Atif Ahmed

Phase II study of cixutumumab in combination with temsirolimus in pediatric patients and young adults with recurrent or refractory sarcoma: A report from the children's oncology group

The combined inhibition of insulin‐growth factor type 1 receptor (IGF‐1R) and the mammalian target of rapamycin (mTOR) has shown activity in preclinical models of pediatric sarcoma and in adult sarcoma patients. We evaluated the activity of the anti‐IGF‐1R antibody cixutumumab with the mTOR inhibitor temsirolimus in patients with relapsed or refractory Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, and other soft tissue sarcoma, using the recommended dosages from a pediatric phase I trial.

Undifferentiated Sinonasal Carcinoma in a Patient With Nevoid Basal Cell Carcinoma Syndrome

Nevoid basal cell carcinoma syndrome is an autosomal dominant multisystem disorder characterized by developmental anomalies and occurrence of multiple basal cell carcinomas and other tumors in early childhood. In this article, the authors report a case of a 19-year-old African American male with nevoid basal cell carcinoma syndrome and a history of medulloblastoma at age 2, meningioma at age 14, thyroid follicular adenomas with papillary carcinoma at age 15, and 2 basal cell carcinomas at ages 16 and 18. Recently, he developed sinonasal undifferentiated carcinoma (SNUC). The radiology and pathology of the sinonasal carcinoma are presented in this report. Review of the literature reveals that this is the first case of SNUC occurring in a patient with nevoid basal cell carcinoma syndrome.

PATHOLOGY TEACH AND TELL: FIBRINOGEN STORAGE DISEASE IN A CHILD WITH HYPOFIBRINOGENEMIA AND DECREASED CERULOPLASMIN

The authors present a clinical case of a patient with mild liver disease and coagulopathy. The diagnosis was reached through careful histologic examination of liver biopsy. Electron microscopy played an important role in confirming the diagnosis.

A Fryns syndrome-like phenotype with mosaic t(1;22)(q12;p12) chromosomal translocation.

We report a case of Fryns syndrome-like phenotype with chromosomal translocation. Not all such cases have chromosomal abnormalities hence we suggest that this condition is associated with genetic heterogeneity and variable clinical manifestations.

Arthrogryposis and pterygia as lethal end manifestations of genetically defined congenital myopathies

Arthrogryposis multiplex congenita affects approximately 1 in 3,000 individuals of different ethnic backgrounds and displays an equal incidence in males and females. The underlying mechanism for congenital contracture of the joints is decreased fetal movement during intrauterine development. This disorder is associated with over 400 medical conditions and 350 known genes that display considerable variability in phenotypic expression. In this report, four fetal or perinatal autopsy cases of arthrogryposis were studied by gross morphology, microscopic histopathologic examination, and whole genome sequencing of postmortem DNA. Two stillborn sibling fetuses with arthrogryposis, pterygia, and amyoplasia had compound heterozygous pathogenic variants in NEB. A neonate with a histopathologic diagnosis of nemaline myopathy had a heterozygous de novo pathogenic variant in ACTA1. Another stillborn infant with pterygia and arthrogryposis had a heterozygous de novo likely pathogenic variant in BICD2. These cases demonstrate the utility of whole genome sequencing as the principal diagnostic method of lethal forms of skeletal muscle disorders that present with arthrogryposis and muscle amyoplasia/hypoplasia. Molecular diagnosis provides an opportunity for studying patterns of inheritance and for family counseling concerning future pregnancies.

Pediatric gastrointestinal stromal tumor in association with neuroblastoma

Pediatric gastrointestinal stromal tumors (GISTs) are rare in children where they usually occur in the second decade. They represent 2.5% of all pediatric non-rhabdomyosarcomatous soft tissue sarcomas and 1.4–2.6% of all GISTs (1–6). Pediatric GISTs can occur as sporadic, familial or in association with certain syndromes. Predisposing syndromal conditions contribute to a minority of cases and include type I neurofibromatosis (7), Carney triad and Carney-Stratakis syndrome (8, 9), where GISTs coexist with extraadrenal paraganglioma with or without pulmonary chondroma.

Immunohistochemical expression of endothelial nitric oxide synthase and C-kit in the placenta of complete hydatidiform mole.

