Simultaneously characterization of tumoral angiogenesis and vasculogenesis in stem cell-derived teratomas.

Tumor neovascularization may occur via both angiogenic and vasculogenic events. In order to investigate the vessel formation during tumor growth, we developed a novel experimental model that takes into account the differentiative and tumorigenic properties of Embryonic Stem cells (ESCs). Leukemia Inhibitory Factor-deprived murine ESCs were grafted on the top of the chick embryo chorionallantoic membrane (CAM) in ovo. Cell grafts progressively grew, forming a vascularized mass within 10 days. At this stage, the grafts are formed by cells with differentiative features representative of all three germ layers, thus originating teratomas, a germinal cell tumor. In addition, ESC supports neovascular events by recruiting host capillaries from surrounding tissue that infiltrates the tumor mass. Moreover, immunofluorescence studies demonstrate that perfused active blood vessels within the tumor are of both avian and murine origin because of the simultaneous occurrence of angiogenic and vasculogenic events. In conclusion, the chick embryo ESC/CAM-derived teratoma model may represent a useful approach to investigate both vasculogenic and angiogenic events during tumor growth and for the study of natural and synthetic modulators of the two processes.

Factors Associated With Perioperative Complications in the Treatment of Pediatric Retroperitoneal Teratoma.

BACKGROUND: Perioperative complications are common during the surgical treatment of pediatric retroperitoneal teratoma (RPT). Some clinical and radiographic features could be associated with perioperative complications. This study was designed to identify the factors associated with such complications. MATERIALS AND METHODS: We retrospectively analyzed the clinical data of RPT patients who underwent surgical treatment at the Department of Pediatric Surgery of The Affiliated Hospital of Qingdao University between January 2008 and January 2020, including demographics, imaging data, intraoperative findings, perioperative complications, pathological data, and outcomes. RESULTS: A total of 91 patients were included in this study, including 30 boys and 61 girls. Of these, 71 patients (78%) were 1 y old or younger. Thirty-eight patients (41%) had perioperative complications (44 intraoperative and 7 postoperative). Preoperative imaging studies showed that the tumor distorted adjacent arteries, veins, and organs in all patients. More veins and organs were displaced and distorted by the tumor in patients who had perioperative complications. Multivariate analysis showed that the number of organs compressed and distorted by the tumor was significantly related to perioperative complications (odds ratio 1.69, 95% confidence interval 1.19-2.41). CONCLUSIONS: Surgical treatment of RPT is complex and challenging. As majority are benign, a complete excision is usually curative. The number of organs compressed and distorted by the tumor is positively related to perioperative complications.

Preoperative giant sacrococcygeal teratoma embolization in a newborn - A case report and a review. / Embolización preoperatoria de teratoma sacrococcigéo gigante en un recién nacido. Reporte de un caso y revisión.

Sacrococcygeal teratoma (SCT) is the most frequent congenital germ cell tumor. Patients have a higher risk of perinatal complications and death, with bleeding and cardiac decompensation being the most common causes of neonatal mortality. This is the case of a 35-week preterm newborn with a large SCT diagnosed at ultrasound screening in the second trimester. Preoperative selective embolization of the middle sacral artery and total surgical resection were performed postnatally with minimal blood loss. The patient was discharged at 25 days of life with a normal physical examination. Selective embolization prior to giant SCT resection is feasible and appears as a safe and useful technique in the control of perioperative bleeding.

El teratoma sacrococcígeo (TSC) es el tumor congénito de células germinales más frecuente. Los pacientes afectados tienen un mayor riesgo de complicaciones perinatales y muerte, siendo la hemorragia y la descompensación cardiaca las causas más comunes de mortalidad neonatal. Presentamos el caso de un recién nacido pretérmino de 35 semanas con un TSC de gran tamaño diagnosticado por ecografía en el segundo trimestre. La embolización selectiva preoperatoria de la arteria sacra media y la resección quirúrgica total postnatal se realizaron con una mínima pérdida de sangre. El paciente fue dado de alta a los 25 días de vida con un examen físico normal. La embolización selectiva antes de la cirugía de resección del TSC gigante es factible y aparece como una técnica segura y útil en el control del sangrado perioperatorio.

