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Uterus transplantation (UTx) has emerged as a revolutionary treatment for absolute uterine factor infertility, made possible by extensive preclinical research. Animal studies have played a pivotal role in advancing UTx to clinical practice. We highlight Japan's contribution, including non‐human primate research and regulatory progress, leading to its anticipated clinical implementation. The expansion of UTx in the Asia‐Oceania region underscores its global impact. Further refinements in surgical techniques, optimization of immunosuppressive regimens, and establishment of clear patient eligibility criteria will be crucial for ensuring the long‐term success and sustainability of UTx programs worldwide. This letter acknowledges the Swedish team's foundational efforts in establishing UTx as a viable reproductive technology.

Uterus transplantation (UTx) is a potential option for women with uterine factor infertility to have a child. The clinical features indicating irreversible rejection of the uterus are unknown. In our experimental series of allogeneic UTx in cynomolgus macaques, six female macaques were retrospectively examined, which were unresponsive to treatment with immunosuppressants (i.e. irreversible rejection). Clinical features including general condition, hematology, uterine size, indocyanine green (ICG) fluorescence imaging by laparotomy, and histopathological findings of the removed uterus were evaluated. In all cases, general condition was good at the time of diagnosis of irreversible rejection and thereafter. Laboratory evaluation showed temporary increases in white blood cells, lactate dehydrogenase and C-reactive protein, then these levels tended to decrease gradually. In transabdominal ultrasonography, the uterus showed time-dependent shrinkage after transient swelling at the time of diagnosis of irreversible rejection. In laparotomy, a whitish transplanted uterus was observed and enhancement of the transplanted uterus was absent in ICG fluorescence imaging. Histopathological findings in each removed uterus showed hyalinized fibrosis, endometrial deficit, lymphocytic infiltration and vasculitis. These findings suggest that uterine transplantation rejection is not fatal, in contrast to rejection of life-supporting organs. Since the transplanted uterus with irreversible rejection atrophies naturally, hysterectomy may be unnecessary.

Background A Sister Mary Joseph’s nodule is an umbilical metastasis from an intra-abdominal or pelvic malignancy, associated with a poor prognosis. Three possible metastatic pathways for Sister Mary Joseph’s nodule have been postulated: hematogenous spread, lymphatic dissemination, and direct invasion. However, detailed analyses of these metastatic pathways, particularly those involving gene expression profiling, are lacking in literature. We investigated the metastatic patterns of Sister Mary Joseph’s nodule by performing RNA microarray analysis of the primary tumor and each metastatic site in a case of fallopian tube cancer presenting with Sister Mary Joseph’s nodule and inguinal lymph node metastases. Case presentation A 48-year-old Japanese woman presented with swelling in an inguinal lymph node. Positron emission tomography-computed tomography imaging revealed multiple lymph node metastases, right ovarian tumor, umbilical metastasis, and peritoneal dissemination. The patient underwent a laparoscopic right adnexal resection, left inguinal lymph node biopsy, and umbilical resection. Pathological examination confirmed the diagnosis of primary high-grade serous carcinoma of the right fallopian tube. Metastatic high-grade serous carcinoma was identified in the lymph nodes and umbilical tissue. Tumor tissue samples were collected from the primary lesion, umbilical metastasis, and inguinal lymph node metastasis for RNA microarray analysis. The results showed that genes involved in cell adhesion, migration, and stromal remodeling associated with the metastatic processes were more highly expressed in both inguinal lymph node metastasis and Sister Mary Joseph’s nodule than in the primary lesion. Interestingly, distinct differences in gene expression profiles were observed between umbilical and lymph node metastases, suggesting different metastatic mechanisms. Conclusion Our findings suggest differences in the RNA expression patterns between Sister Mary Joseph’s nodule and lymph node metastases in fallopian tube cancer, indicating the possibility of distinct metastatic mechanisms. Further examination of similar cases and longitudinal studies are necessary to elucidate the metastatic patterns of Sister Mary Joseph’s nodule. This case highlights the potential value of molecular profiling for understanding the complex metastatic processes in gynecological malignancies.

Uterus transplantation (UTx) is now an alternative to surrogacy and adoption for women with uterine factor infertility to have children; however, there are still unresolved clinical and technical issues. One of these is that the graft failure rate after transplantation is somewhat higher than that of other life-saving organ transplants, which is a critical concern. Herein, we summarize the details of 16 graft failures after UTx with living or deceased donors using the published literature in order to learn from these negative outcomes. To date, the main causes of graft failure are vascular factors (arterial and/or venous thrombosis, atherosclerosis, and poor perfusion). Many recipients with thrombosis develop graft failure within one month of surgery. Therefore, it is necessary to devise a safe and stable surgical technique with higher success rates for further development in the UTx field.

The increasing incidence of obesity and diabetes due to changes in diet, earlier menarche, delayed menopause, late marriage, and declining birth rate have resulted in an increase in the number of endometrial cancer cases over the last few decades. Although surgical therapy is sufficient for early endometrial cancer, there is no effective therapy for patients with advanced and recurrent endometrial cancer. The oncogenic mechanism of endometrial cancer involves microsatellite instability (MSI) caused by dysfunction of DNA mismatch repair genes in 30% of patients. Immune checkpoint inhibitors, including anti-programmed death (PD)-1 and anti-PD-ligand 1 antibodies, are of interest as novel anticancer drugs; however, these drugs are currently expensive, and there is a need to select patients who will benefit from their use. The use of MSI analysis as a predictive biomarker for the therapeutic efficacy of these drugs may be useful for reducing the costs of drug therapy.

