J. Richard Smith

Abdominal radical trachelectomy: a fertility‐preserving option for women with early cervical cancer

Abdominal radical trachelectomy is a fertility‐preserving alternative to radical hysterectomy or chemoradiation for young women with stage IA2 to IB cervical cancers. Thirty‐three patients were offered this procedure. The mean age was 30.5 years (range 23–37). Three procedures were abandoned because of positive pelvic nodes (two patients) and involvement of the margin between the amputated cervix and uterine fundus (one patient). Of the remaining 30 patients, 10 had stage IA2 tumours, 15 had stage IB1 and 5 had stage IB2. During follow up of a median of 47 months (mean 32 months, range 14–75 months), no recurrences have been detected. A normal menstrual pattern resumed within eight weeks of surgery in all but two patients. Five patients attempted to conceive. Three women have fallen pregnant, resulting in one first trimester miscarriage and two caesarean section deliveries at term. Our experience suggests that abdominal radical trachelectomy provides a method of treating women with stage IA2 to IB cervical cancers with conservation of fertility without apparently compromising recurrence or survival rates. It appears to provide equivalent oncological safety to a standard Wertheim hysterectomy using a technique familiar to all practising gynaecologic oncologists.

Abdominal radical trachelectomy during pregnancy to preserve pregnancy and fertility.

BACKGROUND: For 10,000–40,000 women each year, cervical cancer complicates pregnancy. Current therapy usually terminates the pregnancy and results in the loss of future fertility. Abdominal radical trachelectomy is a fertility-preserving alternative to radical hysterectomy for young women with cervical cancer. CASES: We report five pregnancies complicated by cervical cancer treated by abdominal radical trachelectomy with preservation of the concurrent pregnancy and the birth of two healthy term infants. CONCLUSION: Pregnancy complicated by concurrent cervical cancer can be managed with abdominal radical trachelectomy during pregnancy while preserving future fertility.

Human uterus retrieval from a multi-organ donor

OBJECTIVE: To determine if a uterus can be retrieved for reproductive organ transplantation and to describe the surgical technique. METHODS: We participated in a local organ donor network retrieval team for over 6 months. Heart-beating, brain-dead multi-organ donors were identified through an existing donor network following routine protocols. RESULTS: After institutional review board and organ donor network approval of the uterus transplantation project, approximately 1,800 eligible organ donors were identified as required by legislation. Multi-organ procurement surgery took place in approximate 150 of these, with nine specifically consented for the uterus retrieval. Regularly performed multi-organ transplantation retrievals included the uterus without complications in eight donors. Pedicles used included the ovarian, uterine, or internal iliac vessels. After retrieval, serial histology sections throughout the period of cold ischemia, taken every 15–30 minutes, showed no signs of change over 12 hours of cold ischemia. CONCLUSION: The human uterus can be obtained from local organ donor networks using existing protocols. LEVEL OF EVIDENCE: III

Use of abdominal radical trachelectomy to treat cervical cancer greater than 2 cm in diameter

Objective Invasive cervical cancer is one of the most common cancers, with 500,000 new cases diagnosed annually. Fertility preservation has become an important component of the overall quality of life of many cancer survivors. Expert opinion has suggested that fertility-sparing surgery should be limited to those patients diagnosed with cervical cancer less than 2 cm in diameter. Our objective was to report our abdominal radical trachelectomy (ART) experience in the opposite group of patients—those with a cervical cancer more than 2 cm in diameter. Methods Between 1999 and 2006, a total of 45 patients with cervical carcinoma at International Federation of Gynecology and Obstetrics stage IB1-IB2 measuring more than 2 cm in diameter underwent fertility-sparing ART and pelvic lymphadenectomy at the 3 institutions where the authors are based (Budapest, Hungary; London, United Kingdom; New York, United States). They were followed up for more than 5 years. Results For 69% of patients (n = 31), completed ART was considered to have been curative, and no adjuvant treatment was advised. Of those patients, 93.5% (n = 29) were alive at the time of follow-up. Thirty-one percent of patients (n = 14) underwent immediate completion of radical hysterectomy. Three of 8 patients who wished to fall pregnant delivered healthy neonates. Conclusions The 5-year survival rate (93.5%) for this case series is equal (or better) to rates reported in the literature for patient treated with radical hysterectomy. Our survival data seem to support the hypothesis that ART is a safe treatment option for patients with invasive cervical cancer lesions of more than 2 cm.

Mechanism of human chorionic gonadotrophin-mediated immunomodulation in pregnancy

Human chorionic gonadotrophin (hCG) is released within hours of fertilization and has a profound ability to downregulate maternal cellular immunity against trophoblastic paternal antigens. It also promotes angiogenic activity of the extravillous trophoblast, and impairment of this function may lead to inadequate placentation and an increased risk of preeclampsia. There is increasing evidence that hCG alters the activity of dendritic cells via an upregulation of indoleamine 2,3-dioxygenase activity. This reduces T-cell activation and cytokine production, as well as encouraging Treg cell recruitment to the fetal–maternal interface. These changes are critical in promoting maternal tolerance. hCG is also able to increase the proliferation of uterine natural killer cells, while reducing the activity of cytotoxic peripheral blood natural killer cells. There are rare reports of autoantibodies directed against hCG or the luteinizing hormone/hCG receptor in women with recurrent miscarriage. These autoantibodies are more frequent in women with thyroid autoimmunity. This may explain the association between thyroid autoimmunity and impaired fertility. Downregulating these anti-hCG and anti-luteinizing hormone/hCG receptor autoantibodies may be helpful in some women with early miscarriage or recurrent failed in vitro fertilization.

