Browsing by Subject "Thymoma"
Now showing 1 - 7 of 7
Results Per Page
Sort Options
Item A phase II study of buparlisib in relapsed or refractory thymomas(Frontiers Media, 2022-10-18) Abu Zaid, Mohammad I.; Radovich, Milan; Althouse, Sandra; Liu, Hao; Spittler, Aaron J.; Solzak, Jeffrey; Badve, Sunil; Loehrer, Patrick J.; Medicine, School of MedicinePurpose: 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.Item AB018. Local recurrence of thymoma following minimally invasive resection: a retrospective case series(AME, 2023-12-30) Davis, Hannah O.; Heldman, Emily M.; Laniak, Louis J.; Wuthrich, Brice S.; Badve, Sunil S.; Mesa, Hector A.; Kesler, Kenneth A.; Maniar, Rohan; Loehrer, Patrick J.; Pathology and Laboratory Medicine, School of MedicineBackground: Surgery remains the mainstay treatment for non-metastatic thymic epithelial tumors (TETs) and has traditionally been performed via an open approach. Minimally invasive techniques have gained popularity with the aim of decreasing postoperative morbidity. However, there is concern that these techniques could increase the risk of local relapse. We undertook a retrospective institutional review of thymoma patients presenting for evaluation of local disease after surgery utilizing minimally invasive approaches. Methods: A database of TET patients evaluated at Indiana University from 1997 to 2022 was queried. From this database, we identified and reviewed 19 thymoma patients who underwent minimally invasive surgery and subsequently developed local recurrence. Results: The median age in this cohort was 46 years (range, 14–70 years) and included 9 female and 10 male patients. At the time of initial surgery, the distribution of stages was I (n=5), II (n=10), and III (n=3) and WHO histologic classifications were A/AB (n=3) and B1-3 (n=15); one patient’s initial pathology could not be determined. The median tumor size was 6.2 cm (range, 3–10.2 cm). Seventeen patients were operated on at outside institutions, while two had their surgeries at Indiana University. Surgical approaches included unilateral video-assisted thoracic surgery (VATS) (n=7), unilateral robot-assisted thoracic surgery (RATS) (n=8), bilateral VATS (n=2), and the Chamberlain procedure (n=2). Fifteen patients had R0 resections, while 4 had microscopic positive surgical margins (R1). Seven patients received adjuvant radiation therapy. All patients had pleural recurrence ipsilateral to the surgical approach. Ten patients also had mediastinal recurrence; 8 of whom had R0 resection during the initial surgery. The median time to recurrence was 31 months (range, 6–130 months). Conclusions: Our cohort of patients who presented for evaluation of thymoma recurrence after a minimally invasive surgical approach had median tumor size greater than 5 cm and higher World Health Organization (WHO) classifications. Relapses were identified as late as 10 years following surgery. While it remains unclear whether local recurrence was related to dissemination during surgery, the finding of ipsilateral pleural space relapse in all cases is strongly suggestive. This case series demonstrates the need for carefully controlled studies and long-term follow-up to determine optimal surgical approaches for thymoma.Item Clinicogenomic Landscape of Metastatic Thymic Epithelial Tumors(American Society of Clinical Oncology, 2023) Ardeshir-Larijani, Fatemeh; Schneider, Bryan P.; Althouse, Sandra K.; Radovich, Milan; Masood, Ashiq; Perna, Fabiana; Salman, Huda; Loehrer, Patrick J.; Medicine, School of MedicineBackground: Despite favorable clinical outcomes, a subset of patients with thymic epithelial tumors (TETs) develop metastasis. The Cancer Genome Atlas (TCGA) provides genomic data on primary TETs (pTETs). This study assessed the molecular alterations and uncovered targetable pathways in metastatic TETs (mTETs). Methods: From 2015 to 2020, 49 patients with stage IV TETs underwent Clinical Laboratory Improvement Amendments-based sequencing using whole-exome sequencing (n = 33), panel-based testing (n = 12), and/or liquid biopsy (n = 24). Specimens were obtained from a metastatic organ (n = 36) or relapsed primary mediastinal mass (n = 