IU Indianapolis ScholarWorks :: Browsing by Author "Loehrer, Patrick J."

Browsing by Author "Loehrer, Patrick J."

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A Gene Signature to Determine Metastatic Behavior in Thymomas
(Public Library of Science, 2013-07-24) Gökmen-Polar, Yesim; Cook, Robert W.; Goswami, Chirayu Pankaj; Wilkinson, Jeff; Maetzold, Derek; Stone, John F.; Oelschlager, Kristen M.; Vladislav, Ioan Tudor; Shirar, Kristen L.; Kesler, Kenneth A.; Loehrer, Patrick J.; Badve, Sunil; Medicine, School of Medicine
Purpose: Thymoma represents one of the rarest of all malignancies. Stage and completeness of resection have been used to ascertain postoperative therapeutic strategies albeit with limited prognostic accuracy. A molecular classifier would be useful to improve the assessment of metastatic behaviour and optimize patient management. Methods: qRT-PCR assay for 23 genes (19 test and four reference genes) was performed on multi-institutional archival primary thymomas (n = 36). Gene expression levels were used to compute a signature, classifying tumors into classes 1 and 2, corresponding to low or high likelihood for metastases. The signature was validated in an independent multi-institutional cohort of patients (n = 75). Results: A nine-gene signature that can predict metastatic behavior of thymomas was developed and validated. Using radial basis machine modeling in the training set, 5-year and 10-year metastasis-free survival rates were 77% and 26% for predicted low (class 1) and high (class 2) risk of metastasis (P = 0.0047, log-rank), respectively. For the validation set, 5-year metastasis-free survival rates were 97% and 30% for predicted low- and high-risk patients (P = 0.0004, log-rank), respectively. The 5-year metastasis-free survival rates for the validation set were 49% and 41% for Masaoka stages I/II and III/IV (P = 0.0537, log-rank), respectively. In univariate and multivariate Cox models evaluating common prognostic factors for thymoma metastasis, the nine-gene signature was the only independent indicator of metastases (P = 0.036). Conclusion: A nine-gene signature was established and validated which predicts the likelihood of metastasis more accurately than traditional staging. This further underscores the biologic determinants of the clinical course of thymoma and may improve patient management.
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 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.
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 Medicine
Background: 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.
AB025. Evaluation of potential therapeutic immunohistochemical targets with experimental or FDA-approved therapies in thymic epithelial tumor microarrays
(AME, 2023-12-30) Ardeshir-Larijani, Fatemeh; Loehrer, Patrick J.; Maniar, Rohan; Hou, Tieying; DeBrock, Victoria; Mesa, Hector; Pathology and Laboratory Medicine, School of Medicine
Background: Thymus epithelial tumors (TETs) are rare malignancies of the anterior mediastinum. The current standard of care for metastatic TETs is a combination of platinum-based chemotherapy. Here, we have evaluated the experimental and FDA-approved makers in a large TET tissue array with the hope of identifying a new therapeutic option. Methods: A tissue microarray (TMA) containing ninety malignant thymic tumors (A, AB, B1 and B2, n=62, B2/B3 and B3, n=16, and thymic carcinoma, n=12) and seven normal adult thymus were assembled. The protein expressions of GLUT1, TROP2, PSMA, ROS1, ALK, HER2, and PDL-1 were tested with immunohistochemical assays. Expression was quantified using a “staining score (SS)”, which is a 0–3 numerical score that results from the product of the intensity of expression: 0= negative, 1= weak, 2= moderate, 3= strong, and the area of expression in fractions of a percent (0= no expression, 1= 100% area). Expression of HER2 and PDL-1 was quantified according to existing guidelines [HER2 score and combined positive score (CPS)]. Results: Trop-2 had the highest expression in thymic carcinoma (TC) (100%, SS 2.6±0.6) followed by thymoma B2/B3 (78%, SS 1.3±1.3), types A/AB/B1 (54%, SS 1.1±1.1) (P=0.01). In TC, all patients with squamous histology had immunohistochemistry (IHC) SS of 3. Patients with thymoma who had Trop-2 expression experienced significantly worse survival [hazard ratio (HR): 3.3, P=0.008]. GLUT1 was highly expressed in TC (81.8%, SS: 2.1±1, TC vs. normal thymus, P=0.0003). PDL-1 was expressed in all TET tissues (mean, 2.5–52 CPS). No significant expression of ALK, ROS1, or HER2 observed in normal thymus or TETs. Conclusions: Trop-2 expression is a prognostic marker in TETs. High expression of Trop-2 protein in thymoma and TC appears a promising therapeutic target for Trop-2 antibody-drug conjugates.
