Genomics, the diversification of mammals, and the evolution of placentation.

When and why did variations in placental structure and function evolve? Such questions cannot be addressed without a reliable version of mammalian phylogeny. Twenty-five years ago, the mammalian tree was reshaped by molecular phylogenetics. Soon it was shown, in contrast to prevailing theories, that the common ancestor of placental mammals had invasive placentation. Subsequently, evolution of many other features of extraembryonic membranes was addressed. This endeavour stimulated research to fill gaps in our knowledge of placental morphology. Last year the mammalian tree was again revised based on a large set of genomic data. With that in mind, this review provides an update on placentation in the nineteen orders of placental mammals, incorporating much recent data. The principal features such as shape, interdigitation, the interhaemal barrier and the yolk sac are summarized in synoptic tables. The evolution of placental traits and its timing is then explored by reference to the revised mammalian tree. Examples are the early appearance of epitheliochorial placentation in the common ancestor of artiodactyls, perissodactyls, pangolins and carnivores (with reversion to invasive forms in the latter) and later refinements such as the binucleate trophoblast cells and placentomes of ruminants. In primates, the intervillous space gradually evolved from the more basic labyrinth whereas trophoblast invasion of the decidua was a late development in humans and great apes. Only seldom can we glimpse the "why" of placental evolution. The best examples concern placental hormones, including some striking examples of convergent evolution such as the chorionic gonadotropins of primates and equids. In concluding, I review current ideas about what drives placental evolution and identify significant gaps in our knowledge of placentation, including several relevant to the evolution of placentation in primates.

Human liver sinusoidal endothelial cells support the development of functional human pluripotent stem cell-derived Kupffer cells.

In mice, the first liver-resident macrophages, known as Kupffer cells (KCs), are thought to derive from yolk sac (YS) hematopoietic progenitors that are specified prior to the emergence of the hematopoietic stem cell (HSC). To investigate human KC development, we recapitulated YS-like hematopoiesis from human pluripotent stem cells (hPSCs) and transplanted derivative macrophage progenitors into NSG mice previously humanized with hPSC-liver sinusoidal endothelial cells (LSECs). We demonstrate that hPSC-LSECs facilitate stable hPSC-YS-macrophage engraftment for at least 7 weeks. Single-cell RNA sequencing (scRNA-seq) of engrafted YS-macrophages revealed a homogeneous MARCO-expressing KC gene signature and low expression of monocyte-like macrophage genes. In contrast, human cord blood (CB)-derived macrophage progenitors generated grafts that contain multiple hematopoietic lineages in addition to KCs. Functional analyses showed that the engrafted KCs actively perform phagocytosis and erythrophagocytosis in vivo. Taken together, these findings demonstrate that it is possible to generate human KCs from hPSC-derived, YS-like progenitors.

Twin fetuses associated with double amniotic sacs diagnosed using transvaginal ultrasonography: A case report.

BACKGROUND: Conjoined twins are a rare twin malformation commonly presenting as single amniotic sac twinning, with double amniotic sac twinning being extremely rare and poorly reported. Most conjoined twins are females. CASE SUMMARY: A woman of childbearing age conceived naturally, and at 8 wk of gestation, transvaginal ultrasonography showed an embryo and cardiac tube pulsation in both amniotic sacs. On dynamic observation, the two embryos were connected in the lower abdomen, with restricted movement. A repeat transvaginal ultrasound at 11 wk showed that the intestinal tubes of both fetuses were connected in the lower abdomen. The pregnancy was terminated and labor was induced. CONCLUSION: Transvaginal ultrasound may detect conjoined twin malformations in an early stage. Our case provides diagnostic insights for ultrasonographers and can help develop early therapeutic interventions.

Impact of microscopic deposits of yolk sac tumor on recurrence of mature sacrococcygeal teratoma.

