Browsing by Subject "thymoma"

Now showing 1 - 5 of 5
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    A phase II study of buparlisib in relapsed or refractory thymomas
    (Frontiers, 2022-10-17) Abu Zaid, Mohammad I.; Radovich, Milan; Althouse, Sandra; Liu, Hao; Spittler, Aaron J.; Solzak, Jeffrey; Badve, Sunil; Loehrer Sr., Patrick J.; Medicine, School of Medicine
    Purpose To investigate the efficacy and safety of buparlisib, an oral pan-PI3K inhibitor, in relapsed or refractory thymomas. Methods This was a single center, single arm, open label phase II trial of buparlisib in patients with recurrent thymoma who have progressed after at least one prior line of treatment. The primary endpoint was objective response rate (complete response [CR] + partial response [PR]). Secondary endpoints included toxicity; progression free survival (PFS); overall survival (OS); disease control rate (DCR), i.e., the percentage of patients who achieve either PR or CR or stable disease [SD] for at least 4 months. Results Between 10/13/2014 and 1/18/2017, 14 patients with stage IV disease were enrolled. Median age was 58y (23–74). 71% were females and 71% white. All patients had WHO B2 (29%) or B3 (71%) thymoma. Patients received buparlisib for a median of 4.5m (2–33). At a median follow up of 16.6m (2.4–31.3), onr patients (7%) achieved a PR. DCR was 50%. Median PFS was 11.1m (95% CI 2.9 – 18.8). Median OS, updated as of March, 2021 was 22.5m (10.7–31.3). Most common grade 3-4 adverse events related to buparlisib were dyspnea (21%), rash (14%), elevated transaminases (14%), cough (7%), pneumonitis (7%), anxiety (7%), fatigue (7%) and hyperglycemia (7%). Reasons for treatment discontinuation included progression of disease (n= 5), rash (n=4), pulmonary toxicity (n=3), sinusitis (n=1), and disseminated toxoplasmosis plus autoimmune cholangitis (n=1). As of 3/2021, 8 patients have died, 7 due to disease progression and 1 due to central nervous system toxoplasmosis and autoimmune cholangitis. Conclusion Buparlisib showed modest activity in patients with relapsed or refractory thymomas. Further investigation of PI3K pathway targeted therapy in thymoma is warranted. (clinicaltrials.gov ID: NCT02220855). Clinical trial registration clinicaltrials.gov, identifier (NCT02220855)
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    The Integrated Genomic Landscape of Thymic Epithelial Tumors
    (Elsevier, 2018-02) Radovich, Milan; Pickering, Curtis R.; Felau, Ina; Ha, Gavin; Zhang, Hailei; Jo, Heejoon; Hoadley, Katherine A.; Anur, Pavana; Zhang, Jiexin; McLellan, Mike; Bowlby, Reanne; Matthew, Thomas; Danilova, Ludmila; Hegde, Apurva M.; Kim, Jaegil; Leiserson, Mark D. M.; Sethi, Geetika; Lu, Charles; Ryan, Michael; Su, Xiaoping; Cherniack, Andrew D.; Robertson, Gordon; Akbani, Rehan; Spellman, Paul; Weinstein, John N.; Hayes, D. Neil; Raphael, Ben; Lichtenberg, Tara; Leraas, Kristen; Zenklusen, Jean Claude; Pathology and Laboratory Medicine, School of Medicine
    Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral overexpression of muscle autoantigens, and increased aneuploidy.
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    Paraneoplastic Syndromes and Thymic Malignancies: An Examination of the International Thymic Malignancy Interest Group Retrospective Database
    (Elsevier, 2017) Padda, Sukhmani K.; Yao, Xiaopan; Antonicelli, Alberto; Riess, Jonathan W.; Shang, Yue; Shrager, Joseph B.; Korst, Robert; Detterbeck, Frank; Huang, James; Burt, Bryan M.; Wakelee, Heather A.; Badve, Sunil S.; Pathology and Laboratory Medicine, School of Medicine
    Introduction Thymic epithelial tumors (TETs) are associated with paraneoplastic autoimmune (PN/AI) syndromes. Myasthenia gravis is the most common PN/AI syndrome associated with TETs. Methods The International Thymic Malignancy Interest Group (ITMIG) retrospective database was examined to determine (i) baseline and treatment characteristics associated with PN/AI syndromes and (ii) the prognostic role of PN/AI syndromes for patients with TETs. The competing risks model was used to estimate cumulative incidence of recurrence (CIR) and the Kaplan-Meier method was used to calculate overall survival (OS). A Cox proportional hazards model was used for multivariate analysis. Results 6670 patients with known PN/AI syndrome status were identified from 1951-2012. PN/AI syndromes were associated with younger age, female sex, type B1 thymoma, earlier stage, and an increased rate of total thymectomy and complete resection status. There was a statistically significant lower CIR in the PN/AI (+) group compared to the PN/AI (-) group (10-year 17.3% vs. 21.2%, respectively, p=0.0003). The OS was improved in the PN/AI (+) group compared to the PN/AI (-) group (HR 0.63, 95% CI 0.54-0.74, P<0.0001, median OS 21.6 years versus 17.0 years, respectively). However, in the multivariate model for recurrence-free survival and OS, PN/AI syndrome was not an independent prognostic factor. Discussion Previously, there has been mixed data regarding the prognostic role of PN/AI syndromes for patients with TETs. Here, using the largest dataset in the world for TETs, PN/AI syndromes were associated with favorable features (i.e. earlier stage, complete resection status) but were not an independent prognostic factor for TETs.
