Yolk Sac Carcinoma Research Articles

Cytologic features of gynecologic germ cell tumors and carcinomas exhibiting germ cell tumor differentiation.

In this study, the authors sought to describe the cytologic features of primary gynecologic germ cell tumors and carcinomas exhibiting germ cell differentiation because little information currently exists. An institutional database search was performed to identify histologically confirmed gynecologic germ cell tumors and carcinomas with germ cell tumor differentiation. Available cytologic material was reviewed by three observers, and morphologic features were recorded in addition to patient age at original diagnosis, primary tumor site, site(s) from which the examined cytologic material was obtained, and the type of examined cytologic preparations. In total, 15 cytologic specimens from 12 women (aged 19-82years) were identified and included touch preparations of core biopsies from various sites (n=6), fine-needle biopsies (n=2), pelvic washings (n=1), ascitic fluids (n=4), pelvic cyst fluid (n=1), and endometrial aspirate (n=1). Of the 12 patients, seven had primary gynecologic germ cell tumors, four had gynecologic (ovarian and endometrial) tumors exhibiting somatic yolk sac tumor-like differentiation, and the remaining patient had an intestinal-type adenocarcinoma arising within an ovarian teratoma. There was morphologic overlap among many of the cases, although cytoplasmic vacuolation/granular cytoplasm was seen in 75% of primary yolk sac tumors or carcinomas with yolk sac tumor differentiation, and dense/squamoid cytoplasm was seen in 100% of teratomatous elements that were sampled. Germ cell tumors and somatic neoplasms exhibiting germ cell tumor differentiation occurring in adult women share some cytologic features and may be difficult to distinguish from one another, although some tumor types showed characteristic cytomorphologic findings.

Spinal Metastasis of Unknown Primary Accompanied by Neurologic Deficit or Vertebral Instability.

Spinal bone metastases are common. They are mostly localized to the lumbar, thoracic, and cervical spine. The most common primaries to result in spinal metastases include lung, breast, and prostate carcinomas in adults as opposed to leukemia, Ewing sarcoma, rhabdomyosarcoma, and neuroblastoma in children. In patients diagnosed with cancer, bone metastases are found in 40% and spinal metastases in 10%. In this study, we reviewed 25 patients diagnosed with a spinal metastasis of unknown primary who presented with low back pain or acute-onset neurologic deficits and underwent operative treatment. The retrospective study included 25 patients with a spinal metastasis of unknown primary who presented to our clinic with acute-onset vertebral fracture or neurologic deficit. Statistical descriptions were obtained for each patient. Survival analysis was performed using the Kaplan-Meier method. The 25 patients included 17 men (68%) and 8 women (32%), with a mean age of 55 years (range, 14-81 years). Eleven patients (44%) presented with varying degrees of motor deficits ranging from flaccid paralysis to paraplegia. Motor deficits were completely reversed in 4 patients postoperatively. The tumors were localized to the upper thoracic spine (T1-4) in 2 patients, in the midthoracic spine (T5-8) in 2 patients, in the lower thoracic spine (T9-12) in 8 patients, in the cervical 7 in 1 patient, and in the lumbar spine in 12 patients. In 10 patients, the tumor affected multiple spinal regions. Nonosseous tumors were not present in 10 patients. Ten patients had an extradural tumor. Costal involvement was detected in 2 patients. The tumors were pathologically identified as lung cancer (n= 3), lymphoma (n= 5), breast cancer (n= 3), gastric cancer (n= 2), liver cancer (n= 2), prostate cancer (n= 2), renal cell carcinoma (n= 2), malignant melanoma (n= 1), plasmacytoma (n= 1), bladder cancer (n= 1), paraganglioma (n= 1), Ewing sarcoma (n= 1), and yolk sac carcinoma (n= 1). Posterior instrumentation was performed in patients with instability. In addition, decompression was performed in patients with neurologic deficit. Considering that 10% of patients with cancer are diagnosed by vertebral metastasis, presence of malignancy should be suspected and a detailed examination should be performed in patients presenting with vertebral fractures caused by no or minor trauma. Moreover, in patients presenting with neurologic deficit, soft tissue metastases leading to spinal cord compression should be kept in mind and further examinations should be promptly administered.

