IU Indianapolis ScholarWorks :: Browsing by Author "Hanna, Nasser H."

Browsing by Author "Hanna, Nasser H."

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A phase 1 study of combined guadecitabine and cisplatin in platinum refractory germ cell cancer
(Wiley, 2021) Albany, Costantine; Fazal, Zeeshan; Singh, Ratnakar; Bikorimana, Emmanuel; Adra, Nabil; Hanna, Nasser H.; Einhorn, Lawrence H.; Perkins, Susan M.; Sandusky, George E.; Christensen, Brock C.; Keer, Harold; Fang, Fang; Nephew, Kenneth P.; Spinella, Michael J.; Medicine, School of Medicine
Purpose: Germ cell tumors (GCTs) are cured with therapy based on cisplatin, although a clinically significant number of patients are refractory and die of progressive disease. Based on preclinical studies indicating that refractory testicular GCTs are hypersensitive to hypomethylating agents (HMAs), we conducted a phase I trial combining the next-generation HMA guadecitabine (SGI-110) with cisplatin in recurrent, cisplatin-resistant GCT patients. Methods: Patients with metastatic GCTs were treated for five consecutive days with guadecitabine followed by cisplatin on day 8, for a 28-day cycle for up to six cycles. The primary endpoint was safety and toxicity including dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). Results: The number of patients enrolled was 14. The majority of patients were heavily pretreated. MTD was determined to be 30 mg/m2 guadecitabine followed by 100 mg/m2 cisplatin. The major DLTs were neutropenia and thrombocytopenia. Three patients had partial responses by RECIST criteria, two of these patients, including one with primary mediastinal disease, completed the study and qualified as complete responses by serum tumor marker criteria with sustained remissions of 5 and 13 months and survival of 16 and 26 months, respectively. The overall response rate was 23%. Three patients also had stable disease indicating a clinical benefit rate of 46%. Conclusions: The combination of guadecitabine and cisplatin was tolerable and demonstrated activity in patients with platinum refractory germ cell cancer.
A Phase II Study Assessing the Safety and Efficacy of ASP1650 in Male Patients with Relapsed Refractory Germ Cell Tumors
(Springer, 2022) Adra, Nabil; Vaughn, David J.; Einhorn, Lawrence H.; Hanna, Nasser H.; Funt, Samuel A.; Rosales, Matt; Arozullah, Ahsan; Feldman, Darren R.; Medicine, School of Medicine
Claudin6(CLDN6) is a tight junction protein of claudin-tetraspanin family and is of the earliest molecules expressed in embryonic epithelium. CLDN6 is frequently aberrantly expressed in testicular germ-cell tumors(GCT). ASP1650 is a chimeric-mouse/human-IgG1 antibody directed against CLDN6. Two-part, open-label, phase-II trial investigating ASP1650 in patients with relapsed/refractory GCT and no curable options. Part1 was a safety lead-in to establish the recommended-phase-II-dose(RP2D). Part2 was a phase-II study designed to evaluate the antitumor effects of ASP1650. CLDN6 expression was centrally assessed on archival tumor tissue using immunohistochemistry. The primary objectives were to establish the RP2D(safety lead-in) and the antitumor activity(phase-II) of ASP1650. Nineteen male patients were enrolled: 6 patients in 1000 mg/m2 safety lead-in group, and 13 in 1500 mg/m2 group. Median age 37.2 years(range,20-58). Histology was non-seminoma in 17/19 patients. Median number of previous chemotherapy regimens was 3. Thirteen patients had prior high-dose chemotherapy. No dose-limiting toxicity events were reported at any study drug dose. A RP2D of 1500 mg/m2 every 2 weeks was established. No partial or complete responses were observed. The study was stopped at the end of Simon Stage-I due to lack of efficacy. 15/16 subjects with available tissue had CLDN6 positive staining. The mean percent membrane staining was 71.6% and the mean membrane H score was 152.6(SD 76). ASP1650 did not appear to have clinically meaningful single-agent activity in relapsed/refractory GCT. CLDN6 expression seems ubiquitous in all elements of GCT and is worthy of investigation as a diagnostic biomarker and therapeutic target.
