The First 5 Years of Uterus Transplant in the US: A Report From the United States Uterus Transplant Consortium.

Importance: Uterus transplant is a viable surgical treatment for women affected by absolute uterine-factor infertility, which affects 1 in 500 women. Objective: To review transplant and birth outcomes of uterus transplant recipients in the US since the first case in 2016. Design, Setting, and Participants: In this cohort study, 5 years of uterus transplant outcome data were collected from the 3 centers performing uterus transplants in the US: Baylor University Medical Center, Dallas, Texas; Cleveland Clinic, Cleveland, Ohio; and University of Pennsylvania, Philadelphia. A total of 33 women with absolute uterine-factor infertility who underwent uterus transplant between February 2016 and September 2021 were included. Main Outcomes and Measures: Graft survival, live birth, and neonatal outcome. Results: Of the 33 included uterus transplant recipients, 2 (6%) were Asian, 1 (3%) was Black, 1 (3%) was South Asian, and 29 (88%) were White; the mean (SD) age was 31 (4.7) years; and the mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 24 (3.6). Most uterus transplant recipients (31 of 33 [94%]) had a congenitally absent uterus (Mayer-Rokitansky-Küster-Hauser syndrome), and 21 of 33 (64%) received organs from living donors. Mean (range) follow-up was 36 (1-67) months. There was no donor or recipient mortality. One-year graft survival was 74% (23 of 31 recipients). Through October 2021, 19 of 33 recipients (58%) had delivered 21 live-born children. Among recipients with a viable graft at 1 year, the proportion with a live-born child was 83% (19 of 23). The median (range) gestational age at birth of neonates was 36 weeks 6 days (30 weeks, 1 day to 38 weeks), and the median (range) birth weight was 2860 (1310-3940) g (median [range], 58th [6th-98th] percentile). No congenital malformations were detected. Conclusions and Relevance: Uterus transplant is a surgical therapy that enables women with uterine-factor infertility to successfully gestate and deliver children. Aggregate data from US centers demonstrate safety for the recipient, living donor, and child. These data may be used to counsel women with uterine-factor infertility on treatment options.

Benign course of residual inflammation at end of treatment of liver transplant recipients after sofosbuvir based therapy.

BACKGROUND: Persistent inflammation on histology after successful hepatitis C (HCV) treatment has been reported. However, data regarding the long-term impact in liver transplant recipients is limited, particularly after using direct-acting antiviral (DAA) therapies. AIM: To evaluate the impact of successful treatment with DAAs on histological changes and occult HCV and to describe the clinical course of residual inflammation in liver transplant recipients. METHODS: We conducted a case series of 13 chronic HCV infected liver transplant recipients successfully treated with DAAs between December 2013 and May 2014. All patients were treated for 24 wk and had non-detectable serum HCV RNA by the time of biopsy. Only patients with at least one liver biopsy at or after treatment were included. We examined liver biopsies for evidence of residual inflammation and the presence of intrahepatic HCV RNA. RESULTS: Persistent inflammation was seen in 12/13 patients on end of treatment biopsy. Inflammation was still seen in the available five follow-up biopsies (range 38-48 wk after the end of treatment). Intrahepatic HCV RNA was undetectable in all biopsies. All patients had preserved graft function for a mean follow-up of 2.5 years, except one that developed chronic rejection. CONCLUSION: After successful HCV treatment with DAAs, liver transplant recipients may have persistent inflammation on biopsy without evidence of intracellular RNA. The clinical outcome remained favorable in most patients. Further studies with a larger number and longer follow-up are needed to establish the implication of this finding on long-term graft function.

Pilot study to determine the safety and feasibility of deceased donor liver natural killer cell infusion to liver transplant recipients with hepatocellular carcinoma.

