Surgical resection is associated with improved long-term survival of patients with resectable pancreatic head cancer compared to multiagent chemotherapy.

BACKGROUND: Standard of care for resectable pancreatic cancer is a combination of surgical resection (SR) and multiagent chemotherapy (MCT). We aim to determine whether SR or MCT is associated with superior survival for patients receiving only single-modality therapy. METHODS: Patients with stage I-IIb pancreatic head adenocarcinoma who received either MCT or SR were identified in the NCDB (2013-2015). Following a piecewise approach to estimating hazards over the course of follow-up, conditional overall survival (OS) at 30, 60, and 90 days after treatment initiation was estimated using landmark analyses. RESULTS: 3103 patients received MCT alone (60.3%) and 2043 underwent SR alone (39.7%). SR had an OS disadvantage at 30 (HR 3.99, 95% CI 3.12-5.11) and 60 days (HR 1.85, 95% CI 1.4-2.45), but an OS advantage after 90 days (HR 0.59, 95% CI 0.55-0.64). In a landmark analysis conditioned on 90 days survival post treatment initiation, median OS was improved for SR (17.0 vs. 12.2 months, p < 0.0001); SR improved 3-year OS by 21.3% (p < 0.05), despite patients being older (median 72 vs. 67 years, p < 0.0001) with higher Charlson-Deyo comorbidity scores (≥2: 11.2 vs. 8.6%, p = 0.006). CONCLUSION: For patients with resectable pancreatic cancer, SR is associated with superior long-term survival compared to MCT.

Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model.

Sensitized patients are difficult to transplant due to pre-formed anti-donor immunity. We have previously reported successful desensitization using carfilzomib and belatacept in a non-human primate (NHP) model. Here we evaluated selective blockade of the co-stimulatory signal (CD28-B7) with Lulizumab, which preserves the co-inhibitory signal (CTLA4-B7). Five maximally MHC-mismatched pairs of NHPs were sensitized to each other with two sequential skin transplants. Individuals from each pair were randomized to either desensitization with once-weekly Carfilzomib (27mg/m2 IV) and Lulizumab (12.5mg/kg SC) over four weeks, or no desensitization (Control). NHPs then underwent life-sustaining kidney transplantation from their previous skin donor. Rhesus-specific anti-thymocyte globulin was used as induction therapy and immunosuppression maintained with tacrolimus, mycophenolate, and methylprednisolone. Desensitized subjects demonstrated a significant reduction in donor-specific antibody, follicular helper T cells (CD4+PD-1+ICOS+), and proliferating B cells (CD20+Ki67+) in the lymph nodes. Interestingly, regulatory T cell (CD4+CD25+CD127lo) frequency was maintained after desensitization in addition to increased frequency of naïve CD4 T cells (CCR7+CD45RA+) and naïve B cells (IgD+CD27-CD20+) in circulation. This was associated with significant prolongation in graft survival (MST = 5.8 ± 4.0 vs. 64.8 ± 36.3; p<0.05) and lower antibody-mediated rejection scores compared to control animals. However, all desensitized animals eventually developed AMR and graft failure. Desensitization with CFZ and Lulizumab improves allograft survival in allosensitized NHPs, by transient control of the germinal center and shifting of the immune system to a more naive phenotype. This regimen may translate into clinical practice to improve outcomes of highly sensitized transplant patients.

Age-related effects on thymic output and homeostatic T cell expansion following depletional induction in renal transplant recipients.

Thymic output and homeostatic mature cell proliferation both influence T cell repopulation following depletional induction, though the relative contribution of each and their association with recipient age have not been well studied. We investigated the repopulating T cell kinetics in kidney transplant recipients who underwent alemtuzumab induction followed by belatacept/rapamycin-based immunosuppression over 36-month posttransplantation. We focused specifically on the correlation between repopulating T cell subsets and the age of patients. Substantial homeostatic Ki67-expressing T cell proliferation was seen posttransplantation. A repertoire enriched for naïve T (TNaïve ) cells emerged posttransplantation. Analysis by generalized estimating equation linear models revealed a strong negative linear association between reconstituting TNaïve cells and advancing age. A relationship between age and persistence of effector memory cells was shown. We assessed thymic output and found an increase in the frequency of recent thymic emigrants (RTEs, CD4+ CD31+ ) at 12-month posttransplantation. Patients under 30 years of age showed significantly higher levels of CD4+ CD31+ cells than patients over 55 years of age pre- and posttransplantation. IL-7 and autologous mature dendritic cells (mDCs) induced CD57- cell proliferation. In contrast, mDCs, but not IL-7, induced CD57+ cell proliferation. This study establishes the relationship between age and thymic output during T cell homeostatic repopulation after alemtuzumab induction. Trial Registration: ClinicalTrials.gov - NCT00565773.

