A Multidimensional Bioinformatic Platform for the Study of Human Response to Surgery.

OBJECTIVE: To design and establish a prospective biospecimen repository that integrates multi-omics assays with clinical data to study mechanisms of controlled injury and healing. BACKGROUND: Elective surgery is an opportunity to understand both the systemic and focal responses accompanying controlled and well-characterized injury to the human body. The overarching goal of this ongoing project is to define stereotypical responses to surgical injury, with the translational purpose of identifying targetable pathways involved in healing and resilience, and variations indicative of aberrant peri-operative outcomes. METHODS: Clinical data from the electronic medical record combined with large-scale biological data sets derived from blood, urine, fecal matter, and tissue samples are collected prospectively through the peri-operative period on patients undergoing 14 surgeries chosen to represent a range of injury locations and intensities. Specimens are subjected to genomic, transcriptomic, proteomic, and metabolomic assays to describe their genetic, metabolic, immunologic, and microbiome profiles, providing a multidimensional landscape of the human response to injury. RESULTS: The highly multiplexed data generated includes changes in over 28,000 mRNA transcripts, 100 plasma metabolites, 200 urine metabolites, and 400 proteins over the longitudinal course of surgery and recovery. In our initial pilot dataset, we demonstrate the feasibility of collecting high quality multi-omic data at pre- and postoperative time points and are already seeing evidence of physiologic perturbation between timepoints. CONCLUSIONS: This repository allows for longitudinal, state-of-the-art geno-mic, transcriptomic, proteomic, metabolomic, immunologic, and clinical data collection and provides a rich and stable infrastructure on which to fuel further biomedical discovery.

Left lateral segment liver volume is not correlated with anthropometric measures.

BACKGROUND: Liver transplantation is definitive therapy for end stage liver disease in pediatric patients. Living donor liver transplantation (LDLT) with the left lateral segment (LLS) is often a feasible option. However, the size of LLS is an important factor in donor suitability - particularly when the recipient weighs less than 10 kg. In the present study, we sought to define a formula for estimating left lateral segment volume (LLSV) in potential LLS donors. METHODS: We obtained demographic and anthropometric measurements on 50 patients with Computed Tomography (CT) scans to determine whole liver volume (WLV), right liver volume (RLV), and LLSV. We performed univariable and multivariable linear regression with backwards stepwise variable selection (p < 0.10) to determine final models. RESULTS: Our study found that previously reported anthropometric and demographics variables correlated with volume were significantly associated with WLV and RLV. On univariable analysis, no demographic or anthropometric measures were correlated with LLSV. On multivariable analysis, LLSV was poorly predicted by the final model (R2 = 0.10, Coefficient of Variation [CV] = 42.2) relative to WLV (R2 = 0.33, CV = 18.8) and RLV (R2 = 0.41, CV = 15.8). CONCLUSION: Potential LLS living donors should not be excluded based on anthropometric data: all potential donors should be evaluated regardless of their size.

Using Radiographic Domain for Evaluating Indications in Abdominal Wall Transplantation.

BACKGROUND: There is currently no description of abdominal domain changes in small bowel transplantation population or consensus of criteria regarding which patients are at high risk for immediate postoperative abdominal wall complications or would benefit from abdominal wall vascularized composite allotransplantation. METHODS: A retrospective chart review was performed on 14 adult patients receiving intestinal or multivisceral transplantation. Preoperative and postoperative computed tomography scans were reviewed, and multiple variables were collected regarding abdominal domain and volume and analyzed comparing postoperative changes and abdominal wall complications. RESULTS: Patients after intestinal or multivisceral transplantation had a mean reduction in overall intraperitoneal volume in the immediate postoperative period from 9031 cm3 to 7846 cm3 (P = 0.314). This intraperitoneal volume was further reduced to an average of 6261 cm3 upon radiographic evaluation greater than 1 year postoperatively (P = 0.024). Patients with preexisting abdominal wound (P = 0.002), radiation, or presence of ostomy (P = 0.047) were significantly associated with postoperative abdominal wall complications. No preoperative radiographic findings had a significant association with postoperative abdominal wall complications. CONCLUSIONS: Computed tomography imaging demonstrates that intestinal and multivisceral transplant patients have significant reduction in intraperitoneal volume and domain after transplantation in the acute and delayed postoperative setting. Preoperative radiographic abdominal domain was not able to predict patients with postoperative abdominal wall complications. Patients with abdominal wounds, ostomies, and preoperative radiation therapy were associated with acute postoperative abdominal complications and may be considered for need of reconstructive techniques including abdominal wall transplantation.