Liver transplantation (LT) is a viable treatment option for cirrhosis patients with hepatocellular carcinoma (HCC). However, recurrence is the rate-limiting factor of long-term survival. To prevent this, we conducted the phase I study of the adoptive transfer of deceased donor liver-derived natural killer (NK) cells. Liver NK cells were extracted from donor liver graft perfusate and were stimulated in vitro with IL-2. The patient received an intravenous infusion of NK cells 3-5 days after LT. Eighteen LT recipients were treated. There were no severe cell infusion-related adverse events or acute rejection episodes. One patient withdrew from the study because the pathological observation revealed sarcoma instead of HCC. All patients who received this immunotherapy completed the follow-up for at least 2 years without evidence of HCC recurrence (median follow-up, 96 months [range, 17-121 months]). Considering that 9 (52.9%) of the 17 patients pathologically exceeded the Milan criteria, liver NK cell infusion is likely to be useful for preventing HCC recurrence after LT. This is the first-in-human immunotherapy study using deceased donor liver-derived NK cells to prevent HCC recurrence after LT. This treatment was well tolerated and resulted in no HCC recurrence after LT.Clinical trial registration www.clinicaltrials.gov ; NCT01147380; registration date: June 17, 2010.

Uterus transplantation: state of the art in 2021.

PURPOSE: To provide a comprehensive review of uterus transplantation in 2021, including a discussion of pregnancy outcomes of all reported births to date, the donor and recipient selection process, the organ procurement and transplant surgeries, reported complications, postoperative monitoring, preimplantation preparation, and ethical considerations. METHODS: Literature review and expert commentary. RESULTS: Reports of thirty-one live births following uterus transplantation have been published from both living and deceased donors. The proper selection of donors and recipients is a labor-intensive process that requires advanced planning. A multidisciplinary team is critical. Reported complications in the recipient include thrombosis, infection, vaginal stricture, antenatal complications, and graft failure. Graft rejection is a common occurrence but rarely leads to graft removal. While most embryo transfers are successful, recurrent implantation failures in uterus transplant patients have been reported. Rates of preterm delivery are high but appear to be declining; more data, including long-term outcome data, is needed. CONCLUSIONS: Uterus transplantation is an emerging therapy for absolute uterine factor infertility, a condition previously without direct treatment options. It is paramount that reproductive health care providers are familiar with the uterus transplantation process as more patients seek and receive this treatment.

First birth from a deceased donor uterus in the United States: from severe graft rejection to successful cesarean delivery.

Uterus transplantation is the only known potential treatment for absolute uterine factor infertility. It offers a unique setting for the investigation of immunologic adaptations of pregnancy in the context of the pharmacologic-induced tolerance of solid organ transplants, thus providing valuable insights into the early maternal-fetal interface. Until recently, all live births resulting from uterus transplantation involved living donors, with only 1 prior birth from a deceased donor. The Cleveland Clinic clinical trial of uterus transplantation opened in 2015. In 2017, a 35 year old woman with congenital absence of the uterus was matched to a 24 year old parous deceased brain-dead donor. Transplantation of the uterus was performed with vaginal anastomosis and vascular anastomoses bilaterally from internal iliac vessels of the donor to the external iliac vessels of the recipient. Induction and maintenance immunosuppression were achieved and subsequently modified in anticipation of pregnancy 6 months after transplant. Prior to planned embryo transfer, ectocervical biopsy revealed ulceration and a significant diffuse, plasma cell-rich mixed inflammatory cell infiltrate, with histology interpreted as grade 3 rejection suspicious for an antibody-mediated component. Aggressive immunosuppressive regimen targeting both cellular and humoral rejection was initiated. After 3 months of treatment, there was no histologic evidence of rejection, and after 3 months from complete clearance of rejection, an uneventful embryo transfer was performed and a pregnancy was established. At 21 weeks, central placenta previa with accreta was diagnosed. A healthy neonate was delivered by cesarean hysterectomy at 34 weeks' gestation. In summary, this paper highlights the first live birth in North America resulting from a deceased donor uterus transplant. This achievement underscores the capacity of the transplanted uterus to recover from a severe, prolonged rejection and yet produce a viable neonate. This is the first delivery from our ongoing clinical trial in uterus transplantation, including the first reported incidence of severe mixed cellular/humoral rejection as well as the first reported placenta accreta.

