Pancreaticoduodenectomy in the surgical management of primary retroperitoneal sarcoma.

BACKGROUND: In retroperitoneal sarcoma (RPS), the optimal extent of resection must balance adequate disease control with potential for morbidity. We sought to study the frequency and outcomes after a Whipple procedure or pancreaticoduodenectomy (PD) in patients undergoing resection for primary RPS. METHODS: Participating referral centers within the Trans-Atlantic Retroperitoneal Sarcoma Working Group provided retrospective data from January 2007 to December 2016 for patients with primary RPS who underwent PD along with the total number of consecutive resections done during the same time period. Data from participating centers were combined for analysis. RESULTS: In total, 29 patients underwent PD among 2068 resections performed for primary RPS (1.4%). The predominant histologic subtypes were liposarcoma and leiomyosarcoma. All PD patients underwent concomitant resection of additional organs (median: 2, range: 1-5), including 13 patients (45%) who also received vena cava resection. Definitive evidence of microscopic invasion of the duodenum or pancreas was seen in 84% of patients. Postoperatively, 10 patients (34%) had major complications including 8 (28%) that developed a clinically-significant pancreatic leak. One postoperative death (3.4%) occurred. With a median follow-up of 4.8 years, 19 patients (66%) developed disease recurrence. The patterns of recurrence were dependent on histologic subtype. CONCLUSION: Although infrequent, when PD is done for primary RPS, resection of additional organs is often required and major complication rates are moderate. The recurrence rate is overall high and the pattern of recurrence is dictated by histologic subtype.

Invasive fungal infections following liver transplantation.

PURPOSE OF REVIEW: The review outlines the microbiology, presentation, prophylactic strategies, resistance patterns, and consequences of invasive fungal infections (IFIs) in orthotopic liver transplantation (OLT) recipients. RECENT FINDINGS: There has been an increase in the proportion of non-albicans Candida causing IFIs. The biomarkers galactomannan and ß-D-glucan should not be routinely used in the diagnosis of IFIs in OLT recipients due to their limited accuracy. Echinocandins have emerged as noninferior to fluconazole and other prophylactic regimens. Their broad spectrum of activity and side-effect profile are appealing; however, the development of echinocandin resistance, especially in Candida glabrata has been highlighted as one of their limitations. SUMMARY: A significant decline in IFIs but an increase in IFIs caused by non-albicans Candida species has been observed in the model for end-stage liver disease era. Diagnostic tools remain limited. Studies continue to support antifungal prophylaxis individualized to recipient risk with echinocandins now established as an additional option for antifungal prophylaxis. The appropriate duration of antifungal prophylaxis remains ill-defined with some studies advocating targeted therapy based on clinical status and others more prolonged therapy beyond the historically common 4 weeks. However, prolonged therapy with echinocandins can result in resistance.

Can ultrasound common bile duct diameter predict common bile duct stones in the setting of acute cholecystitis?

BACKGROUND: Our aim is assessment of ultrasound (US) common bile duct (CBD) diameter to predict the presence of CBD stones in acute cholecystitis (AC). METHODS: A retrospective review from 2007 to 2011 with codes for ultrasound, magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography, and AC was conducted. RESULTS: The incidence of CBD stones was 1.8%. Two hundred forty eight individuals had US+MRCP+ERCP+AC, of which 48 had CBD stones and 200 did not have CBD stones. US CBD diameter range was 3.6 to 19 mm. Ninety percent of MRCPs were negative, and it delayed care by 2.9 days. Mean CBD diameter was narrower in those negative for CBD stones (5.8 vs 7.08; P = .0043). Groups based on diameter ranges <6, 6 to 9.9, and ≥10 mm demonstrated 14%, 14%, and 39% CBD stones, respectively. CONCLUSIONS: US CBD diameter is not sufficient to identify patients at significant risk for CBD stones. MRCP delayed care by 2.9 days. Intraoperative cholangiography may be more effective, based on the low risk of CBD stones in AC.

Pancreas transplantation.

SPK transplant is the definitive treatment of type 1 diabetes combined with end-stage renal disease. Long-term graft function can lead to improvement in diabetes-related complications and, in patients younger than 50 years, can lead to improved overall survival. PAK transplant and PA transplant do not result in similar improvements in patient survival, but with appropriate patient selection, they can improve quality of life by rendering patients insulin-free. Pancreas transplant is associated with more surgical complications and higher perioperative morbidity and mortality than KTA. Therefore, careful donor and recipient selection along with meticulous surgical technique are mandatory for optimal outcomes.

Human monocytes as intermediaries between allogeneic endothelial cells and allospecific T cells: a role for direct scavenger receptor-mediated endothelial membrane uptake in the initiation of alloimmunity.

