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Infantile metastatic choriocarcinoma is a rare tumor of placental origin that can be observed with or without maternal metastases. A single cutaneous mass may be the only clinically observed sign. Reports of imaging findings are scarce given the extreme rarity of the tumor, and the disease can be rapidly fatal in the absence of prompt diagnosis. In order to promote timely consideration for this malignancy as a differential consideration in the approach to skin lesions in infancy, we present the findings of this neoplasm in an infant. While imaging and clinical characteristics similar to infantile hemangioma were demonstrated at presentation, biopsy and further radiologic investigation revealed multifocal metastatic choriocarcinoma. This case also highlights important differences between these entities, as the T2 hyperintensity and contrast enhancement observed with this choriocarcinoma were predominantly peripheral in location.

Infantile choriocarcinoma (ICC) is a rare, highly malignant form of gestational trophoblastic neoplasia. Rapid diagnosis and initiation of treatment are paramount in reaching a successful outcome. Patients with these tumors typically present with a triad of anemia, hepatomegaly, and precocious puberty. Cutaneous manifestations of ICC are extraordinarily rare with few documented cases. Here, we describe a male neonate who presented to our Dermatology clinic with a rapidly growing, markedly vascular glabellar mass associated with abnormal laboratory values suggestive of Kasabach–Merritt phenomenon. The initial clinical impression of infantile hemangioma led to an initial treatment with propranolol. However, the mass continued to enlarge and a biopsy was obtained. Histology revealed a high-grade, poorly differentiated carcinoma. A robust immunohistochemical battery demonstrated tumor reactivity with Glut-1, GATA3, Glypican-3, CAM5.2, and β-hCG establishing the diagnosis of metastatic choriocarcinoma. The diagnosis was further supported by the elevated serum β-hCG. In addition to the glabellar mass, imaging demonstrated tumor foci in the liver and lung. Clinical investigation of the mother revealed no evidence of disease.

Patients with Down’s syndrome who develop acute myeloid leukemia (AML) are at increased risk of toxicity secondary to chemotherapy regimens. These patients are harder to treat with conventional therapies at relapse. Overall, the use of targeted drug therapy is rising in the pediatric oncology field. Development of drug sensitivity and resistance test allows identification of specific targeted therapies for patient’s with difficult to treat leukemia. Our laboratory is working on the development of a drug sensitivity and resistance screening assay that would provide functionally relevant drug response data of the patient’s leukemia cells. Development of this assay included the preparation of pre-dosed drug library plates allowing for rapid initiation of the assay. AML cells are then added to the plate and treated for 72 hours after which cell viability was determined. Previous work in our laboratory tested a library of 56 anti-cancer and targeted agents on a panel of 16 AML cell lines that included two Down’s syndrome AML cell lines CMK and CMY. Drug dose response data including IC50 values and Area Under the Curve (AUC) were calculated for each cell line. Hierarchical clustering was performed to determine similar responses between cell lines. Down’s syndrome cell lines, CMK and CMY were found to be resistant to most conventional chemotherapeutic agents, but susceptible to targeted therapies such as Navitoclax and 17-AAG. We further tested several cell lines with the drug sensitivity and resistance assay under hypoxic conditions. Our screening results showed improved sensitivity of the CMK and CMY cells to Navitoclax and 17-AAG under normoxic and hypoxic conditions. Validation of the screening results was done using a 10-concentration drug dose response assay. Future studies will explore the mechanism by which the Down’s syndrome AML cells have increased sensitivity to these targeted agents under both normoxic and hypoxic conditions. Furthermore, we will investigate the activity of combinations of these targeted therapies with conventional therapies. The results from these studies could lead to the establishment of improved therapeutic regimens for Down’s syndrome patients with AML. Citation Format: Apurvi R. Patel, Justin J. Montoya, Daniel H. Wai, David W. Lee, Robert J. Arceci, David O. Azorsa. Application of drug sensitivity and resistance testing to identify novel therapeutic agents for Down syndrome patients with AML [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 4077. doi:10.1158/1538-7445.AM2017-4077

