Browsing by Author "Gardner, Thomas A."
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Item 1021. VP22 Mediates Tumor Vasculature Specific Targeting(Elsevier, 2004-05-01) Raikwar, Sudhanshu P.; Gardner, Thomas A.; Kao, Chinghai; Urology, School of MedicineItem Adenoviral Vectors Expressing Human Endostatin–Angiostatin and Soluble Tie2: Enhanced Suppression of Tumor Growth and Antiangiogenic Effects in a Prostate Tumor Model(Elsevier, 2005-12-01) Raikwar, Sudhanshu P.; Temm, Constance J.; Raikwar, Nandita S.; Kao, Chinghai; Molitoris, Bruce A.; Gardner, Thomas A.; Urology, School of MedicineAngiogenesis is essential for prostate cancer development and metastasis. Antiangiogenic therapy targeting tumor neovasculature, therefore, represents a promising approach for prostate cancer treatment. We hypothesized that adenoviral-mediated delivery of a combination of antiangiogenic factors might have an enhanced antitumor response. We developed the adenoviral vectors Ad-hEndo-angio, expressing a unique, chimeric human endostatin–angiostatin fusion protein, and Ad-sTie2, expressing a soluble form of endothelium-specific receptor tyrosine kinase Tie2. Matrigel angiogenesis assays using Ad-hEndo-angio revealed significant inhibition of tubular network formation and endothelial sprouting compared to Ad-sTie2. In vivo studies in a bilateral PC-3 tumor xenograft model following either intratumoral or systemic administration of Ad-hEndo-angio led to enhanced tumor growth suppression compared to Ad-sTie2. A novel finding is that an intratumoral, combination therapy employing one-half the dose of Ad-hEndo-angio as well as Ad-sTie2 led to a complete regression of the injected, as well as the contralateral uninjected, tumor and prolonged the tumor-free survival in 80% of the animals. In addition, a novel, real-time, intravital imaging modality was used to monitor antiangiogenic responses following adenoviral-mediated gene transfer. These results suggest that a combinatorial antiangiogenic gene therapy approach involving Ad-hEndo-angio and Ad-sTie2 could become a novel form of treatment for localized human prostate cancer.Item ANTI-TUMOR AND RADIO-SENSITIZING PROPERTIES OF AD-IU2, A PROSTATE-SPECIFIC REPLICATION-COMPETENT ADENOVIRUS ARMED WITH TRAIL(2009-03-18T18:58:00Z) Jimenez, Juan Antonio; Gardner, Thomas A.; Kao, Chinghai; Crabb, David W.; Harrington, Maureen A.; Roman, AnnIn this thesis, I investigated the preclinical utility and antitumor efficacy of TRAIL delivered by Ad-IU2, a prostate-specific replication-competent adenovirus (PSRCA), against androgen-independent prostate cancer. Through transcriptional control of adenoviral early genes E1a, E1b and E4, as well as TRAIL by two bidirectional prostate-specific enhancing sequences (PSES), expression of TRAIL as well as adenoviral replication was limited to prostate-specific antigen and prostate-specific membrane antigen (PSA/PSMA)-expressing cells. Ad-IU2 replicated efficiently in and was restricted to PSA/PSMA-positive prostate cancer cells and induced 5-fold greater apoptosis in androgen-independent CWR22rv and C4-2 prostate cancer cells than the PSRCA control not expressing TRAIL. Ad-IU2 exhibited superior killing efficiency in PSA/PSMA-positive prostate cancer cells at doses 5 to 8-fold lower than that required by a non-TRAIL expressing PSRCA to produce a similar effect. This enhanced cytotoxic effect was not observed in non-prostatic cells, however. As an enhancement of its therapeutic efficacy, Ad-IU2 exerted a bystander effect through either direct cell-to-cell contact or soluble factors present in conditioned media from Ad-IU2-infected cells. In vivo, Ad-IU2, as compared to a control PSRCA, markedly suppressed the growth of subcutaneous CWR22rv xenografts at six weeks post-treatment (3.1 vs. 17.1-fold growth of tumor). The treatment of androgen-independent prostate cancer with Ad-IU2 prior to external beam radiation therapy (EBRT) significantly reduced clonogenic survival with dose reduction factors of 4.91 and 2.43 for CWR22rv and C4-2 cells, respectively. Radio-sensitization by Ad-IU2 was restricted to PSA/PSMA-positive cells. Combinatorial radio-gene therapy