AIDS-Related Non-Hodgkin’s Lymphoma in Sub-Saharan Africa: Current Status and Realities of Therapeutic Approach
(Wiley, 2012) Mwamba, Peter M.; Mwanda, Walter O.; Busakhala, Naftali W.; Strother, R. Matthew; Loehrer, Patrick J.; Remick, Scot C.; Medicine, School of Medicine
Today AIDS-related non-Hodgkin's lymphoma (AR-NHL) is a significant cause of morbidity and mortality in HIV-infected patients the world over, and especially in sub-Saharan Africa. While the overall incidence of AR-NHL since the emergence of combination antiretroviral therapy (cART) era has declined, the occurrence of this disease appears to have stabilized. In regions of the world where access to cART is challenging, the impact on disease incidence is less clear. In the resource-rich environment it is clinically well recognized that it is no longer appropriate to consider AR-NHL as a single disease entity and rather treatment of AIDS lymphoma needs to be tailored to lymphoma subtype. While intensive therapeutic strategies in the resource-rich world are clearly improving outcome, in AIDS epicenters of the world and especially in sub-Saharan Africa there is a paucity of data on treatment and outcomes. In fact, only one prospective study of dose-modified oral chemotherapy and limited retrospective studies with sufficient details provide a window into the natural history and clinical management of this disease. The scarcities and challenges of treatment in this setting provide a backdrop to review the current status and realities of the therapeutic approach to AR-NHL in sub-Saharan Africa. More pragmatic and risk-adapted therapeutic approaches are needed.
Cardiovascular disease in thymic cancer patients
(Frontiers Media, 2024-09-10) Khemka, Abhishek; Clasen, Suparna C.; Loehrer, Patrick J.; Roberts, Anna R.; Golzarri-Arroyo, Lilian; Badve, Sunil S.; Raman, Subha V.; Hui, Siu L.; Schleyer, Titus K. L.; Medicine, School of Medicine
Introduction: Cancer patients may have increased risk for adverse cardiac events, but our understanding of cardiovascular risk in thymic cancer patients is not clear. We sought to characterize baseline cardiometabolic risk factors before thymic cancer diagnosis and the potential association between cancer treatment and subsequent cardiac events. Methods: This was a retrospective cohort study evaluating patients with thymic cancer from 2003 to 2020 compared to age- and sex-matched controls without cancer. Baseline cardiovascular risk factors, cancer characteristics, and incidence of cardiac events were collected from the health information exchange. Multivariable regression was used to examine the impact of cardiovascular risk factors and cancer therapies. Results: We compared 296 patients with pathology-confirmed thymic cancer to 2,960 noncancer controls. Prior to cancer diagnosis, thymic cancer patients (TCPs) had lower prevalence of hypertension, dyslipidemia, and diabetes mellitus and similar rates of obesity, tobacco use, and pre-existing cardiovascular disease (CVD) compared to controls. After diagnosis, high-risk TCPs (>2 cardiovascular risk factors or pre-existing CVD) had higher risk for cardiac events (HR 3.73, 95% CI 2.88-4.83, p < 0.001). In the first 3 years after diagnosis, TCPs had higher incidence of cardiac events (HR 1.38, 95% CI 1.01-1.87, p = 0.042). High-risk TCPs who received radiotherapy or chemotherapy had higher risk of cardiac events (HR 4.99, 95% CI 2.30-10.81, p < 0.001; HR 6.24, 95% CI 2.84-13.72, p < 0.001). Discussion/conclusion: Compared to noncancer controls, TCPs experienced more cardiac events when adjusted for risk factors. Patients with multiple cardiovascular risk factors receiving radiotherapy or chemotherapy had higher incidence of cardiac events.