Preoperative selective embolization with vascular coiling of giant sacrococcygeal teratoma.

Sacrococcygeal teratoma is one of the most common congenital tumors. Its optimal management requires interdisciplinary care by obstetricians, radiologists, pediatric surgeons, and neonatologists. Early surgery entailing complete tumor excision is the main therapy aim, but a substantial risk of life-threatening complications remains, especially uncontrollable intraoperative hemorrhage. To reduce the risk of bleeding in a female neonate with a giant sacrococcygeal teratoma, we successfully coil-embolized the tumor's main feeding arteries. Her subsequent complete surgical resection was uneventful, and the child is well with favorable reconstructive and functional status of all involved and adjacent organ systems.

Clinical Monitoring of Sacrococcygeal Teratoma.

BACKGROUND: Sacrococcygeal teratomas (SCT) are often highly vascularized and may result in high-output cardiac failure, polyhydramnios, fetal hydrops, and demise. Delivery is guided by the SCT to fetus volume ratio (SCTratio), SCT growth rate, and cardiac output indexed for weight (CCOi). METHODS: We compared measurements and outcome in 12 consecutive fetuses referred with SCT. Adverse outcomes were: fetal surgery, delivery < 32 gestational weeks or neonatal demise. Only SCTratio and CCOi were used to manage the cases. SCT vascularization index (VI%) was derived from the 3D virtual organ computer-aided analysis (VOCAL) software. The SCTModel (modified from acardiac twins) calculated a hypothetical SCT draining vein size and derived a risk line, using diameters of the superior and inferior vena cava, the azygous and umbilical veins. VI% and a model of systemic and umbilical venous volumes (SCTModel) were tested as indicators for outcome in SCT. RESULTS: Fetuses were monitored from 20.1 to 36.4 gestational weeks and 5/12 had adverse outcomes: 1 had successful open fetal surgery at 23.8 weeks and delivered at term, 4 delivered at < 32 weeks with 3/4 having neonatal demise between 25 and 29 weeks. VI% was significantly higher in cases with adverse outcomes (mean 10.3 [8.9-11.6] vs. 4.4 [3.4-5.3], p < 0.0001). The additional fraction of the fetal cardiac output required to perfuse the SCT-draining vein (XSCO%) (p = 0.46), SCTratio (p = 0.08), and CCOi (p = 0.64) were not significant. All cases with adverse outcome had VI% > 8%. The SCTModel risk line predicted nonadverse outcomes well but lacked data in 2/5 cases with adverse outcomes. CONCLUSIONS: VI% is a significant indicator of SCT cases with adverse outcomes and combined with SCTratio may guide timing of delivery better than current measures.

Laparoscopic Division of Median Sacral Artery and Dissection of Types III and IV Sacrococcygeal Teratomas to Decrease Intraoperative Hemorrhagic Complications: Case Series and Review of the Literature.

INTRODUCTION: Sacrococcygeal teratoma (SCT) is the most common teratoma presenting at birth. Life-threatening bleeding is a major complication during tumor excision in children. In this study we demonstrate our technique for laparoscopic division of median sacral artery (MSA) during dissection of SCT in 2 pediatric patients as a safe technique to minimize risk of hemorrhage. METHODS: Two female infants diagnosed with types III and IV SCTs underwent preoperative evaluation in the postnatal period. The first patient was an 18-month-old girl who presented with metastatic type IV teratoma, resected after neoadjuvant therapy, and the second patient was a 6-day-old girl with prenatal diagnosis of cystic type III teratoma. Using laparoscopy in both patients, the presacral space was reached by opening the peritoneal reflection with blunt dissection and the MSA was identified. Then it was carefully isolated and divided with 3 or 5 mm sealing device. The pelvic components of the tumors were partially dissected using laparoscopy. The first patient's tumor resection was completed using a posterior sagittal approach and the second patient required a standard Chevron incision. Along with the description of our technique, a review of the current literature for the management of SCT and MSA was performed. RESULTS: Both patients underwent successful laparoscopic division of the MSA and resection of the SCTs without complications. CONCLUSION: Laparoscopic MSA division before SCT excision offers a safe approach that can reduce the risk of hemorrhage during surgery.