10), whereas four patients underwent a liquid biopsy only. Data on pTETs were derived from the TCGA. Results: Compared with the pTET data set, patients with mTETs were younger (54 years v 60.5 years, P = .009) and had more aggressive histologies, with the most common tumor type being thymic carcinoma (n = 22, 40.7%) and B3 thymoma (n = 15, 27.8%). GTF2I was the most altered gene in primary thymomas (48.80%, n = 60). In metastatic thymoma and thymic carcinoma, TP53 was the most common genetic alteration (31% and 36%, respectively). In mTETs, the genomic alteration occurred in the TP53/CDK, EGFR/RAS, and PI3K/mTOR pathways. Biopsies obtained from distant metastasis were more commonly found to contain targetable mutations. There was an overlap of 61% (22 of 36) between tissue and liquid biopsy genomic alterations. Conclusion: Clinically actionable genomic alterations are frequently observed in mTETs, indicating a value of repeat biopsy (preferably from a metastatic site of TETs for sequencing at the time of recurrence (TCGA data).Item Genomic clustering analysis identifies molecular subtypes of thymic epithelial tumors independent of World Health Organization histologic type(Impact Journals, 2021-06-08) Padda, Sukhmani K.; Gökmen-Polar, Yesim; Hellyer, Jessica A.; Badve, Sunil S.; Singh, Neeraj K.; Vasista, Sumanth M.; Basu, Kabya; Kumar, Ansu; Wakelee, Heather A.; Pathology and Laboratory Medicine, School of MedicineFurther characterization of thymic epithelial tumors (TETs) is needed. Genomic information from 102 evaluable TETs from The Cancer Genome Atlas (TCGA) dataset and from the IU-TAB-1 cell line (type AB thymoma) underwent clustering analysis to identify molecular subtypes of TETs. Six novel molecular subtypes (TH1-TH6) of TETs from the TCGA were identified, and there was no association with WHO histologic subtype. The IU-TAB-1 cell line clustered into the TH4 molecular subtype and in vitro testing of candidate therapeutics was performed. The IU-TAB-1 cell line was noted to be resistant to everolimus (mTORC1 inhibitor) and sensitive to nelfinavir (AKT1 inhibitor) across the endpoints measured. Sensitivity to nelfinavir was due to the IU-TAB-1 cell line’s gain-of function (GOF) mutation in PIK3CA and amplification of genes observed from array comparative genomic hybridization (aCGH), including AURKA, ERBB2, KIT, PDGFRA and PDGFB, that are known upregulate AKT, while resistance to everolimus was primarily driven by upregulation of downstream signaling of KIT, PDGFRA and PDGFB in the presence of mTORC1 inhibition. We present a novel molecular classification of TETs independent of WHO histologic subtype, which may be used for preclinical validation studies of potential candidate therapeutics of interest for this rare disease.Item A large microRNA cluster on chromosome 19 is a transcriptional hallmark of WHO type A and AB thymomas(SpringerNature, 2016-02-16) Radovich, Milan; Solzak, Jeffrey P.; Hancock, Bradley A.; Conces, Madison L.; Atale, Rutuja; Porter, Ryan F.; Zhu, Jin; Glasscock, Jarret; Kesler, Kenneth A.; Badve, Sunil S.; Schneider, Bryan P.; Loehrer, Patrick J.; Department of Surgery, IU School of MedicineBACKGROUND: Thymomas are one of the most rarely diagnosed malignancies. To better understand its biology and to identify therapeutic targets, we performed next-generation RNA sequencing. METHODS: The RNA was sequenced from 13 thymic malignancies and 3 normal thymus glands. Validation of microRNA expression was performed on a separate set of 35 thymic malignancies. For cell-based studies, a thymoma cell line was used. RESULTS: Hierarchical clustering revealed 100% concordance between gene expression clusters and WHO subtype. A substantial differentiator was a large microRNA cluster on chr19q13.42 that was significantly overexpressed in all A and AB tumours and whose expression was virtually absent in the other thymomas and normal tissues. Overexpression of this microRNA cluster activates the PI3K/AKT/mTOR pathway. Treatment of a thymoma AB cell line with a panel of PI3K/AKT/mTOR inhibitors resulted in marked reduction of cell viability. CONCLUSIONS: A large microRNA cluster on chr19q13.42 is a transcriptional