Browsing by Author "Wang, Xiaoyan"
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Item A massive 13.5 cm sclerosing pneumocytoma in a 61-year-old female(Elsevier, 2021) Boham, Sampson K.; Kesler, Kenneth A.; Geib, Merideth E.; Wang, Xiaoyan; Pathology and Laboratory Medicine, School of MedicineSclerosing pneumocytoma (previously called pulmonary sclerosing hemangioma) is a very rare benign pulmonary neoplasm. Diagnosis of this tumor can be problematic especially on the small biopsy specimens. Here, we report a massive 13.5 cm sclerosing pneumocytoma in a 61-year-old female who presented with progressive shortness of breath and underwent lobectomy procedure. Radiological findings, gross and histological features, immunohistochemical staining profile as well as differential diagnoses are discussed in detail. The purpose of this case study is to increase awareness of this entity among physicians and to further aid in proper clinical management.Item Clues to Recognition of Fumarate Hydratase-Deficient Renal Cell Carcinoma: Findings From Cytologic and Limited Biopsy Samples(Wiley, 2018) Shyu, Irene; Mirsadraei, Leili; Wang, Xiaoyan; Robila, Valentina; Mehra, Rohit; McHugh, Jonathan B.; Chen, Ying-Bei; Udager, Aaron M.; Gill, Anthony J.; Cheng, Liang; Amin, Mahul B.; Lin, Oscar; Smith, Steven Christopher; Pathology and Laboratory Medicine, School of MedicineBackground: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is rare and highly aggressive and is believed to arise mostly in the setting of hereditary leiomyomatosis-RCC syndrome with a germline mutation of FH. Because of the aggressiveness of these tumors and a frequent lack of ascertainable family history, these tumors may first present as metastases and be sampled by cytology. The cytologic findings of FH-deficient RCC have not previously been reported. Methods: Cytologic and limited biopsy samples from patients with FH-deficient RCC were reviewed retrospectively. Results: In total, 24 cytologic and limited biopsy samples from 19 patients (6 women and 13 men; age range, 22-69 years) who had FH-deficient RCC and metastasis at presentation were evaluated. These included 21 cytology samples ranging from malignant effusions (n = 7) to metastases (n = 11), to samples of primary kidney tumors (n = 3). The samples exhibited cells, often in clusters and abortive papillae, with voluminous, finely vacuolated cytoplasm and large, pleomorphic nuclei with prominent, viral inclusion-like nucleoli. A distinctive finding of peripheral cytoplasmic clearing frequently was apparent, and intranuclear cytoplasmic pseudoinclusions were less frequent. Of 7 cell block and biopsy samples, several of which represented sampling from the same patient, all demonstrated tissue fragments that had discernable morphologic patterns associated with FH-deficient RCC, including tubulocystic and intracystic papillary growth. Conclusions: Features characteristic and suggestive of FH-deficient RCC may be identified in cytologic and small biopsy samples. Although the current samples were identified retrospectively in well characterized cases of FH-deficient RCC, the authors argue that, with appropriate clinical correlation, these features are sufficiently distinctive to trigger recognition and confirmatory workup.Item Evidence of a dual histogenetic pathway of sacrococcygeal teratomas(Wiley, 2017-01) Emerson, Robert E.; Kao, Chia-Sui; Eble, John N.; Grignon, David J.; Wang, Mingsheng; Zhang, Shaobo; Wang, Xiaoyan; Fan, Rong; Masterson, Timothy A.; Roth, Lawrence M.; Cheng, Liang; Department of Pathology and Laboratory Medicine, IU School of MedicineAims Sacrococcygeal teratomas are rare tumours that occur most frequently in neonates, although adult cases also occur. The molecular pathogenesis of these tumours and their long-term prognosis is uncertain. We investigated the i(12p) status of a large number of primary sacrococcygeal teratomas in both children and adults, including cases with malignant germ cell tumour elements. Methods and results Fifty-four sacrococcygeal teratoma specimens from 52 patients were identified, and available follow-up information was obtained. Fluorescence in-situ hybridization analysis was performed to identify isochromosome 12p [i(12p)] abnormalities on paraffin blocks of the tumours. Among the 48 paediatric patients, there were 44 teratomas and four tumours with combined teratoma and yolk sac tumour (one of whom also had primitive neuroectodermal tumour). The teratomas