Clinical benefit of a precision medicine based approach for guiding treatment of refractory cancers
(Impact Journals, 2016-08-30) Radovich, Milan; Kiel, Patrick J.; Nance, Stacy M.; Niland, Erin E.; Parsley, Megan E.; Ferguson, Meagan E.; Jiang, Guanglong; Ammakkanavar, Natraj R.; Einhorn, Lawrence H.; Cheng, Liang; Nassiri, Mehdi; Davidson, Darrell D.; Rushing, Daniel A.; Loehrer, Patrick J.; Pili, Roberto; Hanna, Nasser; Callaghan, J. Thomas; Skaar, Todd C.; Helft, Paul R.; Shahda, Safi; O’Neil, Bert H.; Schneider, Bryan P.; Medicine, School of Medicine
Patients and methods: Patients with metastatic solid tumors who had progressed on at least one line of standard of care therapy were referred to the Indiana University Health Precision Genomics Program. Tumor samples were submitted for DNA & RNA next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry for actionable targets. A multi-disciplinary tumor board reviewed all results. For each patient, the ratio of progression-free survival (PFS) of the genomically guided line of therapy divided by the PFS of their prior line was calculated. Patients whose PFS ratio was ≥ 1.3 were deemed to have a meaningful improvement in PFS. Results: From April 2014-October 2015, 168 patients were evaluated and 101 patients achieved adequate clinical follow-up for analysis. 19 of 44 (43.2%) patients treated with genomically guided therapy attained a PFS ratio ≥ 1.3 vs. 3 of 57 (5.3%) treated with non-genomically guided therapy (p < 0.0001). Similarly, overall PFS ratios (irrespective of cutoff) were higher for patients with genomically guided therapy vs non-genomically guided therapy (p = 0.05). Further, patients treated with genomically guided therapy had a superior median PFS compared to those treated with non-genomically guided therapy (86 days vs. 49 days, p = 0.005, H.R. = 0.55, 95% C.I.:0.37-0.84). Conclusion: Patients with refractory metastatic cancer who receive genomically guided therapy have improved PFS ratios and longer median PFS compared to patients who do not receive genomically guided therapy.
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 Medicine
Background: 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).
Contribution of Environment and Genetics to Pancreatic Cancer Susceptibility
(Public Library of Science, 2014-03-20) Hocevar, Barbara A.; Kamendulis, Lisa M.; Pu, Xinzhu; Perkins, Susan M.; Wang, Zheng-Yu; Johnston, Erica L.; DeWitt, John M.; Li, Lang; Loehrer, Patrick J.; Klaunig, James E.; Chiorean, E. Gabriela; Medicine, School of Medicine
Several risk factors have been identified as potential contributors to pancreatic cancer development, including environmental and lifestyle factors, such as smoking, drinking and diet, and medical conditions such as diabetes and pancreatitis, all of which generate oxidative stress and DNA damage. Oxidative stress status can be modified by environmental factors and also by an individual's unique genetic makeup. Here we examined the contribution of environment and genetics to an individual's level of oxidative stress, DNA damage and susceptibility to pancreatic cancer in a pilot study using three groups of subjects: a newly diagnosed pancreatic cancer group, a healthy genetically-unrelated control group living with the case subject, and a healthy genetically-related control group which does not reside with the subject. Oxidative stress and DNA damage was evaluated by measuring total antioxidant capacity, direct and oxidative DNA damage by Comet assay, and malondialdehyde levels. Direct DNA damage was significantly elevated in pancreatic cancer patients (age and sex adjusted mean ± standard error: 1.00±0.05) versus both healthy unrelated and related controls (0.70±0.06, p<0.001 and 0.82±0.07, p = 0.046, respectively). Analysis of 22 selected SNPs in oxidative stress and DNA damage genes revealed that CYP2A6 L160H was associated with pancreatic cancer. In addition, DNA damage was found to be associated with TNFA −308G>A and ERCC4 R415Q polymorphisms. These results suggest that measurement of DNA damage, as well as select SNPs, may provide an important screening tool to identify individuals at risk for development of pancreatic cancer.
COVID-19, Social Justice, and Clinical Cancer Research
(Oxford University Press, 2020-10-15) Doroshow, James H.; Prindiville, Sheila; McCaskill-Stevens, Worta; Mooney, Margaret; Loehrer, Patrick J.; Medicine, School of Medicine
The COVID-19 pandemic and related socioeconomic events have markedly changed the environment in which cancer clinical trials are conducted. These events have resulted in a substantial, immediate-term decrease in accrual to both diagnostic and therapeutic cancer investigations as well as substantive alterations in patterns of oncologic care. The sponsors of clinical trials, including the United States National Cancer Institute, as well as the cancer centers and community oncology practices that conduct such studies, have all markedly adapted their models of care, usage of health care personnel, and regulatory requirements in the attempt to continue clinical cancer investigations while maintaining high levels of patient safety. In doing so, major changes in clinical trials practice have been embraced nationwide. There is a growing consensus that the regulatory and clinical research process alterations that have been adopted in response to the pandemic (such as the use of telemedicine visits to reduce patient travel requirements and the application of remote informed consent procedures) should be implemented long term. The COVID-19 outbreak has also refocused the oncologic clinical trials community on the need to bring clinical trials closer to patients by dramatically enhancing clinical trial access, especially for minority and underserved communities that have been disproportionately affected by the pandemic. In this Commentary, changes to the program of clinical trials supported by the National Cancer Institute that could improve clinical trial availability, effectiveness, and diversity are proposed.

Browsing by Author "Loehrer, Patrick J."

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