Complete hydatidiform mole is an abnormal conceptus characterized by hydropic villi accompanied by proliferating trophoblasts. Its pathogenesis is largely unknown. Endothelial nitric oxide synthase is induced by vascular endothelial growth factor and has been implicated in the pathogenesis of preeclampsia and other physiologic conditions in the placenta. C-kit is the tyrosine kinase receptor and is involved in tumor formation elsewhere in the body. Using standard immunohistochemical protocols, we studied the expression of C-kit and endothelial nitric oxide synthase in the placenta of 10 patients with complete hydatidiform mole. Cytoplasmic and nuclear staining with endothelial nitric oxide synthase was identified in the cytotrophoblast and intermediate trophoblast layers in all cases, with high staining in 7/10 and 6/8 cases, respectively. Minimal staining is identified in the syncytiotrophoblast layer. Hofbauer stromal cells were identified in 9 cases and showed low staining intensity in 7/9 cases. Cytoplasmic C-kit staining was diffuse and of low intensity. The cytotrophoblast, the syncytiotrophoblast, intermediate trophoblast, and the stromal cells had low C-kit staining intensity in 8/10, 8/10, 7/9, and 5/9 cases. These results indicate that C-kit and endothelial nitric oxide are expressed in the placentas of complete hydatidiform mole and may play a role in the pathogenesis of trophoblastic proliferation in this condition.

Potential Value of YAP Staining in Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a common malignancy of soft tissue, subclassified as alveolar (ARMS), pleomorphic (PRMS), spindle cell/sclerosing (SRMS), and embryonal (ERMS) types. The Yes-associated protein (YAP) is a member of the Hippo pathway and a transcriptional regulator that controls cell proliferation. We have studied the immunohistochemical expression of YAP in different RMSs, arranged in tissue microarray (TMA) and whole slide formats. Pertinent clinical data including patient age, gender, tumor location, and clinical stage were collected. Out of 96 TMA cases, 30 cases (31%) were pleomorphic, 27 (28%) were embryonal, 24 (25%) alveolar, and 15 (16%) spindle cell. Positive nuclear YAP staining was seen in the PRMS (17/30, 56.7%), SRMS (7/15, 46.7%), ERMS (19/27 or 70%), and less in ARMS (37.5%). YAP nuclear staining was significantly more prevalent in ERMS than ARMS (p=0.02). Of the 41 whole slide cases, nuclear staining was detected in all ARMS but was restricted in distribution to <30% of the cells, in contrast to ERMS and SRMS, which had diffuse or >30% staining. These results highlight the role of YAP in RMS tumorigenesis, a fact that can be useful in engineering targeted therapy. Restricted nuclear YAP staining (<30% of cells) may be of value in the diagnosis of ARMS.

Pediatric Ovarian Growing Teratoma Syndrome

Ovarian immature teratoma is a germ cell tumor that comprises less than 1% of ovarian cancers and is treated with surgical debulking and chemotherapy depending on stage. Growing teratoma syndrome (GTS) is the phenomenon of the growth of mature teratoma elements with normal tumor markers during or following chemotherapy for treatment of a malignant germ cell tumor. These tumors are associated with significant morbidity and mortality due to invasive and compressive growth as well as potential for malignant transformation. Current treatment modality is surgical resection. We discuss a 12-year-old female who presented following resection of a pure ovarian immature teratoma (grade 3, FIGO stage IIIC). Following chemotherapy and resection of a pelvic/liver recurrence demonstrating mature teratoma, she underwent molecular genetics based chemotherapeutic treatment. No standardized management protocol has been established for the treatment of GTS. The effect of chemotherapeutic agents for decreasing the volume of and prevention of expansion is unknown. We review in detail the history, diagnostic algorithm, and previous reported pediatric cases as well as treatment options for pediatric patients with GTS.

Engraftment of donor mesenchymal stem cells in chimeric BXSB includes vascular endothelial cells and hepatocytes

Somatic tissue engraftment was studied in BXSB mice treated with mesenchymal stem cell transplantation. Hosts were conditioned with nonlethal radiation prior to introducing donor cells from major histocompatibility complex-matched green fluorescent protein transgenic mice. Transplant protocols differed for route of injection, ie, intravenous (i.v.) versus intraperitoneal (i.p.), and source of mesenchymal stem cells, ie, unfractionated bone marrow cells, ex vivo expanded mesenchymal stem cells, or bone chips. Tissue chimerism was determined after short (10–12 weeks) or long (62 weeks) posttransplant follow-up by immunohistochemistry for green fluorescent protein. Engraftment of endothelial cells was seen in several organs including liver sinusoidal cells in i.v. treated mice with ex vivo expanded mesenchymal stem cells or with unfractionated bone marrow cells. Periportal engraftment of liver hepatocytes, but not engraftment of endothelial cells, was found in mice injected i.p. with bone chips. Engraftment of adipocytes was a common denominator in both i.v. and i.p. routes and occurred during early phases post-transplant. Disease control was more robust in mice that received both i.v. bone marrow and i.p. bone chips compared to mice that received i.v. bone marrow alone. Thus, the data support potential use of mesenchymal stem cell transplant for treatment of severe lupus. Future studies are needed to optimize transplant conditions and tailor protocols that may in part be guided by fat and endothelial biomarkers. Furthermore, the role of liver chimerism in disease control and the nature of cellular communication among donor hematopoietic and mesenchymal stem cells in a chimeric host merit further investigation.