Thomas Gardner
Indiana University, Urology, Faculty Member
Data support chemotherapy combined with antiangiogenic therapy in metastatic urothelial cancer (mUC) and muscle-invasive bladder cancer (MIBC). We investigated the efficacy and safety of gemcitabine, cisplatin, and sunitinib (GCS) in mUC... more
Data support chemotherapy combined with antiangiogenic therapy in metastatic urothelial cancer (mUC) and muscle-invasive bladder cancer (MIBC). We investigated the efficacy and safety of gemcitabine, cisplatin, and sunitinib (GCS) in mUC and MIBC in parallel phase II trials. Trial 1 enrolled 36 patients with mUC who were chemotherapy naive; trial 2 enrolled 9 patients with MIBC. The primary endpoints for trials 1 and 2 were response rate and pathologic complete response, respectively. GCS was given as first-line treatment for patients with mUC and as neoadjuvant therapy for patients with MIBC. The Simon minimax 2-stage design was used for an objective response rate in trial 1 and for the pathologic complete response rate in trial 2. The initial trial 1 GCS dose was gemcitabine 1000 mg/m(2) intravenously, days 1 and 8; cisplatin 70 mg/m(2) intravenously, day 1; and sunitinib 37.5 mg orally daily, days 1 to 14 of a 21-day cycle. These doses proved intolerable. The doses of gemcitabine and cisplatin were subsequently reduced to 800 and 60 mg/m(2), respectively, without an improvement in drug delivery, and the trial was closed. This lower-dose regimen was applied in trial 2, which was stopped early due to excess toxicity. Grade 3 to 4 hematologic toxicities occurred in 70% (23/33) of patients in trial 1 and 22% (2/9) of patients in trial 2. In trial 1, the response rate was 49% (95% CI, 31%-67%); in trial 2, the pathologic complete response was 22% (2/9). Due to early closure secondary to toxicity, the sample sizes of both trials were small. Delivery of GCS was hampered by excessive toxicity in both advanced and neoadjuvant settings.
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Objectives. To present our preliminary clinical results of transrectal high-intensity focused ultrasound (HIFU) in Stage T1b-2N0M0 prostate cancer. Efforts are being made to provide minimally invasive alternative treatment options with... more
Objectives. To present our preliminary clinical results of transrectal high-intensity focused ultrasound (HIFU) in Stage T1b-2N0M0 prostate cancer. Efforts are being made to provide minimally invasive alternative treatment options with equal efficacy and fewer side effects. HIFU delivers ultrasound energy with rapid thermal necrosis of tissue in the focal region without damaging the surrounding tissue.Methods. We performed 28 HIFU treatments
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A novel method for the production of adenoviral vectors on a scale sufficient to support most research applications and early phase clinical trials is presented. This method utilizes serum-free cell culture medium and a hollow fiber cell... more
A novel method for the production of adenoviral vectors on a scale sufficient to support most research applications and early phase clinical trials is presented. This method utilizes serum-free cell culture medium and a hollow fiber cell culture apparatus. Significantly less time and space are required than in conventional methods, and the resulting adenovirus is collected in a much smaller volume, simplifying the purification steps. The protocol described is a reproducible, convenient, biologically safe, and environmentally sound method for the production of adenoviral vectors for laboratory use and has the potential to scale-up the adenovirus production for clinical use.
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To evaluate trends in utilization of robotic-assistance in partial nephrectomy and assess the association between cost and utilization. Using the 2009 to 2012 Nationwide Inpatient Sample database, we identified all adult (>17 years)... more
To evaluate trends in utilization of robotic-assistance in partial nephrectomy and assess the association between cost and utilization. Using the 2009 to 2012 Nationwide Inpatient Sample database, we identified all adult (>17 years) patients undergoing partial nephrectomy for localized primary renal malignancy. Coding for robotic-assistance (17.4x) began in the final quarter of 2008. The primary outcome was total hospital cost exclusive of physician fees. A multiple linear regression model was used to adjust for patient and hospital characteristics. Between 2009 and 2012, there were 32,664 (58%) open, 3,498 (6%) laparoscopic, and 20,350 (36%) robot-assisted partial nephrectomies performed in the United States. Between 2009 and 2012, the total number of partial nephrectomies semiannually increased by 93% (5,114 to 9,845) with robotic partial nephrectomies (RPN) representing more than 80% of the increase. RPN increased from 1,029 cases in the first half of 2009 to 4,840 in the last...
