Browsing by Author "Kaimakliotis, Hristos Z."
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Item Anti-tumor activity and mechanistic characterization of APE1/Ref-1 inhibitors in bladder cancer(American Association for Cancer Research, 2019-08-14) Fishel, Melissa L.; Xia, Hanyu; McGeown, Jack; McIlwain, David W.; Elbanna, May; Craft, Ariel A.; Kaimakliotis, Hristos Z.; Sandusky, George E.; Zhang, Chi; Pili, Roberto; Kelley, Mark R.; Jerde, Travis J.; Pharmacology and Toxicology, School of MedicineBladder cancer is the ninth most common cause of cancer-related deaths worldwide. Although cisplatin is used routinely in treating bladder cancer, refractory disease remains lethal for many patients. The recent addition of immunotherapy has improved patient outcomes; however, a large cohort of patients does not respond to these treatments. Therefore, identification of innovative molecular targets for bladder cancer is crucial. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein involved in both DNA repair and activation of transcription factors through reduction-oxidation (redox) regulation. High APE1/Ref-1 expression is associated with shorter patient survival time in many cancer types. In this study, we found high APE1/Ref-1 expression in human bladder cancer tissue relative to benign urothelium. Inhibition of APE1/Ref-1 redox signaling using APE1/Ref-1-specific inhibitors attenuates bladder cancer cell proliferation in monolayer, in three-dimensional cultures, and in vivo. This inhibition corresponds with an increase in apoptosis and decreased transcriptional activity of NF-κB and STAT3, transcription factors known to be regulated by APE1/Ref-1, resulting in decreased expression of downstream effectors survivin and Cyclin D1 in vitro and in vivo. We also demonstrate that in vitro treatment of bladder cancer cells with APE1/Ref-1 redox inhibitors in combination with standard-of-care chemotherapy cisplatin is more effective than cisplatin alone at inhibiting cell proliferation. Collectively, our data demonstrate that APE1/Ref-1 is a viable drug target for the treatment of bladder cancer, provide a mechanism of APE1/Ref-1 action in bladder cancer cells, and support the use of novel redox-selective APE1/Ref-1 inhibitors in clinical studies. SIGNIFICANCE: This work identifies a critical mechanism for APE1/Ref-1 in bladder cancer growth and provides compelling preclinical data using selective redox activity inhibitors of APE1/Ref-1 in vitro and in vivo.Item The changing reality of urothelial bladder cancer: should non-squamous variant histology be managed as a distinct clinical entity?(Wiley, 2015-08) Monn, M. Francesca; Kaimakliotis, Hristos Z.; Cary, K. Clint; Bihrle, Richard; Pedrosa, Jose A.; Masterson, Timothy A.; Foster, Richard S.; Gardner, Thomas A.; Cheng, Liang; Koch, Michael O.; Department of Urology, IU School of MedicineObjectives To assess the effect of non-squamous differentiation (non-SQD) variant histology on survival in muscle-invasive bladder urothelial cancer (UC). Patients and Methods A cohort of 411 radical cystectomy (RC) cases performed with curative intent for muscle-invasive primary UC was identified between 2008 and June 2013. Survival analysis was evaluated using Kaplan–Meier methodology comparing non-variant (NV) + SQD histology to non-SQD variant histology (non-SQD variants). Multivariable cox proportional hazards regression assessed all-cause and disease-specific mortality. Results Of the 411 RC cases, 77 (19%) had non-SQD variant histology. The median overall survival (OS) for non-SQD variant histology was 28 months, whereas the NV+SQD group had not reached the median OS at 74 months (log-rank test P < 0.001). After adjusting for sex, age, pathological stage, and any systemic chemotherapy, patients with non-SQD variant histology at RC had a 1.57-times increased adjusted risk of all-cause mortality (P = 0.027) and 1.69-times increased risk of disease-specific mortality (P = 0.030) compared with NV+SQD patients. Conclusions While SQD behaves similarly to NV, non-SQD variant histology portends worse OS and disease-specific survival regardless of neoadjuvant or adjuvant chemotherapy and pathological stage. Non-SQD variants of UC could perhaps be considered a distinct clinical entity in UC with goals for developing new treatment algorithms through novel clinical trials.Item 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 Does Squamous Differentiation Portend Worse Outcomes in Urothelial Bladder Cancer?