Recipient monocytes, T cells, and donor endothelial cells (ECs) are recognized as critical components of allograft rejection. We have recently shown that human monocytes infiltrate vascularized allografts before clinical rejection and have thus hypothesized that monocytes, rather than costimulation-poor ECs, initiate an alloimmune response. However, the nature of the interactions between ECs, monocytes, and T cells has been incompletely defined. Specifically, it is not clear whether these cells interact in a hierarchical manner, nor is it apparent what constitutes an interaction. We therefore studied human ECs, monocytes, and T cells in various isolated in vitro combinations to define the salient features of their contact and to determine whether their interactions were sequential in nature. We find that T cells proliferate poorly to allogeneic ECs and autologous monocytes but well to autologous monocytes following allogeneic EC contact. We show that monocytes gain their stimulatory capacity by phagocytizing allogeneic but not autologous EC membranes in a process governed by scavenger receptors. This process facilitates the subsequent presentation of intact donor HLA molecules to T cells (semidirect presentation). Moreover, monocytes are receptive to T cell help only after exposure to ECs and require CD4+ T cells to optimally express costimulatory molecules and foster Ag presentation. Our results indicate that monocytes engage allogeneic ECs through scavenger receptors and are then primed to facilitate T cell activation in a codependent manner. This reciprocal codependence allows for monocytes to serve as a regulated bridge between the allograft and T cells.

Is tolerance induction the answer to adolescent non-adherence?

By definition, tolerance will eliminate the problem of adolescent medication non-adherence. Although adolescents' propensity toward non-adherence makes them at first glance to be particularly attractive candidates for tolerance trials, there are also immunologic, psychosocial and ethical barriers that temper enthusiasm for their inclusion at present. Limits in emotional and cognitive maturity are combined during the teenage years with adult-like immunologic maturity to lessen the potential for successful implementation of tolerance and near tolerance strategies. Alternatively, an interval step to tolerance in adolescents is to eliminate the medications most likely contributing to non-adherence through harsh side effects such as steroids and calcineurin inhibitors. This manuscript will review the general topic of transplantation tolerance with specific attention given to the application of pro-tolerant therapies in adolescent recipients.

IDEC-131 (anti-CD154), sirolimus and donor-specific transfusion facilitate operational tolerance in non-human primates.

CD154-specific antibody therapy prevents allograft rejection in many experimental transplant models. However, initial clinical transplant trials with anti-CD154 have been disappointing suggesting the need for as of yet undetermined adjuvant therapy. In rodents, donor antigen (e.g., a donor blood transfusion), or mTOR inhibition (e.g., sirolimus), enhances anti-CD154's efficacy. We performed renal transplants in major histocompatibility complex-(MHC) mismatched rhesus monkeys and treated recipients with combinations of the CD154-specific antibody IDEC-131, and/or sirolimus, and/or a pre-transplant donor-specific transfusion (DST). Therapy was withdrawn after 3 months. Triple therapy prevented rejection during therapy in all animals and led to operational tolerance in three of five animals including donor-specific skin graft acceptance in the two animals tested. IDEC-131, sirolimus and DST are highly effective in preventing renal allograft rejection in primates. This apparently clinically applicable regimen is promising for human renal transplant trials.

Challenges in therapeutic strategies for transplantation: where now from here?

The current standard of care in transplantation reliably achieves acceptable graft and patient survival but still depends on life long immunosuppression in most patients. Current strategies employ medications that, in general, inhibit distal events mediating rejection, namely T cell activation and cytotoxicity. They do not typically interfere with initial allorecognition or the factors that influence the direction of an immune response (towards cytotoxicity as opposed to anergy or regulation). Given the exponential amplification of immune responses, these proximal targets may be more efficient in preventing rejection. Recent laboratory investigations have identified several approaches, e.g., costimulation blockade, depletion, and hematopoietic chimerism, that influence the initial stages of the alloimmune response, or establish self-perpetuating means of eliminating rejection without chronic immunosuppression. This manuscript reviews methods of immune manipulation that the authors view as promising for future exploitation and transfer to the clinic. These therapies are similar in that they are viewed as attempts to influence the ability of the body to mount an immune response and its subsequent direction, as opposed to supplying late effector phase inhibition. While it is recognized as unlikely that any one therapy will universally lead to tolerance, the authors propose that these concepts will make immunosuppressive drug minimization more readily successful.

The clinical application of monoclonal antibody therapies in renal transplantation.

Monoclonal antibodies have become valuable tools for the precise clinical manipulation of the immune system. These highly specific proteins have proven their usefulness in both the treatment and prevention of organ transplant rejection. Indeed, they are the centrepieces of many evolving regimens designed to reduce or eliminate the need for chronic immunosuppression. This manuscript will review the monoclonal antibodies that have made their way into the clinic either as experimental therapies or approved drugs. It will provide a general overview of this class of agents and their mechanisms of action. Standard therapies and potential new applications will be described.