Abstract 3861: Development of testicular cancer patient derived xenograft models to test combination therapies targeting PI3K/Akt and MDM2

Abstract Metastatic testicular cancer (TC) is highly sensitive to cisplatin-based chemotherapy. However, patients with advanced disease in the poor prognosis group only have a 50% 5-year survival resulting from chemoresistance. Previous data showed that both the PI3K/Akt pathway and the MDM2/p53 axis are involved in cisplatin resistance of TC cells. In this study we aim to establish and characterize TC patient-derived xenografts (PDX) in order to investigate PI3K/Akt and/or MDM2 inhibition as possible treatment options for TC. Excised and minced (8mm3) primary TC tissue was implanted subcutaneously into male NSG mice to obtain a first generation PDX model (F1). Animals were sacrificed when tumor volume exceeded 1500 mm3. The tumor was harvested and minced. Small pieces (8mm3) were implanted in a second generation (F2), as well as stored in FCS-5% DMSO to establish a biobank. In a panel of TC cell lines, combination treatment of Akt inhibition with or without cisplatin or Nutlin-3a was performed. Cleaved caspase-3 staining was assessed to measure apoptosis, and western blot was used to determine the effect of different treatments on sub-cellular localization and phosphorylation status of MDM2. We have established 3 TC PDX models. Histology of the primary tumors included the following subtypes: mixed germ cell tumors with embryonal- and yolk sac carcinoma and teratoma components. Engraftment efficacy was 100% and tumor growth initiated within 4-5 weeks after implantation. Interestingly, we successfully implanted a biopsy taken from a metastatic lesion of a patient presenting with progressive refractory disease after receiving standard chemotherapy. Histology of the different PDX generations was comparable to the patient material, although a loss of the teratoma component was observed. In our cell line panel, Akt inhibition using MK2206 sensitized the acquired cisplatin resistant cell line TeraCP towards cisplatin treatment, whereas an additive effect was observed in other cell lines. Combination of Akt and MDM2 inhibition was highly synergistic in apoptosis induction in all cell lines. No relation was observed between the synergistic effect of Akt combined with MDM2 inhibition and sub-cellular localization or phosphorylation levels of MDM2. Taken together, we have successfully established 3 TC PDX models, including a chemo-resistant model. The biobank is currently being expanded. Combined Akt and MDM2 inhibition resulted in synergistic induction of apoptosis, and these combinations or other novel therapies will be tested in established TC PDX models. Supported by Dutch Cancer Society grant RUG 2014-6691 and CONACYT grant 381543 Citation Format: Gerda de Vries, Ximena Rosas-Plaza, Marcel A. van Vugt, Albert J.H. Suurmeijer, Jourik A. Gietema, Steven de Jong. Development of testicular cancer patient derived xenograft models to test combination therapies targeting PI3K/Akt and MDM2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3861. doi:10.1158/1538-7445.AM2017-3861

Pathology of Aging in NOD scid gamma Female Mice.

In the past decade, NOD.Cg- Prkdcscid Il2rgtm1Wjl/SzJ (NSG, NOD scid gamma) mice have become a model of choice in several areas of biomedical research; however, comprehensive data on their spontaneous age-related pathology are not currently available in the literature. The prevalence of spontaneous morbidity affecting aged NSG female breeders enrolled in a parasitology study was documented with classification of neoplastic and non-neoplastic (inflammatory, metabolic, degenerative) lesions. Malignant mammary neoplasms were most commonly diagnosed, often accompanied by pulmonary metastases, while a low frequency of lymphoma and histiocytic sarcoma was documented. The major inflammatory conditions were suppurative pleuropneumonia and bronchopneumonia with abscess formation, from which Pasteurella pneumotropica was commonly isolated, followed by otitis media. Both inflammatory and degenerative lesions of the genital tract were identified, along with neoplasms such as endometrial yolk sac carcinomas and granulosa cell tumors. Novel conditions identified included renal tubular degeneration and necrosis associated with 2 concurrent types of intranuclear inclusions, focal or multifocal hyperostosis of the skull, and neuroendocrine tumors of the mesometrium. The majority of degenerative lesions that affected the genital tract, endocrine, and skeletal systems did not represent the actual underlying cause of death but rather were considered incidental findings. This study indicates that both inflammatory and neoplastic conditions contribute to morbidity and mortality in experimentally manipulated aged female NSG mice.