Evolving ethical issues with advances in uterus transplantation.

While uterus transplantation was once considered only a theoretical possibility for patients with uterine factor infertility, researchers have now developed methods of transplantation that have led to successful pregnancies with multiple children born to date. Because of the unique and significant nature of this type of research, it has been undertaken with collaboration not only with scientists and physicians but also with bioethicists, who paved the initial path for research of uterus transplantation to take place. As the science of uterus transplantation continues to advance, so too must the public dialogue among obstetrician/gynecologists, transplant surgeons, bioethicists, and other key stakeholders in defining the continued direction of research in addition to planning for the clinical implementation of uterus transplantation as a therapeutic option. Given the rapid advances in this field, the time has come to revisit the fundamental questions raised at the inception of uterus transplantation and, looking forward, determine the future of this approach given emerging data on the procedure's impact on individuals, families, and society.

New Frontier: Role of the Radiologist in Uterine Transplantation.

Uterine transplantation (UT) is a novel treatment for absolute uterine factor infertility (AUFI) that is currently being performed under experimental protocols in multiple medical centers worldwide. At the time of this publication, there have been at least 10 live births by women with a transplanted uterus. As successful outcomes from this innovative procedure increase, it is likely that more centers will perform UT. Imaging is performed in multiple steps of the UT process, including preoperative imaging of potential donors and recipients, posttransplant surveillance, and monitoring of pregnancy. Fetal imaging is performed by maternal-fetal medicine professionals, but most imaging examinations in UT are performed by radiologists. Given the significant role of imaging in this groundbreaking surgery, radiologists must be familiar with the causes of AUFI and the role of imaging in establishing this diagnosis. Radiologists working in medical centers where UT is performed should understand the role of imaging in preoperative planning and postoperative surveillance. While data regarding complications of UT are preliminary at best, radiologists must be aware of the risk of vascular compromise and graft failure and their imaging features. The authors provide a brief history of UT and define the radiologist's role in pre- and postoperative imaging assessments.©RSNA, 2019.

Uterus transplantation: organ procurement in a deceased donor model.

OBJECTIVE: To demonstrate our technique of uterine procurement from a deceased donor. DESIGN: This video uses live action footage from surgery and detailed illustrations to review the steps and techniques involved in deceased donor procurement surgery. SETTING: Academic medical center. PATIENT(S): A deceased multiorgan donor. INTERVENTION(S): Trial organ procurement of a viable uterus from a deceased donor. MAIN OUTCOME MEASURE(S): Procurement time and associated features of suitability of dissected specimen. RESULT(S): This video article describes the advantages of a deceased donor model over a live donor model, including eliminating the risk of surgical complications to a living donor, avoidance of ethical issues inherent in live donation, easier access to generous vascular pedicles for anastomosis, and faster procurement time. This video also outlines the key steps to a successful uterine procurement using illustrations and live action footage from a trial organ procurement. CONCLUSION(S): Uterine transplantation is an emerging surgical treatment for patients with absolute uterine factor infertility. Continued practice is essential in preparing for a deceased donor uterine procurement. The process continues to be refined and adapted as new information becomes available toward the goal of safe, efficient, ethical, and effective surgical treatment of absolute uterine factor infertility.

Decreased survival in hepatitis C patients with monomorphic post-transplant lymphoproliferative disorder after liver transplantation treated with frontline immunochemotherapy.

Post-transplant lymphoproliferative disorder (PTLD) develops in 1-3% of liver transplant recipients and no consensus exists about therapeutic management. From 2006 to 2016, 1489 liver transplants were performed at our institution with 20 patients (incidence 1.3%) developing PTLD. Hepatitis C virus (HCV) was the leading cause (n = 10) of liver transplant in PTLD patients. Diffuse large B-cell lymphoma was the most frequent histologic subtype (n = 17), and we report our experience in the management of these patients. Patients were treated with frontline immunochemotherapy without immunosuppression reduction. All evaluable patients achieved a complete remission. Statistically significant decreased survival was identified in HCV-positive patients. Six patients (60%) exhibited increases in HCV RNA levels during therapy. Four patients (40%) developed graft failure and three of them (30%) died from liver dysfunction. This is the first study providing evidence of decreased survival in HCV-positive PTLD patients after liver transplant receiving immunochemotherapy.