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.

Decreased graft loss following implementation of the kidney allocation score (KAS).

BACKGROUND: The Kidney Allocation System (KAS) was developed to improve equity and utility in organ allocation. We examine the effect of this change on kidney graft distribution and survival. METHODS: UNOS data was used to identify first-time adult recipients of a deceased donor kidney-alone transplant pre-KAS (Jan 2012-Dec 2014, n = 26,612) and post-KAS (Jan 2015-Dec 2017, n = 30,701), as well as grafts recovered Jan 2012-Jun 2019. RESULTS: Post-KAS, kidneys were more likely to experience cold ischemia time >24 h (20.0% vs. 18.8%, p < 0.001) and experienced more delayed graft function, though competing risks modeling demonstrated a lower hazard of graft loss post-KAS, HR 0.90 (95% CI 0.84-0.97, p = 0.007). Post-policy, KDPI >85% kidneys were more likely to be shared regionally (37% vs. 14%), and more likely to be discarded (60.6% vs. 54.9%) after the policy change. KDPI >85% graft and patient survival did not change. CONCLUSIONS: Implementation of the KAS has increased sharing of high-KDPI kidneys and has decreased the hazard of graft loss without an impact on patient survival.

Synchronous Abdominal Wall and Small-bowel Transplantation: A 1-year Follow-up.

Abdominal wall-vascularized composite allotransplantation (AW-VCA) has evolved as a technically feasible but challenging option in the rare event of abdominal wall reconstruction in patients whose abdomen cannot be closed by applying conventional methods. The authors conducted the first synchronous child-to-adult recipient AW-VCA using an arteriovenous loop technique. This article presents a 1-year follow-up of the patient's postoperative course. Frequent skin biopsies were performed in accordance with Duke Institutional Review Board protocol, with 3 episodes of rejection treated with high-dose steroids and Thymoglobulin (Genzyme Corp, Cambridge, Mass.). The patient developed an opportunistic fungal brain abscess secondary to immunosuppression, which led to temporary upper extremity weakness. Future considerations for AW-VCA include a modified surgical technique involving utilization of donor vein graft for arteriovenous loop formation. In addition, reduction in postoperative biopsy schedule and changes in immunosuppression regimen may lead to improved outcomes and prevent unnecessary high-dose immunosuppression.

Surgical Techniques for Revascularization in Abdominal Wall Transplantation.

BACKGROUND: Abdominal wall vascularized composite allotransplantation (AW-VCA) can be considered as a technically feasible option for abdominal wall reconstruction in patients whose abdomen cannot be closed using traditional methods. However, successful initial abdominal wall revascularization in the setting of visceral organ transplantation can pose a major challenge as graft ischemia time, operating in a limited surgical field, and variable recipient and donor anatomy must be considered. Several techniques have been reported to accomplish abdominal wall revascularization. METHODS: A literature review was performed using PubMed for articles related to "abdominal wall transplantation (AWT)." The authors of this study sorted through this search for relevant publications that describe abdominal wall transplant anatomy, technical descriptions, and outcomes of various techniques. RESULTS: A total of four distinct revascularization techniques were found in the literature. Each of these techniques was described by the respective authors and reported varying patient outcomes. Levi et al published a landmark article in 2003 that described technical feasibility of AWT with anastomosis between donor external iliac and inferior epigastric vessels with recipient common iliac vessels in end-to-side fashion. Cipriani et al described a microsurgical technique with anastomosis between donor and recipient inferior epigastric vessels in an end-to-end fashion. Giele et al subsequently proposed banking the abdominal wall allograft in the forearm to reduce graft ischemia time. Recently, Erdmann et al described the utilization of an arteriovenous loop for synchronous revascularization of abdominal wall and visceral transplants for reduction of ischemia time, operative time, while eliminating the need for further operations. CONCLUSION: Vascularized composite allotransplantation continues to advance with improving immunotherapy and outcomes in solid organ transplantation. Optimizing surgical techniques remains paramount as the field continues to grow. Refinement of the presented methods will continue as additional evidence and outcomes become available in AW-VCA.

Comparison between liver transplantation and resection for hilar cholangiocarcinoma: A systematic review and meta-analysis.

