Multilevel Analysis of the Neovascularization and Integration Process of a Nonvascularized Rectus Fascia Transplantation.

Background: Failure to close the abdominal wall after intestinal transplantation (ITx) or multivisceral Tx remains a surgical challenge. An attractive method is the use of nonvascularized rectus fascia (NVRF) in which both layers of the donor abdominal rectus fascia are used as an inlay patch without vascular anastomosis. How this graft integrates over time remains unknown. The study aims to provide a multilevel analysis of the neovascularization and integration process of the NVRF. Methods: Three NVRF-Tx were performed after ITx. Clinical, radiological, histological, and immunological data were analyzed to get insights into the neovascularization and integration process of the NVRF. Moreover, cryogenic contrast-enhanced microfocus computed tomography (microCT) analysis was used for detailed reconstruction of the vasculature in and around the NVRF (3-dimensional histology). Results: Two men (31- and 51-y-old) and 1 woman (49-y-old) underwent 2 multivisceral Tx and 1 combined liver-ITx, respectively. A CT scan showed contrast enhancement around the fascia graft at 5 days post-Tx. At 6 weeks, newly formed blood vessels were visualized around the graft with Doppler ultrasound. Biopsies at 2 weeks post-Tx revealed inflammation around the NVRF and early fibrosis. At 6 months, classical 2-dimensional histological analysis of a biopsy confirmed integration of the fascia graft with strong fibrotic reaction without signs of rejection. A cryogenic contrast-enhanced microCT scan of the same biopsy revealed the presence of microvasculature, enveloping and penetrating the donor fascia. Conclusions: We showed clinical, histological, and microCT evidence of the neovascularization and integration process of the NVRF after Tx.

New insights in immunomodulation for intestinal transplantation.

Tolerance is the Holy Grail of solid organ transplantation (SOT) and remains its primary challenge since its inception. In this topic, the seminal contributions of Thomas Starzl at Pittsburgh University outlined foundational principles of graft acceptance and tolerance, with chimerism emerging as a pivotal factor. Immunologically, intestinal transplantation (ITx) poses a unique hurdle due to the inherent characteristics and functions of the small bowel, resulting in increased immunogenicity. This necessitates heavy immunosuppression (IS) while IS drugs side effects cause significant morbidity. In addition, current IS therapies fall short of inducing clinical tolerance and their discontinuation has been proven unattainable in most cases. This underscores the unfulfilled need for immunological modulation to safely reduce IS-related burdens. To address this challenge, the Leuven Immunomodulatory Protocol (LIP), introduced in 2000, incorporates various pro-tolerogenic interventions in both the donor to the recipient, with the aim of facilitating graft acceptance and improving outcome. This review seeks to provide an overview of the current understanding of tolerance in ITx and outline recent advances in this domain.

Treatment of Complex Desmoid Tumors in Familial Adenomatous Polyposis Syndrome by Intestinal Transplantation.

Background: Desmoid tumors are fibroblastic lesions which often have an unpredictable and variable clinical course. In the context of familial adenomatous polyposis (FAP), these frequently occur intra-abdominally, especially in the small-bowel mesentery resulting in sepsis, fistulation, and invasion of the abdominal wall and retroperitoneum. In selected cases where other modalities have failed, the most radical option is to perform a total enterectomy and intestinal transplantation (ITx). In this study, we present our center's experience of ITx for desmoid in patients with FAP. Methods: We performed a retrospective review of our prospectively collected database between 2007 and 2022. All patients undergoing ITx for FAP-related desmoid were included. Results: Between October 2007 and September 2023, 144 ITx were performed on 130 patients at our center. Of these, 15 patients (9%) were for desmoid associated with FAP (7 modified multivisceral transplants, 6 isolated ITx, and 2 liver-containing grafts). The median follow-up was 57 mo (8-119); 5-y patient survival was 82%, all with functioning grafts without local desmoid recurrence. These patients presented us with several complex surgical issues, such as loss of abdominal domain, retroperitoneal/abdominal wall involvement, ileoanal pouch-related issues, and the need for foregut resection because of adenomatous disease. Conclusions: ITx is a viable treatment in selected patients with FAP and extensive desmoid disease. The decision to refer for ITx can be challenging, particularly the timing and sequence of treatment (simultaneous versus sequential exenteration). Delays can result in additional disease burden, such as secondary liver disease or invasion of adjacent structures.