INTRODUCTION: Sacrococcygeal teratomas (SCT) with malignant histology frequently recur and are treated aggressively, but risk factors and surveillance protocols are less established for mature tumors. In particular, prior studies have not investigated whether microscopic deposits of yolk sac tumor (YST) in otherwise mature teratomas lead to higher recurrence rates. METHODS: We reviewed patients with mature SCTs resected at our institution from 2011 to 2021 and analyzed tumor characteristics, treatment, and outcomes. RESULTS: We identified 56 patients with mature SCT, of which 9 (16%) demonstrated microscopic YST. Following surgery, 7/56 (13%) patients developed local recurrence at a mean of 1.2 ± 0.7 years, while no patients developed metastases. Recurrence was more likely in patients with microscopic YST [5/9 (56%) vs. 2/47 (4%), p = 0.021] and positive margins [6/24 (35%) vs. 1/32 (3.1%), p = 0.030]. A solid tumor component tended to increase recurrence risk as well [6/29 (21%) vs. 1/27 (4%), p = 0.053]. Five patients demonstrated malignant recurrence and were all detected by a rising alpha-fetoprotein (AFP), while two patients demonstrated recurrence of mature teratoma and were detected on surveillance magnetic resonance imaging (MRI). CONCLUSIONS: Microscopic foci of YST may increase recurrence risk for patients with mature SCT. Such patients might benefit from closer postoperative surveillance with serial AFP measurements and MRI.

Ultrasonographic and clinicopathological features of pelvic yolk sac tumors in women: a single-center retrospective analysis.

Objectives: Yolk sac tumors (YSTs) are rare and highly malignant ovarian malignancies that have a very poor prognosis. The aim of this study is to delineate the ultrasound and clinicopathological features of female pelvic YSTs to better understand the disease. Methods: This study was a retrospective analysis of the clinicopathological and ultrasound imaging data from 16 YST patients who received treatment at our hospital between January 2012 and August 2023. Then, the ultrasound imaging characteristics were compared with pathological findings. Results: Among the 16 patients, various degrees of serum AFP increase were observed, and CA125 levels increased in 58.33% (7 out of 12) of patients. Thirteen patients (81.25%) had tumors located in ovary, two patients (12.5%) had tumors located in the sacrococcygeal region, and one patient (6.25%) had tumors located in the mesentery. Pathologically, nine patients presented with simple yolk sac tumors and seven with mixed germ cell tumors. According to the ultrasound manifestations, YST lesions can be classified into three types. (1) the cystic type, was diagnosed in two patients who presented with a large cystic mass with regular morphology and clear boundary and dense liquid within the cyst; and (2) the cystic-solid mixed type, was diagnosed in 4 patients. On 2D ultrasound, the lesions showed a cystic-solid mixed echo, and color Doppler showed a rich blood flow signal in the solid region and cystic separation. made up of four cases. (3) In ten patients with the solid type, 2D ultrasound showed solid uniform echoes with clear boundaries. The "fissure sign" was observed in the lesion. Color Doppler displayed rich blood flow in the solid part, and PW showed low to moderate resistance index of artery (RI:0.21-0.63). On contrast-enhanced ultrasound (CEUS), rapid and high enhancement in the solid part and cystic separation was observed in 2 patients. Conclusions: Combining ultrasound features with clinical information and tumor markers provides reliable clues for the diagnosis of YST. The application of two-dimensional ultrasound and CEUS combined with patient tumor marker levels can provide a robust reference for determining the necessity of fertility-preserving surgery and postoperative chemotherapy, which can improve clinical decision-making and patient consultation.

Human yolk sac-derived innate lymphoid-biased multipotent progenitors emerge prior to hematopoietic stem cell formation.

Hematopoietic stem cell (HSC)-independent lymphopoiesis has been elucidated in murine embryos. However, our understanding regarding human embryonic counterparts remains limited. Here, we demonstrated the presence of human yolk sac-derived lymphoid-biased progenitors (YSLPs) expressing CD34, IL7R, LTB, and IRF8 at Carnegie stage 10, much earlier than the first HSC emergence. The number and lymphopoietic potential of these progenitors were both significantly higher in the yolk sac than the embryo proper at this early stage. Importantly, single-cell/bulk culture and CITE-seq have elucidated the tendency of YSLP to differentiate into innate lymphoid cells and dendritic cells. Notably, lymphoid progenitors in fetal liver before and after HSC seeding displayed distinct transcriptional features, with the former closely resembling those of YSLPs. Overall, our data identified the origin, potential, and migratory dynamics of innate lymphoid-biased multipotent progenitors in human yolk sac before HSC emergence, providing insights for understanding the stepwise establishment of innate immune system in humans.

Half-life of serum alpha-fetoprotein in prepubertal testicular yolk sac tumors: an index significantly associated with prognosis.