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190 Background: The optimal sequence and combination of life-extending anticancer therapies in mCRPC pts remains unknown. Sipuleucel-T (sip-T), an autologous cellular immunotherapy approved for the therapy of asymptomatic or minimally... more
190 Background: The optimal sequence and combination of life-extending anticancer therapies in mCRPC pts remains unknown. Sipuleucel-T (sip-T), an autologous cellular immunotherapy approved for the therapy of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC) pts, was evaluated in combination with abiraterone acetate and prednisone (abi) in the phase II STAMP trial (NCT01487863), with pts randomly assigned to receive CON sip-T + abi or SEQ sip-T followed by abi. The combination was well-tolerated and did not alter the immune response parameters that correlate with overall survival (OS) (Small Clin Can Res 2015). Here, we present long-term follow-up of clinical outcomes, including OS. Methods: mCRPC pts were randomized 1:1 to CON or SEQ therapy with sip-T and abi. Abi began 1 day after (CON) or at wk 10 (SEQ) after the first sip-T infusion and continued for 26 wk of therapy, after which continued abi therapy was permitted. Long-term clinical...
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Articular cartilage is comprised of three histologic zones that exhibit different Young's moduli. In addition, with age and disease the moduli can be altered. Therefore,diagnosis of joint diseases can be accomplished by detecting... more
Articular cartilage is comprised of three histologic zones that exhibit different Young's moduli. In addition, with age and disease the moduli can be altered. Therefore,diagnosis of joint diseases can be accomplished by detecting biomechanical properties of articular cartilage. In this report we investigate the feasibility of ultrasound elastography of bovine articular cartilage (n=5) employing instantaneous static compression using high-resolution (55MHz) ultrasound elastography in vitro as a potential arthroscopic technique. Elastograms were computed using cross-correlation technique and a gradient operator. The elastograms revealed near-zero strains within the samples, except at the articular surface and the interface between zones 1 and 2. The boundary conditions associated with the loading technique implemented herein that have to allow for a large acoustic window during imaging represent a fundamental challenge toward imparting local strains to the articular cartilage. Des...
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Osteocalcin (OC), a noncollagenous bone matrix protein, is expressed in high levels by osteoblasts. To determine whether the OC promoter mediates cell-specific gene expression in cells of osteoblast lineage, we constructed a recombinant... more
Osteocalcin (OC), a noncollagenous bone matrix protein, is expressed in high levels by osteoblasts. To determine whether the OC promoter mediates cell-specific gene expression in cells of osteoblast lineage, we constructed a recombinant adenovirus, Ad-OC-TK, which contains the OC promoter that drives the expression of herpes simplex virus thymidine kinase (TK). We tested the expression of TK by this virus in osteoblast cell lines as well as in non-osteoblastic cell lines by assessing the enzyme activity of TK in vitro. Whereas the OC promoter failed to drive the expression of the TK gene in several non-osteoblastic cell lines such as WH, a human bladder transitional carcinoma, and NIH 3T3, an embryonic mouse fibroblast cell line, the OC promoter mediated high levels of expression in osteoblast cell lines including murine ROS and human MG-63 cells. The addition of acyclovir (ACV), a pro-drug for the inhibition of cell proliferation, resulted in the induction of osteoblast-specific ce...
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Childhood osteogenic sarcoma (OS) is a rare bone cancer occurring primarily in adolescents. The North American pediatric cooperative groups have performed a series of clinical treatment trials in this disease over the past several... more
Childhood osteogenic sarcoma (OS) is a rare bone cancer occurring primarily in adolescents. The North American pediatric cooperative groups have performed a series of clinical treatment trials in this disease over the past several decades, and biology studies of tumor tissue have been an important study component. A meeting was held in Bethesda, Maryland on November 29-30, 2001, sponsored by the NIH Office of Rare Diseases, the Children's Oncology Group, and the National Cancer Institute-Cancer Therapy Evaluation Program with the general objectives: (a) to review the current state of knowledge regarding OS biology; (b) to identify, prioritize, and support the development of biology studies of potential clinical relevance in OS; and (c) to discuss the available tissue resources and the appropriate methods for analysis of OS samples for the conduct of biology studies. This report summarizes the information presented and discussed by the meeting participants.
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The SonablateTM system for transrectal image-guided high intensity focused ultrasound (TR-HIFU) treatment of prostate diseases has been in clinical use since 1992. Recently, we developed the third generation of the system, call... more
The SonablateTM system for transrectal image-guided high intensity focused ultrasound (TR-HIFU) treatment of prostate diseases has been in clinical use since 1992. Recently, we developed the third generation of the system, call SonablateTM 500, with major improvements aimed specifically toward localized prostate cancer treatment. Salient features of the SonablateTM 500 include: (1) PC-based digital technology, (2) multifocal lengths probe with split beam transducer to cover a wide range of tissue depths (2.5–4.5 cm), (3) an upgraded treatment planning and control software with safety features such as reflectivity index measurement (RIMTM) and transducer tissue measurement (TTMTM); and (4) 3-D volume image rendering of the prostate. The SonablateTM 500 platform was tested in an in vivo canine experimental study in which the entire prostate was ablated. The prostate ultrasound images before and post HIFU treatment show very good correlation to the planned lesion. Histology delineated ...
