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Purpose To identify prognostic factors after hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). Methods We retrospectively reviewed the combined experience at Toronto General Hospital and Hospital Vall d’Hebron managing HCC recurrence after LT ( n  = 121) between 2000 and 2012. We analyzed prognostic factors by uni- and multi-variate analysis. Median follow-up from LT was 29.5 (range 2–129.4) months. Median follow-up from HCC recurrence was 12.2 (range 0.1–112.5) months. Results At recurrence, 31.4 % were treated with curative-intent treatments (surgery or ablation), 42.1 % received palliative treatment, and 26.4 % received best supportive care. The 1-, 3-, and 5-year survivals, respectively, after HCC recurrence were 75, 60, and 31 %, vs. 60, 19, and 12 %, vs. 52, 4, and 5 % ( p  < 0.001). By multivariate analysis, not being amenable to a curative-intent treatment [hazard ratio (HR) 4.7, 95 % confidence interval (CI) 2.7–8.3, p  < 0.001], α-fetoprotein of ≥100 ng/mL at the time of HCC recurrence (HR 2.1, 95 % CI 1.3–2.3, p  = 0.002) and early recurrence (<12 months) after LT (HR 1.6, 95 % CI 1.1–2.5, p  = 0.03) were found to be poor prognosis factors. A prognostic score was devised on the basis of these three independent variables. Patients were divided into three groups, as follows: good prognosis, 0 points ( n  = 22); moderate prognosis, 1 or 2 points ( n  = 84); and poor prognosis, 3 points ( n  = 15). The 1-, 3-, and 5-year actuarial survival for each group was 91, 50, and 50 %, vs. 52, 7, and 2 %, vs. 13, 0, and 0 %, respectively ( p  < 0.001). Conclusions Patients with HCC recurrence after transplant amenable to curative-intent treatments can experience significant long-term survival (~50 % at 5 years), so aggressive management should be offered. Poor prognosis factors after recurrence are not being amenable to a curative-intent treatment, α-fetoprotein of ≥100 ng/mL, and early (<1 year) recurrence after LT.

A study of Triassic sandstones in the central North Sea, UK, has shown that combined detrital zircon and apatite geochronology and apatite trace element analysis is a powerful tool for reconstructing provenance for sandstones with diagenetically impoverished heavy mineral suites. Sandstones in the earlier part of the succession (Bunter Sandstone Member and Judy Sandstone Member) have characteristics that indicate derivation from Moinian–Dalradian metasediments affected by Caledonian tectonothermal events, in conjunction with a Palaeoproterozoic-Archaean source unaffected by Caledonian metamorphism. Palaeogeographic reconstructions indicate that the sediment cannot have been input directly from either of these cratonic areas. This, in conjunction with the presence of common rounded apatite, indicates that recycling is the most likely possibility. The zircon-apatite association in the younger Joanne Sandstone Member sandstones indicates derivation from lithologies with mid-Proterozoic zircons (either crystalline basement or metasediments in the Caledonian Nappes), subjected to Caledonian metamorphism to generate early Palaeozoic apatites. This combination is compatible with a source region in southern and western Norway. The low degree of textural maturity associated with the detrital apatite, together with the unimodal Caledonian age grouping, indicates the Joanne sandstones have a strong first-cycle component.

Interleukin (IL)-35 is a newly identified inhibitory cytokine used by T regulatory cells to control T cell-driven immune responses. However, the therapeutic potential of native, biologically active IL-35 has not been fully examined. Expression of the heterodimeric IL-35 cytokine was targeted to β-cells via the rat insulin promoter (RIP) II. Autoimmune diabetes, insulitis, and the infiltrating cellular populations were analyzed. Ectopic expression of IL-35 by pancreatic β-cells led to substantial, long-term protection against autoimmune diabetes, despite limited intraislet IL-35 secretion. Nonobese diabetic RIP-IL35 transgenic mice exhibited decreased islet infiltration with substantial reductions in the number of CD4(+) and CD8(+) T cells, and frequency of glucose-6-phosphatase catalytic subunit-related protein-specific CD8(+) T cells. Although there were limited alterations in cytokine expression, the reduced T-cell numbers observed coincided with diminished T-cell proliferation and G1 arrest, hallmarks of IL-35 biological activity. These data present a proof of principle that IL-35 could be used as a potent inhibitor of autoimmune diabetes and implicate its potential therapeutic utility in the treatment of type 1 diabetes.

