Noah M Hahn

Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, United States

Are you Noah M Hahn?

Claim your profile

Publications (43)300.58 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Plasmacytoid variant (PCV) urothelial cancer (UC) of the bladder is rare, with poor clinical outcomes. We sought to identify factors that may better inform expectations of tumor behavior and improve management options in patients with PCV UC.
    Urologic oncology. 06/2014;
  • Source
    Costantine Albany, Noah M Hahn
    [Show abstract] [Hide abstract]
    ABSTRACT: Defects within apoptotic pathways have been implicated in prostate cancer (PCa) tumorigenesis, metastatic progression and treatment resistance. A hallmark of cancers is the ability to derail apoptosis by inhibiting the apoptotic signal, reducing the expression of apoptotic proteins and/or amplifying survival signals through increased production of antiapoptotic molecule. This review describes associations between heat shock proteins (HSPs) and the human androgen receptor (AR), the role of HSPs and other stress-induced proteins in PCa development and emerging strategies in targeting these protective proteins to treat PCa.
    Asian Journal of Andrology 04/2014; · 2.14 Impact Factor
  • C Albany, N M Hahn
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer (PC) is the most commonly diagnosed non-skin cancer and the second leading cause of cancer death among American men. Bone is by far the most common site for metastasis. The median survival of patients from the development of bone metastases is ∼3 years. During this period, patients are at increased risk of skeletal-related events (SREs) including: intractable bone pain, pathological fractures and spinal-cord compression. Several novel bone-targeted agents including bisphosphonates, receptor activator of nuclear factor κB (RANK) ligand monoclonal antibodies, endothelin receptor antagonists, bone-seeking radioisotopes, selective estrogen receptor (ER) modulators and tyrosine kinase inhibitors are now available and under evaluation in clinical trials in PC patients with bone metastases. This review article will provide an overview of the multiple emerging novel bone-targeted therapies in PC.Prostate Cancer and Prostatic Disease advance online publication, 25 March 2014; doi:10.1038/pcan.2014.12.
    Prostate cancer and prostatic diseases 03/2014; · 2.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives Plasmacytoid variant (PCV) urothelial cancer (UC) of the bladder is rare, with poor clinical outcomes. We sought to identify factors that may better inform expectations of tumor behavior and improve management options in patients with PCV UC. Materials and methods A retrospective analysis of the Indiana University Bladder Cancer Database between January 2008 and June 2013 was performed comparing 30 patients with PCV UC at cystectomy to 278 patients with nonvariant (NV) UC at cystectomy who underwent surgery for muscle-invasive disease. Multivariable logistic regression was used to assess precystectomy variables associated with non–organ-confined disease at cystectomy and Cox regression analysis to assess variables associated with mortality. Results Patients with PCV UC who were diagnosed with a higher stage at cystectomy (73% pT3-4 vs. 40%, P = 0.001) were more likely to have lymph node involvement (70% vs. 25%, P<0.001), and positive surgical margins were found in 40% of patients with PCV UC vs. 10% of patients with NV UC (P<0.001). Median overall survival and disease-specific survival were 19 and 22 months for PCV, respectively. Median overall survival and disease-specific survival had not been reached for NV at 68 months (P<0.001). Presence of PCV UC on transurethral resection of bladder tumor was associated with non–organ-confined disease (odds ratio = 4.02; 95% CI: 1.06–15.22; P = 0.040), and PCV at cystectomy was associated with increased adjusted risk of mortality (hazard ratio = 2.1; 95% CI: 1.2–3.8; P = 0.016). Conclusions PCV is an aggressive UC variant, predicting non–organ-confined disease and poor survival. Differentiating between non–muscle- and muscle-invasive disease in patients with PCV UC seems less important than the aggressive nature of this disease. Instead, any evidence of PCV on transurethral resection of bladder tumor may warrant aggressive therapy.