included 37 mature teratomas and 11 immature teratomas (four grade 1, two grade 2, and five grade 3). The 44 teratomas lacking a yolk sac tumour component were all negative for i(12p). The four tumours with a yolk sac tumour component were all positive for i(12p). The four adult cases all lacked non-teratomatous germ cell tumour components, immature elements, and i(12p). Follow-up information was available for 32 patients. Two patients with teratoma had recurrence, but were alive with no evidence of disease after long-term follow-up. One patient with combined teratoma and yolk sac tumour had recurrence 7 months after resection. The other patients were alive with no evidence of disease at last follow-up. Conclusions Our data suggest that paediatric sacrococcygeal teratomas should be considered as two distinct groups with divergent histogenetic pathways. The prognosis of these tumours is excellent, despite rare recurrence.Item Fine needle aspiration cytology of hepatic metastases of neuroendocrine tumors: A 20‐year retrospective, single institutional study(Wiley, 2018-01) Saeed, Omer A.; Cramer, Harvey; Wang, Xiaoyan; Wu, Howard H.; Pathology and Laboratory Medicine, School of MedicineBackground Fine needle aspiration (FNA) is considered an excellent technique for documenting metastatic neuroendocrine tumors (NETs). This study aims to evaluate the accuracy of FNA in diagnosing metastatic NETs to the liver and determining the grade and origin of these metastases. Methods Our laboratory information system was searched from 1997 to 2016 to identify all cases of metastatic NETs to the liver that were sampled by FNA. The cytopathology and surgical pathology reports as well as the patients' electronic medical records were reviewed. The cytohistologic type and grade of the metastatic NETs, as well as the site of the patient's primary were recorded. Results High‐grade NETs, including small cell and poorly differentiated neuroendocrine carcinomas, constituted 62% (167/271) of the cases, while low‐grade NETs, including well differentiated NET (grade1 and grade 2), pheochromocytomas, paragangliomas, and carcinoid tumors of lung, constituted 38% (104/271) of cases. The most common diagnosis was metastatic small cell carcinoma accounting for 45% (122/271) of cases. The most common primary sites were lung (44%; 119/271) followed by pancreas (19%; 51/271). The FNA diagnosis was confirmed by histopathology in 121 cases that had a concurrent biopsies or resection specimens. Conclusions FNA is an accurate method for diagnosing metastatic NETs to the liver. There were significantly more high‐grade (62%) than low‐grade (38%) metastatic NETs to the liver. In our practice, lung (44%) and pancreas (19%) were the most common primary sites of metastatic NETs involving the liver. In 16% of the cases, a primary site could not be established.Item IND-Enabling Studies for a Clinical Trial to Genetically Program a Persistent Cancer-Targeted Immune System(American Association for Cancer Research, 2019-02-01) Puig-Saus, Cristina; Parisi, Giulia; Garcia-Diaz, Angel; Krystofinski, Paige E.; Sandoval, Salemiz; Zhang, Ruixue; Champhekar, Ameya S.; McCabe, James; Cheung-Lau, Gardenia C.; Truong, Nhat A.; Vega-Crespo, Agustin; Komenan, Marie Desiles S.; Pang, Jia; Macabali, Mignonette H.; Saco, Justin D.; Goodwin, Jeffrey L.; Bolon, Brad; Seet, Christopher S.; Montel-Hagen, Amelie; Crooks, Gay M.; Hollis, Roger P.; Campo-Fernandez, Beatriz; Bischof, Daniela; Cornetta, Kenneth; Gschweng, Eric H.; Adelson, Celia; Nguyen, Alexander; Yang, Lili; Witte, Owen N.; Baltimore, David; Comin-Anduix, Begonya; Kohn, Donald B.; Wang, Xiaoyan; Cabrera, Paula; Kaplan-Lefko, Paula J.; Berent-Maoz, Beata; Ribas, Antoni; Medical and Molecular Genetics, School of MedicinePURPOSE: To improve persistence of adoptively transferred T-cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application. EXPERIMENTAL DESIGN: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were coadministered to myelodepleted HLA-A2/Kb mice within a formal Good Laboratory Practice (GLP)-compliant study to demonstrate safety, persistence, and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, Good Manufacturing Practice (GMP)-compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use. RESULTS: TCR genetically modified and ex vivo-cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and coadministration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSC's differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality. CONCLUSIONS: Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471.Item Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency(American Society of Hematology, 2021) Reinhardt, Bryanna; Habib, Omar; Shaw, Kit L.; Garabedian, Elizabeth; Carbonaro-Sarracino, Denise A.; Terrazas, Dayna; Fernandez, Beatriz Campo; De Oliveira, Satiro; Moore, Theodore B.; Ikeda, Alan K.; Engel, Barbara C.; Podsakoff, Gregory M.; Hollis, Roger P.; Fernandes, Augustine; Jackson, Connie; Shupien, Sally; Mishra, Suparna; Davila, Alejandra; Mottahedeh, Jack; Vitomirov, Andrej; Meng, Wenzhao; Rosenfeld, Aaron M.; Roche, Aoife M.; Hokama, Pascha; Reddy, Shantan; Everett, John; Wang, Xiaoyan; Luning Prak, Eline T.; Cornetta, Kenneth; Hershfield, Michael S.; Sokolic, Robert; De Ravin, Suk See; Malech, Harry L.; Bushman, Frederic D.; Candotti, Fabio; Kohn, Donald B.; Medical and Molecular Genetics, School of MedicinePatients lacking functional adenosine deaminase activity have severe combined immunodeficiency (ADA SCID), which can be treated with ADA enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT), or autologous HSCT with gene-corrected cells (gene therapy [GT]). A cohort of 10 ADA SCID patients, aged 3 months to 15 years, underwent GT in a phase 2 clinical trial between 2009 and 2012. Autologous bone marrow CD34+ cells were transduced ex vivo with the MND (myeloproliferative sarcoma virus, negative control region deleted, dl587rev primer binding site)-ADA gammaretroviral vector (gRV) and infused following busulfan reduced-intensity conditioning. These patients were monitored in a long-term follow-up protocol over 8 to 11 years. Nine of 10 patients have sufficient immune reconstitution to protect against serious infections and have not needed to resume ERT or proceed to secondary allogeneic HSCT. ERT was restarted 6 months after GT in the oldest patient who had no evidence of benefit from GT. Four of 9 evaluable patients with the highest gene marking and B-cell numbers remain off immunoglobulin replacement therapy and responded to vaccines. There were broad ranges of responses in normalization of ADA enzyme activity and adenine metabolites in blood cells and levels of cellular and humoral immune reconstitution. Outcomes were generally better in younger patients and those receiving higher doses of gene-marked CD34+ cells. No patient experienced a leukoproliferative event after GT, despite persisting prominent clones with vector integrations adjacent to proto-oncogenes. These long-term findings demonstrate enduring efficacy of GT for ADA SCID but also highlight risks of genotoxicity with gRVs.Item Molecular classification of human papilloma virus-negative head and neck squamous cell carcinomas: Cell cycle-based classifier and prognostic signature(Public Library of Science, 2023-10-30) Gu, Hao; Li, Tingxuan; Beeraka, Narasimha M.; Zheng, Yufei; Zhang, Xintan; Song, Ruixia; Zhou, Runze; Wang, Xiaoyan; Sukocheva, Olga; Fan, Ruitai; Liu, Junqi; Pediatrics, School of MedicineThe molecular classification of human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs) remains questionable. Differentially expressed genes were detected between tumor and normal tissues and GSEA showed they are associated with cell cycle pathways. This study aimed to classify HPV-negative HNSCCs based on cell cycle-related genes. The established gene pattern was correlated with tumor progression, clinical prognosis, and drug treatment efficacy. Biological analysis was performed using HNSCC patient sample data obtained from the Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Gene Expression Omnibus (GEO) databases. All samples included in this study contained survival information. RNA sequencing data from 740 samples were used for the analysis. Previously characterized cell cycle-related genes were included for unsupervised consensus clustering. Two subtypes of HPV-negative HNSCCs (C1, C2) were identified. Subtype C1 displayed low cell cycle activity, 'hot' tumor microenvironment (TME), earlier N stage, lower pathological grade, better prognosis, and higher response rate to the immunotherapy and targeted therapy. Subtype C2 was associated with higher cell cycle activity, 'cold' TME, later N stage, higher pathological grade, worse prognosis, and lower response rate to the treatment. According to the nearest template prediction method, classification rules were established and verified. Our work explored the molecular mechanism of HPV-negative