Impact of Postoperative Chemotherapy on the Survival of Patients with High-Grade Gastroenteropancreatic Neuroendocrine Carcinoma.

BACKGROUND: This study aimed to determine whether postoperative chemotherapy is associated with a survival benefit for patients with poorly differentiated neuroendocrine carcinoma (NEC) of the stomach, small bowel, or pancreas. METHODS: Patients were identified in the National Cancer Database (NCDB) between 2004 and 2014. Inverse probability of treatment weighting (IPTW) was used to reduce selection bias. To compare the overall survival (OS) of patients in different treatment groups, IPTW-adjusted Kaplan-Meier curves and Cox proportional hazards models were used. RESULTS: The inclusion criteria were met by 759 patients. The diagnosis was NEC of the stomach for 195 patients (25.7%), NEC of the small intestine for 278 patients (36.6%), and NEC of the pancreas for 286 patients (37.7%). Overall, 213 patients (28.1%) received postoperative chemotherapy after curative resection. For the patients who received chemotherapy, IPTW-adjusted survival showed no OS benefit. However, subgroup analysis demonstrated improved OS with observation (OB) for patients with NEC of the small intestine (hazard ratio [HR], 1.436; 95% confidence interval [CI] 1.13-1.823; P = 0.003), T3 or T4 primary tumor (HR, 1.258; 95% CI 1.08-1.465; P = 0.003), node-positive disease (HR, 1.238; 95% CI 1.040-1.475; P = 0.0165), or positive resection margin (HR, 1.4283; 95% CI 1.02-2.00; P = 0.038). CONCLUSIONS: In this national database analysis, postoperative chemotherapy was not associated with improved survival for patients with poorly differentiated gastroenteropancreatic (GEP) NECs. These findings highlight the need for continued efforts to understand better which patients in this high-risk population will benefit from additional systemic therapy and the need for continued development of more effective therapies for these patients.

Coagulation, inflammation, and CD46 transgene expression in neonatal porcine islet xenotransplantation.

BACKGROUND: Thrombosis is a known consequence of intraportal islet transplantation, particularly for xenogeneic islets. To define the origins of thrombosis after islet xenotransplantation and relate it to early inflammation, we examined porcine islets transplanted into non-human primates using a dual-transplant model to directly compare islet characteristics. METHODS: α1,3-Galactosyltransferase gene-knockout (GTKO) islets with and without expression of the human complement regulatory transgene CD46 (hCD46) were studied. Biologically inert polyethylene microspheres were used to examine the generic pro-thrombotic effects of particle embolization. Immunohistochemistry was performed 1 and 24 hours after transplantation. RESULTS: Xeno-islet transplantation activated both extrinsic and intrinsic coagulation pathways. The intrinsic pathway was also initiated by microsphere embolization, while extrinsic pathway tissue factor (TF) and platelet aggregation were more specific to engrafted islets. hCD46 expression significantly reduced TF, platelet, fibrin, and factor XIIIa accumulation in and around islets but did not alter intrinsic factor activation. Layers of TF+ cells emerged around islets within 24 hours, particularly co-localized with vimentin, and identified as CD3+ and CD68+ cells inflammatory cells. CONCLUSIONS: These findings detail the origins of thrombosis following islet xenotransplantation, relate it to early immune activation, and suggest a role for transgenic hCD46 expression in its mitigation. Layers of TF-positive inflammatory cells and fibroblasts around islets at 24 hours may have important roles in the progressive events of thrombosis, inflammatory cell recruitment, rejection, and the ultimate outcome of transplanted grafts. These suggest that the strategies targeting these elements could yield more progress toward successful xenogeneic islet engraftment and survival.