    Urologic Oncology: Seminars and Original Investigations. 01/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Elevated markers of bone turnover are prognostic for shorter survival in castration-resistant prostate cancer. We aimed to determine the prognostic value of bone turnover markers in metastatic hormone-sensitive prostate cancer. Markers of bone turnover (urine deoxypyridinoline [DPD] and N-telopeptide, serum bone alkaline phosphatase (AP), and osteocalcin [OC]) from baseline and after 6 months of study were assessed in men enrolled in a prospective metastatic prostate cancer trial with androgen deprivation therapy (ADT) with or without risedronate (ClinicalTrials.gov, NCT00216060). Serum samples were collected from 63 patients with bone involvement and a median follow-up of 39.7 months. A multivariate model using Cox regression-which included prostate-specific antigen (PSA) nadir, bisphosphonate treatment, and extent of metastases-showed that suppression of bone turnover markers after 6 months of therapy compared with baseline was significantly associated with longer skeletal-related event (SRE)-free survival. ADT without bisphosphonate therapy was also associated with a decline in markers of bone turnover, presumably resulting from direct anticancer activity. Elevated baseline bone turnover markers were not prognostic. Failure to suppress bone turnover while receiving ADT, even when otherwise responding to therapy, may identify patients with hormone-sensitive metastatic prostate cancer who are destined for a shorter time to SREs and progression.
    Clinical Genitourinary Cancer 10/2013; · 1.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Models to predict the outcome of patients with metastatic urothelial cancer (UC), based on pretreatment variables, have previously been developed. However, patients often request "updated" prognostic estimates based upon their response to treatment. Data were pooled from 317 patients enrolled in 8 trials evaluating first-line cisplatin-based chemotherapy in metastatic UC. Variables were combined in the Cox proportional hazards model to produce a nomogram to predict survival from the end of treatment. The nomogram was validated externally using data from a phase III trial. The median survival from end of treatment was 10.65 months (95% confidence interval; 9.20-13.24); 69% of patients had died. Baseline and posttreatment variables were evaluated. Baseline performance status, baseline number of visceral metastatic sites, baseline white blood counts, and response to treatment were included in the final model. The nomogram achieved a bootstrap-corrected concordance index of 0.68. Upon external validation, the nomogram achieved a concordance index of 0.67. A model derived from pretreatment and posttreatment variables was constructed to predict survival from the completion of first-line chemotherapy in patients with metastatic UC. This model may be useful for patient counseling and for stratification of trials exploring "maintenance" therapy.
    Urologic Oncology 09/2013; · 3.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The identification of mutations in epidermal growth factor receptor (EGFR) and translocations involving anaplastic lymphoma kinase (ALK) in lung adenocarcinoma has drastically changed understanding of the disease and led to the development of targeted therapies. Adenocarcinoma of the urinary bladder is rare and poorly understood at the molecular level. We undertook this study to determine whether EGFR mutations, increases in EGFR copy number, or ALK translocations are present in these tumors. Twenty-eight cases of primary bladder adenocarcinoma were analyzed. For EGFR mutational analysis, PCR-amplified products were analyzed on the Q24 Pyrosequencer with Qiagen EGFR Pyro Kits. All cases were analyzed via fluorescence in situ hybridization (FISH) using Vysis ALK Break Apart FISH Probes for detection of ALK chromosomal translocation and Vysis Dual Color Probes to assess for increased gene copy number of EGFR. None of the 28 cases examined showed mutational events in EGFR or ALK rearrangements. EGFR polysomy was seen in 10 out of 28 (36%) cases. No correlation with EGFR polysomy was seen in the tumors with respect to age, histologic subtypes, pathologic stage, or lymph node metastasis. In summary, EGFR mutations and ALK rearrangements do not appear to be involved in the development of primary adenocarcinoma of the urinary bladder. A subgroup of cases (36%), however, demonstrated increased gene copy number of EGFR by FISH.Modern Pathology advance online publication, 26 July 2013; doi:10.1038/modpathol.2013.132.
    Modern Pathology 07/2013; · 5.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Urinary bladder squamous cell carcinoma and urothelial carcinoma with squamous differentiation are often high-grade and high-stage tumors that are thought to be associated with a poorer prognosis and response to therapy compared with urothelial carcinoma without divergent differentiation. Therefore, recognition of a squamous component is increasingly important in guiding prognosis and therapy. We investigated the expression of MAC387, desmoglein-3, and TRIM29 in pure squamous cell carcinoma and urothelial carcinoma with squamous differentiation to determine whether they have utility as diagnostic biomarkers for squamous differentiation. Eighty-four cases were retrieved from participating institutions including 51 pure urinary bladder squamous cell carcinomas and 33 urothelial carcinomas with squamous differentiation. MAC387, desmoglein-3, and TRIM29 antibodies demonstrated positive staining in pure squamous cell carcinoma in 51 (100%), 46 (90%), and 48 (93%) cases, respectively. Urothelial carcinoma with squamous differentiation showed reactivity for MAC387, desmoglein-3, and TRIM29 in the squamous component for 32 (97%), 26 (79%), and 32 (97%) cases, respectively. MAC387 demonstrated a sensitivity of 99% and a specificity of 70% for squamous differentiation, whereas desmoglein-3 yielded a sensitivity of 86% and a specificity of 91%. No urothelial component showed greater than 10% labeling for desmoglein-3. TRIM29 labeling showed a sensitivity of 95%, but a poorer specificity of 33%. In summary, MAC387 and desmoglein-3 are reliable diagnostic markers for supporting the morphologic impression of squamous differentiation in urinary bladder carcinoma. Desmoglein-3 shows high specificity, whereas TRIM29 was most likely to demonstrate labeling in areas without light microscopically recognizable squamous differentiation.
