-dependent synaptic plasticity has not been explored. In this study, we report that activation of MC4R enhances synaptic plasticity through the regulation of dendritic spine morphology and abundance of AMPA receptors. We show that activation of postsynaptic MC4R increases the number of mature dendritic spines and enhances surface expression of AMPA receptor subunit GluA1, resulting in synaptic accumulation of GluA1-containing AMPA receptors. Moreover, MC4R stimulates surface GluA1 trafficking through phosphorylation of GluA1 at Ser845 in a Gα(s)-cAMP/PKA-dependent manner. Blockade of protein kinase A (PKA) signaling abolishes the MC4R-mediated enhancement of neurotransmission and hippocampal long-term potentiation. Importantly, in vivo application of MC4R agonists increases LTP in the mouse hippocampal CA1 region. These findings reveal that MC4R in the hippocampus plays a critical role in the regulation of structural and functional plasticity.

The heterogeneity of tumor samples is a major challenge in the analysis of high-throughput profiling of tumor biopsies and cell lines. The measured aggregate signals of multigenerational progenies often represent an average of several tumor subclones with varying genomic aberrations and different gene expression levels. The goal of the present study was to integrate copy number analyses from SNP-arrays and karyotyping, gene expression profiling, and pathway analyses to detect heterogeneity, identify driver mutations, and explore possible mechanisms of tumor evolution. We showed the heterogeneity of the studied samples, characterized the global copy number alteration profiles, and identified genes whose copy number status and expression levels were aberrant. In particular, we identified a recurrent association between two BRAF(V600E) and BRAF(V600K) mutations and changes in DKK1 gene expression levels, which might indicate an association between the BRAF and WNT pathways. These findings show that the integrated approaches used in the present study can robustly address the challenging issue of tumor heterogeneity in high-throughput profiling.

Right-sided diverticulitis remains an exceedingly rare condition in the pediatric population. The clinical presentation mimics acute appendicitis, and the correct diagnosis is often difficult to make prior to operative exploration. We report two cases of cecal diverticulitis, and discuss the diagnosis and management of this disease, with a review of the literature.

Constitutive cell surface receptor kinase signaling and persistent phosphorylation/inactivation of the retinoblastoma (pRb) family of proteins (pRb, p107 and p130, known as pocket proteins) have been implicated in conferring uncontrolled growth to melanoma cells. However, the signals linking receptor kinase activity to neutralization of pocket proteins have not yet been fully elucidated. We therefore used specific chemical inhibitors to examine pRb regulation in melanoma cells. The most efficient agent, AG1024, known as an inhibitor of insulin-like growth factor 1 receptor and insulin receptor, arrested melanoma cell growth in vitro at nanomolar concentrations within 24 h of application. AG1024 inhibited the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and restored pRb tumor suppressive function. The latter was observed by the reduction in the phosphorylated forms of pRb, p107 and p130, and the formation of growth suppressive DNA binding complexes consisting of pRb and E2F1 or E2F3. The loss of phosphorylated forms of pRb at early time points after AG1024 application was not associated with suppression of cyclin-dependent kinases 2 and 4 activity but rather with proteasomal and nonproteasomal degradation. Thus, inhibition of melanoma cell proliferation by AG1024 is mediated by inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase 2 signaling and activation of pRb by a mechanism involving protein degradation.