resulted in accumulation of cells in G1 phase and a perturbation of the radiation-induced G2 phase arrest. This multi-modal approach combining viral lysis, apoptosis-inducing gene therapy, and radiation therapy could have great impact in achieving complete local tumor control while reducing radiation dose and associated treatment morbidities. This would result in improvement of the clinical outcome of patients with high risk prostate cancer.Item CD4+ T cell mediated tumor immunity following transplantation of TRP-1 TCR gene modified hematopoietic stem cells(2013-12-10) Ha, Sung Pil; Touloukian, Christopher E.; Broxmeyer, Hal E.; Gardner, Thomas A.; Harrington, Maureen A.; He, Johnny J.Immunotherapy for cancer has held much promise as a potent modality of cancer treatment. The ability to selectively destroy diseased cells and leave healthy cells unharmed has been the goal of cancer immunotherapy for the past thirty years. However, the full capabilities of cancer immunotherapies have been elusive. Cancer immunotherapies have been consistently hampered by limited immune reactivity, a diminishing immune response over time, and a failure to overcome self-tolerance. Many of these deficiencies have been borne-out by immunotherapies that have focused on the adoptive transfer of activated or genetically modified mature CD8+ T cells. The limitations inherent in therapies involving terminally differentiated mature lymphocytes include limited duration, lack of involvement of other components of the immune system, and limited clinical efficacy. We sought to overcome these limitations by altering and enhancing long-term host immunity by genetically modifying then transplanting HSCs. To study these questions and test the efficiency of gene transfer, we cloned a tumor reactive HLA-DR4-restricted CD4+ TCR specific for the melanocyte differentiation antigen TRP-1, then constructed both a high expression lentiviral delivery system and a TCR Tg expressing the same TCR genes. We demonstrate with both mouse and human HSCs durable, high-efficiency TCR gene transfer, following long-term transplantation. We demonstrate the induction of spontaneous autoimmune vitiligo and a TCR-specific TH1 polarized memory effector CD4+ T cell population. Most importantly, we demonstrate the destruction of subcutaneous melanoma without the aid of vaccination, immune modulation, or cytokine administration. Overall, these results demonstrate the creation of a novel translational model of durable lentiviral gene transfer, the induction of spontaneous CD4+ T cell immunity, the breaking of self-tolerance, and the induction of anti-tumor immunity.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 Comparison of Robot-Assisted Nephrectomy with Laparoscopic and Hand-Assisted Laparoscopic Nephrectomy(Society of Laparoscopic & Robotic Surgeons, 2010-07) Boger, Michelle; Lucas, Steven M.; Popp, Sara C.; Gardner, Thomas A.; Sundaram, Chandru P.; Urology, School of MedicineObjective: To compare the initial perioperative outcomes of our robot-assisted laparoscopic nephrectomies with laparoscopic and hand-assisted nephrectomies performed by 2 experienced laparoscopic surgeons. Patients and Methods: We retrospectively evaluated all patients who underwent laparoscopic (LN), hand-assisted (HALN), and robot-assisted laparoscopic nephrectomy (RALN) for benign and malignant diseases between August 2006 and December 2008. Data collected included patient age, body mass index, operative times, estimated blood loss, complications, and hospital stay. Radical nephrectomy was performed for renal neoplasms, and simple nephrectomy was performed for suspected benign diseases. In addition, average direct costs and total costs were calculated for each laparoscopic approach. Results: Forty-six patients underwent LN, 20 underwent HALN, and 13 underwent RALN. The median operative time was 171, 210, and 168 minutes, respectively. LN, HALN, and RALN groups had similar median EBL [(100mL (IQR=113mL), 100mL (IQR=150mL), and 100mL (IQR=125mL); P=0.695], length of hospital stay [2.0d (IQR=1.0d), 3.0d (IQR=2.0d), and 2.0d (IQR=3.0d); P=0.233], and postoperative morphine equivalent analgesic