(Elsevier, 2015-11) Yang, David Y.; Monn, M. Francesca; Kaimakliotis, Hristos Z.; Cho, Jane S.; Cary, K. Clint; Pedrosa, Jose A.; Bihrle, Richard; Cheng, Liang; Koch, Michael O.; Department of Urology, IU School of MedicineIntroduction Interest on the impact of variant histology in bladder cancer prognosis is increasing. Although squamous differentiation is the most well characterized, only recently have less common variants gained increased recognition. We assessed whether squamous differentiation conferred a worse prognosis than nonvariant urothelial bladder cancer in a contemporary cohort of patients treated with radical cystectomy given the increased awareness of other less common variants. Methods We identified patients with squamous differentiation or nonvariant histology on transurethral resection of bladder tumor and/or cystectomy pathology during a 10-year period. Disease specific and overall survival were evaluated using Kaplan-Meier methodology. Cox regression was used to assess variables associated with mortality. Results Between 2003 and 2013, 934 patients underwent cystectomy for urothelial bladder cancer. Overall 617 nonvariant and 118 squamous differentiation cases were identified, and the remainder was nonsquamous differentiation variant histology. Overall 75% of patients with squamous differentiation had muscle invasive disease at diagnosis compared with 59% of those with nonvariant histology (p=0.002). Nonorgan confined disease at cystectomy was more common in patients with squamous differentiation (57% vs 44%, p=0.009). Among cases on neoadjuvant chemotherapy 20% (9 of 45) of nonvariant and 13% (1 of 8) of squamous differentiation were pT0N0 (p=0.527). Median followup was 52 months. Adjusted for demographics, pathological stage and chemotherapy, squamous differentiation was not associated with an increased risk of disease specific (HR 1.35, 95% CI 0.90–2.04, p=0.150) or all cause mortality (HR 0.90, 95% CI 0.60–1.25, p=0.515). Conclusions In a contemporary cohort of urothelial bladder cancer with recognition and characterization of less commonly described variants, squamous differentiation is not associated with a worse disease specific and all cause mortality when compared to a pure nonvariant cohort.Item Functional and Clinicopathologic Outcomes Using a Modified Vescica Ileale Padovana Technique(IOS Press, 2015-01-01) Flack, Chandra K.; Monn, M. Francesca; Kaimakliotis, Hristos Z.; Koch, Michael O.; Urology, School of MedicineObjective: To evaluate the clinicopathologic and functional outcomes of a modified Vescica ileale Padovana (VIP) neobladder technique. Methods: Data for 160 patients at a single institution who underwent radical cystectomy and orthotopic VIP neobladdItem Human papillomavirus (HPV)-induced neoplasia in the urinary bladder: a missing link?(2016) Alexander, Riley E.; Wang, Lisha; Lopez-Beltran, Antonio; Emerson, Robert E.; Montironi, Rodolfo; Pedrosa, Jose A.; Kaimakliotis, Hristos Z.; Koch, Michael O.; Cheng, Liang; Department of Pathology and Laboratory Medicine, IU School of MedicineThe discovery that the role human papillomavirus (HPV) plays in the induction of human cancer represents an important achievement in oncologic research. It has taken on even greater importance since the development of vaccines, which promise the hope of preventing these cancers from ever occurring. Because of these important implications, many have attempted to determine a possible role for the virus in cancers of the urinary bladder-an organ in close anatomic proximity to the