Comparison of Magnetic Resonance Imaging and Serum Biomarkers for Detection of Human Pluripotent Stem Cell-Derived Teratomas.

The use of cells derived from pluripotent stem cells (PSCs) for regenerative therapies confers a considerable risk for neoplastic growth and teratoma formation. Preclinical and clinical assessment of such therapies will require suitable monitoring strategies to understand and mitigate these risks. Here we generated human-induced pluripotent stem cells (iPSCs), selected clones that continued to express reprogramming factors after differentiation into cardiomyocytes, and transplanted these cardiomyocytes into immunocompromised rat hearts post-myocardial infarction. We compared magnetic resonance imaging (MRI), cardiac ultrasound, and serum biomarkers for their ability to delineate teratoma formation and growth. MRI enabled the detection of teratomas with a volume >8 mm(3). A combination of three plasma biomarkers (CEA, AFP, and HCG) was able to detect teratomas with a volume >17 mm(3) and with a sensitivity of more than 87%. Based on our findings, a combination of serum biomarkers with MRI screening may offer the highest sensitivity for teratoma detection and tracking.

Perlecan maintains microvessel integrity in vivo and modulates their formation in vitro.

Perlecan is a heparan sulfate proteoglycan assembled into the vascular basement membranes (BMs) during vasculogenesis. In the present study we have investigated vessel formation in mice, teratomas and embryoid bodies (EBs) in the absence of perlecan. We found that perlecan was dispensable for blood vessel formation and maturation until embryonic day (E) 12.5. At later stages of development 40% of mutant embryos showed dilated microvessels in brain and skin, which ruptured and led to severe bleedings. Surprisingly, teratomas derived from perlecan-null ES cells showed efficient contribution of perlecan-deficient endothelial cells to an apparently normal tumor vasculature. However, in perlecan-deficient EBs the area occupied by an endothelial network and the number of vessel branches were significantly diminished. Addition of FGF-2 but not VEGF(165) rescued the in vitro deficiency of the mutant ES cells. Furthermore, in the absence of perlecan in the EB matrix lower levels of FGFs are bound, stored and available for cell surface presentation. Altogether these findings suggest that perlecan supports the maintenance of brain and skin subendothelial BMs and promotes vasculo- and angiogenesis by modulating FGF-2 function.

MIF produced by bone marrow-derived macrophages contributes to teratoma progression after embryonic stem cell transplantation.

Although stem cell therapy holds promise as a potential treatment in a number of diseases, the tumorigenicity of embryonic stem cells (ESC) and induced pluripotent stem cells remains a major obstacle. In vitro predifferentiation of ESCs can help prevent the risk of teratoma formation, yet proliferating neural progenitors can generate tumors, especially in the presence of immunosuppressive therapy. In this study, we investigated the effects of the microenvironment on stem cell growth and teratoma development using undifferentiated ESCs. Syngeneic ESC transplantation triggered an inflammatory response that involved the recruitment of bone marrow (BM)-derived macrophages. These macrophages differentiated into an M2 or angiogenic phenotype that expressed multiple angiogenic growth factors and proteinases, such as macrophage migration inhibitory factor (MIF), VEGF, and matrix metalloproteinase 9, creating a microenvironment that supported the initiation of teratoma development. Genetic deletion of MIF from the host but not from ESCs specifically reduced angiogenesis and teratoma growth, and MIF inhibition effectively reduced teratoma development after ESC transplantation. Together, our findings show that syngeneic ESC transplantation provokes an inflammatory response that involves the rapid recruitment and activation of BM-derived macrophages, which may be a crucial driving force in the initiation and progression of teratomas.

Retroperitoneal vascular surgery for the treatment of giant growing teratoma syndrome.