Anti-thymoglobulin induction improves neonatal porcine xenoislet engraftment and survival.

Porcine islet xenotransplantation is a viable strategy to treat diabetes. Its translation has been limited by the pre-clinical development of a clinically available immunosuppressive regimen. We tested two clinically relevant induction agents in a non-human primate (NHP) islet xenotransplantation model to compare depletional versus nondepletional induction immunosuppression. Neonatal porcine islets were isolated from GKO or hCD46/GKO transgenic piglets and transplanted via portal vein infusion in diabetic rhesus macaques. Induction therapy consisted of either basiliximab (n = 6) or rhesus-specific anti-thymocyte globulin (rhATG, n = 6), combined with a maintenance regimen using B7 costimulation blockade, tacrolimus with a delayed transition to sirolimus, and mycophenolate mofetil. Xenografts were monitored by blood glucose levels and porcine C-peptide measurements. Of the six receiving basiliximab induction, engraftment was achieved in 4 with median graft survival of 14 days. All six receiving rhATG induction engrafted with significantly longer xenograft survival at 40.5 days (P = 0.03). These data suggest that depletional induction provides superior xenograft survival to nondepletional induction, in the setting of a costimulation blockade-based maintenance regimen.

A comparative study of human-and rhesus-specific antithymocyte globulins in Rhesus macaques.

Rabbit antithymocyte globulin (RATG) preparations are widely used in transplantation. They are developed in vivo against thymocytes and contain polyclonal antibodies specific for myriad cellular targets. The rhesus monkey is commonly used as a preclinical transplant model, but the fidelity of commercially available human-specific RATGs to anticipate the effects of RATGs in rhesus has not been established. We therefore developed two rhesus-specific ATGs (rhATG) and compared them to human-specific RATG (huATG, Thymoglobulin® ) in rhesus monkeys, assessing the magnitude and phenotype of depletion peripherally and in lymph nodes. Four primates were assigned to each group and received 20 mg/kg of drug. Depletion, repopulation, and changes in lymphocyte subsets were evaluated in peripheral blood and lymph nodes by flow cytometry over four months. We observed similar qualitative changes in lymphocyte subsets, but a generally more profound depletion with huATG compared to either rhATG. Peripheral homeostatic proliferation rather than thymic output was the major mechanism for repopulation with all RATGs. Repopulation was slower but qualitatively similar when examining RATGs in additional animals receiving concomitant chronic immunosuppression. Depletional induction is similar to human- and rhesus-specific RATGs in rhesus macaques. Both rhesus- and human-specific agents appear appropriate for preclinical modeling of clinical RATG use.

Definition and Analysis of Textbook Outcome: A Novel Quality Measure in Kidney Transplantation.

BACKGROUND: "Textbook outcome" (TO) is a novel composite quality measure that encompasses multiple postoperative endpoints, representing the ideal "textbook" hospitalization for complex surgical procedures. We defined TO for kidney transplantation using a cohort from a high-volume institution. METHODS: Adult patients who underwent isolated kidney transplantation at our institution between 2016 and 2019 were included. TO was defined by clinician consensus at our institution to include freedom from intraoperative complication, postoperative reintervention, 30-day intensive care unit or hospital readmission, length of stay > 75th percentile of kidney transplant patients, 90-day mortality, 30-day acute rejection, delayed graft function, and discharge with a Foley catheter. Recipient, operative, financial characteristics, and post-transplant patient, graft, and rejection-free survival were compared between patients who achieved and failed to achieve TO. RESULTS: A total of 557 kidney transplant patients were included. Of those, 245 (44%) achieved TO. The most common reasons for TO failure were delayed graft function (N = 157, 50%) and hospital readmission within 30 days (N = 155, 50%); the least common was mortality within 90 days (N = 6, 2%). Patient, graft, and rejection-free survival were significantly improved among patients who achieved TO. On average, patients who achieved TO incurred approximately $50,000 less in total inpatient charges compared to those who failed TO. CONCLUSIONS: TO in kidney transplantation was associated with favorable post-transplant outcomes and significant cost-savings. TO may offer transplant centers a detailed performance breakdown to identify aspects of perioperative care in need of process improvement.