requirements [33mg (IQR=43mg), 45mg (IQR=50mg), and 30mg (IQR=16mg); P=0.766]. Three patients (6%) in the LN group had complications, 2 (10%) in the HALN group had complications, and 4 (30%) in the RALN group had complications. The average total direct operating room costs were $5,500, $6,979, and $6,869 for the LN, HALN, and RALN groups, respectively. Conclusions: Early experience with robotic assistance for radical and simple nephrectomy offers no significant advantage over traditional laparoscopic or hand-assisted approaches. It was also more costly.Item Impact of obesity on male urethral sling outcomes(Sage, 2020-06-09) Monn, M. Francesca; Jarvis, Hannah V.; Gardner, Thomas A.; Mellon, Matthew J.; Urology, School of MedicineBackground: The impact of obesity on AdVance male urethral sling outcomes has been poorly evaluated. Anecdotally, male urethral sling placement can be more challenging due to body habitus in obese patients. The objective of this study was to evaluate the impact of obesity on surgical complexity using operative time as a surrogate and secondarily to evaluate the impact on postoperative pad use. Methods: A retrospective cohort analysis was performed using all men who underwent AdVance male urethral sling placement at a single institution between 2013 and 2019. Descriptive statistics comparing obese and non-obese patients were performed. Results: A total of 62 patients were identified with median (IQR) follow up of 14 (4–33) months. Of these, 40 were non-obese and 22 (35.5%) were obese. When excluding patients who underwent concurrent surgery, the mean operative times for the non-obese versus obese cohorts were 61.8 min versus 73.7 min (p = 0.020). No Clavien 3–5 grade complications were noted. At follow up, 47.5% of the non-obese cohort and 63.6% of the obese cohort reported using one or more pads daily (p = 0.290). Four of the five patients with a history of radiation were among the patients wearing pads following male urethral sling placement. Conclusion: Obese men undergoing AdVance male urethral sling placement required increased operative time, potentially related to operative complexity, and a higher proportion of obese compared with non-obese patients required postoperative pads for continued urinary incontinence. Further research is required to better delineate the full impact of obesity on male urethral sling outcomes.Item Müllerian Adenosarcoma of the Urinary Bladder: Clinicopathologic and Immunohistochemical Features with Novel Genetic Aberrations(Elsevier, 2017-04) Sanfrancesco, Joseph; Williamson, Sean R.; Kum, Jennifer B.; Zhang, Shaobo; Wang, Mingsheng; Lopez-Beltran, Antonio; Montironi, Rodolfo; Gardner, Thomas A.; Cheng, Liang; Department of Pathology and Laboratory Medicine, IU School of MedicineMüllerian adenosarcoma is a biphasic neoplasm most commonly of the uterus and less frequently of the ovary. It has been rarely described to occur in other sites such as peritoneum and liver. In this study, we report the clinicopathologic, immunohistochemical and molecular features of a primary müllerian adenosarcoma of the urinary bladder in a 62-year-old woman. To our knowledge, this is the first report of müllerian adenosarcoma primary to the urinary bladder in the literature. Light microscopy showed a biphasic epithelial and stromal tumor with benign-appearing glands surrounded by endometrial-type stroma that is densely cellular with increased mitotic figures. The stroma surrounding the glands is more cellular than the intervening areas, which are more loose and edematous. Immunohistochemistry profile included positive staining for Pax2/8 within the glands, for CD10 and WT-1 within the spindled stroma, and for estrogen and progesterone receptors in both. Staining for desmin, GATA3, p63, and human papilloma virus (HPV) is negative. Molecular analyses identified mutations in AKT1 E17K, FLT3 D835N, KRAS G12D and HRAS G12S. These novel molecular aberrations have yet to be reported in the medical literature. X chromosome inactivation analysis revealed a clonal pattern in the stromal component and a non-clonal pattern in the epithelial component. Currently, the patient is disease/recurrence-free