Despite major advancements in pediatric leukemia therapy, toxicities and morbidity from chemotherapy regimens have been detrimental. Advances in genomic research as well as precision medicine have helped identify specific mutations that may be susceptible to targeted therapy in leukemic patients. Overall, the use of targeted drug therapy is rising in the pediatric oncology field. To complement genomic analysis of leukemia patients, our laboratory is working on the development of a drug sensitivity and resistance screening library, that would provide functionally relevant drug response data of the patient's leukemia cells. Development of this assay included the preparation of pre-dosed library plates allowing for rapid initiation of the assay. Cells were treated for 72 hours and cell viability was determined. Preliminary work in our laboratory used a library of 56 anti-cancer and targeted agents, which were tested on 16 AML cell lines and 10 ALL cell lines. Biological replicates were preformed for each cell line and drug response data in the form of IC50s and Area Under the Curve (AUC) were calculated. Hierarchical clustering was performed to determine similar responses between cell lines. Our results identified several cell lines that showed hypersensitivity to specific drugs. Among them, the AML cell line KG-1a showed sensitivity to three FGFR inhibitors including Ponatinib, which was previously reported. Validation of the screening results was done using a 10-concentration drug dose response assay. Further testing will include expansion of our drug library and application to ex vivo patient samples. The results from these studies can lead to the establishment of a drug sensitivity and resistance assay that could provide specifically engineered therapies for each patient. This form of personalized therapy would lead to diminished toxicities from systemic therapies as well as allow increased cure rates. Citation Format: Apurvi Patel, Justin J. Montoya, Daniel H. Wai, Robert J. Arceci, David O. Azorsa. Establishment of drug sensitivity and resistance testing using focused drug libraries to develop targeted therapies for patients with leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4766.

Cancer is primarily a disease characterized by aberrant gene expression that is manifested by the overexpression of key genes that support tumor development and maintenance. In many instances, oncogenic drivers are frequently ‘undruggable’ because of structural challenges, the inability to effectively inhibit high concentrations of overexpressed proteins, and the development of drug resistance mutations. An alternative therapeutic approach is to directly inhibit gene transcription by targeting unique secondary DNA structures, called G-quadruplexes, that are associated with subsets of promoters. Our laboratory investigated the activity of a class of compounds termed G-quadruplex Interacting Drugs (GQIDs) that are able to shut down the expression of specific genes used by tumor cells for growth and survival. We tested the activity of two GQIDs GQC-05 and GSA-1103 on cell growth of a panel of eight pediatric and eight adult AML cell lines. Drug dose response analysis showed IC50 values ranging from approximately 10 nM to 1 µM for GQC-05 and from 40 nM to 2 µM for GSA-1103. The AML cell lines had different sensitivities to each GQID indicating a different mechanism of action for each compound. Three AML cell lines that were highly resistant to cytarabine were among the more sensitive to GQC-05. Four cell lines sensitive to GQC-05 had high expression of either c-myc and/or bcl-2, both of which are potential targets of these two GQIDs. Furthermore, treatment of cells with the GQC-05 decreased expression of c-myc and bcl-2. These studies will help define a novel approach of repressing key drivers of leukemia by targeting selective promoter structures. Validation of such an approach for AML will have important implications for testing this therapeutic approach to other childhood cancers in order to improve the length and quality of survival. Citation Format: Apurvi Patel, Justin J. Montoya, Megan Turnidge, Marya Sabir, Daniel H. Wai, David W. Lee, Vijay Gokhale, Eiman Aleem, Laurence J. Hurley, Robert J. Arceci, David O. Azorsa. Targeting promoter regions of oncogenic drivers in pediatric AML cells using G-quadruplex Interacting Drugs (GQIDs). [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B24.