PURPOSE: To evaluate the association between serum alpha-fetoprotein (AFP) half-life (HL) and prognosis in prepubertal children with elevated AFP values 3 to 4 weeks after surgery for testicular yolk sac tumors (YST). METHODS: Prepubertal patients with testicular YST treated with radical orchiectomy between January 2016 and December 2022 were retrospectively reviewed. Negative outcomes were defined as relapse, metastasis or death. Univariate and multivariate logistic regression analyses were conducted to select risk factors for negative outcomes. RESULTS: A total of 42 patients were eventually enrolled into the study. Patients were divided into non-negative and negative outcomes groups, consisting of 35 and 7 patients, respectively. Thirty-five patients were stage I, two cases were stage II, and five cases were stage IV, according to the Children's Oncology Group staging system. The overall survival (OS) rate was 100%. Average AFP values significantly decreased after resection (P < 0.001). A significant positive correlation was shown between pre- and postoperative AFP values (r = 0.60, P < 0.001). Long AFP HL was considered as an independent risk factor for negative outcomes in YST patients underwent radical orchiectomy (P = 0.04). The cut-off value for AFP HL was 5.78 days, regardless of age division. CONCLUSION: Testicular YST is a relatively rare disease in children with an OS of 100%, and salvage chemotherapy is effective even in grade IV patients. The postoperative AFP HL was significantly associated with prognosis in prepubertal patients with testicular YST. The cut-off value for AFP HL is 5.78 days regardless of the effect of physiological AFP elevation.

The developmental pattern related to fatty acid uptake and oxidation in the yolk sac membrane and jejunum during embryogenesis in Muscovy duck.

This study aimed to investigate the developmental change of body growth and gene expression related to fatty acid uptake and oxidation in the yolk sac membrane (YSM) and jejunum during embryogenesis in Muscovy ducks. The weights of embryos and yolk sac (YS) (5 embryos per replicate, n = 6) were recorded on embryonic days (E)16, E19, E22, E25, E28, E31, and the day of hatch (DOH). The fat and fatty acid contents in YSM, jejunal histology, and gene expression related to fatty acid metabolism in YSM and jejunum were determined in each sampling time. Among the nonlinear models, the maximum growth is estimated at 2.83 (E22.5), 2.67 (E22.1), and 2.60 (E21.3) g/d using logistic, Gompertz, and Von Bertalanffy models, respectively. The weight of YS, and ether extract-free YS as well as the amounts of fat and fatty acids in YS decreased (P < 0.05) linearly, whereas the villus height, crypt depth, villus height/crypt depth, and musculature thickness in jejunum increased (P < 0.05) linearly during embryogenesis. The mRNA expression of CD36, SLC27A4, and FABP1 related to fatty acid uptake as well as the mRNA and protein expressions of PPARα and CPT1 related to fatty acid oxidation increased in a quadratic manner (P < 0.05) in both YS and jejunum, and the maximum values were achieved during E25 to E28. In conclusion, the maximum growth rate of Muscovy duck embryos was estimated at 2.60 to 2.83 g/d on E21.3 to E23.5, while the accumulations of lipid and fatty acid in YS were decreased in association with the increased absorptive area of morphological structures in jejunum. The gene and protein expression involved in fatty acid metabolism displayed a similar enhancement pattern between YSM and jejunum during E25 to E28, suggesting that fatty acid utilization could be strengthened to meet the energy demand for embryonic development.

Variations in germ cell tumor histology by age and implications for cancer-specific survival among pediatric and adult males: A population-based study.