HNSCCs in the view of cell cycle and might provide new sights for personalized anti-cancer treatment.Item Parathyroid hormone-related peptide induced hypercalcemia of pregnancy due to mammary hyperplasia(Oxford University Press, 2024-06-20) Jodeh, Wade; Sparks, Payton J.; Higgins, Jasmine M.; Tom, Alan; Anilovich, Natanie; Moit, Harley; Korff, Lisa; Hadad, Ivan; Wang, Xiaoyan; Imel, Erik A.; Donegan, Diane M.; Surgery, School of MedicineMaternal Parathyroid Hormone-related Protein (PTHrP) is involved in the placental transport of calcium. Autonomous overproduction of PTHrP is a rare cause of hypercalcemia in pregnancy. Prior cases of PTHrP-induced hypercalcemia in pregnancy have been managed with either dopamine agonists, fetal delivery, termination of pregnancy, or mastectomy. However, PTHrP level normalization following mastectomy has not previously been documented. Herein, we present a 39-year-old female hospitalized at 19 weeks of gestation for acute encephalopathy due to PTHrP induced hypercalcemic crisis (calcium 15.8 mg/dL, PTHrp 46.5 pmol/L [normal 0-3.4]). Mammary hyperplasia resulting in gigantomastia significantly impaired her ability to ambulate and perform activities of daily living. She remained hypercalcemic during hospitalization despite aggressive hydration, calcitonin, and 2 weeks of dopamine agonist treatment. Bisphosphonate therapy was not administered due to pregnancy and potential effects on the fetus. Our patient underwent bilateral mastectomy along with excision of a large axillary mass. The pathology of all three specimens revealed mammary stromal hyperplasia. PTHrP was undetectable on post-op day 2 and calcium normalized by post-op day 3. At discharge, she was able to ambulate independently. To our knowledge, this is the first reported case of PTHrP induced hypercalcemia related to gigantomastia, documenting resolution of hypercalcemia, and PTHrP levels following mastectomy. Mastectomy is a potential option in the second trimester for pregnant patients with PTHrP induced severe hypercalcemia due to gigantomastia, refractory to treatment with dopamine agonist therapy.Item Precision Treatment of Advanced Lung Adenocarcinoma With Coexisting EGFR, ALK, and ROS1 Mutations: A Case Report(Elsevier, 2021) Zhang, Yaping; Wang, Hui; Wang, Xiaoyan; Li, Shuai; Fang, Hongming; Medicine, School of MedicineItem Preclinical Demonstration of Lentiviral Vector-mediated Correction of Immunological and Metabolic Abnormalities in Models of Adenosine Deaminase Deficiency(Nature Publishing Group, 2014-03) Carbonaro, Denise A.; Zhang, Lin; Jin, Xiangyang; Montiel-Equihua, Claudia; Geiger, Sabine; Carmo, Marlene; Cooper, Aaron; Fairbanks, Lynette; Kaufman, Michael L.; Sebire, Neil J.; Hollis, Roger P.; Blundell, Michael P.; Senadheera, Shantha; Fu, Pei-Yu; Sahaghian, Arineh; Chan, Rebecca Y.; Wang, Xiaoyan; Cornetta, Kenneth; Thrasher, Adrian J.; Kohn, Donald B.; Gaspar, H. Bobby; Department of Medical & Molecular Genetics, IU School of MedicineGene transfer into autologous hematopoietic stem cells by γ-retroviral vectors (gRV) is an effective treatment for adenosine deaminase (ADA)–deficient severe combined immunodeficiency (SCID). However, current gRV have significant potential for insertional mutagenesis as reported in clinical trials for other primary immunodeficiencies. To improve the efficacy and safety of ADA-SCID gene therapy (GT), we generated a self-inactivating lentiviral vector (LV) with a codon-optimized human cADA gene under the control of the short form elongation factor-1α promoter (LV EFS ADA). In ADA−/− mice, LV EFS ADA displayed high-efficiency gene transfer and sufficient ADA expression to rescue ADA−/− mice from their lethal phenotype with good thymic and peripheral T- and B-cell reconstitution. Human ADA-deficient CD34+ cells transduced with 1–5 × 107 TU/ml had 1–3 vector copies/cell and expressed 1–2x of normal endogenous levels of ADA, as assayed in vitro and by transplantation into immune-deficient mice. Importantly, in vitro immortalization assays demonstrated that LV EFS ADA had significantly less transformation potential compared to gRV vectors, and vector integration-site analysis by nrLAM-PCR of transduced human cells grown in immune-deficient mice showed no evidence of clonal skewing. These data demonstrated that the LV EFS ADA vector can effectively transfer the human ADA cDNA and promote immune and metabolic recovery, while reducing the potential for vector-mediated insertional mutagenesis.