Uterine allotransplantation in a rabbit model using aorto-caval anastomosis: a long-term viability study

OBJECTIVE Uterine transplantation (UTx) has been proposed as a treatment option for women diagnosed with absolute uterine factor infertility. Allogeneic UTx has been attempted in a number of animal models, but achieving an adequate blood supply for the transplanted uterus still presents the biggest challenge. Microvascular re-anastomosis was unsuccessful in a number of animal models. The aim was to assess whether a large vessel aortic-caval vascular patch technique can bring about long-term graft survival after allogeneic UTx in a rabbit model. STUDY DESIGN A longitudinal study involving uterine cross transplantations (n=9 donors, n=9 recipients) was performed in New Zealand white rabbits using an aortic-caval macrovascular patch harvested as part of the uterine allograft. All rabbits were allogeneic and of proven fertility, with at least one previous litter each. The end result of the donor graft harvest was a total hysterectomy transecting across the vagina and the most lateral aspects of the uterine horns together with an aortic-caval macrovascular patch (aorta, inferior vena cava, common and internal iliacs, and uterine arterial and venous tree). Tacrolimus (500 μg twice daily) was administered for immunosuppression post-transplant. The recipients were closely monitored until death or euthanasia. RESULTS In this case series, long-term rabbit survival was 11% (n=1). Surgical survival was 56% (n=5). Three rabbits (UTx #3, #4 and #8) died intra-operatively as a result of blood aspiration, ventricular hematoma, and massive hemorrhage. Three does (#1, #2, #7 and #9) died within the first 24 h as a result of the veno-vena and anastomosis breakdown. Does #6 and #9 died secondary to pre-operative pneumonia and a pulmonary embolus, respectively. Only one rabbit survived longer than a month. CONCLUSION Our method used a macrovascular patch technique to ensure adequate blood supply to the donor uterine graft. We have demonstrated the feasibility of uterine allotransplantation using this technique in the rabbit, but were unable to demonstrate a higher long-term survival percentage because of issues related to using a rabbit model.

Achieving an early pregnancy following allogeneic uterine transplantation in a rabbit model

OBJECTIVE Uterine transplantation (UTx) has been proposed as a treatment option for women diagnosed with absolute uterine factor infertility (AUFI). The goal of UTx remains achieving pregnancy and live birth of a healthy neonate following allogeneic UTx. Our aim was to assess whether fertility was possible following allogeneic uterine transplantation (UTx), when the recipient had demonstrated long-term survival and had been administered immunosuppression. STUDY DESIGN Nine allogeneic UTx in New Zealand White rabbits were performed using a pre-determined protocol. Tacrolimus was the immunosuppressant selected. Embryos were transferred into both cornua of the sole living recipient via a mini-midline laparotomy. The pregnancy was monitored with regular reproductive profiles and serial trans-abdominal ultrasound to measure conceptus growth (gestation sac and crown rump length (CRL)). RESULTS In the sole surviving doe a gestation sac was visualised on ultrasound from Day 9 (D9) after embryo transfer. Gestation sac diameter and CRL increased from D9 to D16 but by D18 the gestation sac had reduced in size. The fetus was no longer visible, suggesting fetal resorption had occurred. Subsequent scans on D22 and D25 did not demonstrate a gestation sac. Scheduled necropsy on D27 and histopathology confirmed evidence of a gravid uterus and presence of a gestational sac. A single episode of acute rejection occurred on D13. CONCLUSION Pregnancy was achieved after rabbit allogeneic UTx but serial ultrasound suggested that fetal demise occurred prior to scheduled necropsy. The study represents only the third example of conception and pregnancy following an animal allogeneic UTx.

Test of long‐term uterine survival after allogeneic transplantation in rabbits

To see if: (i) a large vessel aortocaval vascular patch technique may bring about long‐term graft survival after allogeneic uterine transplantation (UTn) in a rabbit model; and (ii) fertility can be achieved following natural mating post‐allogeneic UTn.

Immunology of Uterine Transplantation A Review

The idea of using organ transplantation to solve quality-of-life issues was first introduced a century ago, with cornea transplants and thrusted before the world again in 1998, following a controversial hand transplant. Uterus transplantation (UTn) has been proposed as another quality-of-life transplant for the cure of permanent uterine factor infertility. In order to proceed in humans, a greater appreciation of the immunological mechanisms that underlie UTn is desirable. Allogeneic UTn (animal model) was first described by 2 studies in 1969. The first and only human UTn, performed in 2000, was an early attempt with limited use of animal model experiments prior to moving onto the human setting. Since then, work using rat, mouse, ovine, goat, and nonhuman primate models has demonstrated that the uterus is a very different but manageable organ immunologically compared to other transplanted organs. Therefore, specifically exploring immunological issues relating to UTn is a valuable and necessary part of the inevitable scientific process leading to successful human UTn.

Uterine Transplantation, Abdominal Trachelectomy, and Other Reproductive Options for Cancer Patients

More and more women with cancer issues are now raising fertility concerns as survival improves and childbearing is delayed. Pregnancy is no longer contraindicated in cancer patients including breast and endometrial cancer survivors. In fact, survival in patients treated for breast cancer who subsequently become pregnant is actually higher than that in patients who do not become pregnant. “Therapeutic” abortions are no longer recommended. Assisted reproductive technology (ART) have been associated with ovarian neoplasms, but the association is probably not causal. Neither ART nor hormone replacement is contraindicated in cancer patients. Our institution is very supportive of patients and the difficult decisions cancer survivors face. Using a program of counseling and close collaboration between oncologists, perinatologists, and reproductive endocrinologists, informed patients are offered every possible option, including ART and uterine transplantation, to achieve their family planning objectives.