PURPOSE: Few studies have quantified differences in histology and implications for survival between male children and adults with germ cell tumors (GCT). We evaluated these differences and associations with cancer-specific survival (CSS) using Surveillance, Epidemiology, and End Results (SEER) cancer registries. METHODS: SEER (1988-2016) was used to identify male patients 0 to 40 years of age diagnosed with seminoma and nonseminomatous GCT (NSGCT). Demographic and tumor characteristics were tabulated with histology distributions compared by age group (0-4, 12-18, 19-40 years old). CSS was evaluated in multivariable Cox proportional hazards regression models. RESULTS: Among 27,204 patients identified, 1,538 (5.7%) were pediatric (0-18 years). Seminoma (54.3%) predominated in adult patients (ages 19-40). Among 0 to 4 years-old, yolk sac tumor (71.2%) and teratoma (21.5%) were most common. Mixed GCT (52.7%) was most prevalent among 12 to 18 years-old with seminoma, embryonal, and teratoma occurring in 12 to 15% each. Relative to pediatric patients, adult patients had similar CSS for seminoma but worse CSS for NSGCT on Kaplan-Meier curves with 9 years mean follow-up. Choriocarcinoma and yolk sac tumors carried the worst prognosis relative to seminoma for both children (HR 5.7 and HR 11.1, respectively, both P < 0.01) and adults (HR 4.6 and HR 4.6, respectively, both P < 0.01) adjusted for stage. CONCLUSION: Histology of GCTs vary by age with yolk sac tumors and teratoma predominating for male patients 0 to 4 years, mixed GCT for 12 to 18 years, and seminoma for 19 to 40 years. Pediatric patients with NSGCT had higher CSS than their adult counterparts. Mixed GCT represented an increasing proportion of GCT over the study period. Age, stage, and histology impact CSS in both pediatric and adult populations.

Germ Cell Tumor of the Testis: Lethal Subtypes of a Curable Cancer.

Germ cell tumor of the testis (GCT) is a curable cancer even when it is widely metastatic; however, outcomes can differ based on tumor histology. Chemo-resistance in certain phenotypes, such as teratoma and yolk sac tumor, contributes to poor clinical outcomes in some patients with GCT. Despite this resistance to S-YSTemic therapy, many of these tumor subtypes remain amenable to surgical resection and possible cure. In this study, we report on a series of seven patients highlighting two chemo-resistant subtypes of nonseminomatous germ cell tumor (NSGCT), sarcomatoid yolk sac tumor (S-YST), and epithelioid trophoblastic tumor (ETT) for which early resection rather than additional salvage chemotherapy or high-dose intense chemotherapy might provide a superior clinical outcome and enhance cure rate.

Origin and flow-mediated remodeling of the murine and human extraembryonic circulation systems.

The transduction of mechanical stimuli produced by blood flow is an important regulator of vascular development. The vitelline and umbilico-placental circulations are extraembryonic vascular systems that are required for proper embryonic development in mammalian embryos. The morphogenesis of the extraembryonic vasculature and the cardiovascular system of the embryo are hemodynamically and molecularly connected. Here we provide an overview of the establishment of the murine and human vitelline and umbilico-placental vascular systems and how blood flow influences various steps in their development. A deeper comprehension of extraembryonic vessel development may aid the establishment of stem-cell based embryo models and provide novel insights to understanding pregnancy complications related to the umbilical cord and placenta.

Ovarian Germ Cell Tumors in North-Western India: A Comprehensive 3-Year Retrospective Study of 145 Cases at a Tertiary Cancer Hospital.

Germ cell tumors encompass a broad spectrum of neoplasms arising from germ cell lineage, demonstrating varying histological profiles and clinical presentations. These tumors encompass a range of benign and malignant entities. While global trends provide insights into their prevalence, specific regional variations, such as those within North-Western India, remain less explored. This study seeks to bridge this knowledge gap by examining the prevalence and characteristics of germ cell tumors within a tertiary cancer hospital. In this retrospective analysis, all cases of germ cell tumors diagnosed over a 3-year period in the specified tertiary cancer hospital were included. Cases with incomplete records or inadequate pathological data were excluded. Data encompassing histological subtypes, patient age distribution, clinical presentations, and histopathological features were collected and analyzed. The study comprised 145 cases of germ cell tumors. Teratomas were the most prevalent subtype, with mature teratomas accounting for the majority. The highest incidence occurred within the 21-30-year age group with a mean age of 24.77 years. Abdominal mass (56%) and abdominal pain (34%) were the prominent clinical presentations. Benign cases constituted the majority 85.5%. Solid tumors (p < 0.00001) and tumors more than 10 cm (p .029028) were found to have a high propensity to be malignant, which was proven to be statistically significant. This study comprehensively explains germ cell tumors' prevalence, clinical features, and histopathological subtypes in a tertiary cancer hospital in North-Western India. The predominance of teratomas, particularly mature ones, aligns with global trends. The age distribution and clinical presentations reflect common patterns. The diverse histopathological appearances underscore the heterogeneous nature of germ cell tumors. This study offers valuable insights for clinical management and further regional research.