Empiric nasogastric decompression after pancreaticoduodenectomy is not necessary.

BACKGROUND: The aim of the present study was to evaluate the impact of routine NGT decompression after PD on postoperative outcomes in the era of an enhanced recovery after surgery (ERAS) protocol. MATERIALS AND METHODS: A retrospective review of all patients undergoing PD between January 2015 and October 2017 at our institution was performed comparing routine post-operative NGT decompression versus omission. The incidence of delayed gastric emptying, post-operative pancreatic fistula, hospital length of stay, operative time, 30-day readmission rate as well the time to first oral intake were evaluated. RESULTS: Out of 149 patients who underwent PD, 65 maintained post-operative NGT decompression while post-operative NGT decompression was omitted in 84 patients. No differences were noted in delayed gastric emptying rates (both p>0.05). The median length of stay (9 days for NGT group versus 8.5 days for no NGT group) and 30-day readmission rates (13.8% versus 15.5%, respectively) were similar (p=0.781). Compared with patients who had routine post-operative NGT placed, those who had omission of a post-operative NGT had a lower need for reinsertion, shorter time to PO intake, and a lower likelihood of extended length of stay. CONCLUSIONS: In the era of ERAS protocols, we observed no association between routine post-operative NGT decompression after PD and improved postoperative outcomes.

Kidney transplantation using alemtuzumab, belatacept, and sirolimus: Five-year follow-up.

Kidney transplant outcomes are limited by toxicities associated with calcineurin inhibitors and steroids. This trial was conducted to determine whether a costimulation blockade (CoB)-based regimen could achieve acceptable long-term outcomes and graft survival could be maintained solely with CoB. Forty patients underwent alemtuzumab induction followed by belatacept and sirolimus maintenance therapy. Patients were offered weaning to belatacept monotherapy after 1 year and followed for 5 years. Five-year patient and graft survival rates were 100% and 95%, respectively. Graft function remained stable with a mean estimated glomerular filtration rates of 67 ± 21 and 71 ± 19 at 36 and 60 months, respectively. There was no clinical rejection in the first year; subclinical rejection was detected by protocol biopsy in 4 patients. Twelve patients were successfully weaned to belatacept monotherapy. Cytomegalovirus and Epstein-Barr virus reactivations were well controlled, but 9 patients experienced transient BK viremia during the first year. Alemtuzumab produced profound lymphopenia followed by gradual T cell and more rapid B cell reconstitution to a repertoire deviated toward naïve cells with increased regulatory T cells. This regimen effectively prevents allograft rejection without using steroids or calcineurin inhibitors, enriches for naïve cells susceptible to control with CoB, and permits control of rejection with belatacept monotherapy in selected patients.

Outcomes in Kidney Transplantation Between Veterans Affairs and Civilian Hospitals: Considerations in the Context of the MISSION Act.

OBJECTIVE: We sought to compare kidney transplantation outcomes between Veterans Affairs (VA) and non-VA transplant centers. SUMMARY BACKGROUND DATA: Transplant care at the VA has previously been scrutinized due to geographic and systematic barriers. The recently instituted MISSION Act entered effect June 6th, 2019, which enables veteran access to surgical care at civilian hospitals if certain eligibility criteria are met. METHODS: We evaluated observed-to-expected outcome ratios (O:E) for graft loss and mortality using the Scientific Registry of Transplant Recipients database for all kidney transplants during a 15-year period (July 1, 2001-June 30, 2016). Of 229,188 kidney transplants performed during the study period, 1508 were performed at VA centers (N = 7), 7750 at the respective academic institutions affiliated with these VA centers, and 227,680 at non-VA centers nationwide (N = 286). RESULTS: Aggregate O:E ratios for mortality were lower in VA centers compared with non-VA centers at 1 month and 1 year (O:E = 0.27 vs 1.00, P = 0.03 and O:E = 0.62 vs 1.00, P = 0.03, respectively). Graft loss at 1 month and 1 year was similar between groups (O:E = 0.65 vs 1.00, P = 0.11 and O:E = 0.79 vs 1.00, P = 0.15, respectively). Ratios for mortality and graft loss were similar between VA centers and their respective academic affiliates. Additionally, a subgroup analysis for graft loss and mortality at 3 years (study period January 1, 2009-December 31, 2013) demonstrated no significant differences between VA centers, VA-affiliates, and all non-VA centers. CONCLUSIONS: Despite low clinical volume, VA centers offer excellent outcomes in kidney transplantation. Veteran referral to civilian hospitals should weigh the benefit of geographic convenience and patient preference with center outcomes.