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We evaluated semen quality and pregnancy rates achieved with sperm obtained by rectal probe ejaculation. A series of 183 rectal probe ejaculation procedures performed by 1 of us (J. F. E.) on 40 anejaculatory men was reviewed. Motile... more
We evaluated semen quality and pregnancy rates achieved with sperm obtained by rectal probe ejaculation. A series of 183 rectal probe ejaculation procedures performed by 1 of us (J. F. E.) on 40 anejaculatory men was reviewed. Motile sperm were recovered from 95% of men undergoing rectal probe ejaculation. Live births were recorded for 15 of 33 couples (45%) via intrauterine insemination (10) or in vitro fertilization (5). Three of the latter 5 pregnancies were achieved with intracytoplasmic sperm injection. Motile sperm are obtained from most men undergoing rectal probe ejaculation and pregnancy rates obtained with these sperm are improved by in vitro fertilization.
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Recent evidence suggests that androgens stimulate growth of human prostate cancer partly by regulating expression of growth factors such as vascular endothelial growth factor (VEGF) in vitro and in vivo. In this study, we used CWR22Rv1, a... more
Recent evidence suggests that androgens stimulate growth of human prostate cancer partly by regulating expression of growth factors such as vascular endothelial growth factor (VEGF) in vitro and in vivo. In this study, we used CWR22Rv1, a novel androgen-responsive but androgen-independent human prostate cancer model, to evaluate the effect of androgen withdrawal on tumor growth, expression of VEGF and the cell proliferation marker Ki-67, and angiogenesis. A time-release testosterone pellet was implanted three days before inoculation of CWR22Rv1 cells in the mice. The tumor volumes were measured every three days. Serum PSA was measured on days 1, 12, 20, 27 and 34 post inoculation. Castration was performed on the 20th day post inoculation. Immunohistochemical assays were used to evaluate cell proliferation and microvessel density. Enzyme-linked immunosorbent assay (ELISA) was used to quantify VEGF expression. The average tumor volumes in the castration group on the 27th and 34th days...
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BACKGROUND The expression of the MN/carbonic anhydrase IX (CA IX) protein is detected in renal cell carcinoma (RCC). A tumor-specific MN promoter was designed and evaluated. MATERIALS AND METHODS Western blot, reverse transcription-PCR... more
BACKGROUND The expression of the MN/carbonic anhydrase IX (CA IX) protein is detected in renal cell carcinoma (RCC). A tumor-specific MN promoter was designed and evaluated. MATERIALS AND METHODS Western blot, reverse transcription-PCR and Northern blot for MN expression were performed on Hela cells, LNCaP and four human RCC cell lines. The MN promoter (554 bp) was cloned into pGL3 luciferase reporter vectors and their activities were tested. RESULTS Hela cells, SKRC-31 and SKRC-38 expressed high levels of MN RNA and MN protein. The MN promoter has 5- to 10-fold higher activity in MN-positive cell lines than in MN-negative cell lines. It could enhance the activity of the basic SV40 early promoter (6 to 25 fold) in MN-positive cells but not in MN-negative cells. CONCLUSION MN expression in RCC may derive from altered expression of transcriptional factor(s), which binds to the MN enhancer element, and can be used for tumor specific toxic gene therapy for RCC.
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Renal cell carcinoma (RCC) is the third most common urologic neoplasm and its age-adjusted incidence has been increasing annually. Despite advances in cancer research and current therapy strategies, the effective treatment of advanced RCC... more
Renal cell carcinoma (RCC) is the third most common urologic neoplasm and its age-adjusted incidence has been increasing annually. Despite advances in cancer research and current therapy strategies, the effective treatment of advanced RCC remains elusive. Over the past two decades, clinical and genetic studies have shown that kidney cancer is not a single disease entity, rather a spectrum of different forms. This understanding has translated into therapies targeted against specific genetic targets. In this review, we highlight the scientific principles, current applications, and future direction of renal cell cancer gene therapy. _____________________________________________________________________________________________________________
INTRODUCTION AND OBJECTIVE:Complication rates following cystectomy range from 40-80% with 75% of complications being related to the urinary diversion. Reported complication following continent cuta...