Anatomy of the Internal Iliac Vein: Implications for Uterine Transplant.

STUDY OBJECTIVE: Uterine transplantation has proven feasible since the first live birth reported in 2014. To enable attachment of the uterus in the recipient, long vascular pedicles of the uterine and internal iliac vessels were obtained during donor hysterectomy, which required a prolonged laparotomy to the living donors. To assist further attempts at uterine transplantation, our video serves to review literature reports of internal iliac vein anatomy and demonstrate a laparoscopic dissection of cadaver pelvic vascular anatomy. DESIGN: Observational (Canadian Task Force Classification III). SETTING: Academic anatomic laboratory. Institutional Review Board ruled that approval was not required for this study. INTERVENTION: Literature review and laparoscopic dissection of cadaveric pelvic vasculature, focusing on the internal iliac vein. MEASUREMENTS AND MAIN RESULTS: Although the internal iliac artery tends to have minimal anatomic variation, its counterpart, the internal iliac vein, shows much variation in published studies [1,2]. Relative to the internal iliac artery, the vein can lie medially or laterally. Normal anatomy is defined as some by meeting 2 criteria: bilateral common iliac vein formed by ipsilateral external and internal iliac vein at a low position and bilateral common iliac vein joining to form a right-sided inferior vena cava [2]. Reports show 79.1% of people have normal internal iliac vein anatomy by these criteria [2]. The cadaver dissection revealed internal iliac vein anatomy meeting criteria for normal anatomy. CONCLUSION: Understanding the complexity and variations of internal iliac vein anatomy can assist future trials of uterine transplantation.

Uterine viability in the baboon after ligation of uterine vasculature: a pilot study to assess alternative perfusion and venous return for uterine transplantation.

OBJECTIVE: To assess, in two separate groups of baboons, uterine viability after ligation of the uterine veins and uterine viability after ligation of both the uterine arteries and veins, respectively. DESIGN: Prospective, observational study. SETTING: Baboon breeding colony. ANIMAL(S): Six naïve female Papio hamadryas baboons with indicators of normal reproductive function. INTERVENTION(S): Three baboons underwent surgical interruption of the uterine veins bilaterally, and three baboons underwent surgical interruption of the uterine arteries and the uterine veins bilaterally. All baboons also underwent colpotomy, cervico-vaginal reanastomosis, and intraoperative near-infrared fluorescence imaging after vessel ligation. In the postoperative period, transabdominal sonography, vaginoscopy, and endocervical biopsy were performed on all animals. MAIN OUTCOME MEASURE(S): Postoperative uterine and ovarian viability. RESULT(S): Near-infrared imaging confirmed intraoperative perfusion of the uterus and cervico-vaginal anastomosis in all cases. In all subjects, sonography revealed normal uteri, and vaginoscopy revealed well-healed anastomoses. Endocervical biopsies (five of six) demonstrated pathologically normal endocervical tissue without evidence of necrosis. Cyclical sex skin turgescence and menstruation were unanimously observed. CONCLUSION(S): Disruption of bilateral uterine vessels does not affect uterine or ovarian viability in the baboon. Bilateral uterine artery and vein ligation furthers development of a minimally invasive approach to donor hysterectomy.

CD52-Negative NK Cells Are Abundant in the Liver and Less Susceptible to Alemtuzumab Treatment.