Adenocarcinoma Harboring EGFR-RAD51 Fusion Treated with Osimertinib: A Case Report
(Elsevier, 2024-04) Lai, Sunny Y.; Richardson, Noah H.; Tran, Mya; Hanna, Nasser H.; Shields, Misty D.; Medicine, School of Medicine
EGFR mutations are among the most common driver mutations in lung adenocarcinoma. Rare alterations, such as the EGFR-RAD51 fusion, respond to treatment with EGFR tyrosine kinase inhibitors but can be missed by limited genomic sequencing panels. Here, we report a case of metastatic lung adenocarcinoma in a never-smoker patient who initially did not have a targetable alteration identified on two different sequencing panels. The initial response to combination chemoimmunotherapy was short-lived. A rare EGFR-RAD51 fusion was then identified using a more in-depth sequencing panel. The patient experienced a dramatic and durable response to osimertinib. This case highlights the rarity of EGFR-RAD51 fusions, the efficacy of EGFR tyrosine kinase inhibitors, and the importance of a thorough search for targetable alterations in never-smokers with lung adenocarcinoma.
Impact of smoke-free ordinance strength on smoking prevalence and lung cancer incidence
(PLOS, 2021-04-16) Nguyen, Ryan H.; Vater, Laura B.; Timsina, Lava R.; Durm, Gregory A.; Rupp, Katelin; Wright, Keylee; Spitznagle, Miranda H.; Paul, Brandy; Jalal, Shadia I.; Carter-Harris, Lisa; Hudmon, Karen S.; Hanna, Nasser H.; Loehrer, Patrick J.; Ceppa, DuyKhanh P.; Surgery, School of Medicine
Background: Smoke-free ordinances (SFO) have been shown to be effective public health interventions, but there is limited data on the impact SFO on lung cancer outcomes. We explored the effect of county-level SFO strength with smoking prevalence and lung cancer incidence in Indiana. Methods: We obtained county-level lung cancer incidence from the Indiana State Cancer Registry and county-level characteristics from the Indiana Tobacco Prevention and Cessation Commission's policy database between 1995 and 2016. Using generalized estimating equations, we performed multivariable analyses of smoking prevalence and age-adjusted lung cancer rates with respect to the strength of smoke-free ordinances at the county level over time. Results: Of Indiana's 92 counties, 24 had a SFO by 2011. In 2012, Indiana enacted a state-wide SFO enforcing at least moderate level SFO protection. Mean age-adjusted lung cancer incidence per year was 76.8 per 100,000 population and mean smoking prevalence per year was 25% during the study period. Counties with comprehensive or moderate SFO had a smoking prevalence 1.2% (95% CI [-1.88, -0.52]) lower compared with counties with weak or no SFO. Counties that had comprehensive or moderate SFO also had an 8.4 (95% CI [-11.5, -5.3]) decrease in new lung cancer diagnosis per 100,000 population per year compared with counties that had weak or no SFO. Conclusion: Counties with stronger smoke-free air ordinances were associated with decreased smoking prevalence and fewer new lung cancer cases per year. Strengthening SFO is paramount to decreasing lung cancer incidence.
LAL deficiency induced myeloid-derived suppressor cells as targets and biomarkers for lung cancer
(BMJ, 2023) Zhao, Ting; Liu, Sheng; Hanna, Nasser H.; Jalal, Shadia; Ding, Xinchun; Wan, Jun; Yan, Cong; Du, Hong; Pathology and Laboratory Medicine, School of Medicine
Background: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells in tumor microenvironment, which suppress antitumor immunity. Expansion of various MDSC subpopulations is closely associated with poor clinical outcomes in cancer. Lysosomal acid lipase (LAL) is a key enzyme in the metabolic pathway of neutral lipids, whose deficiency (LAL-D) in mice induces the differentiation of myeloid lineage cells into MDSCs. These Lal -/- MDSCs not only suppress immune surveillance but also stimulate cancer cell proliferation and invasion. Understanding and elucidating the underlying mechanisms of MDSCs biogenesis will help to facilitate diagnosis/prognosis of cancer occurrence and prevent cancer growth and spreading. Methods: Single-cell RNA sequencing (scRNA-seq) was performed to distinguish intrinsic molecular and cellular differences between normal versus Lal -/- bone marrow-derived Ly6G+ myeloid populations in mice. In humans, LAL expression and metabolic pathways in various myeloid subsets of blood samples of patients with non-small cell lung cancer (NSCLC) were assessed by flow cytometry. The profiles of myeloid subsets were compared in patients with NSCLC before and after the treatment of programmed death-1 (PD-1) immunotherapy. Results: scRNA-seq of Lal -/- CD11b+Ly6G+ MDSCs identified two distinctive clusters with differential gene expression patterns and revealed a major metabolic shift towards glucose utilization and reactive oxygen species (ROS) overproduction. Blocking pyruvate dehydrogenase (PDH) in glycolysis reversed Lal -/- MDSCs' capabilities of immunosuppression and tumor growth stimulation and reduced ROS overproduction. In the blood samples of human patients with NSCLC, LAL expression was significantly decreased in CD13+/CD14+/CD15+/CD33+ myeloid cell subsets. Further analysis in the blood of patients with NSCLC revealed an expansion of CD13+/CD14+/CD15+ myeloid cell subsets, accompanied by upregulation of glucose-related and glutamine-related metabolic enzymes. Pharmacological inhibition of the LAL activity in the blood cells of healthy participants increased the numbers of CD13+ and CD14+ myeloid cell subsets. PD-1 checkpoint inhibitor treatment in patients with NSCLC reversed the increased number of CD13+ and CD14+ myeloid cell subsets and PDH levels in CD13+ myeloid cells. Conclusion: These results demonstrate that LAL and the associated expansion of MDSCs could serve as targets and biomarkers for anticancer immunotherapy in humans.