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4526Background: FGFR3 aberrations are common in low grade non-muscle invasive bladder cancer (NMIBC) tumors but decrease in frequency in metastatic UC. This multisite single-arm trial assessed the ...
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300 Background: Detection of advanced prostate cancer has historically relied on radionuclide bone scanning and cross-sectional imaging with varying degrees of sensitivity and specificity based on the clinical scenario. In the current... more
300 Background: Detection of advanced prostate cancer has historically relied on radionuclide bone scanning and cross-sectional imaging with varying degrees of sensitivity and specificity based on the clinical scenario. In the current era, use of NaF and Choline based whole body scans have led to increased detection, but access to these scan can be limited and expense can be prohibitive. Similar to choline based scanning, acetate is metabolically active in cancer, including prostate. Methods: Fifty-six men previously diagnosed with prostate cancer with PSA recurrences after some failed primary treatment, have undergone whole body C-11 Acetate PET scans at Indiana University since June of 2013. Patient demographics, prior treatments, PSA values, prior imaging, post-scan therapies, and therapeutic outcomes have been recorded prospectively and updated as follow-up information becomes available. Results: Analysis of these initial 56 men demonstrated 31/56 men had a C-11 Acetate PET scan...
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452 Background: The Cancer Genome Atlas project identified a distinct cluster of hypermethylated muscle-invasive UC tumors in one third of patients. It is unknown if this epigenetic biology persists or changes in UC metastases. The... more
452 Background: The Cancer Genome Atlas project identified a distinct cluster of hypermethylated muscle-invasive UC tumors in one third of patients. It is unknown if this epigenetic biology persists or changes in UC metastases. The present study aimed to identify uniquely hypermethylated regions in UC metastases compared to their matched primary tumors. Methods: UC patients with paired formalin fixed paraffin embedded tissue samples ( > 75% tumor) from primary and metachronous metastatic tumors were identified. DNA methylation was analyzed on the Illumina HiSeq platform by double-enzyme reduced representation bisulfite sequencing (dRRBS). Results were analyzed by BS-seq within BSmooth open source software. Alignment and methylation estimation was done using Bismark open source software. CpG regions with coverage < 2 in more than 66% of samples were removed to reduce false positive results. Differentially methylated regions (DMRs) in metastases compared to primary tumors were d...
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148 Background: Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic or minimally symptomatic mCRPC. Sipuleucel-T prepared using 10μg/mL PA2024 (PAP-GM-CSF antigen) stimulates immune responses and prolongs overall... more
148 Background: Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic or minimally symptomatic mCRPC. Sipuleucel-T prepared using 10μg/mL PA2024 (PAP-GM-CSF antigen) stimulates immune responses and prolongs overall survival (OS). ProACT is an ongoing phase 2 study to evaluate immune responses and OS of sipuleucel-T when manufactured using 3 different concentrations of PA2024. Here we report data from the FDA-approved concentration, 10μg/mL PA2024 (n=40). Pts with asymptomatic or minimally symptomatic mCRPC (n=120) received sipuleucel-T manufactured using 2, 5 or 10μg/mL PA2024 for a total of 3 infusions with 2-wk intervals. Peripheral immune responses were evaluated 2, 4 and 6 mo after 1(st) infusion by serum ELISA (n=40), and B cell activation phenotype was characterized during the manufacture of the product by flow cytometry (n=19). During product manufacture both mature and memory B cells were activated; the percentage of B cells that had a mature phenotype (defin...
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ABSTRACT Despite recent advances in early detection and conventional therapies, prostate cancer continues to be the second-leading cause of cancer mortality in American men. Advanced prostate cancer progresses, metastasizes, and becomes... more
ABSTRACT Despite recent advances in early detection and conventional therapies, prostate cancer continues to be the second-leading cause of cancer mortality in American men. Advanced prostate cancer progresses, metastasizes, and becomes resistant to treatment. Clinical evaluation of gene therapy for prostate cancer has demonstrated its safety, and early success warrants further study. In combination with conventional therapies, which are limited by treatment-related morbidity and toxicity, molecular therapy for advanced prostate cancer shows great promise. In this chapter, we review the current status of gene therapy approaches for prostate cancer, which include corrective gene therapy, oncolytic viral therapy, cytotoxic gene therapy, and immunotherapy.