Beta-Catenin Alterations in Postchemotherapy Yolk Sac Tumor, Postpubertal-Type With Enteroblastic Features.

Postchemotherapy postpubertal-type yolk sac tumors (YST) with glandular and solid phenotypes are aggressive and commonly resistant to systemic chemotherapy. These neoplasms show morphologic features that significantly overlap with those of somatic carcinomas with "enteroblastic" or "fetal" phenotype (the preferred terminology depends on the site of origin). They often present as late or very late recurrences, and their diagnosis is challenging because they frequently affect patients in an age group at risk for carcinomas of somatic origin. Recently, we incidentally identified examples of postchemotherapy glandular and solid YST with "enteroblastic" phenotypes and nuclear expression of beta-catenin, prompting us to further evaluate the prevalence of this phenomenon. We found nuclear expression of beta-catenin in 10 (29%) of 34 such tumors. A subset of cases with nuclear beta-catenin expression was further analyzed with a DNA sequencing panel (n = 6) and fluorescence in situ hybridization for isochromosome 12p [i(12p); n = 5]. Sequencing identified exon 3 CTNNB1 variants in 3 (50%) of 6 analyzed cases, and fluorescence in situ hybridization was positive for i(12p) in 5 of 5 cases. In conclusion, a significant subset of postchemotherapy YST with glandular or solid architecture and "enteroblastic" phenotype demonstrates beta-catenin alterations, suggesting that activation of Wnt signaling may play a role in the progression of these neoplasms. Moreover, nuclear beta-catenin expression in these tumors represents a potential diagnostic pitfall given that carcinomas of true somatic origin with overlapping morphology may also be positive for this marker.

Extragonadal germ cell tumors: A clinicopathologic study with emphasis on molecular features, clinical outcomes and associated secondary malignancies.

Extragonadal germ cell tumors (EGCTs) are rare, representing <5% of all germ cell tumors (GCTs). Whilst EGCTs share morphological and immunohistochemical features with their gonadal counterparts, they tend to be more aggressive and are frequently associated with secondary somatic malignancies. The aim of our study was to evaluate the clinical, morphological and immunohistochemical features, and to analyze tumors for chromosomal abnormalities of 12p, in addition to any novel genetic alterations, in a series of EGCTs. Seventy-seven EGCTs were included. Anterior mediastinum was the most common anatomic site, followed by central nervous system, retroperitoneum, sacroccygeal area, and neck. Whole genome SNP array identified isochromosome 12p in 26% of tumors. Additional cytogenetic abnormalities included the presence of gain of chr 21 in 37% of tumors. Somatic-type malignancies were identified in 8% of patients. Disease progression (metastasis and/or recurrence) was documented in 8 patients, most of whom died from their relapse. Three patients who died of disease had somatic-type malignancies. Mediastinal seminomas had a significantly better overall survival when compared to mediastinal non-seminomatous GCTs. Our study demonstrates that EGCTs share similar histologic features, but diverse clinical outcomes compared to their gonadal counterparts. Outcomes vary according to anatomic location and histologic subtypes. Our data corroborate that somatic-type malignancies are frequently encountered in mediastinal EGCTs and that their presence portends a poorer prognosis.

Prognostic factors of 87 ovarian yolk sac tumor (OYST) patients and molecular characteristics of persistent and recurrent OYST.

OBJECTIVE: We aimed to explore the characteristics of OYST, particularly for persistent and recurrent OYST, in order to explore potential treatment options and thereby improve patient outcomes. METHODS: We retrospectively reviewed the clinical records of all patients with OYST at Fudan university Shanghai Cancer Center from December 3, 2005 to November 27, 2020. Furthermore, and performed whole-exome sequencing on 17 paired OYST (including 8 paired persistent and recurrent OYST) tumor and blood samples to elucidate the aberrant molecular features. RESULTS: Totally, 87 OYST patients were included between 2007/03/13 and 2020/11/17. With a median follow-up of 73 [3-189] months, 22 patients relapsed or disease persisted. Overall, 17 patients died with a median overall survival of 21 [3-54] months. Univariate and multivariate analysis revealed tumor histology and residual lesions were independently associated with event free survival and overall survival, cycles to AFP normalization were another independent risk factor for overall survival. For the 8 persistent and recurrent OYST: cancer driver genes including ANKRD36, ANKRD62, DNAH8, MUC5B, NUP205, RYR2, STARD9, MUC16, TTN, ARID1A and PIK3CA were frequently mutated; cell cycle, ABC transporters, HR, NHEJ and AMPK signal pathway demonstrated as the most significantly enriched pathways; TMB, DNA MMR gene mutation and MSI were significantly higher. Mutation signature 11, 19 and 30 were the dominant contributors in persistent and recurrent OYST mutation. CONCLUSION: Persistent and recurrent OYST associated with poor prognosis, and probably susceptible to immune checkpoint blockade therapy. Molecular characteristics contributed to predict the persistence and recurrence of OYST.