OBJECTIVE: To evaluate whether an aggressive surgical policy, which included vascular surgery with standard retroperitoneal lymph node dissection (RPLND), would be justified for managing bulky retroperitoneal growing teratoma syndrome (GTS). METHODS: Data were collected retrospectively from a series of 12 patients who, from 1992 to 2010, underwent radical RPLND for bulky GTS (retroperitoneal mass≥10 cm in diameter). For complete resection, vascular procedures and nephrectomy were performed. RESULTS: Median tumor diameter was 100 mm before and 140 mm (range 100-300) after chemotherapy. Two patients underwent iterative RPLND. In addition to RPLND, patients underwent aortic section with aortic anastomosis (n=6), inferior vena cava resection (n=3), both the latter and the former (n=1), and aortic graft with left nephrectomy (n=2). There were no operative deaths; 3 patients had complications (25%), but none were related to extended procedures. The median hospital stay was 15 days. Median follow up was 59 months (range 10-162). One patient died of metastatic cutaneous melanoma 112 months after RPLND, 10 patients survived and are disease-free, and one patient had a para-aortic recurrence. CONCLUSION: A 100% complete resection rate, long-term survival, no mortality, and acceptable morbidity were achieved when vascular surgery and left nephrectomy were combined with standard RPLND for bulky GTS.

Enhancing safety of laparoscopic vascular control for neonatal sacrococcygeal teratoma.

Life-threatening bleeding is a hazard of major tumor excision in children. However, fatalities from inadvertent arterial ligation should not be overlooked. Sacrococcygeal teratoma is the commonest neonatal tumor. Laparotomy to ligate the median sacral artery has been used to preempt potentially fatal resectional bleeding. Use of laparoscopy to achieve the same is an evolving technique, with only 7 neonatal cases described. As such, the Idea, Development, Exploration, Assessment, Long-term study (IDEAL) guidelines on surgical innovation recommend case reports addressing proof of concept, technical factors and safety tips. Fortunately, mistaken arterial division is so far unreported during laparoscopic median sacral artery ligation. However, as uptake widens, anatomical distortion by tumor and surgeon disorientation at endosurgery are risk factors for even such inconceivable complications. We report a successful case of laparoscopic vascular control for neonatal sacrococcygeal teratoma and demonstrate an observation that serves as a useful safety check for this procedure (as well as the open alternative).

Damage control operation for massive sacrococcygeal teratoma.

Surgical resections of massive sacrococcygeal teratomas (SCTs) carry significant risk due to baseline hemodynamic instability and the potential for significant hemorrhage. In this case report, a fetus with sacrococcygeal teratoma developed high-output cardiac instability at 32 weeks' gestation. After urgent cesarian delivery, a damage-control operation using Teflon-pledgeted mattress sutures allowed for hemodynamic control of bleeding into the tumor. One week later, after subsequent fluid resuscitation and stabilization, an elective staged resection of the complete mass including the pelvic portion was performed. The patient was discharged home on postoperative day 30 and was doing well at her most recent clinic visit at 30 months of age.

Bioluminescence reporter gene imaging characterize human embryonic stem cell-derived teratoma formation.

Human embryonic stem (hES) cells have a potential use for the repair and regeneration of injured tissues. However, teratoma formation can be a major obstacle for hES-mediated cell therapy. Therefore, tracking the fate and function of transplanted hES cells with noninvasive imaging could be valuable for a better understanding of the biology and physiology of teratoma formation. In this study, hES cells were stably transduced with a double fusion reporter gene consisting of firefly luciferase and enhanced green fluorescent protein. Following bioluminescence imaging and histology, we demonstrated that engraftment of hES cells was followed by dramatically increasing signaling and led to teratoma formation confirmed by histology. Studies of the angiogenic processes within teratomas revealed that their vasculatures were derived from both differentiated hES cells and host. Moreover, FACS analysis showed that teratoma cells derived from hES cells expressed high levels of CD56 and SSEA-4, and the subcultured SSEA-4(+) cells showed a similar cell surface marker expression pattern when compared to undifferentiated hES cells. We report here for the first time that SSEA-4(+) cells derived from teratoma exhibited multipotency, retained their differentiation ability in vivo as confirmed by their differentiation into representative three germ layers.

High expression of NPY receptors in the human testis.

NPY receptors represent novel molecular therapeutic targets in cancer and obesity. However, the extent of NPY receptor expression in normal human tissues is poorly investigated. Based on the role of NPY in reproductive functions, the NPY receptor expression was studied in 25 normal human testes and, additionally, 24 testicular tumors using NPY receptor autoradiography. In the normal testis, Leydig cells strongly expressed NPY receptor subtype Y2, and small arterial blood vessels Y1. Y2 receptors were found to be functional with agonist-stimulated [(35)S]GTPγS binding autoradiography. Full functional integrity of the NPY system was further suggested by the immunohistochemical detection of NPY peptide in nerve fibers directly adjacent to Leydig cells and arteries. Germ cell tumors expressed Y1 and Y2 on tumor cells in 33% and Y1 on intratumoral blood vessels in 50%. Based on its strong NPY receptor expression in Leydig cells and blood vessels, the normal human testis represents a potentially important physiological and pharmalogical NPY target.