Long-Term Survival of Good-Risk Germ Cell Tumor Patients After Postchemotherapy Retroperitoneal Lymph Node Dissection: A Comparison of BEP × 3 vs. EP × 4 and Treating Institution
(Elsevier, 2017) Cary, Clint; Jacob, Joseph M.; Albany, Costantine; Masterson, Timothy A.; Hanna, Nasser H.; Einhorn, Lawrence H.; Foster, Richard S.; Urology, School of Medicine
Background Patients with International Germ Cell Cancer Collaborative Group (IGCCCG) good-risk testicular cancer might receive either 4 cycles of etoposide and cisplatin (EP × 4) or 3 cycles of bleomycin, etoposide, and cisplatin (BEP × 3). We sought to examine differences in survival after retroperitoneal lymph node dissection (PC-RPLND) between patients who received EP × 4 compared with BEP × 3. Patients and Methods The Indiana University Testis Cancer database was queried to identify IGCCCG good-risk PC-RPLND patients who received either EP × 4 or BEP × 3 induction chemotherapy. The primary outcome was overall survival (OS). Kaplan–Meier plots were generated for the EP × 4 and BEP × 3 groups and compared using the log rank test. Cox regression analysis was used to determine risk of mortality. Results A total of 223 patients met inclusion criteria between 1985 and 2011. Induction chemotherapy consisted of EP × 4 in 45 (20%) patients and BEP × 3 in 178 (80%). Most patients (78%) received their chemotherapy at outside institutions and were subsequently referred for PC-RPLND. The location of treating institution did not influence outcomes significantly when similar chemotherapy regimens were compared in this good-risk cohort. The 10-year OS for the EP × 4 and BEP × 3 groups were 91% and 98%, respectively (log rank P < .01). The adjusted risk of death in the EP × 4 group showed a nonsignificant trend of 3 times greater compared with the BEP × 3 group (hazard ratio, 3.1; 95% confidence interval, 0.8-12.0; P = .10). Conclusion The regimen of BEP × 3 resulted in a trend toward improved survival, however, this did not reach statistical significance. The location of treating institution seems less important in this risk group of patients.
Lysosomal acid lipase, CSF1R, and PD-L1 determine functions of CD11c+ myeloid-derived suppressor cells
(The American Society for Clinical Investigation, 2022-09-08) Zhao, Ting; Liu, Sheng; Ding, Xinchun; Johnson, Erica M.; Hanna, Nasser H.; Singh, Kanhaiya; Sen, Chandan K.; Wan, Jun; Du, Hong; Yan, Cong; Pathology and Laboratory Medicine, School of Medicine
Lysosomal acid lipase (LAL) is a key enzyme in the metabolic pathway of neutral lipids. In the blood of LAL-deficient (Lal-/-) mice, increased CD11c+ cells were accompanied by upregulated programmed cell death ligand 1 (PD-L1) expression. Single-cell RNA sequencing of Lal-/- CD11c+ cells identified 2 distinctive clusters with a major metabolic shift toward glucose utilization and reactive oxygen species overproduction. Pharmacologically blocking pyruvate dehydrogenase in glycolysis not only reduced CD11c+ cells and their PD-L1 expression but also reversed their capabilities of T cell suppression and tumor growth stimulation. Colony-stimulating factor 1 receptor (CSF1R) played an essential role in controlling Lal-/- CD11c+ cell homeostasis and function and PD-L1 expression. Pharmacological inhibition of LAL activity increased CD11c, PD-L1, and CSF1R levels in both normal murine myeloid cells and human blood cells. Tumor-bearing mice and human patients with non-small cell lung cancer also showed CD11c+ cell expansion with PD-L1 and CSF1R upregulation and immunosuppression. There were positive correlations among CD11c, PD-L1, and CSF1R expression and negative correlations with LAL expression in patients with lung cancer or melanoma using The Cancer Genome Atlas database and patient samples. Therefore, CD11c+ cells switched their functions to immune suppression and tumor growth stimulation through CSF1R/PD-L1 upregulation and metabolic reprogramming.
Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors
(Oxford, 2018-02) Albany, Costantine; Adra, Nabil; Snavely, A. C.; Cary, C.; Masterson, T. A.; Foster, R. S.; Kesler, Kenneth; Ulbright, Thomas M.; Cheng, Liang; Chovanec, Michal; Taza, Fadi; Brames, Mary J.; Hanna, Nasser H.; Einhorn, Lawrence H.; Medicine, School of Medicine
Background To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. Patients and methods We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin–etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with ‘distant’ disease. The Kaplan–Meier method was used to estimate PFS and OS. Results With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER ‘distant’ cohort between 2000 and 2014, P-value <0.0001. Conclusion The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER ‘distant’ cohort.
Outcomes in Patients With Postchemotherapy Residual Nonretroperitoneal Disease in Nonseminomatous Germ Cell Tumors
(American Medical Association, 2024) King, Jennifer; Ashkar, Ryan; Kesler, Kenneth; Althouse, Sandra K.; Hanna, Nasser H.; Einhorn, Lawrence H.; Adra, Nabil; Medicine, School of Medicine
This case-control study assesses the association between teratoma in the primary tumor or postchemotherapy resections and survival outcomes.
Outcomes of patients with stage III non-small cell lung cancer (NSCLC) that harbor a STK11 mutation
(AME, 2021) An, Josiah; Yan, Melissa; Yu, Nanmeng; Chennamadhavuni, Adithya; Furqan, Muhammad; Mott, Sarah L.; Loeffler, Bradley T.; Kruser, Timothy; Sita, Timothy L.; Feldman, Lawrence; Nguyen, Ryan; Pasquinelli, Mary; Hanna, Nasser H.; Hejleh, Taher Abu; Medicine, School of Medicine
Background: STK11 mutation (STK11m ) in patients (pts) with stage IV non-small cell lung cancer (NSCLC) is associated with inferior survival and poor response to immune checkpoint inhibitors (ICI). The significance of STK11m in stage III NSCLC pts treated with concurrent chemoradiation (CCRT) with or without consolidation ICI is unknown. Methods: Stage III NSCLC patients who received CCRT and had known STK11 mutational status were included in this retrospective study. The data on the STK11m pts were collected from 4 cancer institutions. A cohort of pts with wild type STK11 (STK11w ) from the University of Iowa served as a comparison group. Patient demographics and clinical characteristics were collected. Cox regression models were used to explore the effect of STK11 mutation on survival. Results: 75 pts with stage III NSCLC who had known STK11 mutational status were identified. 16/75 (21%) had STK11m . 5/16 with STK11 m did not receive CCRT so they were excluded from the analysis. The clinical and demographic characteristics for the 11 STK11m and 59 STK11w pts were not statistically different (STK11m vs. STK11w ): mean age: 57 vs. 64 yrs, non-squamous histology: 8/11 (73%) vs. 37/59 (63%), KRAS mutation: 3/11 (27%) vs. 11/59 (19%), TP53 mutation: 6/11 (55%) vs. 15/59 (25%), PD-L1 ≥50%: 1/8 (13%) vs. 10/32 (31%), and consolidation ICI 6/11 (55%) vs. 17/59 (29%). Regarding the 6 STK11m pts who received ICI (4 pembrolizumab, 2 durvalumab), the median number of ICI infusions was 8 (range, 3-17) vs. 6 (range, 1-25) in the 17 pts with STK11w who received ICI (durvalumab). After adjusting for performance status and cancer stage, multivariable analysis showed that progression free survival (PFS) for the STK11m pts was significantly worse than STK11 w pts (HR =2.25; 95% CI, 1.03-4.88, P=0.04), whereas overall survival (OS) showed no significant difference for STK11m vs. STK11w patients (HR 1.47, 95% CI, 0.49-4.38, P=0.49). Conclusions: In stage III NSCLC patients who received CCRT, STK11m was associated with worse PFS compared to STK11w . Larger studies are needed to further explore the prognostic implications of STK11m in stage III NSCLC and whether ICI impacts survival for this subgroup.

Browsing by Author "Hanna, Nasser H."

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