B cells in transplant tolerance and rejection: friends or foes?

Our understanding of the role of B cells in organ transplantation remains incomplete and continues to grow. The majority of research has focused on the detrimental role of antibodies that drive the development of pathogenesis of the transplanted organ. However, it has been shown that not all donor-specific antibodies are harmful and in some circumstances can even promote tolerance through the mechanism of accommodation. Furthermore, B cells can have effects on transplanted organs through their interaction with T cells, namely antigen presentation, cytokine production, and costimulation. More recently, the role and importance of Bregs was introduced to the field of transplantation. Due to this functional and ontogenetic heterogeneity, targeting B cells in transplantation may bring undesired immunologic side effects including increased rejection. Therefore, the selective control of B cells that contribute to the humoral response against donor antigens will continue to be an important and challenging area of research and potentially lead to improved long-term transplant outcomes.

Textbook Outcomes in Liver Transplantation.

BACKGROUND: Textbook outcome (TO) is an emerging concept within multiple surgical domains, which represents a novel effort to define a standardized, composite quality benchmark based on multiple postoperative endpoints that represent the ideal "textbook" hospitalization. We sought to define TO for liver transplantation (LT) using a cohort from a high procedural volume center. METHODS: Patients who underwent LT at our institution between 2014 and 2017 were eligible for the study. The definition of TO was determined by clinician consensus at our institution to include freedom from: mortality within 90 days, primary allograft non-function, early allograft dysfunction (EAD), rejection within 30 days, readmission with 30 days, readmission to the ICU during index hospitalization, hospital length of stay > 75th percentile of all liver transplant patients, red blood cell (RBC) transfusion requirement greater than the 75th percentile for all liver transplant patients, Clavien-Dindo Grade III complication (re-intervention), and major intraoperative complication. RESULTS: Two hundred and thirty-one liver transplants with complete data were performed within the study period. Of those, 71 (31%) achieved a TO. Overall, the most likely event to lead to failure to achieve TO was readmission within 30 days (n = 57, 37%) or reoperation (n = 49, 32%). Overall and rejection-free survival did not differ significantly between the 2 groups. Interestingly, patients who achieved TO incurred approximately $60,000 less in total charges than those who did not. When we limit this to charges specifically attributable to the transplant episode, the difference was approximately $50,000 and remained significantly less for those that achieved TO. CONCLUSIONS: Here, we present the first definition of TO in LT. Though not associated with long-term outcomes, TO in LT is associated with a significantly lower charges and costs of the initial hospitalization. A multi-institutional study to validate this definition of TO is warranted.

Secondary lymphoid tissue and costimulation-blockade resistant rejection: A nonhuman primate renal transplant study.

Naïve T cell activation requires antigen presentation combined with costimulation through CD28, both of which optimally occur in secondary lymphoid tissues such as lymph nodes and the spleen. Belatacept impairs CD28 costimulation by binding its ligands, CD80 and CD86, and in doing so, impairs de novo alloimmune responses. However, in most patients belatacept is ineffective in preventing allograft rejection when used as a monotherapy, and adjuvant therapy is required for control of costimulation-blockade resistant rejection (CoBRR). In rodent models, impaired access to secondary lymphoid tissues has been demonstrated to reduce alloimmune responses to vascularized allografts. Here we show that surgical maneuvers, lymphatic ligation, and splenectomy, designed to anatomically limit access to secondary lymphoid tissues, control CoBRR and facilitate belatacept monotherapy in a nonhuman primate model of kidney transplantation without adjuvant immunotherapy. We further demonstrate that animals sustained on belatacept monotherapy progressively develop an increasingly naïve T and B cell repertoire, an effect that is accelerated by splenectomy and lost at the time of belatacept withdrawal and rejection. These pilot data inform the role of secondary lymphoid tissues on the development of CoBRR and the use of costimulation molecule-focused therapies.