    Human pathology 06/2013; · 3.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: The current study was conducted to develop a pretreatment prognostic model for patients with unresectable and/or metastatic urothelial cancer who were treated with first-line, cisplatin-based chemotherapy. METHODS: Individual data were pooled from 399 patients who were enrolled on 8 phase 2 and 3 trials evaluating cisplatin-based, first-line chemotherapy in patients with metastatic urothelial carcinoma. Variables selected for inclusion in the model were combined in a Cox proportional hazards model to produce a points-based nomogram with which to predict the median, 1-year, 2-year, and 5-year survival. The nomogram was validated externally using data from a randomized trial of the combination of methotrexate, vinblastine, doxorubicin plus cisplatin versus docetaxel plus cisplatin. RESULTS: The median survival of the development cohort was 13.8 months (95% confidence interval, 12.1 months-16.0 months); 68.2% of the patients had died at the time of last follow-up. On multivariable analysis, the number of visceral metastatic sites, Eastern Cooperative Oncology Group performance status, and leukocyte count were each found to be associated with overall survival (P < .05), whereas the site of the primary tumor and the presence of lymph node metastases were not. All 5 variables were included in the nomogram. When subjected to internal validation, the nomogram achieved a bootstrap-corrected concordance index of 0.626. When applied to the external validation cohort, the nomogram achieved a concordance index of 0.634. Calibration plots suggested that the nomogram was well calibrated for all predictions. CONCLUSIONS: Based on routinely measured pretreatment variables, a nomogram was constructed that predicts survival in patients with unresectable and/or metastatic urothelial cancer who are treated with cisplatin-based chemotherapy. This model may be useful in patient counseling and clinical trial design. Cancer 2013. © 2013 American Cancer Society.
    Cancer 05/2013; · 5.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Use of progression-free survival (PFS) as a clinical trial endpoint in first-line treatment of patients with metastatic urothelial carcinoma (UC) is attractive, but would be enhanced by establishing a correlation between PFS and overall survival (OS). METHODS: Data was pooled from 7 phase 2 and 3 trials evaluating cisplatin-based chemotherapy in metastatic UC. An independent cohort of patients enrolled on a phase 3 trial was used for external validation. Landmark analyses for progression at 6 and 9 months after treatment initiation were performed to minimize lead-time bias. A proportional hazards model was used to assess the utility of PFS for predicting OS. RESULTS: A total of 364 patients were included in the initial cohort. The median PFS was 8.21 months (95% confidence interval = 7.43, 8.39) and the median OS was 13.50 months (95% confidence interval = 11.80, 15.67). In the landmark analysis, the median OS for patients who progressed at 6 months was 3.87 months compared with 15.06 months for those patients who did not progress (P < .0001) and the median OS for patients who progressed at 9 months was 5.65 months compared with 21.39 months for those patients who did not progress (P < .0001). A Fleischer model demonstrated a statistically significant dependent correlation between PFS and OS. The findings were externally validated in an independent cohort. CONCLUSIONS: PFS at 6 and 9 months predicted OS in this analysis of patients with metastatic UC treated with first-line cisplatin-based chemotherapy and could potentially serve as endpoints in (randomized) phase 2 trials to screen the activity of novel regimens. Cancer 2013. © 2013 American Cancer Society.