BACKGROUND: Hilar cholangiocarcinoma (hCCA) is a rare and aggressive malignancy with R0 resection being currently the only option for long-term survival. With the improvement in the outcomes of liver transplantation (LT), the indications for LT have expanded to include other malignant tumors, such as hCCA. The aim of the present analysis is to demonstrate and critically evaluate the outcomes of LT compared to resection with curative intent in patients with hCCA. METHODS: We systematically searched the literature for articles published up to May 2018. The following algorithm was applied ((hilar cholangiocarcinoma) OR (perihilar cholangiocarcinoma) OR klatskin$ OR (bile duct neoplasm) OR cholangiocarcinoma) AND (transplant$ OR graft$). RESULTS: Neoadjuvant treatment with chemotherapy and radiation therapy was far more common in the LT group, with very few patients having received preoperative therapy in the resection group (p = 0.0005). Moreover, length of hospital stay was shorter after LT than after resection (p<0.00001). In contrast, no difference was found between the two treatment methods concerning postoperative mortality (p = 0.57). There was a trend towards longer overall survival after LT in comparison with resection. This was not obvious in the first year postoperatively, however, the advantage of LT over resection became obvious at 3 years after the operation (p = 0.02). CONCLUSIONS: In non-disseminated unresectable tumors, LT seems to have a non-inferior survival. In the same patients, neoadjuvant chemoradiotherapy and/or strict selection criteria may contribute to superior survival outcomes compared to curative-intent resection. Due to the scarcity of level 1 evidence, it remains unclear whether LT should be increasingly considered for technically resectable early stage hCCA.

Small bowel and abdominal wall transplantation: A novel technique for synchronous revascularization.

Abdominal wall transplantation (AWT) was introduced in 1999 in the context of reconstruction of complex abdominal wall defects in conjunction with visceral organ transplantation. As of recently, 38 cases of total AWT have been performed worldwide, about half of which were performed in the United States. While AWT is technically feasible, one of the major challenges presenting to the reconstructive surgeon is time to revascularization of the donor abdominal wall (AW), given the immediate proximity of the visceral organ and AWT. The authors report a novel AW revascularization technique during a synchronous small bowel and AWT in a 37-year-old man.

Lymphocyte depletion and risk of acute rejection in renal transplant recipients at increased risk for delayed graft function.

Delayed graft function (DGF) is a risk factor for acute rejection (AR) in renal transplant recipients, and KDIGO guidelines suggest use of lymphocyte-depletion induction when DGF is anticipated. We analyzed the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database to assess the impact of induction immunosuppression on the risk of AR in deceased kidney recipients based on pretransplant risk of DGF using a validated model. Recipients were categorized into 4 groups based upon the induction immunosuppression: (1) Rabbit anti-thymocyte globulin (rATG); (2) Alemtuzumab (C1H); (3) IL2-receptor antagonists (IL2-RA; basiliximab or daclizumab), and (4) No antibody induction. The primary endpoint for analysis was a composite endpoint of treated AR or graft failure by 1-year posttransplantation. Compared to no antibody induction, rATG and C1H had consistently lower adjusted odds of the composite endpoint across all risk strata for DGF risk, whereas IL2-Ra was associated with increased adjusted odds of the composite endpoint with increasing DGF risk. When the induction agents were compared, rATG and C1H were associated with decreasing adjusted odds for the composite endpoint with increasing risk of DGF, especially at the higher risk spectrum of DGF. Consideration must be given to use of lymphocyte-depletion induction when the anticipated risk of DGF is increased.

Pancreas Transplantation: Indications, Techniques, and Outcomes.

Pancreas transplantation treats insulin-dependent diabetes with or without concurrent end-stage renal disease. Pancreas transplantation increases survival versus no transplant, increases survival when performed as simultaneous pancreas-kidney versus deceased-donor kidney alone, and improves quality of life. Careful donor and recipient selection are paramount to good outcomes. Several technical variations exist for implantation: portal versus systemic vascular drainage and jejunal versus duodenal versus bladder exocrine drainage. Complications are most frequently technical in the first year and immunologic thereafter. Graft rejection is challenging to diagnose and is treated selectively. Islet cell transplantation currently has inferior outcomes to whole-organ pancreas transplantation.

Application of a Novel CT-Based Iliac Artery Calcification Scoring System for Predicting Renal Transplant Outcomes.

