A human organoid model of aggressive hepatoblastoma for disease modeling and drug testing

Hepatoblastoma is the most common childhood liver cancer. Although survival has improved significantly over the past few decades, there remains a group of children with aggressive disease who do not respond to current treatment regimens. There is a critical need for novel models to study aggressive hepatoblastoma as research to find new treatments is hampered by the small number of laboratory models of the disease. Organoids have emerged as robust models for many diseases, including cancer. We have generated and characterized a novel organoid model of aggressive hepatoblastoma directly from freshly resected patient tumors as a proof of concept for this approach. Hepatoblastoma tumor organoids recapitulate the key elements of patient tumors, including tumor architecture, mutational profile, gene expression patterns, and features of Wnt/β-catenin signaling that are hallmarks of hepatoblastoma pathophysiology. Tumor organoids were successfully used alongside non-tumor liver organoids from the same patient to perform a drug screen using twelve candidate compounds. One drug, JQ1, demonstrated increased destruction of liver organoids from hepatoblastoma tumor tissue relative to organoids from the adjacent non-tumor liver. Our findings suggest that hepatoblastoma organoids could be used for a variety of applications and have the potential to improve treatment options for the subset of hepatoblastoma patients who do not respond to existing treatments

Pancreaticoduodenectomy for the treatment of pancreatic neoplasms in children: A Pediatric Surgical Oncology Research Collaborative study

BackgroundTo better characterize short- term and long- term outcomes in children with pancreatic tumors treated with pancreaticoduodenectomy (PD).MethodsPatients 21 years of age or younger who underwent PD at Pediatric Surgical Oncology Collaborative (PSORC) hospitals between 1990 and 2017 were identified. Demographic, clinical information, and outcomes (operative complications, long- term pancreatic function, recurrence, and survival) were collected.ResultsSixty- five patients from 18 institutions with a median age of 13 years (4 months- 22 years) and a median (IQR) follow- up of 2.8 (4.3) years were analyzed. Solid pseudopapillary tumor of the pancreas (SPN) was the most common histology. Postoperative complications included pancreatic leak in 14% (n = 9), delayed gastric emptying in 9% (n = 6), marginal ulcer in one patient, and perioperative (30- day) death due to hepatic failure in one patient. Pancreatic insufficiency was observed in 32% (n = 21) of patients, with 23%, 3%, and 6% with exocrine, or endocrine insufficiencies, or both, respectively. Children with SPN and benign neoplasms all survived. Overall, there were 14 (22%) recurrences and 11 deaths (17%). Univariate analysis revealed non- SPN malignant tumor diagnosis, preoperative vascular involvement, intraoperative transfusion requirement, pathologic vascular invasion, positive margins, and need for neoadjuvant chemotherapy as risk factors for recurrence and poor survival. Multivariate analysis only revealed pathologic vascular invasion as a risk factor for recurrence and poor survival.ConclusionThis is the largest series of pediatric PD patients. PD is curative for SPN and benign neoplasms. Pancreatic insufficiency is the most common postoperative complication. Outcome is primarily associated with histology.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156233/2/pbc28425.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156233/1/pbc28425_am.pd

Pancreaticoduodenectomy for the treatment of pancreatic neoplasms in children: A Pediatric Surgical Oncology Research Collaborative study

Background: To better characterize short-term and long-term outcomes in children with pancreatic tumors treated with pancreaticoduodenectomy (PD). Methods: Patients 21 years of age or younger who underwent PD at Pediatric Surgical Oncology Collaborative (PSORC) hospitals between 1990 and 2017 were identified. Demographic, clinical information, and outcomes (operative complications, long-term pancreatic function, recurrence, and survival) were collected. Results: Sixty-five patients from 18 institutions with a median age of 13 years (4 months-22 years) and a median (IQR) follow-up of 2.8 (4.3) years were analyzed. Solid pseudopapillary tumor of the pancreas (SPN) was the most common histology. Postoperative complications included pancreatic leak in 14% (n = 9), delayed gastric emptying in 9% (n = 6), marginal ulcer in one patient, and perioperative (30-day) death due to hepatic failure in one patient. Pancreatic insufficiency was observed in 32% (n = 21) of patients, with 23%, 3%, and 6% with exocrine, or endocrine insufficiencies, or both, respectively. Children with SPN and benign neoplasms all survived. Overall, there were 14 (22%) recurrences and 11 deaths (17%). Univariate analysis revealed non-SPN malignant tumor diagnosis, preoperative vascular involvement, intraoperative transfusion requirement, pathologic vascular invasion, positive margins, and need for neoadjuvant chemotherapy as risk factors for recurrence and poor survival. Multivariate analysis only revealed pathologic vascular invasion as a risk factor for recurrence and poor survival. Conclusion: This is the largest series of pediatric PD patients. PD is curative for SPN and benign neoplasms. Pancreatic insufficiency is the most common postoperative complication. Outcome is primarily associated with histology

Esophageal adenocarcinoma and squamous cell carcinoma in children and adolescents: Report of 3 cases and comprehensive literature review