INT-767-A Dual Farnesoid-X Receptor (FXR) and Takeda G Protein-Coupled Receptor-5 (TGR5) Agonist Improves Survival in Rats and Attenuates Intestinal Ischemia Reperfusion Injury.

Intestinal ischemia is a potentially catastrophic emergency, with a high rate of morbidity and mortality. Currently, no specific pharmacological treatments are available. Previous work demonstrated that pre-treatment with obeticholic acid (OCA) protected against ischemia reperfusion injury (IRI). Recently, a more potent and water-soluble version has been synthesized: Intercept 767 (INT-767). The aim of this study was to investigate if intravenous treatment with INT-767 can improve outcomes after IRI. In a validated rat model of IRI (60 min ischemia + 60 min reperfusion), three groups were investigated (n = 6/group): (i) sham: surgery without ischemia; (ii) IRI + vehicle; and (iii) IRI + INT-767. The vehicle (0.9% NaCl) or INT-767 (10 mg/kg) were administered intravenously 15 min after start of ischemia. Endpoints were 7-day survival, serum injury markers (L-lactate and I-FABP), histology (Park-Chiu and villus length), permeability (transepithelial electrical resistance and endotoxin translocation), and cytokine expression. Untreated, IRI was uniformly lethal by provoking severe inflammation and structural damage, leading to translocation and sepsis. INT-767 treatment significantly improved survival by reducing inflammation and preserving intestinal structural integrity. This study demonstrates that treatment with INT-767 15 min after onset of intestinal ischemia significantly decreases IRI and improves survival. The ability to administer INT-767 intravenously greatly enhances its clinical potential.

Intestinal Donation and Utilization: Single-Center Analysis Within Eurotransplant.

Intestinal donor criteria are classically kept strict, thereby limiting donor supply. Indications for intestinal transplantation (ITx) are rare, but improved outcome and new emerging indications lead to increased demand and relaxing donor criteria should be considered. We sought to compare the donor criteria of intestines transplanted at our center with predefined (per protocol) criteria, and to determine how relaxing donor criteria could impact the potential donor pool. Donor criteria used in 22 consecutive ITx at our center between 2000 and 2020 were compared with predefined criteria. Next, multiorgan donors effectively offered by our Donor Network to Eurotransplant between 2014 and 2020 were retrospectively screened, according to predefined and effectively used intestinal donation criteria. Finally, utilization rate of offered intestines was calculated. In our ITx series, the effectively used donor criteria were less strict than those initially predefined. With these relaxed criteria, a favorable 5-year graft/patient survival of 75% and 95%, respectively was reached. Applying these relaxed criteria would lead to a 127% increase in intestinal offers. Paradoxically, 70% of offered intestines were not used. In conclusion, a significant increase in intestinal donation could be obtained by relaxing donor criteria, while still achieving excellent outcome. Offered intestines are underutilized.

Intravenous Polyethylene Glycol Alleviates Intestinal Ischemia-Reperfusion Injury in a Rodent Model.

Intestinal ischemia-reperfusion injury (IRI) is a common clinical entity, and its outcome is unpredictable due to the triad of inflammation, increased permeability and bacterial translocation. Polyethylene glycol (PEG) is a polyether compound that is extensively used in pharmacology as an excipient in various products. More recently, this class of products have shown to have potent anti-inflammatory, anti-apoptotic, immunosuppressive and cell-membrane-stabilizing properties. However, its effects on the outcome after intestinal IRI have not yet been investigated. We hypothesized that PEG administration would reduce the effects of intestinal IRI in rodents. In a previously described rat model of severe IRI (45 min of ischemia followed by 60 min of reperfusion), we evaluated the effect of IV PEG administration at different doses (50 and 100 mg/kg) before and after the onset of ischemia. In comparison to control animals, PEG administration stabilized the endothelial glycocalyx, leading to reduced reperfusion edema, bacterial translocation and inflammatory reaction as well as improved 7-day survival. These effects were seen both in a pretreatment and in a treatment setting. The fact that this product is readily available and safe should encourage further clinical investigations in settings of intestinal IRI, organ preservation and transplantation.