    Cancer 05/2013; · 5.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Although urothelial cancer is more common in men, women with urothelial cancer have inferior survival outcomes. The potential existence of gender-related disparities in patients with metastatic urothelial cancer has not been extensively explored. PATIENTS AND METHODS: Individual patient data were pooled from 8 phase II and phase III trials evaluating first-line cisplatin-based combination chemotherapy in patients with metastatic urothelial carcinoma. Adverse events, treatment delivery, response proportions, and survival outcomes were compared between male and female patients. RESULTS: Of the 543 patients included in the analysis, 100 patients (18%) were women. There was no significant difference in the number of cycles of chemotherapy administered or in the proportions of patients experiencing severe toxicities when comparing male and female patients. There was no difference in the survival distributions between male and female patients (P = .08); the median survival of male patients was 11.7 months (95% confidence interval [CI], 10.5-13.2) compared with 16.2 months for female patients (95% CI, 12.8-20.4). There was no significant difference in survival between men and women when controlling for baseline performance status and/or the presence of visceral metastases. CONCLUSION: Female patients with metastatic urothelial cancer tolerate cisplatin-based chemotherapy similarly to male patients and achieve comparable clinical outcomes. Although gender-associated survival disparities in patients with metastatic urothelial cancer cannot be completely ruled out, if such disparities exist, they are unlikely related to tolerability or efficacy of chemotherapy.
    Clinical Genitourinary Cancer 05/2013; · 1.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: There have been no improvements in the treatment of metastatic urothelial cancer in the past several decades. A census of contemporary clinical research in this disease was performed to identify potential barriers and opportunities. METHODS: These authors performed a search for clinical trials exploring interventions in muscle-invasive and metastatic urothelial cancer, using the ClinicalTrials.gov registry. Data extracted from the registry included title, recruitment status, interventions, sponsor, phase, enrollment, study design, and study sites. RESULTS: Among 120 eligible trials exploring interventions in muscle-invasive and metastatic urothelial cancer, 73% were phase 2 and 73% were nonrandomized. The majority (63%) involved treatment in the metastatic disease state. The median planned enrollment size per trial was 45 patients (interquartile range, 47 patients). The majority of trials (55%) involved ≤ 3 study sites. Trials most commonly explored interventions in the first-line metastatic (30%) or second-line metastatic (37%) settings. Targeted therapeutics were studied in 58% of the trials. Among 56 trials that completed enrollment, the median time to complete accrual was 50 months (range, 10-109 months), and these trials enrolled a median of 40 patients per trial (interquartile range, 44 patients). CONCLUSIONS: The majority of contemporary clinical trials in muscle-invasive and metastatic urothelial cancer are small, nonrandomized, phase 2 trials involving 1 to 3 study sites. Enhanced communication and collaboration among the urothelial cancer community, and other stakeholders, is needed to facilitate the design and conduct of trials capable of expediting progress in this disease. Cancer 2013;. © 2013 American Cancer Society.
    Cancer 03/2013; · 5.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE: Cisplatin-based chemotherapy is standard first-line treatment for metastatic urothelial carcinoma. However, cisplatin is frequently avoided in elderly patients due to concerns regarding toxicities. We analyzed the efficacy, and tolerability, of cisplatin-based chemotherapy in elderly patients. METHODS: Individual patient data were pooled from 8 phase II and III trials evaluating cisplatin-based first-line chemotherapy in patients with metastatic urothelial carcinoma. Adverse events, treatment delivery, response proportions, and survival outcomes were compared between patients aged<70 vs.≥70 years. RESULTS: Of the 543 patients included, 162 patients (30%) were≥70 years old. The majority (93%) of elderly patients were aged 70 to 79 years. There was no significant difference in the proportions of patients experiencing Grade 3 to 4 renal failure, febrile neutropenia, or treatment-related death between younger and older patient cohorts. The median survival of the patients≥70 years was 12.1 months compared to 12.8 months for patients<70 years (P = 0.91). There was no significant difference in survival between age groups when controlling for baseline performance status or the presence of visceral metastases or both. CONCLUSIONS: Fit septuagenarians, with adequate renal function, tolerate cisplatin-based chemotherapy similarly to their younger counterparts and achieve comparable clinical outcomes.
    Urologic Oncology 02/2013; · 3.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Only in recent years have phospholipase A enzymes (PLAs) emerged as cancer targets. In this work, we report the first detection of elevated PLA activities in plasma from patients with colorectal, lung, pancreatic, and bladder cancers as compared to healthy controls. Independent sets of clinical plasma samples were obtained from two different sites. The first set was from patients with colorectal cancer (CRC; n = 38) and healthy controls (n = 77). The second set was from patients with lung (n = 95), bladder (n = 31), or pancreatic cancers (n = 38), and healthy controls (n = 79). PLA activities were analyzed by a validated quantitative fluorescent assay method and subtype PLA activities were defined in the presence of selective inhibitors. The natural PLA activity, as well as each subtype of PLA activity was elevated in each cancer group as compared to healthy controls. PLA activities were increased in late stage vs. early stage cases in CRC. PLA activities were not influenced by sex, smoking, alcohol consumption, or body-mass index (BMI). Samples from the two independent sites confirmed the results. Plasma PLA activities had approximately 70% specificity and sensitivity to detect cancer. The marker and targeting values of PLA activity have been suggested.