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The expression of the MN/carbonic anhydrase IX (CA IX) protein is detected in renal cell carcinoma (RCC). A tumor-specific MN promoter was designed and evaluated. Western blot, reverse transcription-PCR and Northern blot for MN expression... more
The expression of the MN/carbonic anhydrase IX (CA IX) protein is detected in renal cell carcinoma (RCC). A tumor-specific MN promoter was designed and evaluated. Western blot, reverse transcription-PCR and Northern blot for MN expression were performed on Hela cells, LNCaP and four human RCC cell lines. The MN promoter (554 bp) was cloned into pGL3 luciferase reporter vectors and their activities were tested. Hela cells, SKRC-31 and SKRC-38 expressed high levels of MN RNA and MN protein. The MN promoter has 5- to 10-fold higher activity in MN-positive cell lines than in MN-negative cell lines. It could enhance the activity of the basic SV40 early promoter (6 to 25 fold) in MN-positive cells but not in MN-negative cells. MN expression in RCC may derive from altered expression of transcriptional factor(s), which binds to the MN enhancer element, and can be used for tumor specific toxic gene therapy for RCC.
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... Author(s): Thomas A. Gardner; Michael O. Koch; Arieh Shalhav; Richard Bihrle MD; Richard S. Foster MD; Christopher Steidle; Ivan Grunberger; Alan Seftel; Martin Resnick; James Cochran; Victor Rao; Narendra T. Sanghvi. ...
The benefits of laparoscopic surgery with robotic assistance (da Vinci Robotic Surgical System, Intuitive Surgical, Sunnyvale, CA) includes elimination of tremor, motion scaling, 3D laparoscopic vision, and instruments with 7 degrees of... more
The benefits of laparoscopic surgery with robotic assistance (da Vinci Robotic Surgical System, Intuitive Surgical, Sunnyvale, CA) includes elimination of tremor, motion scaling, 3D laparoscopic vision, and instruments with 7 degrees of freedom. The benefit of robotic assistance could be most pronounced with reconstructive procedures, such as pyeloplasty. We aimed to compare laparoscopic pyeloplasty, with and without robotic assistance, during a surgeon's initial experience to determine whether robotic assistance has distinct advantages over the pure laparoscopic technique. We retrospectively compared the first 7 laparoscopic pyeloplasties with the first 7 robotic pyeloplasties performed by a single surgeon. All patients were preoperatively evaluated with computed tomographic angiography with 3D reconstruction to image crossing vessels at the ureteropelvic junction. All patients were followed up by lasix renograms and routine clinic visits. Patients were similar with respect to ...
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Research Interests: Biology, Apoptosis, Medicine, Western blotting, Molecular Biology Cancer, and 13 moreVirulence, Humans, Mice, Female, Animals, Male, Molecular Cancer Therapeutics, Base Sequence, Breast Neoplasms, Genetic Therapy, reverse transcriptase polymerase chain reaction, Prostatic neoplasms, and Pharmacology and pharmaceutical sciences
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Retrospective studies have shown laparoscopic cytoreductive nephrectomy (LCN) to be a safe procedure in selected patients. The objective of this article is to identify characteristics that may predict when a laparoscopic procedure may... more
Retrospective studies have shown laparoscopic cytoreductive nephrectomy (LCN) to be a safe procedure in selected patients. The objective of this article is to identify characteristics that may predict when a laparoscopic procedure may offer improved postoperative outcome and whether it affects the timing of postoperative systemic therapy compared with open surgery. A cohort of 43 LCN cases were matched with 43 open cytoreductive nephrectomy (OCN) cases based on both pathologic size of tumor and stage. Eleven cases were laparoscopic converted to open nephrectomy. Cases excluded from the analysis were adjacent organ involvement, inferior vena cava involvement, and bulky lymphadenopathy. Data analysis of 11 variables was performed using the t test, log-rank, and Wilcoxon tests. Significance was at P = 0.05. Survival data were calculated using the Kaplan-Meier estimate. Significant differences between LCN vs OCN were estimated blood loss (mean 277 ml vs 816 ml) and length of hospitalization (3.2 days vs 5.1 days). The median size of tumor for LCN cases was 7.5 cm and for OCN, 9.5 cm. The mean size of tumor of LCN vs laparoscopic converted to open cases was 6.8 cm vs 11.2 cm, and this difference was significant. There was no significant difference in postoperative performance status, time to commencement of systemic treatment, or in survival time between both groups. This study provides further evidence that a laparoscopic approach with cytoreductive nephrectomy in metastatic renal-cell carcinoma is a safe option for tumors 10 cm and smaller. The approach (laparoscopic vs open) had no effect on postoperative complications or time to systemic therapy. Procedures with tumors larger than 10 cm were more likely to be converted to an open procedure. Tumors larger than 10 cm may be best approached via an open procedure, especially in the presence of involvement of adjacent organs or bulky lymphadenopathy.