Outcome After Intestinal Transplantation From Living Versus Deceased Donors: A Propensity-matched Cohort Analysis of the International Intestinal Transplant Registry.

OBJECTIVE: To describe the worldwide experience with living donation (LD) in intestinal transplantation (ITx) and compare short-term and long-term outcomes to a propensity-matched cohort of deceased donors. BACKGROUND: ITx is a rare life-saving procedure for patients with complicated intestinal failure (IF). Living donation (LD)-ITx has been performed with success, but no direct comparison with deceased donation (DD) has been performed. The Intestinal Transplant Registry (ITR) was created in 1985 by the Intestinal Transplant Association to capture the worldwide activity and promote center's collaborations. METHODS: Based on the ITR, 4156 ITx were performed between January 1987 and April 2019, of which 76 (1.8%) were LD, including 5 combined liver-ITx, 7 ITx-colon, and 64 isolated ITx. They were matched with 186 DD-ITx for recipient age/sex, weight, region, IF-cause, retransplant, pretransplant status, ABO compatibility, immunosuppression, and transplant date. Primary endpoints were acute rejection and 1-/5-year patient/graft survival. RESULTS: Most LDs were performed in North America (61%), followed by Asia (29%). The mean recipient age was: 22 years; body mass index: 19kg/m²; and female/male ratio: 1/1.4. Volvulus (N=17) and ischemia (N=17) were the most frequent IF-causes. Fifty-two percent of patients were at home at the time of transplant. One-/5-year patient survival for LD and DD was 74.2/49.8% versus 80.3/48.1%, respectively ( P =0.826). One-/5-year graft survival was 60.3/40.6% versus 69.2/36.1%, respectively ( P =0.956). Acute rejection was diagnosed in 47% of LD versus 51% of DD ( P =0.723). CONCLUSION: Worldwide, LD-ITx has been rarely performed. This retrospective matched ITR analysis revealed no difference in rejection and in patient/graft survival between LD and DD-ITx.

Protective Effect of Oxygen and Isoflurane in Rodent Model of Intestinal Ischemia-Reperfusion Injury.

Animal research in intestinal ischemia-reperfusion injury (IRI) is mainly performed in rodent models. Previously, intraperitoneal (I.P.) injections with ketamine-xylazine mixtures were used. Nowadays, volatile anesthetics (isoflurane) are more common. However, the impact of the anesthetic method on intestinal IRI has not been investigated. We aim to analyze the different anesthetic methods and their influence on the extent of intestinal IRI in a rat model. Male Sprague-Dawley rats were used to investigate the effect of I.P. anesthesia on 60 min of intestinal ischemia and 60 min of reperfusion in comparison to hyperoxygenation (100% O2) and volatile isoflurane anesthesia. In comparison to I.P. anesthesia with room air (21% O2), supplying 100% O2 improved 7-day survival by cardiovascular stabilization, reducing lactic acidosis and preventing vascular leakage. However, this had no effect on the intestinal epithelial damage, permeability, and inflammatory response observed after intestinal IRI. In contrast to I.P. + 100% O2, isoflurane anesthesia reduced intestinal IRI by preventing ongoing low-flow reperfusion hypotension, limiting intestinal epithelial damage and permeability, and by having anti-inflammatory effects. When translating the aforementioned results of this study to clinical situations, such as intestinal ischemia or transplantation, the potential protective effects of hyperoxygenation and volatile anesthetics require further research.

Closing the abdomen: update on the current surgical toolkit.

PURPOSE OF REVIEW: Achieving abdominal wall closure after intestinal transplantation (ITx) is one of the crucial surgical challenges. This problem is present in 25-50% of all transplants due to reduction in abdominal domain, fistulae and extensive adhesions due to previous surgeries. Failure to achieve closure is an independent risk factor for mortality and graft loss. The aim of this paper is to summarize the current options to achieve this. RECENT FINDINGS: Successful closure of the abdomen requires a tension-free repair. Primary closure of the fascia can be reinforced with synthetic or biological mesh. For more complex fascial defects bridging mesh, nonvascularised or vascularised rectus fascia can be utilised. If all components of the abdominal wall are affected, then a full-thickness abdominal wall transplantation may be necessary. SUMMARY: A variety of successful techniques have been described by different groups to enable abdominal wall closure after ITx. Emerging developments in preoperative imaging, reconstructive surgery and immunology have expanded the surgical toolkit available. Crucial is a tailor-made approach whereby patients with expected closure issues are identified prior to surgery and the simplest technique is chosen.