    PLoS ONE 01/2013; 8(2):e57081. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: Delivery of GCS was hampered by excessive toxicity in both advanced and neoadjuvant settings.
    Clinical Genitourinary Cancer 12/2012; · 1.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSESeveral reports suggest that cisplatin is associated with an increased risk of thromboembolism. However, because the excess risk of venous thromboembolic events (VTEs) with cisplatin-based chemotherapy has not been well described, we conducted a systemic review and meta-analysis of randomized controlled trials evaluating the incidence and risk of VTEs associated with cisplatin-based chemotherapy. METHODS PubMed was searched for articles published from January 1, 1990, to December 31, 2010. Eligible studies included prospective randomized phase II and III trials evaluating cisplatin-based versus non-cisplatin-based chemotherapy in patients with solid tumors. Data on all-grade VTEs were extracted. Study quality was calculated using Jadad scores. Incidence rates, relative risks (RRs), and 95% CIs were calculated using a random effects model.ResultsA total of 8,216 patients with various advanced solid tumors from 38 randomized controlled trials were included. The incidence of VTEs was 1.92% (95% CI, 1.07 to 2.76) in patients treated with cisplatin-based chemotherapy and 0.79% (95% CI, 0.45 to 1.13) in patients treated with non-cisplatin-based regimens. Patients receiving cisplatin-based chemotherapy had a significantly increased risk of VTEs (RR, 1.67; 95% CI, 1.25 to 2.23; P = .01). Exploratory subgroup analysis revealed the highest RR of VTEs in patients receiving a weekly equivalent cisplatin dose > 30 mg/m(2) (2.71; 95% CI, 1.17 to 6.30; P = .02) and in trials reported during 2000 to 2010 (1.72; 95% CI, 1.27 to 2.34; P = .01). CONCLUSION Cisplatin is associated with a significant increase in the risk of VTEs in patients with advanced solid tumors when compared with non-cisplatin-based chemotherapy.
    Journal of Clinical Oncology 11/2012; · 18.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cisplatin has been associated with an increased risk of arterial thromboembolic events (ATEs). However, because this association is mostly based on case reports and retrospective studies, we conducted a systemic review and meta-analysis of randomized controlled trials evaluating the incidence and risk of ATEs associated with cisplatin. Eligible studies included prospective randomized phase II and III trials evaluating cisplatin-based vs non-cisplatin-based chemotherapy in patients with solid tumors, which were identified from PubMed articles published between 1990 and 2010. Incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using a random effects model. A total of 8216 patients from 38 trials were included. Among patients treated with cisplatin-based chemotherapy, the summary incidence of ATEs was 0.67% (95% CI = 0.40% to 0.95%), and the RR of ATEs was 1.36 (95% CI = 0.86 to 2.17; P = .19). No increase in ATEs was detected in any prespecified subgroup.
    CancerSpectrum Knowledge Environment 10/2012; · 14.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Muscle-invasive bladder cancer (MIBC) is a disease with a pattern of predominantly distant and early recurrences. Neoadjuvant cisplatin-based combination chemotherapy has demonstrated improved outcomes for MIBC. To review the data supporting perioperative chemotherapy and emerging regimens for MIBC. Medline databases were searched for original articles published before April 1, 2012, with the search terms bladder cancer, urothelial cancer, radical cystectomy, neoadjuvant chemotherapy, and adjuvant chemotherapy. Proceedings from the last 5 yr of major conferences were also searched. Novel and promising drugs that have reached clinical trial evaluation were included. The major findings are addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed. Cisplatin-based neoadjuvant combination chemotherapy is an established standard, improving overall survival in MIBC. Pathologic complete response appears to be an intermediate surrogate for survival, but this finding requires further validation. Definitive data to support adjuvant chemotherapy do not exist, and there are no data to support perioperative therapy in cisplatin-ineligible patients. Utilization of neoadjuvant cisplatin is low, attributable in part to patient/physician choice and the advanced age of patients, who often have multiple comorbidities including renal and/or cardiac dysfunction. Trials are using the neoadjuvant paradigm to detect incremental pathologic response to chemobiologic regimens and brief neoadjuvant single-agent therapy to screen for the biologic activity of agents.