Novel pharmacological therapies are in development for cancer, ranging from conventional chemotherapeutic drugs to molecular targeted drugs, antibody-based drugs, and immune checkpoint inhibitors, which are developed using new technologies. However, the increasing cost of new drug development is increasing the costs of national healthcare and putting pressure on government finances worldwide. Under these circumstances, drug repositioning (i.e. discovering novel effects of existing drugs, thereby allowing their use to treat other diseases) has become a major focus because of reliability and cost reduction. It is becoming increasingly clear that statins (currently used for treating dyslipidemia) can be effective in the prevention of coronary disease, heart failure, and arrhythmia. Epidemiological as well as basic research studies and epidemiological surveys have showed that statins have a suppressive effect on cancers and that they have an antitumor effect on colorectal, prostate, breast, cervical, endometrial, and ovarian cancers. Given the pharmacological mechanism of action of statins, they may have an antitumor effect on cancer types in which the mevalonate pathway is activated as well as on tumors with p53 mutations. To investigate this further, it would be necessary to conduct a large-scale survey after confirming the clinical background of patients as well as their mutational status, and therefore, great hope has been placed on the role of academia and public institutions. Thus, there is an urgent need for researchers to be actively involved in investigator-initiated clinical trials.

No study has reported an animal model of uterus transplantation (UTx) using cynomolgus macaques. We aimed to establish a surgical technique of allogeneic UTx assuming the recovery of a uterus from a deceased donor in cynomolgus macaques. Four allogeneic UTxs were performed in female cynomolgus macaques. Donor surgeries comprised en bloc recovery of organs with iliac vessels on both sides, and/or abdominal aorta/vena cava after sufficient perfusion from one femoral artery or external iliac artery. Before perfusion, 150 mL of whole blood was obtained from the donor for subsequent blood transfusion to the recipient. Four uterine grafts were orthotopically transplanted to recipients. End-to-side anastomosis was performed to the iliac vessels on one side in case 1 and iliac vessels on both sides in case 2; aorto-aorto/cavo-caval anastomosis was performed in cases 3 and 4. Arterial blood flow of the uterine grafts was determined by intraoperative indocyanine green (ICG) angiography. ICG angiography results showed sufficient blood flow to all uterine grafts, and anaemia did not progress. Under appropriate immune suppression, all recipients survived for more than 90 days post-transplantation, without any surgical complications. We describe a surgical technique for allogeneic UTx in cynomolgus macaques.

Though assisted reproduction technology has been developed, a treatment for absolute uterine factor infertility (AUFI), such as defects in the uterus, has not yet been established. Regenerative medicine has been developed and applied clinically over recent years; however, whole solid organs still cannot be produced. Though uterine regeneration has the potential to be a treatment for AUFI, there have been only a few studies on uterine regeneration involving the myometrium in vivo. In the present report, those relevant articles are reviewed. A literature search was conducted in PubMed with a combination of key words, and 10 articles were found, including nine in rat models and one in a mouse model. Of these studies, eight used scaffolds and two were performed without scaffolds. In four of these studies, scaffolds were re-cellularized with various cells. In the remaining four studies, scaffolds were transplanted alone, or other structures were used. Though the methods differed, the injured uterus recovered well, morphologically and functionally, in every study. Only 10 articles were relevant to our investigation, but the results were favorable, if limited to partial regeneration. Recently, uterus transplantation (UTx) has been investigated as a treatment for AUFI. However, UTx has many problems in the medical, ethical and social fields. Though the artificial uterus was also researched and some improvements in this technology were reported, it will take long time for this to reach a clinically applicable stage. Though the results of uterine regeneration studies were promising, these studies were conducted using animal models, so further human studies and trials are needed.

Delivery following uterus transplantation (UTx)—an approach for treating uterine factor infertility—has not been reported in nonhuman primate models. Here, six female major histocompatibility complex (MHC)-defined cynomolgus macaques that underwent allogeneic UTx were evaluated. Antithymocyte globulin and rituximab were administered to induce immunosuppression and a triple maintenance regimen was used. Menstruation resumed in all animals with long-term survival, except one, which was euthanized due to infusion associated adverse reaction to antithymocyte globulin. Donor-specific antibodies (DSA) were detected in cases 2, 4, and 5, while humoral rejection occurred in cases 4 and 5. Post-transplant lymphoproliferative disorder (PTLD) developed in cases 2 and 3. Pregnancy was attempted in cases 1, 2, and 3 but was achieved only in case 2, which had haploidentical donor and recipient MHCs. Pregnancy was achieved in case 2 after recovery from graft rejection coincident with DSA and PTLD. A cesarean section was performed at full-term. This is the first report of a successful livebirth following allogeneic UTx in nonhuman primates, although the delivery was achieved via UTx between a pair carrying haploidentical MHCs. Experimental data from nonhuman primates may provide important scientific knowledge needed to resolve unsolved clinical issues in UTx.