Combined liver-intestinal and multivisceral transplantation for neuroendocrine tumors extending beyond the liver: A systematic literature review.

BACKGROUND: Neuroendocrine tumors (NET) have an increasing incidence and are characterized by an invasive and metastatic presentation, rendering a curative resection not always feasible. For some patients the only life-saving option would be a multivisceral transplantation (MvTx). This systematic review aims to summarize the reported experience on combined liver-intestinal and MvTx for NET according PRISMA-guidelines. METHODS: PubMed, EMBASE and Cochrane Controlled Trial Reports were searched until April 7, 2020. Structured data abstraction was performed, and methodological quality assessed. RESULTS: Fourteen single-center and three multicenter retrospective studies reported on 1 combined liver-intestinal and 38 MvTx for NET. Nine previously unreported MvTx were added to the analysis. This review found that: i) overall patient survival of 51.2% is attainable; ii) recurrence of 35% is similar to recurrence after liver transplantation for NET; and iii) NET with diffuse abdominal presentation, normally considered a contraindication, could actually benefit from radical resection and MvTx. Data on tailoring of immunosuppression and (neo-)adjuvant treatment are limited, and further studies are needed to optimize post-transplant management. CONCLUSIONS: Although results are encouraging, the reported MvTx experience for NET is limited and requires more detailed prospective multicenter studies and appropriate follow-up and reporting.

Recanalization of portal axis after cavoportal hemitransposition in a liver transplant recipient with complete splanchnic thrombosis.

BACKGROUND: Diffuse splanchnic thrombosis may render standard LTx difficult or even technically impossible. A 19-year-old woman with acute-on-chronic Budd-Chiari syndrome and complete splanchnic thrombosis underwent conventional LTx. Only limited anatomical portal inflow could be restored, and urgent re-transplantation for recurrent splanchnic vein thrombosis became necessary. METHODS: At re-transplant, and in addition to the reestablishment of some portal inflow through the preserved original porto (native)-portal (graft) connection, a cavoportal shunt was created (first partial via 30% tapering of the vena cava, but eventually complete by total occlusion of the vena cava). RESULTS: The postoperative course was then uneventful, and interestingly, the native portomesenteric axis gradually reopened. Two years post-transplant, the liver graft is perfused via both physiological and non-physiological sources. Liver function is normal. There is no IVC syndrome and no residual PHT. She is leading a normal life. CONCLUSION: Creation of CPHT, in addition to the preservation of portal inflow from the native splanchnic system, should be considered in patients with diffuse splanchnic thrombosis, when sufficient physiological portal inflow cannot be restored at the time of LTx, but in whom the splanchnic circulation may reopen up later.

Multivisceral Transplantation for Diffuse Portomesenteric Thrombosis: Lessons Learned for Surgical Optimization.

Background: Multivisceral transplantation entails the en-bloc transplantation of stomach, duodenum, pancreas, liver and bowel following resection of the native organs. Diffuse portomesenteric thrombosis, defined as the complete occlusion of the portal system, can lead to life-threatening gastrointestinal bleeding, malnutrition and can be associated with liver and intestinal failure. Multivisceral transplantation is the only procedure that offers a definitive solution by completely replacing the portal system. However, this procedure is technically challenging in this setting. The aim of this study is to describe our experience, highlight the challenges and propose technical solutions. Materials and Methods: We performed a retrospective analysis of our cohort undergoing multivisceral transplantation for diffuse portomesenteric thrombosis at our institution from 2000 to 2020. Donor and recipient demographics and surgical strategies were reviewed in detail and posttransplant complications and survival were analyzed. Results: Five patients underwent MVTx. Median age was 47 years (23-62). All had diffuse portomesenteric thrombosis with life-threatening variceal bleeding. Major blood loss during exenteration was avoided by combining two techniques: embolization of the native organs followed by a novel, staged extraction. This prevented major perioperative blood loss [median intra-operative transfusion of 3 packed red blood cell units (0-5)]. Median CIT was 330 min (316-416). There was no perioperative death. One patient died due to invasive aspergillosis. Four others are alive and well with a median follow-up of 4.1 years (0.3-5.9). Conclusions: Multivisceral transplantation should be considered in patients with diffuse portomesenteric thrombosis that cannot be treated by any other means. We propose a standardized surgical approach to limit the operative risk and improve the outcome.