Overcoming a travel burden to high-volume centers for treatment of retroperitoneal sarcomas is associated with improved survival.

BACKGROUND: Guidelines recommend treatment of retroperitoneal sarcomas (RPS) at high-volume centers. However, high-volume centers may not be accessible locally. This national study compared outcomes of RPS resection between local low-volume centers and more distant high-volume centers. METHODS: Patients treated for RPS were identified from the National Cancer Database (1998-2012). Travel distance and annual hospital volume were divided into quartiles. Two groups were identified: (1) short travel to low-volume hospitals (ST/LV), (2) long travel to high-volume hospitals (LT/HV). Outcomes were adjusted for clinical, tumor, and treatment characteristics. RESULTS: Two thousand five hundred ninety-nine patients met the inclusion criteria. The LT/HV cohort was younger and more often white (p < 0.01). The LT/HV group had more comorbidities, higher tumor grade, and more often radical resections and radiotherapy (all p < 0.05). The ST/LV group underwent significantly more R2 resections (4.4% vs. 2.6%, p = 0.003). Thirty-day mortality was significantly lower in the LT/HV group (1.2% vs. 2.8%, p = 0.0026). Five-year survival was better among the LT/HV group (63% vs. 53%, p < 0.0001). After adjustment, the LT/HV group had a 27% improvement in overall survival (HR 0.73, p = 0.0009). CONCLUSIONS: This national study suggests that traveling to high-volume centers for the treatment of RPS confers a significant short-term and long-term survival advantage, supporting centralized care for RPS.

Robotic-Assisted Nissen Fundoplication with the Senhance® Surgical System: Technical Aspects and Early Results.

INTRODUCTION: Robotic-assisted surgery continues to evolve. Technical advantages are reported for intracorporal suturing, a technique with a long learning curve in conventional laparoscopy. The success of laparoscopic fundoplication relies on precise suturing at the hiatus and of the fundal wrap. Therefore, robotic assistance can be a useful tool for this particular procedure. In March 2017, the Senhance® Surgical System (Transenterix, Inc., Morrisville, North Carolina) was introduced into robotic-assisted procedures at the St. Marien-Krankenhaus, Siegen, Germany. MATERIALS AND METHODS: Between March 2017 and July 2019, we performed 36 surgeries of the upper GI tract with the Senhance® Surgical System. Eighteen patients underwent the classic Nissen fundoplication and are the subject of this study. All patients gave informed consent for robotic assistance with prospective data acquisition and analysis. RESULTS: Seven male and 11 female patients were included in the study. The median age of the cohort was 58.5 years (range 30-81 years) and the median body mass index (BMI) was 30.4 kg/m2 (range 22.7-40.1 kg/m2). The median total operative time was 95.5 minutes (range 68-194 minutes) and, despite the small sample size, we observed a significant learning curve throughout the study period (p<0.05). Before the introduction of the Senhance® Ultrasonic energy device, conversion to laparoscopic fundoplication was necessary in two patients. We performed one re-do laparoscopy on the day of surgery due to pain without any significant intraoperative findings and one laparoscopic revision to Toupet fundoplication after seven months due to dysphagia. CONCLUSION: This first report of robotic-assisted Nissen fundoplication with the Senhance® Surgical System demonstrates technical feasibility. After successful introduction of the Senhance® Ultrasonic, our conversion rate to standard laparoscopic surgery was significantly reduced.

Robotic Inguinal Hernia Repair (TAPP) First Experience with the New Senhance Robotic System.