Giant seminoma case with very small yolk sac and embryo carcinoma components, detected by intensive histopathological examination

We experienced the giant seminoma with 18×10×10cm sized and about 2.6kg weight of 25year old patient. We intensively examined the histological tissue type distributions in this giant seminoma. Most of the tumor consisted of seminoma components. In addition, the tumor included the very small fragments of yolk sac tumor and embryonal carcinoma component at the root part of the seminoma mass. This shows that intensive histological examination may contribute to the finding of other embryonic component of the large seminoma. This may show that leaving the seminoma growing may generate the other embryonic tumor component, not always big enough to find out in a routine procedure, during the growth, in the different way from the original mixed cell germ tumor.

Giant Mediastinal Germ Cell Tumour: An Enigma of Surgical Consideration.

We present a case of 16-year-old male, who was referred from private centre for dyspnoea, fatigue, and orthopnea. The chest radiograph revealed complete opacification of left chest which was confirmed by computed tomography as a large left mediastinal mass measuring 14 × 15 × 18 cm. The diagnostic needle core biopsy revealed mixed germ cell tumour with possible combination of embryonal carcinoma, yolk sac, and teratoma. After 4 cycles of neoadjuvant BEP regime, there was initial response of tumour markers but not tumour bulk. Instead of classic median sternotomy or clamshell incision, posterolateral approach with piecemeal manner was chosen. Histology confirmed mixed germ cell tumour with residual teratomatous component without yolk sac or embryonal carcinoma component. Weighing 3.5 kg, it is one of the largest mediastinal germ cell tumours ever reported. We describe this rare and gigantic intrathoracic tumour and discuss the spectrum of surgical approach and treatment of this exceptional tumour.

Spontaneous Nonmetastatic Choriocarcinoma, Yolk Sac Carcinoma, Embryonal Carcinoma, and Teratoma in the Testes of a Swiss Albino Mouse

A 12-week-old Swiss Albino mouse was presented with unilateral (left) testicular enlargement of approximately 1.5 cm in diameter and the right testicle mildly reduced in size and weight. Histopathology evaluation revealed three distinct neoplasms in the left testicle: choriocarcinoma, yolk sac carcinoma, and embryonal carcinoma. Teratoma was diagnosed in the right testicle. The histomorphological and immunohistochemical characteristics of the tumor are presented here. To the best of the authors' knowledge, this is the first report of spontaneous nonmetastasizing choriocarcinoma, yolk sac carcinoma, embryonal carcinoma, and teratoma in testes of a Swiss albino mouse.

Ultrasound microbubble-mediated delivery of the siRNAs targeting MDR1 reduces drug resistance of yolk sac carcinoma L2 cells

BackgroundMDR1 gene encoding P-glycoprotein is an ATP-dependent drug efflux transporter and related to drug resistance of yolk sac carcinoma. Ultrasound microbubble-mediated delivery has been used as a novel and effective gene delivery method. We hypothesize that small interfering RNA (siRNA) targeting MDR1 gene (siMDR1) delivery with microbubble and ultrasound can down-regulate MDR1 expression and improve responsiveness to chemotherapeutic drugs for yolk sac carcinoma in vitro.MethodsRetroviral knockdown vector pSEB-siMDR1s containing specific siRNA sites targeting rat MDR1 coding region were constructed and sequence verified. The resultant pSEB-siMDR1 plasmids DNA were encapsulated with lipid microbubble and the DNA release were triggered by ultrasound when added to culture cells. GFP positive cells were counted by flow cytometry to determine transfection efficiency. Quantitative real-time PCR and western blot were performed to determine the mRNA and protein expression of MDR1. P-glycoprotein function and drug sensitivity were analyzed by Daunorubicin accumulation and MTT assays.ResultsTransfection efficiency of pSEB-siMDR1 DNA was significantly increased by ultrasound microbubble-mediated delivery in rat yolk sac carcinoma L2 (L2-RYC) cells. Ultrasound microbubble-mediated siMDR1s delivery effectively inhibited MDR1 expression at both mRNA and protein levels and decreased P-glycoprotein function. Silencing MDR1 led to decreased cell viability and IC50 of Vincristine and Dactinomycin.ConclusionsOur results demonstrated that ultrasound microbubble-mediated delivery of MDR1 siRNA was safe and effective in L2-RYC cells. MDR1 silencing led to decreased P-glycoprotein activity and drug resistance of L2-RYC cells, which may be explored as a novel approach of combined gene and chemotherapy for yolk sac carcinoma.