Following robot assisted abdominal surgery, the pain can be moderate in severity. Neuraxial analgesia may decrease the activity of the detrusor muscle, reduce the incidence of bladder spasm and provide effective somatic and visceral analgesia. In this systematic review, we assessed the role of neuraxial analgesia in robot assisted abdominal surgery. Systematic review. Robot assisted abdominal surgery. Adults. Subsequent to a search of the electronic databases, observational studies and randomized controlled trials that assessed the effect of neuraxial analgesia instituted at induction of anesthesia or intraoperatively in adult and robot assisted abdominal surgery were considered for inclusion. The outcomes of observational studies as well as randomized controlled trials which were not subjected to meta-analysis were presented in descriptive terms. Meta-analysis was conducted if an outcome of interest was reported by two or more randomized controlled trials. We included 19 and 11 studies that investigated spinal and epidural analgesia in adults, respectively. The coprimary outcomes were the pain score at rest at 24 h and the cumulative intravenous morphine consumption at 24 h. Spinal analgesia with long acting neuraxial opioid did not decrease the pain score at rest at 24 h although it reduced the cumulative intravenous morphine consumption at 24 h by a mean difference (95%CI) of 14.88 mg (−22.13–-7.63; p < 0.0001, I2 = 50%) with a low and moderate quality of evidence, respectively, on meta-analysis of randomized controlled trials. Spinal analgesia with long acting neuraxial opioid had a beneficial effect on analgesic indices till the second postoperative day and a positive influence on opioid consumption up to and including the 72 h time point. The majority of studies demonstrated the use of spinal analgesia with long acting neuraxial opioid to lead to no difference in the incidence of postoperative nausea and vomiting, and the occurrence of pruritus was found to be increased with spinal analgesia with long acting neuraxial opioid in recovery but not at later time points. No difference was revealed in the incidence of urinary retention. The evidence in regard to the quality of recovery-15 score at 24 h and hospital length of stay was not fully consistent, although most studies indicated no difference between spinal analgesia and control for these outcomes. Epidural analgesia in robot assisted abdominal surgery was shown to decrease the pain on movement at 12 h but it had not been studied with respect to its influence on the pain score at rest at 24 h or the cumulative intravenous morphine consumption at 24 h. It did not reduce the pain on movement at later time points and the evidence related to the hospital length of stay was inconsistent. Spinal analgesia with long acting neuraxial opioid had a favourable effect on analgesic indices and opioid consumption, and is recommended by the authors, but the evidence for spinal analgesia with short acting neuraxial opioid and epidural analgesia was limited. •Spinal analgesia with long acting neuraxial opioid decreased the cumulative intravenous morphine consumption at 24 h•Spinal analgesia with long acting neuraxial opioid had a positive influence on analgesic indices and opioid consumption•Epidural analgesia had limited evidence to support its use

Background Post-operative pain management is a critical component of perioperative care. Patients at risk of poorly controlled post-operative pain may benefit from early measures to optimize pain management. We sought to identify risk factors for post-operative pain and opioid consumption in patients undergoing liver resection. Methods This is a multi-institutional prospective nested cohort study of patients undergoing open liver resection. Opioid consumption and pain scores were collected following surgery. To estimate the effects of patient factors on opioid consumption (oral morphine equivalents—OME) and on pain scores (NRS-11), we used generalized linear models and multivariable linear regression model, respectively. Results One hundred and fifty-three patients who underwent open liver resection between 2013 and 2016 were included in the study. The mean patient age was 62.2 years, and 43.3% were female. Younger patients were significantly more likely to use more opioids in the early post-operative period (16.7 OME/10 years, p  < 0.001). Patient factors that were significantly associated with increased NRS-11 pain scores also included younger patient age (difference in pain score of 0.3/10 years with cough and 0.2/10 years at rest, p  < 0.01 for both) as well as a history of analgesic use (difference in pain score of 0.9 with cough and 0.6 at rest, p  < 0.01 and p  = 0.07, respectively). Conclusion Younger patients and those with a history of analgesic use are more likely to report higher post-operative pain and require higher doses of opioids. Early identification of these patients, and measures to better manage their pain, may contribute to optimal perioperative care.