hallmark of type A and AB thymomas. Furthermore, this cluster activates the PI3K pathway, suggesting the possible exploration of PI3K inhibitors in patients with these subtypes of tumour. This work has led to the initiation of a phase II clinical trial of PI3K inhibition in relapsed or refractory thymomas (http://clinicaltrials.gov/ct2/show/NCT02220855).Item Minimally invasive surgery in the management of resectable thymoma: a retrospective analysis from the National Cancer Database(AME, 2021) Salfity, Hai V.; Timsina, Lava; Ceppa, DuyKhanh P.; Birdas, Thomas J.; Surgery, School of MedicineBackground: Thymomas are relatively uncommon tumors traditionally resected via open sternotomy. Despite the appeal of minimally invasive techniques, concerns persist regarding their oncologic efficacy. We hypothesized that minimally-invasive thymectomies for resectable thymomas are oncologically safe when compared to open thymectomy. Methods: The National Cancer Database (NCDB) was queried for patients with thymoma undergoing resection as the first mode of treatment between 2010-2015. Patient demographics, tumor characteristics and perioperative outcomes were examined for each approach (robotic, thoracoscopic, or open). The primary endpoints were rates of complete (R0) resection and need for adjuvant radiotherapy. Chi-square and Student's t-test and logistic regression were used for analysis. Results: A total of 2,312 patients were identified. The utilization of myocardial infarction (MI) surgery increased during the study period (robotic: 7.6% to 19.5%; thoracoscopic: 9.3% to 18.4%, both P<0.0001). Median tumor size was higher and mediastinal invasion was more common in open thymectomies. R0 resection was more common in robotic and adjuvant radiotherapy was less frequent in thoracoscopic thymectomies. In multivariate analysis absence of mediastinal invasion (P<0.0001) was the only prognostic factor for R0 resection. Positive margins, mediastinal invasion (both P<0.0001) and younger age (P<0.01) were the only predictors of the need for adjuvant radiotherapy. Conclusions: Utilization of MI approaches for resectable thymoma has increased from 2010 to 2015. After adjusting for tumor size and mediastinal invasion, minimally-invasive thymectomy was not associated with lower R0 resection rates or increased use of adjuvant radiotherapy. MI thymectomy for resectable thymoma is oncologically equivalent to open thymectomy.Item What Have We Learned from Molecularly Informed Clinical Trials on Thymomas and Thymic Carcinomas-Current Status and Future Directions?(MDPI, 2024-01-18) Maniar, Rohan; Loehrer, Patrick J.; Medicine, School of MedicineThymic epithelial tumors (TETs), which include thymomas and thymic carcinomas, are a rare, heterogeneous group of malignancies that originate from the thymus gland. As an important organ of immune cell development, thymic tumors, particularly thymomas, are often associated with paraneoplastic autoimmune disorders. The advances in targeted therapies for both solid and hematologic malignancies have resulted in improved patient outcomes, including better and more durable efficacy and improved toxicity. Targeted therapies have also been investigated in the treatment of TETs, though the results have largely been modest. These have included somatostatin-receptor-targeting therapies, KIT- and EGFR-directed tyrosine kinase inhibitors, epigenetic modulators, anti-angiogenesis agents, and agents targeting the cell proliferation and survival pathways and cell cycle regulators. Numerous investigated treatments have failed or underperformed due to a lack of a strong biomarker of efficacy. Ongoing trials are attempting to expand on previous experiences, including the exploration of effective drugs in early-stage disease. Novel combination therapy strategies are also undergoing evaluation, with the goal of augmenting efficacy and understanding the toxicity while expanding the biomarkers of efficacy and safety. With advances in technology to improve target identification and drug delivery, old targets may become new opportunities, and the subsequently developed drugs may find their place in the treatment of thymic tumors.