OBJECTIVE: The objective of our study was to assess whether the degree and distribution of iliac artery calcifications as determined by a CT-based calcium scoring system correlates with outcomes after renal transplant. MATERIALS AND METHODS: A retrospective review of renal transplant recipients who underwent CT of the pelvis within 2 years before surgery yielded 131 patients: 75 men and 56 women with a mean age of 52 years. Three radiologists assigned a separate semiquantitative score for calcification length, circumferential involvement, and morphology for the common iliac arteries and for the external iliac arteries. The operative and clinical notes were reviewed to determine which iliac arterial segment was used for anastomosis, the complexity of the operation, and whether delayed graft function (DGF) occurred. Renal allograft survival and patient survival were calculated using the Kaplan-Meier technique. RESULTS: Excellent interobserver agreement was noted for each calcification score category. The common iliac arteries showed significantly higher average calcification scores than the external iliac arteries for all categories. Advanced age and diabetes mellitus were independently predictive of higher scores in each category, whereas hypertension, cigarette smoking, hyperlipidemia, and sex were not. Based on multivariate analysis, only the calcification morphology score of the arterial segment used for anastomosis was independently predictive of a higher rate of surgical complexity and of DGF. None of the scores was predictive of graft or patient survival. However, patients with CT evidence of iliac arterial calcification had a lower 1-year survival after transplant than those who did not (92% vs 98%, respectively; p = 0.05). CONCLUSION: Only the calcification morphology score of the arterial segment used for anastomosis was significantly predictive of surgical complexity and of DGF. Routine pretransplant CT for calcification scoring in patients of advanced age or those with diabetes mellitus may enable selection of the optimal artery for anastomosis to optimize outcomes.

Outcomes in kidney transplant recipients from older living donors.

BACKGROUND: Previous studies demonstrate that graft survival from older living kidney donors (LD; age>60 years) is worse than younger LD but similar to deceased standard criteria donors (SCD). Limited sample size has precluded more detailed analyses of transplants from older LD. METHODS: Using the United Network for Organ Sharing database from 1994 to 2012, recipients were categorized by donor status: SCD, expanded criteria donor (ECD), or LD (by donor age: <60, 60-64, 65-69, ≥70 years). Adjusted models, controlling for donor and recipient risk factors, evaluated graft and recipient survivals. RESULTS: Of 250,827 kidney transplants during the study period, 92,646 were LD kidneys, with 4.5% of these recipients (n=4,186) transplanted with older LD kidneys. The use of LD donors 60 years or older increased significantly from 3.6% in 1994 to 7.4% in 2011. Transplant recipients with older LD kidneys had significantly lower graft and overall survival compared to younger LD recipients. Compared to SCD recipients, graft survival was decreased in recipients with LD 70 years or older, but overall survival was similar. Older LD kidney recipients had better graft and overall survival than ECD recipients. CONCLUSIONS: As use of older kidney donors increases, overall survival among kidney transplant recipients from older living donors was similar to or better than SCD recipients, better than ECD recipients, but worse than younger LD recipients. With increasing kidney donation from older adults to alleviate profound organ shortages, the use of older kidney donors appears to be an equivalent or beneficial alternative to awaiting deceased donor kidneys.

The need for inducing tolerance in vascularized composite allotransplantation.

Successful hand and face transplantation in the last decade has firmly established the field of vascularized composite allotransplantation (VCA). The experience in VCA has thus far been very similar to solid organ transplantation in terms of the morbidity associated with long-term immunosuppression. The unique immunological features of VCA such as split tolerance and resistance to chronic rejection are being investigated. Simultaneously there has been laboratory work studying tolerogenic protocols in animal VCA models. In order to optimize VCA outcomes, translational studies are needed to develop less toxic immunosuppression and possibly achieve donor-specific tolerance. This article reviews the immunology, animal models, mixed chimerism & tolerance induction in VCA and the direction of future research to enable better understanding and wider application of VCA.

Immunosuppressive protocols and immunological challenges related to hand transplantation.

There are many immunological challenges related to hand transplantation. Curbing the immune system's ability to effectively mount an immune response against the graft is the goal. As the various components of the immune response are defined and their mechanisms of action delineated, more specific immunosuppressive agents and protocols have been developed. Complications related to immunosuppression in hand transplant recipients are similar to incidences among solid organ recipients. With longer follow-up, the increased cardiovascular risk factors or the development of a neoplasm will likely cause mortality. Standardizing immunosuppression in hand transplantation with the long-term goal of minimization is critically needed.

Development of an upper extremity transplant program.

Starting a hand transplant program poses tremendous challenges. Solid organ transplantation and hand replantation are time-tested procedures and are now standard of care. Hand transplantation is the amalgamation of the scientific principles of reconstructive surgery and the concepts of organ transplantation. Thus, for any hand transplant program to be successful, there must be collaboration within a multidisciplinary team comprising a core group of hand and transplant surgeons. Such a joint effort can overcome the challenges that are inherent in a complex therapeutic option that integrates different disciplines and organizations during the planning, procedural, and posttransplant phases.