Liver transplantation (LT) which is currently an established therapy for sma1l, early stage hepatocellular carcinoma (HCC) in patients with cirrhosis requires in most cases long waiting period. Tumor development during the waiting period may be associated with vascular invasion which is a strong factor of postoperative recurrence. Therefore, local treatment of the tumor including trans-arterial chemoembolization (TACE), percutaneous radiofrequency (RF) or partial liver resection can be used before transplantation. In the present paper we reviewed the efficacy of these treatments prior to LT. Although, TACE induced complete tumor necrosis in some patients there is no convincing arguments showing that this treatment reduces the rate of drop out before LT, nor improves the survival after LT. Although, RF can induce complete necrosis in the majority of small tumors (<2.5 cm), there is no data demonstrating that this treatment reduce the rate of drop out before LT, nor improves the survival after LT. It has been showed that both short and long term survival after LT was not compromised by previous partial liver resection of HCC. However, there is no data demonstrating that liver resection before LT, which can be used either as a bridge treatment or as a primary treatment, improves the survival after LT. The current data suggest that there is no role for pre-transplant therapy for HCC within Milano criteria transplanted within six months. On the opposite, if the waiting time is predicted to be prolonged, the risk of tumor progression and either drop-off from the list or interval dissemination with post-transplant tumor recurrence is recognized. In this setting, bridge therapy can reduce that risk but its efficacy has to be determined.

On the Pathogenicity of Autoantigen-Specific T-Cell Receptors Amanda R. Burton 1 , Erica Vincent 1 , Paula Y. Arnold 1 , Greig P. Lennon 1 , Matthew Smeltzer 2 , Chin-Shang Li 3 , Kathryn Haskins 4 , John Hutton 5 , Roland M. Tisch 6 , Eli E. Sercarz 7 , Pere Santamaria 8 , Creg J. Workman 1 and Dario A.A. Vignali 1 1 Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 2 Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee 3 Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, Californnia 4 Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado 5 Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, Colorado 6 Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 7 Division of Immune Regulation, Torrey Pines Institute for Molecular Studies, San Diego, California 8 Julia McFarlane Diabetes Research Centre and the Department of Microbiology and Infectious Diseases, Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada Corresponding author: Dr. Dario Vignali, Department of Immunology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794. E-mail: dario.vignali{at}stjude.org Abstract OBJECTIVE— Type 1 diabetes is mediated by T-cell entry into pancreatic islets and destruction of insulin-producing β-cells. The relative contribution of T-cells specific for different autoantigens is largely unknown because relatively few have been assessed in vivo. RESEARCH DESIGN AND METHODS— We generated mice possessing a monoclonal population of T-cells expressing 1 of 17 T-cell receptors (TCR) specific for either known autoantigens (GAD65, insulinoma-associated protein 2 (IA2), IA2β/phogrin, and insulin), unknown islet antigens, or control antigens on a NOD.scid background using retroviral-mediated stem cell gene transfer and 2A-linked multicistronic retroviral vectors (referred to herein as retrogenic [Rg] mice). The TCR Rg approach provides a mechanism by which T-cells with broad phenotypic differences can be directly compared. RESULTS— Neither GAD- nor IA2-specific TCRs mediated T-cell islet infiltration or diabetes even though T-cells developed in these Rg mice and responded to their cognate epitope. IA2β/phogrin and insulin-specific Rg T-cells produced variable levels of insulitis, with one TCR producing delayed diabetes. Three TCRs specific for unknown islet antigens produced a hierarchy of insulitogenic and diabetogenic potential (BDC-2.5 > NY4.1 > BDC-6.9), while a fourth (BDC-10.1) mediated dramatically accelerated disease, with all mice diabetic by day 33, well before full T-cell reconstitution (days 42–56). Remarkably, as few as 1,000 BDC-10.1 Rg T-cells caused rapid diabetes following adoptive transfer into NOD.scid mice. CONCLUSIONS— Our data show that relatively few autoantigen-specific TCRs can mediate islet infiltration and β-cell destruction on their own and that autoreactivity does not necessarily imply pathogenicity. FACS, fluorescence-activated cell sorter GFP, green fluorescent protein HBSS, Hank's Balanced Salt Solution FBS, fetal bovine serum IA2, insulinoma-associated protein 2 ILN, inguinal lymph node HEL, Hen egg white lysozyme PE, phycoerythrin PLN, pancreatic lymph node TCR, T-cell receptor Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 21 February 2008. DOI: 10.2337/db07-1129. C.J.W. and D.A.A.V. share senior authorship of this article. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted February 20, 2008. Received August 12, 2007. DIABETES