Preoperative embolization of giant sacrococcygeal teratoma in a premature newborn.

Resection of a large vascular sacrococcygeal teratoma (SCT) in a newborn has the potential to be a fatal procedure caused by hemolysis, rupture, or bleeding of the tumor. Usually, most blood supply of an SCT is derived from the middle sacral artery. As soon as these arteries have been ligated, further blood loss is minimal. There is only one previous presentation about preoperative embolization of these arteries. We present a case in which the feeding arteries of a giant SCT were embolized in an infant born at 30 weeks and 3 days of gestation. Although bleeding during the surgery was minimal, continuous need of transfusions and life-threatening hyperkalemia created severe problems during surgery, until tumor resection was completed. This is the smallest reported patient in whom SCT was preoperatively treated by embolization.

F3-targeted cisplatin-hydrogel nanoparticles as an effective therapeutic that targets both murine and human ovarian tumor endothelial cells in vivo.

Recent studies indicate that ovarian cancer may be highly responsive to antivascular therapeutics. We have developed an antivascular tumor therapeutic using the F3 peptide to target cisplatin-loaded nanoparticles (F3-Cis-Np) to tumor vessels. We show that although F3-Cis-Np bind with high specificity to both human ovarian tumor cells and tumor endothelial cells in vitro, they only show cytotoxic activity against the tumor endothelial cells. In vivo these nanoparticles bind primarily to tumor endothelial cells. Therapeutic studies in both flank and orthotopic i.p. murine ovarian tumor models, as well as human tumor xenograft models, show rapid tumor regression with treatment. Treatment was associated with significant vascular necrosis consistent with an antivascular effect. Furthermore, treatment was active in both platinum-sensitive and platinum-resistant cell lines. Importantly, we show that F3-Cis-Np bind to human tumor endothelial cells in vitro and to human tumor vessels in vivo. Therapy targeting human vasculature in vivo with F3-Cis-Np led to near complete loss of all human tumor vessels in a murine model of human tumor vasculature. Our studies indicate that F3-targeted vascular therapeutics may be an effective treatment modality in human ovarian cancer.

Embryonic stem cell tumor model reveals role of vascular endothelial receptor tyrosine phosphatase in regulating Tie2 pathway in tumor angiogenesis.

Inhibiting angiogenesis has become an effective approach for treating cancer and other diseases. However, our understanding of signaling pathways in tumor angiogenesis has been limited by the embryonic lethality of many gene knockouts. To overcome this limitation, we used the plasticity of embryonic stem (ES) cells to develop a unique approach to study tumor angiogenesis. Murine ES cells can be readily manipulated genetically; in addition, ES cells implanted subcutaneously in mice develop into tumors that contain a variety of cell types (teratomas). We show that ES cells differentiate into bona fide endothelial cells within the teratoma, and that these ES-derived endothelial cells form part of the functional tumor vasculature. Using this powerful and flexible system, the Angiopoietin/Tie2 system is shown to have a key role in the regulation of tumor vessel size. Endothelial differentiation in the ES teratoma model allows gene-targeting methods to be used in the study of tumor angiogenesis.

Three-dimensional power Doppler sonography in the diagnosis of a cystic sacrococcygeal teratoma mimicking a meningomyelocele: A case report.

Sacrococcygeal teratomas have been diagnosed prenatally on sonograms as masses of cystic, solid, or mixed echogenicity from the sacral area and protruding through the perineum or buttocks. However, a cystic sacrococcygeal teratoma may be misdiagnosed as an anterior sacral meningomyelocele, especially when presenting as a posterior cystic mass. We report a case in which three-dimensional power Doppler imaging was helpful for making a correct prenatal diagnosis of a type 1 cystic sacrococcygeal teratoma, which mimicked a meningomyelocele.