primary sites of HPV-induced neoplasia and one which already has an established oncogenic infectious agent in Schistosoma haematobium. Here we review the current literature exploring this possible role in the most common subtype of cancer of the urinary bladder, urothelial carcinoma, and two much more rare histologic subtypes that have well established roles for HPV-induced neoplasia in other anatomic sites-squamous cell carcinoma and adenocarcinoma.Item Inherited Forms of Bladder Cancer: A review of Lynch Syndrome and Other Inherited Conditions(Future Medicine, 2018-02) Phelan, Aaron; Lopez-Beltran, Antonio; Montironi, Rodolfo; Zhang, Shaobo; Raspollini, Maria R.; Kaimakliotis, Hristos Z.; Koch, Michael O.; Cheng, Liang; Pathology and Laboratory Medicine, School of MedicineEnvironmental factors that play a role in the urothelial carcinogenesis have been well characterized. Current research is continuously exploring potential heritable forms of bladder cancer. Lynch syndrome is a well-known inheritable disease that increases the risk for a variety of cancers, including urothelial carcinomas. Screening of patients with known Lynch syndrome is important to evaluate for development of new primary tumors. Further study may provide more information on what level of follow-up each patient needs. Recent data suggest that mismatch repair mutations confer a greater risk for urothelial cancer. Additional large patient series as well as advancement of molecular testing may provide triage for Lynch syndrome patients in regards to the frequency and type of screening best suited for individual patient.Item Oncologic outcomes and prognostic impact of urothelial recurrences in patients undergoing segmental and total ureterectomy for upper tract urothelial carcinoma(Canadian Urological Association, 2015-04-13) Pedrosa, Jose A.; Masterson, Timothy A.; Rice, Kevin R.; Kaimakliotis, Hristos Z.; Monn, M. Francesca; Bihrle, Richard; Koch, Michael O.; Boris, Ronald S.; Department of Urology, IU School of MedicineINTRODUCTION: We evaluated the impact of urothelial recurrences in a cohort of patients undergoing segmental (SU) and total ureterectomy (TU) as an alternative to nephroureterectomy (NU) for upper tract urothelial carcinoma. METHODS: Between 1999 and 2012, patients who underwent SU, TU and NU for treatment of upper tract urothelial carcinoma were evaluated. Demographic, surgical, pathologic and oncologic data were collected. Recurrence-free (RFS) and disease-specific survival (DSS) were analyzed using Kaplan-Meier and multivariable Cox methods. RESULTS: A total 141 patients were evaluated, 35 underwent SU, 10 TU and 96 NU. Patients who underwent TU were more likely to have bilateral disease (p < 0.01), solitary kidney (p < 0.01), and multifocal disease (p = 0.01). Organ-confined (p < 0.01) and low-grade disease (p < 0.01) were more common in the TU and SU groups compared with NU. At a median follow-up of 56.9 months (range: 0.2-181.1) disease relapse occurred in 88 (55.3%) patients. Localized recurrence occurred in 31.1% of SU/TU group compared to 27.1% (p = 0.62) of the NU group. Neither total nor segmental ureterectomy demonstrated significantly worse RFS (p = 0.26 and p = 0.81), CSS (p = 0.96 and p = 0.52) or overall survival (p = 0.59 and p = 0.55) compared with complete NU. Localized urothelial recurrence did not confer increased risk of cancer-specific (p = 0.73) or overall mortality (p = 0.39). The paper's most important limitations include its retrospective nature and its relatively small number of patients. CONCLUSION: No significant survival differences were demonstrated between surgical approaches for upper tract urothelial cancer. Localized urothelial recurrence after surgical treatment for upper tract urothelial cancer does not affect mortality in this population. TU with ileal-substitution may provide an alternative option for patients with extensive ureteral disease and poor renal function.Item Patients with Muscle-Invasive Bladder Cancer with Nonluminal Subtype Derive