In collaboration with the Canadian Critical Care Society, the Canadian Association of Transplantation and the Canadian Society of Transplantation, the Canadian Council for Donation and Transplantation (CCDT) sponsored a forum entitled \"Medical Management to Optimize Donor Organ Potential,\" 23-25 Feb. 2004, to develop guidelines and recommendations for organ donor management in Canada. Discussions were restricted to the interval of care that begins with neurological determination of death (NDD), commonly called \"brain death,\" and consent to organ donation, and culminates in surgical organ procurement. This period presents a significant opportunity to enhance multi-organ function and improve organ utilization. From Division of Pediatric Critical Care, Montreal Children's Hospital, McGill University Health Centre, Montréal, Que. (Shemie), Cardiac Transplant Program, Toronto General Hospital, University Health Network ([Heather Ross]), GI Transplant Program, Toronto General Hospital, University Health Network ([Paul D. Greig]), General Surgery, ICU and Organ and Tissue Donation Program, The Ottawa Hospital ([Joe Pagliarello]), Trauma and Neurosurgery Intensive Care Unit, St. Michael's Hospital, University of Toronto, Toronto, Ont. ([Andrew J. Baker]), Adult Critical Care, Foothills Hospital, Calgary, Alta. ([Christopher Doig]), Trillium Gift of Life Network (Baker), Canadian Critical Care Society ([Sam D. Shemie], Pagliarello, Baker, Doig, Guest), Canadian Anesthesiologists' Society (Baker), Canadian Organ Replacement Register (Greig), Canadian Society of Transplantation (Greig, Ross, [Sandra Cockfield], Keshavjee, [Vivek Rao], [Peter Nickerson]), Canadian Association of Transplantation ([Tracy Brand], [Kimberly Young]), Kidney Transplant Program, University of Alberta Hospital, Edmonton, Alta. (Cockfield), Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ont. (Keshavjee), Immunogenetics Laboratory, University of Manitoba Health Services Centre, Winnipeg, Man. (Nickerson), Cardiac Transplant Program, University Health Network, University of Toronto, Toronto, Ont. (Rao), Department of Critical Care Medicine, Sunnybrooke and Women's College Hospital, Toronto, Ont. (Guest), Canadian Council for Donation and Transplantation (Shemie, Young, Doig), Saskatchewan Transplant Program (Brand).

Introduction: It is becoming increasingly common to request computed tomography (CT) to rule out space occupying lesions before lumbar puncture (LP), even in patients with no clinical signs. Imaging trends within a busy district general hospital in Oxfordshire, UK were analysed with results used to clarify when imaging should be considered mandatory. Method: A retrospective six month sample was obtained comprising all adults considered for LP. Observed frequencies of abnormal examination findings compared with abnormal investigations were used to determine sensitivity, specificity, positive predictive, and negative predictive values to assess the validity of using a normal clinical examination as a basis for excluding CT. Results: 64 patients were considered for LP. In total, 58 patients underwent LP, with a single patient receiving two. After an abnormal CT scan, six patients did not undergo a planned LP. In all six of these cases subarachnoid haemorrhage was detected, and in all cases this was considered a probable diagnosis. In no case was an LP precluded by an unsuspected space occupying lesion. Neurological examination showed a sensitivity of 0.72 (0.52 to 0.93), specificity 0.78 (0.64 to 0.91), positive predictive value 0.61 (0.41 to 0.83), and negative predictive value 0.85 (0.73 to 0.97). Discussion: The high sensitivity and negative predictive values support normal neurological examination as an effective predictor of normal CT scan. This permits the recommendation in cases where subarachnoid haemorrhage is not suspected, a CT scan can be avoided provided there are no abnormal findings on physical or fundoscopic examination.

Liver resection is accepted treatment for selected patients with colon cancer metastatic to the liver. There remains some controversy regarding the selection criteria, particularly which preoperative features are useful predictors of long survival postresection. One hundred and twenty-three patients who had liver resection for colorectal metastases on the Hepato Pancreatic Biliary Service at The Toronto Hospital between August 1977 and June 1993 were studied. Seventy-seven had solitary lesions, 15 had single lesions with satellite nodules, and 31 had multiple lesions. Synchronous liver metastases were found in 40 patients and 83 patients had metachronous lesions. Fifty-one patients had formal lobectomies and 21 had extended lobectomies. Postoperative complications were seen in 28% of patients, but there were no operative or postoperative deaths. Overall actuarial 5-year survival was 34%. There was a significant difference in survival according to the number of metastases. Patients with single lesions had a 5-year survival of 47% compared with 16% for single lesions with satellite nodules, and 17% for multiple lesions. There were no significant differences in survival based on age, sex, synchronous versus metachronous lesions, status of lymph nodes at the time of original surgery, intraoperative blood replacement, or size of tumor. An aggressive approach to the surgical management of colorectal liver metastases is possible with low risk in centers specializing in liver surgery, and results in prolonged survival in one third of patients. The most reliable predictor of long-term survival is the number of metastases in the liver.