Cost-effectiveness of Intestinal Transplantation Compared to Parenteral Nutrition in Adults.

BACKGROUND: Intestinal transplantation (ITx) is the most expensive abdominal organ transplant. Detailed studies about exact costs and cost-effectiveness compared to home parenteral nutrition (HPN) therapy in chronic intestinal failure are lacking. The aim is to provide an in-depth analysis of ITx costs and evaluate cost-effectiveness compared to HPN. METHODS: To calculate costs before and after ITx, costs were analyzed in 12 adult patients. To calculate the costs of patients with uncomplicated chronic intestinal failure, 28 adults, stable HPN patients were studied. Total costs including surgery, admissions, diagnostics, HPN therapy, medication, and ambulatory care were included. Median (range) costs are given. RESULTS: Costs before ITx were €69 160 (€60 682-90 891) in year 2, and €104 146 (€83 854-186 412) in year 1. After ITx, costs were €172 133 (€122 483-351 407) in the 1st year, €40 619 (€3905-113 154) in the 2nd year, and dropped to €15 743 (€4408-138 906) in the 3rd year. In stable HPN patients, the costs were €83 402 (€35 364-169 146) in the 1st year, €70 945 (€31 955-117 913) in the 2nd year, and stabilized to €60 242 (€29 161-238 136) in the 3rd year. CONCLUSIONS: ITx, although initially very expensive, is cost-effective compared to HPN in adults by year 4, and cost-saving by year 5.

Paneth Cell Alterations During Ischemia-reperfusion, Follow-up, and Graft Rejection After Intestinal Transplantation.

BACKGROUND: Ischemia-reperfusion injury is inevitable during intestinal transplantation (ITx) and executes a key role in the evolution towards rejection. Paneth cells (PCs) are crucial for epithelial immune defense and highly vulnerable to ischemia-reperfusion injury. We investigated the effect of ITx on PC after reperfusion (T0), during follow-up, and rejection. Moreover, we investigated whether PC loss was associated with impaired graft homeostasis. METHODS: Endoscopic biopsies, collected according to center protocol and at rejection episodes, were retrospectively included (n = 28 ITx, n = 119 biopsies) Biopsies were immunohistochemically co-stained for PC (lysozyme) and apoptosis, and PC/crypt and lysozyme intensity were scored. RESULTS: We observed a decrease in PC/crypt and lysozyme intensity in the first week after ITx (W1) compared with T0. There was a tendency towards a larger decline in PC/crypt (P = 0.08) and lysozyme intensity (P = 0.08) in W1 in patients who later developed rejection compared with patients without rejection. Follow-up biopsies showed that the PC number recovered, whereas lysozyme intensity remained reduced. This persisting innate immune defect may contribute to the well-known vulnerability of the intestine to infection. There was no clear evidence that PCs were affected throughout rejection. CONCLUSIONS: This study revealed a transient fall in PC numbers in the early post-ITx period but a permanent reduction in lysozyme intensity following ITx. Further research is needed to determine the potential clinical impact of PC impairment after ITx.

Current state of adult intestinal transplantation in Europe.