BACKGROUND: T-cell depleting strategies have become an integral part of immunosuppressive regimens in organ transplantation. Alemtuzumab is a humanized monoclonal antibody against CD52, a cell-surface antigen on several immune cells. It has been suggested that lymphocyte depletion increases the risk of serious infections. However, this has not been observed with short-term alemtuzumab treatment in an organ transplant setting. For induction therapy using alemtuzumab following liver transplantation, we found that T- and B-cell numbers declined rapidly after alemtuzumab therapy; however, the natural killer (NK) cell number was sustained. NK cells are important effectors of innate immunity. Since the effects of alemtuzumab on NK cell functions, especially those of liver NK cells, are unknown, this study aimed to investigate this in detail. METHODS: To assess the effect of alemtuzumab on NK cells, samples were obtained from 7 organ donors and examined by flow cytometry using Annexin V and propidium iodide. Phenotypical and functional differences within subsets of NK cells with different levels of CD52 expression were determined by flow cytometry and in vitro cytotoxicity assays. RESULTS: CD52 expression on NK cells was lower than that on other lymphocyte subsets. The liver contained a large number of CD52- NK cells compared with the peripheral blood. In vitro treatment of liver-derived NK cells with alemtuzumab did not result in cell death. In contrast, co-incubation with alemtuzumab induced cell death in peripheral blood mononuclear cells and non-NK cells in the liver. Furthermore, CD52- liver NK cells were more cytotoxic and produced more IFN-γ than CD52+ NK cells after cytokine activation. CONCLUSION: The liver contains a large number of CD52- NK cells. These cells are refractory to alemtuzumab and have robust activity. These findings indicate that CD52- NK cells persist and could protect against infection after alemtuzumab-based lymphocyte depletion.

Assessment of an Alternative to the Uterine Vein for Venous Drainage in Human Uterine Transplantation: A Case Series Following Laparoscopic Hysterectomy.

BACKGROUND/AIMS: To determine an alternative to the uterine vein, considering the utero-ovarian vein (UOV) for venous drainage in human uterine transplantation. METHODS: A case series of 10 total laparoscopic hysterectomies was conducted for benign indications and a vascular study was performed ex vivo on the surgical specimen, demonstrating ipsilateral and contralateral flow between the uterine artery (UA) and UOV visualizing anastomoses between these vessels. The flow pattern was documented using heparinized saline and illustrated through fluoroscopy using Isovue-300 dye. RESULTS: Successful cannulation of UA was accomplished in all 10 cases. Ipsilateral flow between the UA and UOV was demonstrated in all except one case, and contralateral flow was observed. Due to the long interval between the time of specimen retrieval and vascular study, the time to cannulation limited the ability to demonstrate ipsilateral and contralateral flow in 2 cases. CONCLUSION: Uterine transplantation has become a viable option for women with absolute uterine factor infertility. However, this surgery requires extensive surgical dissection, and the surgical retrieval of the uterine vein proposes a challenge. We present a potential option for venous drainage in uterine transplant surgery, considering the UOV for venous drainage as an alternative to the uterine vein and a possibility for minimally invasive approach.

Abdominal transplantation for unresectable tumors in children: the zooming out principle.

PURPOSE: To present our experience in abdominal transplantations to manage unresectable abdominal neoplasms in children and to describe the role of extensive surgeries in such cases. METHODS: This is a retrospective study of 22 abdominal transplantations in 21 patients for abdominal tumors over 16 years. Transplantation techniques included liver transplant (LT), multivisceral transplant (MVTx), and intestinal autotransplant (IA). Follow-up intervals ranged from 0.3 to 168 months (median 20 months). RESULTS: LT alone was performed in 15 patients for primary malignant (11) and benign (4) liver tumors. Pathological classification included HB hepatoblastoma (6), HCC hepatocellular cancer (3), hepatic epithelioid hemangioendothelioma HEH (1), angiosarcoma (1), benign vascular tumors (3), and adenoma (1). IA was performed in four patients for lesions involving the root of the mesentery; tumors of the head of pancreas (3) and mesenteric hemangioma (1). MVTx was performed in 2 patients for malignancies; pancreaticoblastoma (1), recurrent hepatoblastoma (1), and in one patient as a rescue procedure after IA failure. Four of the eleven patients who underwent LT for malignant liver tumor had metastatic disease at presentation. Six of them died of recurrent neoplasm (3), transplant-related complications (2), and underlying disease (1). All LT patients who had benign tumors are alive with functioning grafts. All IA patients survived and are on an oral diet, with one patient requiring TPN supplementation. One of the three patients who underwent MVTx died of metastatic disease. CONCLUSIONS: Allo/auto transplantation for abdominal tumors is a valuable modality when conventional treatments fail or are not feasible.