after regular follow-up of approximately 84 months. This case represents the first reported diagnosis of müllerian adenosarcoma arising in the urinary bladder with extensive clinicopathologic, immunohistochemical, and molecular analyses.Item Novel Prostate-Specific Promoter Derived from PSA and PSMA Enhancers(Elsevier, 2002-09) Lee, Sang-Jin; Kim, Hong-Sup; Yu, Rong; Lee, KangRyul; Gardner, Thomas A.; Jung, Chaeyong; Jeng, Meei-Huey; Yeung, Fan; Cheng, Liang; Kao, Chinghai; Pathology and Laboratory Medicine, School of MedicineThe expression of prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA), two well characterized marker proteins, remains highly active in the hormone refractory stage of prostate cancer. In this study, an artificial chimeric enhancer (PSES) composed of two modified regulatory elements controlling the expression of PSA and PSMA genes was tested for its promoter activity and tissue specificity using the reporter system. As a result, this novel PSES promoter remained silent in PSA- and PSMA-negative prostate and non-prostate cancer cell lines, but mediated high levels of luciferase in PSA- and PSMA-expressing prostate cancer cell lines in the presence and absence of androgen. To determine whether PSES could be used for in vivo gene therapy of prostate cancer, a recombinant adenovirus, Ad-PSES-luc, was constructed. Luciferase activity in prostate cancer cell lines mediated by Ad-PSES-luc was 400- to 1000-fold higher than in several other non-prostate cell lines, suggesting the high tissue-specificity of the PSES promoter in an adenoviral vector. Finally, recombinant virus Ad-PSES-luc was injected into mice to evaluate the tissue-discriminatory promoter activity in an experimental animal. Unlike Ad-CMV-luc, the luciferase activity from systemic injection of Ad-PSES-luc was fairly low in all major organs. However, when injected into prostate, Ad-PSES-luc drove high luciferase activity almost exclusively in prostate and not in other tissues. Our results demonstrated the potential use of PSES for the treatment of androgen-independent prostate cancer patients.Item A Parallel Randomized Clinical Trial Examining the Return of Urinary Continence After Robot- Assisted Radical Prostatectomy with or without a Small Intestinal Submucosa Bladder Neck Sling(Elsevier, 2016-07) Bahler, Clinton D.; Sundaram, Chandru P.; Kella, Naveen; Lucas, Steven M.; Boger, Michelle A.; Gardner, Thomas A.; Koch, Michael O.; Department of Urology, IU School of MedicinePurpose Urinary continence is a driver of quality of life after radical prostatectomy. In this study we evaluated the impact of a biological bladder neck sling on the return of urinary continence after robot-assisted radical prostatectomy. Materials and Methods This study compared early continence in patients undergoing robot-assisted radical prostatectomy with a sling and without a sling in a 2-group, 1:1, parallel, randomized controlled trial. Patients were blinded to group assignment. The primary outcome was defined as urinary continence (0 to 1 pad per day) at 1 month postoperatively. Inclusion criteria were organ confined prostate cancer and a prostate specific antigen less than 15 ng/ml. Exclusion criteria were any prior surgery on the prostate, a history of neurogenic bladder and history of pelvic radiation. A chi-squared test was used for the primary outcome. Results A total of 147 patients were randomized (control 74, sling 73) and 92% were available for primary end point analysis at 1 month. There were no significant differences in baseline or perioperative data except that operating room time was 20.1 minutes longer for the sling group (p=0.04). The continence rate was similar between the control and sling groups at 1 month (47.1% vs 55.2%, p=0.34) and 12 months (86.7% vs 94.5%, p=0.15), respectively. Adverse events were similar between the control and sling groups (10.8% vs 13.7%, p=0.59). Conclusions The application of an absorbable urethral sling at robot-assisted radical prostatectomy was well tolerated with no increase in obstructive symptoms in this randomized trial. However, the sling failed to show a significant improvement in continence.