PURPOSE OF REVIEW: In Europe, adult intestinal transplantation (ITx) has continuously evolved since the first successful case in 1989. However, despite several recent innovations, no significant improvement in survival has been seen since 2005, illustrating the unique difficulty of transplanting the intestine. In this review, a subanalysis of adult ITx in Europe is discussed and recent publications on adult ITx in Europe are presented. RECENT FINDINGS: Increased medical and surgical arsenal in the treatment of intestinal failure reduce the need for ITx. At the same time, new indications (diffuse ischemia) have emerged. Static cold storage after vascular flush remains the gold standard but promising results are shown with additional luminal preservation. Pretransplant embolization facilitates multivisceral transplantation. Chronic rejection remains a major difficulty to tackle and currently, liver inclusion is the only effective strategy. Treatment of graft-versus-host-disease remains debated. Quality of life substantially improves after successful ITx. ITx becomes cost-effective three years after transplantation. SUMMARY: ITx remains more challenging than other solid organ transplants. However, long term outcome, particularly after combined liver and ITx, is excellent and similar to other solid organ transplants. Further studies are warranted to tackle the fundamental immunobiological challenge that ITx represents.

Obesity alters adrenergic and chemosensory signaling pathways that regulate ghrelin secretion in the human gut.

Chemosensory signaling in organs such as the mouth and gut contributes to the mechanisms that control metabolism. We investigated the chemosensory pathways that regulate secretion of the hunger hormone ghrelin in response to neurotransmitters, bitter and sweet tastants at the cellular level in the human gut mucosa, and the disturbances in this regulatory pathway induced by obesity. Obesity impaired ghrelin protein production and adrenalin-induced ghrelin secretion in fundic cells, which was counterbalanced by somatostatin. Bitter agonists selective for taste receptor type 2 (TAS2Rs), TAS2R5 and TAS2R10 stimulated ghrelin secretion in fundic cells. The stimulatory effect of the broadly tuned bitter agonist, denatonium benzoate, was selectively blunted by obesity in the small intestine but not in the fundus. Luminal glucose concentrations inhibited ghrelin secretion via sodium-dependent glucose cotransporter and taste receptor type 1 member 3. Obesity altered the sensitivity of the ghrelin cell to glucose in the small intestine but not in the fundus. Sweet taste receptor activation inhibited bitter taste signaling of the ghrelin cell. In conclusion, obesity impairs the sympathetic drive that controls ghrelin release in the fundus and affects the sensitivity of the ghrelin cell to bitter and sweet stimuli in the small intestine but not in the fundus. Region-selective targeting of gut taste receptors in obesity is indicated.-Wang, Q., Liszt, K. I., Deloose, E., Canovai, E., Thijs, T., Farré, R., Ceulemans, L. J., Lannoo, M., Tack, J., Depoortere, I. Obesity alters adrenergic and chemosensory signaling pathways that regulate ghrelin secretion in the human gut.

Cost analysis of chronic intestinal failure.

BACKGROUND & AIMS: Chronic intestinal failure is a complex medical condition which is associated with high costs. These patients require long-term home parenteral nutrition (HPN) and costs are compounded by frequent admissions for the underlying disease and HPN. However, it is unknown what the specific costs subdivisions are and how they evolve over time. The aim of the study was to evaluate the cost dynamics of HPN care in a cohort of stable, long-term intestinal failure patients. METHODS: A retrospective analysis of our single-center long-term (>2 years), benign HPN population was performed. All relevant clinical and financial data were collected: costs of hospital admissions, diagnostics, treatments, out-patient clinics, home care, medication, materials and HPN education. The costs were tabulated and assigned by cause (HPN related, underlying disease-related or -unrelated). Patients with complicated intestinal failure (defined as impending loss of vascular access, liver failure or recurrent fluid/electrolyte disorders) were excluded. Data are presented as median (range). RESULTS: Thirty-seven patients (24 female; age 58.6 ± 13.3 years) were included in the study. HPN duration was 5.3 years (2.1-15.1) at 4.3 infusion days per week (1.5-7). Total cost of the first HPN year was €83,503 (35,364-256,780). HPN-related costs accounted for 69% (€57,593) vs 27% for underlying disease-related costs (€22,505) and 4% for disease-unrelated costs (€3065). HPN complications cost €16,077 in the first year and accounted for 31% of HPN costs. The total cost dropped by 15% in the second year to €71,311. This reduction was due to fewer hospital admissions and fewer HPN complications. This trend continued and by year 5 the annual cost was 40% cheaper compared to year 1 (€58,187 vs €83,503). CONCLUSIONS: HPN related costs accounted for the majority of the total expenses in IF patients. The costs declined after the first year due to a reduction in complications and hospital admissions.