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    A Phase II Study of Pemetrexed in Patients with Recurrent Thymoma and Thymic Carcinoma
    (Elsevier, 2018) Gbolahan, Olumide B.; Porter, Ryan F.; Salter, John T.; Yiannoutsos, Constantin T.; Burns, Matthew; Chiorean, E. Gabriella; Loehrer, Patrick J., Sr.; Medicine, School of Medicine
    Introduction Thymoma and thymic carcinoma (TC) are neoplastic diseases with reported chemosensitivity to a broad range of agents. However, because of the rarity of these diseases, few prospective trials have been conducted in patients with advanced thymic malignancies. We conducted a prospective phase II trial to evaluate the clinical activity of pemetrexed, a multitargeted antifolate agent, in previously treated patients with thymoma and TC. Methods A total of 27 previously treated patients (16 with thymoma and 11 with TC) with advanced, unresectable disease were treated with pemetrexed, 500 mg/m2, intravenously every 3 weeks for a maximum of six cycles or until undue toxicity or progressive disease. All patients received folic acid, vitamin B12, and steroid prophylaxis. Results The median number of cycles administered was 6 (range 1–6). Nine patients with a total of 14 events had grade 3 toxicities; no grade 4 toxicities were noted. In 26 fully evaluable patients, two complete and three partial responses (according to the Response Evaluation Criteria in Solid Tumors) were documented (all in patients with stage IVA thymoma, except for one partial response with stage IVA TC). A total of 14 patients completed the full six cycles of treatment, 7 patients progressed while undergoing therapy, 5 patients discontinued therapy because of intolerance, and 1 patient discontinued therapy because of progressive Morvan syndrome. The median progression-free survival time for all patients was 10.6 months (12.1 months for those with thymoma versus 2.9 months for those with TC). With 23 deaths at data cutoff, the median overall survival time was 28.7 months (46.4 months for those with thymoma versus 9.8 months for those with TC). Conclusions Pemetrexed is an active agent in this heavily pretreated population of patients with recurrent thymic malignancies, especially thymoma.
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    Whole-Genome Sequencing to Identify the Genetic Etiology of a Spontaneous Thymoma Mouse Model
    (JPGN Reports, 2021) Conces, Madison L.; Hancock, Bradley A.; Atale, Rutuja; Solzak, Jeffrey P.; Bunting, Karen; Corvelo, Andre; Field, Loren; Badve, Sunil; Liu, Jianyun; Brutkiewicz, Randy R.; Loehrer, Patrick J.; Radovich, Milan; Pediatrics, School of Medicine
    Background: A mouse model for thymoma was previously created serendipitously by the random introduction of a transgene consisting of a mouse α-cardiac promoter, a constitutively active human transforming growth factor-β, and a simian virus 40 integration sequence into C3HeB/FeJ mice. Previous data demonstrated that the likely cause of thymomas in the thymoma mouse model was due to insertional mutagenesis by the transgene. At the time, fluorescence in situ hybridization was used to localize the transgene to the short arm of chromosome 2 (Chr2qF2-G region). In this exploratory study, we aimed to identify the exact insertion site of the transgene as this could provide clues to the genetic causation of thymomas in humans. Materials and Methods: To identify the insertion site of the transgene, germline DNA from the thymoma mouse model was sequenced using low-pass, fragment-library, whole genome sequencing. Long-insert mate pair whole genome sequencing was employed to traverse the repetitive regions of the mouse’s genome and identify the integration site. Results: The transgene was found to be integrated into a repetitive area of the mouse genome, specifically on Chr2qF1 within the intron of the FAM227B gene. Tandem integration of the transgene was observed with enumeration of an estimated 30 copies. Initial results suggested that a nearby gene, fibroblast growth factor 7 (Fgf7), could be affected by the gene insertion. Conclusions: Whole genome sequencing of this thymoma mouse model identified the region of tandem integration of a transgene on Chr2qF1 that may have potential translational implications in helping to understand the genomic etiology of thymoma in humans.