- Browse by Author
Browsing by Author "Adra, Nabil"
Now showing 1 - 10 of 23
Results Per Page
Sort Options
Item 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 MedicineClaudin6(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.Item Adjuvant Etoposide Plus Cisplatin for Patients With Pathologic Stage II Nonseminomatous Germ Cell Tumors: Is This the Preferred Option?(ASCO, 2020-09) Einhorn, Lawrence H.; Adra, Nabil; Hanna, Nasser; Nichols, Craig; Medicine, School of MedicineItem Adverse Health Outcomes among U.S. Testicular Cancer Survivors after Cisplatin-Based Chemotherapy vs. Surgical Management(Oxford, 2019-10) Agrawal, Vaibhav; Dinh, Paul C., Jr.; Fung, Chunkit; Monahan, Patrick O.; Althouse, Sandra K.; Norton, Kelli; Cary, Clint; Einhorn, Lawrence; Fossa, Sophie D.; Adra, Nabil; Travis, Lois B.; Medicine, School of MedicineWe evaluated for the first time adverse health outcomes (AHOs) among U.S. testicular cancer survivors (TCS) given chemotherapy (n = 381) vs. surgery-only patients (n = 98) managed at a single institution, accounting for non-treatment-related risk factors to delineate chemotherapy’s impact. Chemotherapy consisted largely of bleomycin-etoposide-cisplatin (BEP) administered in 3 or 4 cycles (BEPX3, n = 235; BEPX4, n = 82). Incidence of ≥ 3 AHOs was lowest in surgery-only TCS and increased with BEPX3, BEPX4 and other cisplatin-based regimens (12.2%, 40.8%, 52.5%, 54.8%; P<0.0001). Multivariate modeling assessed associations of risk factors and treatment with hearing impairment, tinnitus, peripheral neuropathy, and Raynaud phenomenon. Risk for each AHO significantly increased with both increasing chemotherapy burden (P < 0.0001) and selected modifiable risk factors (P < 0.05): hypertension (OR = 2.40) and noise exposure (OR ≥ 2.3) for hearing impairment; noise exposure for tinnitus (OR ≥ 1.69); peripheral vascular disease for neuropathy (OR = 8.72), and current smoking for Raynaud phenomenon (OR = 2.41). Clinicians should manage modifiable risk factors for AHOs among TCS.Item Chemotherapy-Related Chronic Myelogenous Leukemia: A Case Series of Patients With Germ Cell Tumor(American Medical Association, 2016-03) Adra, Nabil; Sayar, Hamid; Einhorn, Lawrence H.; Department of Medicine, IU School of MedicineItem Clinicopathological characteristics of ypT0N0 urothelial carcinoma following neoadjuvant chemotherapy and cystectomy(BMJ, 2019-08) Magers, Martin J.; Kaimakliotis, Hristos Z.; Barboza, Marcelo P.; Bandali, Elhaam; Adra, Nabil; Koch, Michael O.; Cheng, Liang; Pathology and Laboratory Medicine, School of MedicineAims To describe a large tertiary care academic centre’s experience with patients who achieve a complete pathological response (ie, ypT0N0) following neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) with emphasis on morphological features present in the RC and clinical outcome. Methods 41 patients with ypT0N0 disease following transurethral resection of bladder tumour (TURBT), NAC and RC with available clinical follow-up information were analysed. Slides from all RCs were reviewed to confirm pathological stage and assess for morphological parameters (eg, foreign body giant cell reaction, dystrophic calcification, scar and fat necrosis). Results With median follow-up of 32.8 months, the recurrence-free survival at 1 and 5 years was 97.4% and 93.5%, while the overall survival at 3 and 5 years was 94.2% and 88.6%, respectively. No patients died of urothelial carcinoma. Stage assigned at TURBT was 1 pTa (2%), 1 pT1 (2%), 38 pT2 (93%) and 1 pT3a (2%). 17 TURBTs demonstrated variant histology, with the majority of these being squamous (65%). The most common morphological features present at RC were scar (100%), foreign body giant cell reaction (80%), chronic inflammation within lamina propria (68%) and dystrophic calcifications (39%). Other morphological features were less common or absent. Conclusion ypT0N0 disease at RC portends an excellent prognosis, regardless of stage or variant histology in the TURBT; scar, foreign body giant cell reaction, chronic inflammation and dystrophic calcifications are often present.Item Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer(American Society of Clinical Oncology, 2021-07-22) Taza, Fadi; Holler, Albert E.; Fu, Wei; Wang, Hao; Adra, Nabil; Albany, Costantine; Ashkar, Ryan; Cheng, Heather H.; Sokolova, Alexandra O.; Agarwal, Neeraj; Kessel, Adam; Bryce, Alan; Nafissi, Nellie; Barata, Pedro; Sartor, A. Oliver; Bastos, Diogo; Smaletz, Oren; Berchuck, Jacob E.; Taplin, Mary-Ellen; Aggarwal, Rahul; Sternberg, Cora N.; Vlachostergios, Panagiotis J.; Alva, Ajjai S.; Su, Christopher; Marshall, Catherine H.; Antonarakis, Emmanuel S.; Medicine, School of MedicineTwo poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration-approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied. Methods: We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with BRCA1/2-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among BRCA1- versus BRCA2-altered mCRPC. Results: A total of 123 patients (13 BRCA1 and 110 BRCA2) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. BRCA1 patients were more likely to have metastatic disease at presentation (69% v 37%; P = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% v 46%; P = .78) in both groups. BRCA1 patients had more monoallelic (56% v 41%; P = .49) and concurrent TP53 (55% v 36%; P = .32) mutations. PSA50 responses in BRCA1- versus BRCA2-altered patients were 23% versus 63%, respectively (P = .01). BRCA2 patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; P = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; P = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; P = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent TP53 mutation were associated with PARP inhibitor sensitivity. Conclusion: PARP inhibitor efficacy is diminished in BRCA1- versus BRCA2-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent TP53 alterations in the BRCA1 group.Item Hypermethylation and global remodelling of DNA methylation is associated with acquired cisplatin resistance in testicular germ cell tumours(Taylor & Francis, 2021-10) Fazal, Zeeshan; Singh, Ratnakar; Fang, Fang; Bikorimana, Emmanuel; Baldwin, Hannah; Corbet, Andrea; Tomlin, Megan; Yerby, Cliff; Adra, Nabil; Albany, Costantine; Lee, Sarah; Freemantle, Sarah J.; Nephew, Kenneth P.; Christensen, Brock C.; Spinella, Michael J.; Medicine, School of MedicineTesticular germ cell tumours (TGCTs) respond well to cisplatin-based therapy. However, cisplatin resistance and poor outcomes do occur. It has been suggested that a shift towards DNA hypermethylation mediates cisplatin resistance in TGCT cells, although there is little direct evidence to support this claim. Here we utilized a series of isogenic cisplatin-resistant cell models and observed a strong association between cisplatin resistance in TGCT cells and a net increase in global CpG and non-CpG DNA methylation spanning regulatory, intergenic, genic and repeat elements. Hypermethylated loci were significantly enriched for repressive DNA segments, CTCF and RAD21 sites and lamina associated domains, suggesting that global nuclear reorganization of chromatin structure occurred in resistant cells. Hypomethylated CpG loci were significantly enriched for EZH2 and SUZ12 binding and H3K27me3 sites. Integrative transcriptome and methylome analyses showed a strong negative correlation between gene promoter and CpG island methylation and gene expression in resistant cells and a weaker positive correlation between gene body methylation and gene expression. A bidirectional shift between gene promoter and gene body DNA methylation occurred within multiple genes that was associated with upregulation of polycomb targets and downregulation of tumour suppressor genes. These data support the hypothesis that global remodelling of DNA methylation is a key factor in mediating cisplatin hypersensitivity and chemoresistance of TGCTs and furthers the rationale for hypomethylation therapy for refractory TGCT patients.Item Long-Term Oncologic Outcomes after Primary Retroperitoneal Lymph Node Dissection: Minimizing the Need for Adjuvant Chemotherapy(AUA, 2020) Douglawi, Antoin; Calaway, Adam; Tachibana, Isamu; Barboza, Marcelo Panizzutti; Speir, Ryan; Masterson, Timothy; Adra, Nabil; Foster, Richard; Einhorn, Lawrence; Cary, Clint; Urology, School of MedicineObjective: To analyze the oncological outcomes of men undergoing primary RPLND and characterize the use of adjuvant chemotherapy and template dissections. Methods: Retrospective review of Indiana University testis cancer database identified patients who underwent a primary RPLND between 01/2007 and 12/2017. Patients and providers were contacted to obtain information regarding adjuvant therapy, recurrence, and survival. Primary outcome was recurrence-free survival (RFS). Kaplan-Meier curves assessed survival differences stratified by pathologic stage, template of dissection, and use of adjuvant chemotherapy. Results: Overall, 274 patients were included. Most men presented with CS-I disease (214, 78%). A modified unilateral template was performed in 257 (94%) and bilateral template in 17 (6%). Overall, 148 (54%) and 126 (46%) of men had Pathologic Stage I (PS-I) and PS-II disease, respectively. Thirteen patients (10%) with PS-II disease were treated with adjuvant chemotherapy. With a median follow-up was 55 months, only 33 (12%) patients recurred. Of the 113 patients with PS-II disease who did not receive chemotherapy, 21 (19%) relapsed and 81% were cured were surgery alone and never recurred. No difference in RFS was noted between modified and bilateral template dissections. Conclusions: The use of adjuvant chemotherapy has been minimal over the past decade. The majority (81%) of men with PS-II disease were cured with RPLND alone and were able to avoid chemotherapy. Modified unilateral template dissection provided excellent oncologic control while minimizing morbidity.Item Metastatic small cell carcinoma of the prostate in an octogenarian with significant response to first-line chemotherapy(OAT, 2017-03) Wood, Anthony; Adra, Nabil; Cheng, Liang; Pili, Roberto; Department of Pathology and Laboratory Medicine, IU School of MedicinePatients with small cell carcinoma of the prostate generally present with metastatic disease and have an estimated life expectancy measured in months. In this brief report, we present a case of rapidly progressive metastatic small cell carcinoma of the prostate in an octogenarian with significant response to split-dosed cisplatin and etoposide. This case report shows that cautious treatment with platinum-based regimens should still be considered in elderly patients given the potential for improvement in performance status and quality of life with chemotherapy. Additionally, this case highlights that platinum-based regimens are still considered the therapeutic backbone of prostate cancers with a mixed small cell carcinoma and adenocarcinoma phenotype.Item 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 MedicineBackground 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.
- «
- 1 (current)
- 2
- 3
- »