Greatest Benefit from Platinum Based Neoadjuvant Chemotherapy(AUA, 2022-03) Lotan, Yair; de Jong, Joep J.; Liu, Vinnie Y. T.; Bismar, Tarek A.; Boorjian, Stephen A.; Huang, Huei-Chung; Davicioni, Elai; Mian, Omar Y.; Wright, Jonathan L.; Necchi, Andrea; Dall'Era, Marc A.; Kaimakliotis, Hristos Z.; Black, Peter C.; Gibb, Ewan A.; Boormans, Joost L.; Urology, School of MedicinePurpose: Neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) in patients with nonmetastatic muscle-invasive bladder cancer (MIBC) confers an absolute survival benefit of 5%–10%. There is evidence that molecular differences between tumors may impact response to therapy, highlighting a need for clinically validated biomarkers to predict response to NAC. Materials and Methods: Four bladder cancer cohorts were included. Inverse probability weighting was used to make baseline characteristics (age, sex and clinical tumor stage) between NAC-treated and untreated groups more comparable. Molecular subtypes were determined using a commercial genomic subtyping classifier. Survival rates were estimated using weighted Kaplan-Meier curves. Cox proportional hazards models were used to evaluate the primary and secondary study end points of overall survival (OS) and cancer-specific survival, respectively. Results: A total of 601 patients with MIBC were included, of whom 247 had been treated with NAC and RC, and 354 underwent RC without NAC. With NAC, the overall net benefit to OS and cancer-specific survival at 3 years was 7% and 5%, respectively. After controlling for clinicopathological variables, nonluminal tumors had greatest benefit from NAC, with 10% greater OS at 3 years (71% vs 61%), while luminal tumors had minimal benefit (63% vs 65%) for NAC vs non-NAC. Conclusions: In patients with MIBC, a commercially available molecular subtyping assay revealed nonluminal tumors received the greatest benefit from NAC, while patients with luminal tumors experienced a minimal survival benefit. A genomic classifier may help identify patients with MIBC who would benefit most from NAC.Item Plasmacytoid/diffuse urothelial carcinoma: a single-institution immunohistochemical and molecular study of 69 patients(Elsevier, 2019-08) Perrino, Carmen M.; Eble, John; Kao, Chia-Sui; Whaley, Rumeal D.; Cheng, Liang; Idrees, Mohammad; Hashemi-Sadraei, Neda; Monn, M. Francesca; Kaimakliotis, Hristos Z.; Bandali, Elhaam; Grignon, David; Pathology and Laboratory Medicine, School of MedicineAccurate diagnosis of plasmacytoid urothelial carcinoma (PUC) is important given its poor prognosis and frequent presentation at high stage. We aim to assess the clinicopathological features, molecular aberrations, and follow-up data in a series of PUC cases from a single tertiary cancer center. Seventy-two urinary bladder, ureteral, and renal pelvic specimens with urothelial carcinoma with plasmacytoid differentiation were identified. Immunohistochemical stains were performed on 48 cases. Among urinary bladder origin markers, GATA3 was most sensitive (96%). Breast carcinoma markers (estrogen receptor, mammaglobin) were usually negative, but progesterone receptor stained 1 case (4%). Neuroendocrine markers CD56 and TTF-1 were each positive in 1 case (4% and 4%, respectively). Gastrointestinal adenocarcinoma marker CDX2 was positive in 4 cases (15%), but nuclear β-catenin was negative in all cases. CD138 was positive in 83% and E-cadherin expression was lost in 57% of cases. Fluorescence in situ hybridization using the UroVysion Bladder Cancer Kit and FGFR3 mutational analysis using polymerase chain reaction were performed on 15 cases; deletion of chromosome 9p21 was common (60%), and FGFR3 mutations were detected in 60% of cases (5 cases had both deletion 9p21 and FGFR3 mutations). Cases were divided into 3 morphologic groups: classic (29%), desmoplastic (35%), and pleomorphic (36%). The 3 morphologic subtypes had distinct survival outcomes (P = .083), with median survival for all patients 18 being months versus 10 months for the desmoplastic group.