INTRODUCTION: This retrospective study was performed to evaluate the safety and feasibility of the new Senhance Robotic System (TransEnterix Inc., Morrisville, North Carolina) for inguinal hernia repairs using the transabdominal preperitoneal approach. MATERIALS AND METHODS: From March to September 2017, 76 inguinal hernia repairs in 64 patients were performed using the Senhance Robotic System. Patients were between 18 and 90 years of age, eligible for a laparoscopic procedure with general anesthesia, had no life-threatening disease with a life expectancy of less than 12 months, and a body mass index (BMI) < 35. A retrospective chart review was performed for a variety of pre-, peri-, and postoperative data including, but not limited to, patient demographics, hernia characteristics, and intraoperative and postoperative complications. RESULTS: Fifty-four male and 10 female patients were included in the study. Median age was 56.5 years (range 22-86 years), and median BMI was 25.9 kg/m2 (range 19.5-31.8 kg/m2). Median docking time was seven minutes (range 2-21 minutes), and median operative time was 48 minutes (range 18-142 minutes). Two cases were converted to standard laparoscopic surgery due to robot malfunction and abdominal wall bleeding, respectively. Median length of stay was one day. CONCLUSION: We report the first series of laparoscopic inguinal hernia repairs using the new Senhance Robotic System. Compared to conventional laparoscopic transabdominal preperitoneal (TAPP) hernia repairs, there was no significant difference in operative time or perioperative complications. Additionally, there was no significant learning curve detected due to its intuitive applicability. Therefore, the Senhance Robotic System promises broad applicability across a range of laparoscopic general surgical operations.

The past, present, and future of costimulation blockade in organ transplantation.

PURPOSE OF REVIEW: Manipulating costimulatory signals has been shown to alter T cell responses and prolong graft survival in solid organ transplantation. Our understanding of and ability to target various costimulation pathways continues to evolve. RECENT FINDINGS: Since the approval of belatacept in kidney transplantation, many additional biologics have been developed targeting clinically relevant costimulation signaling axes including CD40-CD40L, inducible costimulator-inducible costimulator ligand (ICOS-ICOSL), and OX40-OX40L. Currently, the effects of costimulation blockade on posttransplant humoral responses, tolerance induction, and xenotransplantation are under active investigation. Here, we will discuss these pathways as well as preclinical and clinical outcomes of biologics targeting these pathways in organ transplantation. SUMMARY: Targeting costimultion is a promising approach for not only controlling T cell but also B cell responses. Consequently, costimulation blockade shows considerable potential for improving outcomes in antibody-mediated rejection and xenotransplantation.

Tumour-educated circulating monocytes are powerful candidate biomarkers for diagnosis and disease follow-up of colorectal cancer.

OBJECTIVE: Cancer immunology is a growing field of research whose aim is to develop innovative therapies and diagnostic tests. Starting from the hypothesis that immune cells promptly respond to harmful stimuli, we used peripheral blood monocytes in order to characterise a distinct gene expression profile and to evaluate its potential as a candidate diagnostic biomarker in patients with colorectal cancer (CRC), a still unmet clinical need. DESIGN: We performed a case-control study including 360 peripheral blood monocyte samples from four European oncological centres and defined a gene expression profile specific to CRC. The robustness of the genetic profile and disease specificity were assessed in an independent setting. RESULTS: This screen returned 43 putative diagnostic markers, which we refined and validated in the confirmative multicentric analysis to 23 genes with outstanding diagnostic accuracy (area under the curve (AUC)=0.99 (0.99 to 1.00), Se=100.0% (100.0% to 100.0%), Sp=92.9% (78.6% to 100.0%) in multiple-gene receiver operating characteristic analysis). The diagnostic accuracy was robustly maintained in prospectively collected independent samples (AUC=0.95 (0.85 to 1.00), Se=92.6% (81.5% to 100.0%), Sp=92.3% (76.9% to 100.0%). This monocyte signature was expressed at early disease onset, remained robust over the course of disease progression, and was specific for the monocytic fraction of mononuclear cells. The gene modulation was induced specifically by soluble factors derived from transformed colon epithelium in comparison to normal colon or other cancer histotypes. Moreover, expression changes were plastic and reversible, as they were abrogated upon withdrawal of these tumour-released factors. Consistently, the modified set of genes reverted to normal expression upon curative treatment and was specific for CRC. CONCLUSIONS: Our study is the first to demonstrate monocyte plasticity in response to tumour-released soluble factors. The identified distinct signature in tumour-educated monocytes might be used as a candidate biomarker in CRC diagnosis and harbours the potential for disease follow-up and therapeutic monitoring.