    European Urology 06/2012; 62(3):523-33. · 10.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKI) are now approved by regulatory agencies and are important in the treatment of solid tumor malignancies. The risk of fatal adverse events (FAEs) with these agents is not well characterized. PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating sunitinib, sorafenib, pazopanib, and vandetanib in patients with all malignancies. Thirteen eligible randomized controlled trials were included in a meta-analysis and the number of FAEs (defined by the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) criteria) was extracted and study quality was calculated. Incidence rates and relative risks were calculated for all thirteen studies as well as for the subset of patients with renal cell carcinoma. Analysis of the 5164 patients across 13 RCTs revealed that the relative risk was 1.64 (95% CI, 1.16, 2.32; P=0.01; incidence 2.26% vs. 1.26%) for the association of a VEGFR TKI with FAEs using a random-effects model. All exploratory subgroup analyses indicated a trend toward an increase risk of FAEs with VEGFR TKI treatment, though the subgroup analyses reached statistical significance for renal carcinoma studies, studies utilizing placebo as the control arm, and studies evaluating sorafenib. This analysis suggests that VEGFR TKIs are associated with a significant increase in the risk of FAEs in patients with advanced solid tumors.
    Cancer Treatment Reviews 05/2012; 38(7):919-25. · 6.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVES: More than 14,000 people die from invasive urothelial carcinoma (iUC) of the urinary bladder each year in the USA, and more effective therapies are needed. Naturally occurring canine iUC very closely resembles the disease in humans and serves as a highly relevant translational model for novel therapy of human iUC. Work was undertaken to identify new targets for anticancer therapy in dogs with the goal of translating successful therapeutic strategies into humans with iUC. MATERIALS AND METHODS: Microarray expression analyses were conducted on mRNA extracted from canine normal bladder (n = 4) and iUC tissues (n = 4) using Genome Array 1.0 and analyzed by GeneSpring GX 11, with the stringency of P < 0.02 and a ≥2-fold change. The genes thus identified were further analyzed for functional and pathway analysis using Protein ANalysis THrough Evolutionary Relationships (PANTHER) Classification System. In selecting genes for further study, consideration was given for evidence of a role of the gene in human iUC. From these analyses, DNA methyltransferase 1 (DNMT1) was selected for further study. Immunohistochemistry (IHC) of canine normal bladder and iUC tissues was performed to confirm the microarray expression analyses. The effects of targeting DNMT1 in vitro was assessed through MTT assay and Western blot of canine iUC cells treated with 5-azacitidine (5-azaC) and trichostatin A (TSA). RESULTS: DNMT1 was expressed in 0 of 6 normal canine bladder samples and in 10 of 22 (45%) canine iUC samples. The proliferation of canine iUC cells was inhibited by 5-azaC (at concentrations ≥5 μm) and by TSA (at concentrations ≥0.1 μm). Western blot results were supportive of DNMT1-related effects having a role in the antiproliferative activity. CONCLUSIONS: Microarray expression analyses on canine tissues identified DNMT1 as a potentially "targetable" gene. Expression of DNMT1 in canine iUC was confirmed by IHC, and in vitro studies confirmed that drugs that inhibit DNMT1 have antiproliferative effects. These findings are similar to those recently reported in human iUC and are also in line with results of a preclinical (prehuman) trial of 5-azaC in dogs with naturally occurring iUC. DNMT1 has excellent potential as a target for iUC therapy in humans.
    Urologic Oncology 05/2012; · 3.65 Impact Factor

Publication Stats

376 Citations
300.58 Total Impact Points

Institutions

  • 2005–2014
    • Indiana University-Purdue University Indianapolis
      • • Department of Urology
      • • Department of Medicine
      Indianapolis, Indiana, United States
  • 2012–2013
    • Mount Sinai School of Medicine
      • Division of Hematology and Medical Oncology
      Manhattan, New York, United States
    • Indiana University Health
      Bloomington, Indiana, United States
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
    • University of Texas Medical Branch at Galveston
      Galveston, Texas, United States
  • 2009–2013
    • Indiana University-Purdue University School of Medicine
      • Department of Medicine
      Indianapolis, Indiana, United States
  • 2011
    • Boston Medical Center
      Boston, Massachusetts, United States
    • Michael E. DeBakey VA Medical Center
      Houston, Texas, United States