Highly Metastatic Ovarian Yolk Sac Carcinoma in a Rat

We investigated a highly metastatic ovarian yolk sac carcinoma in a 52-week-old female Crl:CD(SD) rat. Macroscopically, the present case had severe ascites, bilateral ovarian masses and numerous nodules in the abdominal and thoracic cavities. Histopathologically, these masses and nodules were generally composed of two types of cells mimicking a parietal and visceral yolk sac. The parietal cells were round to polygonal, contained eosinophilic droplets and were arranged in nests and cords in the eosinophilic matrix. Both the intracytoplasmic droplets and the matrix were stained positively with PAS. The visceral cells were cylindriform, and proliferated in papillary and tubular patterns and occasionally formed Shiller-Duval body-like structures. In the dissemination sites, the neoplastic cells proliferated on the surface of the various tissues and often infiltrated into deeper parts of the tissues. Immunohistochemically, both neoplastic cells were positive for α-fetoprotein and keratin, and the eosinophilic matrix was positive for laminin. Ultrastructurally, the parietal cells had dilated rough endoplasmic reticulums, which were filled with electron-lucent laminated structures. The visceral cells had poorly to moderately developed intracytoplasmic organelles and were interconnected with desmosomes. Taken together, the present tumor was diagnosed as yolk sac carcinoma arising from the ovary and was characterized by not only high metastasis but also invasive infiltration with biphasic proliferation of the parietal and visceral cells.

Report on malignancies in the German juvenile idiopathic arthritis registry

TNF inhibitors have markedly improved the therapeutic options for JIA patients. The report on malignancies observed in children exposed to TNF inhibitors flagged up questions about a potential increased risk especially for lymphoma. Cases with malignancies observed in the German registry have been reviewed to give detailed information on the patients' pretreatment and outcome. From 2001 to 2009, five cases of malignancies were documented in the German JIA biologics registry actually covering 1260 patients, one of each non-Hodgkin's lymphoma, Hodgkin's lymphoma, thyroid carcinoma, yolk sac carcinoma and cervical dysplasia. All patients have been exposed to a number of cytotoxic drugs including MTX, LEF, AZA, CSA before institution of TNF-α blockers. The malignant diagnosis has been given after exposure to etanercept for 3 weeks up to >6 years. Two patients have also been exposed to adalimumab or infliximab. At occurrence of the malignancy, three patients were still on etanercept, four on MTX and one on infliximab. In three patients, the malignancy occurred at adulthood. All patients recovered. While in some of the patients exposed to TNF inhibitors the exposure time was too short for a meaningful relationship, in others the extensive pretreatment may also be causative. Two lymphomas have been observed while other entities occurred only once. JIA patients exposed to biologics or cytotoxic drugs have to be followed carefully and long-term observation has to be continued in adulthood.

A case of metastatic testicular cancer complicated by pulmonary hemorrhage due to choriocarcinoma syndrome

A 40-year-old man was referred to our hospital for treatment of metastatic testicular cancer. Computerized tomography revealed multiple lung, liver, and retroperitoneal lymph node metastases. In addition, magnetic resonance imaging revealed multiple brain metastases. Induction chemotherapy with bleomycin, etoposide, and cisplatin was started the day after a high orchiectomy. The pathological diagnosis of the surgical specimen was yolk sac carcinoma. The serum human chorionic gonadotropin (hCG) was markedly increased to 630,000 mIU/ml, which suggested the presence of a choriocarcinoma element at metastatic sites. The patient subsequently suffered respiratory failure due to pulmonary hemorrhage. Intensive supportive care prevented a fatal outcome. Physicians who treat advanced testicular tumors should be aware of the potential complication of acute pulmonary hemorrhage, called choriocarcinoma syndrome, in cases with a high hCG level, which indicates a rapidly progressive and high-volume choriocarcinoma.