Organ shortage: the greatest challenge facing transplant medicine.

The success of organ transplantation as a treatment for end-stage organ disease has yielded a series of ethical quandaries originating from the issue of organ shortage. Scarcity of organs for transplantation necessitates formulation of just and fair allocation policies as well as ethically viable solutions to bridging the vast gap between organ supply and demand. The concept of "triage" provides a useful paradigm in which to contextualize the organ shortage issue. This entails subjugating the welfare of the individual patient for the benefit of the wider community as an ethically justified response to the challenge of scarcity.

First clinical uterus transplantation trial: a six-month report.

OBJECTIVE: To report the 6-month results of the first clinical uterus transplantation (UTx) trial. This type of transplantation may become a treatment of absolute uterine-factor infertility (AUFI). DESIGN: Prospective observational study. SETTING: University hospital. PATIENT(S): Nine AUFI women and their live uterine donors, the majority being mothers. INTERVENTION(S): Live-donor UTx and low-dose induction immunosuppression. MAIN OUTCOME MEASURE(S): Data from preoperative investigations, surgery and follow-up for 6 months. RESULT(S): Durations of donor and recipient surgery ranged from 10 to 13 hours and from 4 to 6 hours, respectively. No immediate perioperative complications occurred in any of the recipients. After 6 months, seven uteri remained viable with regular menses. Mild rejection episodes occurred in four of these patients. These rejection episodes were effectively reversed by corticosteroid boluses. The two graft losses were because of acute bilateral thrombotic uterine artery occlusions and persistent intrauterine infection. CONCLUSION(S): The results demonstrate the feasibility of live-donor UTx with a low-dose immunosuppressive protocol. CLINICAL TRIAL REGISTRATION NUMBER: NCT01844362.

When and why portal vein thrombosis matters in liver transplantation: a critical audit of 174 cases.

OBJECTIVE: To identify complications associated with different techniques utilized to treat portal vein thrombosis (PVT) during primary liver transplantation and their impact on survival. BACKGROUND: PVT remains an intricate problem in liver transplantation, and the long-term outcomes of patients with PVT who undergo transplantation are not well defined. METHODS: We performed a retrospective cohort analysis of all consecutive adult patients who underwent primary isolated liver transplantation from 1998 to 2009 (median follow-up period, 89 months). The outcomes of patients with PVT were compared with those without PVT. RESULTS: Among 1379 recipients, 174 (12.6%) had PVT at the time of transplantation [83 (48%) complete and 91 (52%) partial]. Among PVT patients with reestablished physiological portal inflow (PVT: physiological group; n = 149), 123 underwent thrombectomies, 16 received interpositional vein grafts, and 10 received mesoportal jump grafts. In 25 patients, physiological portomesenteric venous circulation was not reconstituted (PVT: nonphysiological group; 18 underwent cavoportal hemitranspositions, 6 renoportal anastomoses, and 1 arterialization). The PVT: nonphysiological group suffered a significantly increased incidence of rethrombosis of the portomesenteric veins and gastrointestinal bleeding, with a marginal 10-year overall survival rate of 42% (no PVT, 61%; P = 0.002 and PVT: physiological, 55%; P = 0.043). The PVT: physiological and no PVT groups exhibited comparable survival rates (P = 0.13). No significant differences in survival were observed between complete and partial PVT as long as physiological portal flow was reestablished. CONCLUSIONS: The subset of PVT patients requiring nonphysiological portal vein reconstruction was associated with higher complication rates and suffered diminished long-term prognoses. For the most severe PVT cases, a comprehensive approach is critical to further improve outcomes.