Malignant esophageal tumors are exceedingly rare in children and adolescents. We present 3 cases of esophageal adenocarcinoma (AC) and squamous cell carcinoma (SSC) in patients ≤21 years of age who were treated at our institution between 1950 and 2015. We also undertook an analysis of those cases, combined with cases from a review of the literature, to examine patient demographics, disease characteristics, and outcomes. We identified one patient with AC and two patients with SCC treated at our institution, as well as 19 cases of AC (median age 16) and 23 cases of SCC (median age 15) reported in the literature. Male predominance was noted at a ratio of 2.2 to 1. Dysphagia, weight loss, and anemia were the most common presenting symptoms for both entities. Approximately 84% of AC tumors were located in the distal esophagus and gastroesophageal junction whereas SCC tumors were distributed evenly throughout esophagus. Metastatic disease at presentation was found in 68.4% of patients with AC compared to 30.4% of those with SCC. Survival was not significantly different between SCC and AC (P = 0.36), between genders (P = 0.13), and between patients treated with surgery vs. multimodality therapy (P = 0.15). Metastasis, however, predicted worse outcome (P = 0.0019). We found that adolescent AC and SCC show characteristics similar to such tumors when presenting in adults. Though extremely rare in the adolescent population, these malignant diseases should always be ruled out when young patients present with a short history of dysphagia with signs of clinical deterioration

Unusual abdominal metastases in osteosarcoma

Intraabdominal metastases in the setting of osteosarcoma are very rare. We describe a case of a 17-year-old boy with high-grade right distal femur osteosarcoma who, two years after diagnosis, developed extensive intra abdominal metastases involving the omentum, peritoneum, bowel serosa, psoas muscles and abdominal soft tissue. Awareness of and surveillance for unusual patterns of metastasis may allow for earlier detection, intervention, and palliative care decision-making, which may affect survival and quality of life. This report underlines the need for prospective studies evaluating surveillance guidelines for patients after medical and surgical management of osteosarcoma, especially in cases complicated by pulmonary metastases. Keywords: Pediatric osteosarcoma, Extrapulmonary metastases, Extrapulmonary recurrence, Surveillance imagin

Unicentric Castleman disease in the mediastinum

Castleman disease (CD) is a benign lymphoproliferative disorder that rarely occurs in the pediatric population. This entity arises as either unicentric CD or multicentric CD, and is histopathologically classified as hyaline vascular, plasma cell, or mixed variant. CD is frequently misdiagnosed because it is poorly understood and presents with a variety of symptoms. We present a case of a 15-year-old previously healthy girl with unicentric CD. She presented to an Emergency Department with acute onset of chest pain. Radiographic imaging demonstrated a large right-sided mediastinal mass. Biopsy of the mass demonstrated atypical lymphoid tissue with vascular proliferation and concentric layering of peripheral lymphocytes, consistent with CD, hyaline vascular variant. Following multidisciplinary team discussion, the patient underwent complete resection of the mass. She completely recovered with no evidence of residual or recurrent disease on postoperative imaging

MYOD1-mutant spindle cell and sclerosing rhabdomyosarcoma: an aggressive subtype irrespective of age. A reappraisal for molecular classification and risk stratification

Sclerosing and spindle cell rhabdomyosarcoma is a rare histologic subtype, designated in the latest WHO classification as a stand-alone pathologic entity. Three genomic groups have been defined: an infantile subset of spindle cell rhabdomyosarcoma harboring VGLL2-related gene fusions, a MYOD1-mutant subset commonly associated with sclerosing morphology, and a subset lacking recurrent genetic abnormalities. In this study, we focus on MYOD1-mutant rhabdomyosarcoma to further define their clinicopathologic characteristics and behavior in a larger patient cohort. We investigated 30 cases of MYOD1-mutant rhabdomyosarcoma (12 previously reported and 18 newly diagnosed) with an age range of 2-94 years, including 15 children. All cases showed morphology within the spectrum of spindle cell/sclerosing rhabdomyosarcoma (8 cases showing pure sclerosing morphology, 8 cases\ua0 showing pure spindle cell morphology and 14 cases showing a hybrid phenotype of spindle, sclerosing and primitive undifferentiated areas). All tumors harbored either homozygous or heterozygous MYOD1 (p.L122R) exon 1 mutations. In 10 (33%) cases, a co-existent PIK3CA mutation was identified. Hot-spot mutations in NRAS and HRAS were each identified in a single case, respectively. Follow-up was available on 22 (73%) patients with a median duration of 28 months. Local recurrence was seen in 12 (55%) and distant recurrence in 12 (55%) cases, despite multimodality chemoradiation therapy. At last follow-up, 15 (68%) patients died of the disease, one patient was alive with disease and five had no evidence of disease. The prognosis was equally poor in pediatric and adult patients. In conclusion, MYOD1 mutation defines an aggressive rhabdomyosarcoma subset, with poor outcome and response to therapy, irrespective of age. Given that this distinct molecular subtype is characterized by an aggressive biologic behavior compared to other genetic subtypes of spindle and sclerosing rhabdomyosarcoma, the MYOD1 genotype should be used as a molecular marker in both subclassification and prognostication of rhabdomyosarcoma