Embryonal carcinoma in a cryptorchid testis of a 3-year old

The undescended testis is at an increased risk of malignant transformation. Almost all such tumours occur in the second to fourth decades of life and are usually seminomas. A case of a mixed germ-cell tumour with yolk sac and embryonal carcinoma components arising in one of the hitherto uncorrected bilateral cryptorchid testes of a3-year old child is presented.

The Effects of Chemotherapy on Metastatic Testicular Germ Cell Tumors

Modern chemotherapy combined with surgery can achieve complete cure in over 90% of all patients with malignant testicular germ cell tumors. Even tumors that have already metastasized at the time of orchidectomy are curable by platinum-based multidrug treatment. Chemotherapy related changes can be seen in the residual tumor tissue in metastatic sites. In patients fully responding to chemotherapy these changes include complete necrosis of the tumor cells, and inflammatory-phagocytic response, fibrosis replacing the necrotic tumor tissue, and residual benign somatic tissue tissues in form of teratoma. Epithelial and stromal cells of these teratomas may display nuclear atypia, which is however not a reason for concern and should not be considered an indication for additional chemotherapy. Less commonly the lymph nodes contain cystic trophoblastic tumors. In contrast to metastatic classical biphasic or monophasic choriocarcinoma, cystic trophoblastic tumors portend a favorable clinical outcome. Patients with an incomplete response to chemotherapy and those with recurrences of the malignant tumor contain in metastatic sites foci composed of embryonal carcinoma cells, yolk sac carcinoma, or choriocarcinoma. The latter two subtypes of germ cell neoplasia may recur in several microscopic variant forms. Somatic forms of malignancy (also known as non-germ cell malignancies) that develop occasionally in some treated patients include most often sarcomas and tumors resembling central primitive neuroectodermal neoplasms. These secondary malignancies are usually resistant to chemotherapy. The broad spectrum of morphologic findings in the lymph nodes of patients with treated metastatic testicular germ cell tumors clearly illustrates the importance of meticulous pathologic analysis of tissue changes related to chemotherapy.

Aurora B expression in post-puberal testicular germ cell tumours.

Aurora/Ipl1-related kinases are a conserved family of proteins that are essential for the regulation of chromosome segregation and cytokinesis during mitosis. Aberrant expression and activity of these kinases occur in a wide range of human tumours and have been implicated in mechanisms leading to mitotic spindle aberrations, aneuploidy, and genomic instability. Previous studies of our group have shown that Aurora B expression is restricted to specific germinal cells. In this study, we have evaluated by immunohistochemical analysis Aurora B expression in post-puberal testicular germ cell tumours (22 seminomas, 2 teratomas, 15 embryonal carcinomas, 5 mixed germinal tumours with a prominent yolk sac tumour component and 1 choriocarcinoma). The Aurora B protein expression was detected in all intratubular germ cell tumours, seminomas and embryonal carcinomas analysed but not in teratomas and yolk sac carcinomas. The immunohistochemical data were further confirmed by Western blot analysis. In addition, the kinase Aurora B was vigorously expressed in GC-1 cells line derived from murine spermatogonia. The block of Aurora B function induced by a pharmacological inhibitor significantly reduced the growth of GC-1 cells suggesting that Aurora B is a potential therapeutic target.

Germline Competent Embryonic Stem Cells Derived from Rat Blastocysts

Rats have important advantages over mice as an experimental system for physiological and pharmacological investigations. The lack of rat embryonic stem (ES) cells has restricted the availability of transgenic technologies to create genetic models in this species. Here, we show that rat ES cells can be efficiently derived, propagated, and genetically manipulated in the presence of small molecules that specifically inhibit GSK3, MEK, and FGF receptor tyrosine kinases. These rat ES cells express pluripotency markers and retain the capacity to differentiate into derivatives of all three germ layers. Most importantly, they can produce high rates of chimerism when reintroduced into early stage embryos and can transmit through the germline. Establishment of authentic rat ES cells will make possible sophisticated genetic manipulation to create models for the study of human diseases.

Primary orbital endodermal sinus tumor (yolk sac tumor)

Endodermal sinus tumor, or yolk sac tumor, is the most common malignant neoplasm of germ cell origin and usually occurs in infant testes or ovaries. On rare occasions, the tumor may arise from extragonadal sites, including sacrococcygeal region, uterus, vagina, prostate, retroperitoneum, liver, mediastinum, pineal gland, and third ventricle. The orbit is an unusual location for the primary development of this neoplasm. We report the case of a girl with primary orbital endodermal sinus tumor who was managed with exenteration and chemotherapy with the result of a disease-free survival of 9 years.