Extensive surgical resections for rare pleural neoplasms: a single-center experience with a yolk sac tumor and synovial sarcoma.

BACKGROUND: Pleural neoplasms are rare and can be subdivided into pleural metastasis and primary pleural neoplasms. Non-mesothelioma primary pleural neoplasms are a diverse group of extremely rare pathologies. CASE PRESENTATION: In this case series, we describe the presentation and management of two rare primary pleural neoplasms. A first case describes a primary pleural yolk sac tumor treated with neoadjuvant chemotherapy, extended pleurectomy decortication, and hyperthermic intrathoracic chemotherapy. In a second case we describe the management of a primary pleural synovial sarcoma by neoadjuvant chemotherapy and extrapleural pneumonectomy. A complete resection was obtained in both cases and the post-operative course was uncomplicated. No signs of tumor recurrence were noted during follow-up in the first patient. In the second patient a local recurrence was diagnosed 6 months after surgery. CONCLUSION: Neo-adjuvant chemotherapy followed by extensive thoracic surgery, including hyperthermic intrathoracic chemotherapy, is a feasible treatment strategy for non-mesothelioma primary pleural neoplasms, but careful follow-up is required.

18F-DGPET/CT Imaging of Ovarian Yolk Sac Tumor in a Woman after Induction of Labor: A Case Report.

Introduction: Ovarian yolk sac tumor (OYST) during pregnancy is rare and usually missed. There are few PET/CT studies on OYST in the literature. We reported a case of OYST detected by 18F-FDG PET/CT in a woman after induction of labor. Case Presentation: A 19-year-old woman after induction of labor because of severe malformation presented with abdominopelvic mass, laboratory tests revealed significantly elevated serum alpha-fetoprotein (AFP) level and elevated carbohydrate antigen 125 level. Abdomino-pelvic CT showed a cysticsolid mass of 82×152×167mm arising from the right ovary with abundant intratumoral vessels and intense enhancement in the solid part. Further evaluation of 18F-FDG PET/CT imaging showed significantly increased 18FDG uptake (SUVmax7.7) by the solid component of the ovarian mass and slight 18FDG-avid perihepatic effusion. The mass was resected and was confirmed to be the right OYST, After four courses of chemotherapy, the patient was followed up by PET/CT and had a complete metabolic response. Discussion: 18F-FDG PET/CT is a useful imaging modality for diagnosis and evaluation of OYST.

Yolk Sac Tumor of the Ovary in Mosaic 46XX Turner Syndrome.

Introduction: Correlation of Turner syndrome (TS) with germ cell malignancy is acknowledge in TS patient with Y chromosome material but not otherwise. This case report wishes to highlight yolk sac tumor occurrence in patients with TS 46XX karyotype mosaicism. Case Report: A 23-year-old nulligravid woman was admitted with abdominal mass and vaginal bleeding. She had primary amenorrhea and had already been diagnosed with TS. Her karyotype was 46XX with 5% X mosaicism. Ultrasonography revealed a solid mass measuring 14.05 x 10.99 cm based on the International Ovarian Tumor Analysis (IOTA) simple rule, M1 and M2. During surgery, a solid mass originates from her left ovary measuring 20 x 15 x 15 cm with adhesion to omentum, ileum, and caecum was found. Pathology examination reveals it's an endodermal sinus tumors (EST). Discussion: TS with Y cells are closely linked with germ cell malignancy but not otherwise. It's still unclear what causes the malignancy in such cases. Conclusion: The present report illustrates a rare case of EST occurred in a TS patient with 46XX mosaicism.