Perioperative anticoagulation and antiplatelet therapy in renal transplant: is there an increase in bleeding complication?

BACKGROUND: Renal transplant recipients may have comorbidities requiring anticoagulation or antiplatelet therapy. While the effects of warfarin may be neutralized with plasma infusion, those of aspirin and clopidogrel are not easily reversible and may be associated with an increased risk of bleeding. We conducted this study to evaluate the risk of bleeding complications in patients receiving perioperative anticoagulation or antiplatelet therapy. METHODS: Medical records of patients who underwent renal transplantation from July 1, 2005 to April 30, 2009 were retrospectively reviewed. Patients receiving perioperative anticoagulation or antiplatelet therapy were identified. The incidence of reoperation, transfusion utilization and decrease in serum hemoglobin from pre-operative value (ΔHgb) were compared to those on no therapy. RESULTS: Of the 327 patients identified, 105 received pre-operative anticoagulation or antiplatelet therapy, 28 received therapy post-operatively, while 213 patients received no therapy. The incidence of reoperation, transfusion utilization and ΔHgb were not significantly increased with pre-operative anticoagulation or antiplatelet therapy. With post-operative heparin infusion, the incidence of reoperation and transfusion utilization were significantly increased (p values < 0.001). Patients with activated partial thromboplastin times (aPTT) >80 s experienced significant bleeding complications. CONCLUSION: A supratherapeutic aPTT with post-operative heparin infusion was associated with the greatest risk of bleeding complication.

Minimally invasive liver resection for metastatic colorectal cancer: a multi-institutional, international report of safety, feasibility, and early outcomes.

OBJECTIVE: To evaluate a multicenter, international series on minimally invasive liver resection for colorectal carcinoma (CRC) metastasis. SUMMARY BACKGROUND DATA: Multiple single series have been reported on laparoscopic liver resection for CRC metastasis. We report the first collaborative multicenter, international series to evaluate the safety, feasibility, and oncologic integrity of laparoscopic liver resection for CRC metastasis. METHODS: We retrospectively reviewed all patients who underwent minimally invasive liver resection for CRC metastasis from February 2000 to September 2008 from multiple medical centers from the United States and Europe. The multicenter series of patients were accumulated into a single database. Patient demographics, preoperative, operative, and postoperative characteristics were analyzed. Actuarial overall survival was calculated with Kaplan-Meier analysis. RESULTS: A total of 109 patients underwent minimally invasive liver resection for CRC metastasis. The median age was 63 years (range, 32-88 years) with 51% females. The most common sites of primary colon cancer were sigmoid/rectum (51%), right colon (25%), and left colon (13%). Synchronous liver lesions were present in 11% of patients. For those with metachronous lesions liver lesions, the median time interval from primary colon cancer surgery to liver metastasectomy was 12 months. Preoperative chemotherapy was administered in 68% of cases prior to liver resection. The majority of patients underwent prior abdominal operations (95%). Minimally invasive approaches included totally laparoscopic (56%) and hand-assisted laparoscopic (41%), the latter of which was employed more frequently in the US medical centers (85%) compared with European centers (13%) (P = 0.001). There were 4 conversions to open surgery (3.7%), all due to bleeding. Extents of resection include wedge/segmentectomy (34%), left lateral sectionectomy (27%), right hepatectomy (28%), left hepatectomy (9%), extended right hepatectomy (0.9%), and caudate lobectomy (0.9%). Major liver resections (> or =3 segments) were performed in 45% of patients. Median OR time was 234 minutes (range, 60-555 minutes) and blood loss was 200 mL (range, 20-2500 mL) with 10% receiving a blood transfusion. There were no reported perioperative deaths and a 12% complication rate. Median length of hospital stay for the entire series was 4 days (range, 1-22 days) with a shorter stay in medical centers in the United States (3 days) versus that seen in Europe (6 days) (P = 0.001). Negative margins were achieved in 94.4% of patients. Actuarial overall survivals at 1-, 3-, and 5-year for the entire series were 88%, 69%, and 50%, respectively. Disease-free survivals at 1-, 3-, and 5-year were 65%, 43%, and 43%, respectively. CONCLUSIONS: Minimally invasive liver resection for colorectal metastasis is safe, feasible, and oncologically comparable to open liver resection for both minor and major liver resections, even with prior intra-abdominal operations, in selected patients and when performed by experienced surgeons.