Yolk sac tumor in the nasal cavity

Yolk sac carcinoma (YST) is rare malignant tumor of germ cell origin. It most commonly arises from the gonads but extragonadal sites of origin are reported in 20% of the cases. Head and neck germ cell tumors are uncommon and only a small number are malignant. We present the case of a 48 years old man presenting with a YST of the sinonasal tract and the arterior skull base. The patient underwent an anterior craniofacial resection and postoperative radiotherapy and continues showing no evidence of disease seven years after treatment. We discuss radiological and histological features of this tumor and provide a review of three other cases of YST arising in children.

Lung Fibrosis 10 Years after Cessation of Bleomycin Therapy

Bleomycin (BLM) is a chemotherapeutic agent used for the treatment of several types of malignancy, including germ cell tumors, lymphoma, and certain types of squamous-cell carcinoma. The common adverse effect of BLM is interstitial pneumonitis, followed by pulmonary fibrosis. BLM-induced pneumonitis occurs in up to 46% of patients treated with BLM-containing chemotherapy and lung toxicity usually appears during treatment. Here we describe a patient with lung fibrosis, who presented with slow progressive breathlessness and pneumothorax more than 10 years after cessation of BLM therapy. A 15 year-old girl presented with abnormal shadows on chest X-ray. The patient had a yolk sac carcinoma in the sacral region at 1 year of age and obtained complete remission after being treated with tumor resection, radiation, and several anti-cancer drugs including BLM. There were no abnormal findings in chest X-ray until she reached 3 years of age, when she had developed respiratory distress that worsened with age. The patient had experienced an episode of pneumothorax at 13 years of age. Chest CT at the time revealed interstitial reticular opacities. Radiological findings and pathological examination of the lung tissue obtained during bullectomy with video-assisted thoracic surgery were compatible with BLM-induced pneumonitis. The present study suggests that lung fibrosis may surface more than 10 years after cessation of BLM therapy at the age of 1 year, with no chest radiographic findings 1 year after completion of chemotherapy. The use of BLM in infants requires strict supervision and observation and careful long-term follow up.

Detection of high‐mobility group proteins A1 and A2 represents a valid diagnostic marker in post‐pubertal testicular germ cell tumours

The high-mobility group A (HMGA) non-histone chromosomal proteins HMGA1 and HMGA2 are architectural factors. They are abundantly expressed during embryogenesis and in most malignant neoplasias, whereas their expression is low or absent in normal adult tissues. Their over-expression is known to have a causal role in cellular neoplastic transformation. Previous studies from our group have shown that their expression is restricted to specific germinal cells. In this study we have evaluated, by immunohistochemistry, the expression of HMGA1 and HMGA2 in a series of post-pubertal testicular tumours of different histological types, including 30 seminomas, 15 teratomas, 15 embryonal carcinomas and 10 mixed germinal tumours with a prominent yolk sac tumour component. HMGA1 protein expression was detected in all seminomas and embryonal carcinomas analysed, but not in teratomas or yolk sac carcinomas. Conversely, HMGA2 was present only in embryonal carcinomas and yolk sac carcinomas, but not in seminomas or teratomas. The immunohistochemical data were further confirmed by Western blot and, at the mRNA level, by RT-PCR analyses. These findings indicate that HMGA1 and HMGA2 are differently expressed with respect to the state of differentiation of testicular germ cell tumours (TGCTs), with over-expression of both proteins in pluripotential embryonal carcinoma cells and loss of expression of HMGA1 in yolk sac tumours and of both proteins in the mature adult tissue of teratoma areas. Therefore, the different profiles of HMGA1 and HMGA2 protein expression could represent a valuable diagnostic tool in some cases in which the histological differential diagnosis is problematic.

P-220B Case report : Yolk sac carcinoma originated form retroperitoneum(Oncology, 44th Annual Meeting of Japanese Society of Pediatric Surgeons)

P-220B Case report : Yolk sac carcinoma originated form retroperitoneum(Oncology, 44th Annual Meeting of Japanese Society of Pediatric Surgeons)