H Barton Grossman

Concordia University–Ann Arbor, Ann Arbor, Michigan, United States

Are you H Barton Grossman?

Claim your profile

Publications (423)

  • Mario I. Fernández · Stephen B. Williams · Daniel L. Willis · [...] · Ashish M. Kamat
    [Show abstract] [Hide abstract] ABSTRACT: Objective: To analyze survival in clinically localized, surgically resectable micropapillary bladder cancer patients undergoing radical cystectomy with and without neoadjuvant chemotherapy and develop risk strata based on outcome data. Patients and methods: A review of our database identified 103 patients with surgically resectable (≤cT4acN0cM0) micropapillary bladder cancer who underwent radical cystectomy. Survival estimates were calculated using Kaplan-Meier method and compared using log-rank tests. Classification and regression tree analysis was performed to identify risk groups for survival. Results: For the entire cohort, estimated 5-year overall and disease-specific survival rates were 52% and 58%, respectively. Classification and regression tree analysis identified three risk subgroups: low-risk: cT1, no hydronephrosis; high-risk: ≥cT2, no hydronephrosis; and highest-risk: cTany with tumor-associated hydronephrosis. Five-year disease-specific survival for the low-, high-, and highest-risk groups were 92%, 51%, and 17%, respectively (p<0.001). Patients downstaged at radical cystectomy <pT1 regardless of the use of neoadjuvant chemotherapy had the best survival (5-year disease-specific survival rate, 96% vs. 45% for those not downstaged; p<0.001), while those who were not downstaged despite neoadjuvant chemotherapy had 5-year disease-specific survival of only 17%. Conclusion: In patients with surgically resectable micropapillary bladder cancer, neoadjuvant chemotherapy appears to confer benefit to patients with muscle-invasive disease without hydronephrosis while patients with cT1 disease present no reason to change standard practice of proceeding to upfront radical cystectomy. Patients with hydronephrosis do poorly regardless of treatment paradigm. However, further external validation studies are needed to support the proposed risk stratification before treatment recommendations can be made This article is protected by copyright. All rights reserved.
    Article · Oct 2016 · BJU International
  • [Show abstract] [Hide abstract] ABSTRACT: Rationale: Assessment of patients with asymptomatic microhematuria (aMh) has been a challenge to urologists for decades. The aMh is a condition with a high prevalence in the general population and also an established diagnostic indicator of bladder cancer. Acknowledging aMh needs to be assessed within a complex context, multiple guidelines have been developed to identify individuals at high risk of being diagnosed with bladder cancer. Material & methods: This structured review and consensus of the International Bladder Cancer Network (IBCN) identified and examined 9 major guidelines. These recommendations are partly based on findings from a long-term study on the effects of home dipstick testing, but also on the assumption that early detection of malignancy might be beneficial. Results: Despite similar designs, these guidelines differ in a variety of parameters including definition of aMh, rating of risks, use of imaging modalities, and the role of urine cytology. In addition, recommendations for further follow-up after negative initial assessment are controversial. In this review, different aspects for aMh assessment are analyzed based upon the evidence currently available. Discussion: We question whether adherence to the complicated algorithms as recommended by most guidelines is practical for routine use. Based upon a consensus, the authors postulate a need for better tools. New concepts for risk assessment permitting improved risk stratification and prepone cystoscopy before refined imaging procedures (computed tomography scan and magnetic resonance imaging) are suggested.
    Article · Sep 2016 · Urologic Oncology
  • [Show abstract] [Hide abstract] ABSTRACT: Background A phase 1b trial was conducted to evaluate the duration of interferon-alpha (IFNα) production after intravesical administration of recombinant adenovirus-mediated interferon α2b (Ad-IFN) formulated with the excipient Syn3. The primary aim was to determine whether a second instillation 3 days after initial treatment produced prolonged urinary IFN production. Methods The study enrolled seven patients who experienced recurrent non-muscle invasive bladder cancer after bacillus Calmette–Guerin therapy. Each treatment consisted of intravesical instillation of SCH721015 (Syn3) and Ad-IFN at a concentration of 3 × 1011 particles/mL to a total volume of 75 mL given on days 1 and 4. The patients were followed for 12 weeks, during which the magnitude and duration of gene transfer were determined by urine INFα levels. Drug efficacy was determined by cystoscopy and biopsy, and patients who had no recurrence at 12 weeks were eligible for a second course of treatment. Results Seven patients were treated with an initial course (instillation on days 1 and 4). Two of the patients had a complete response at 12 weeks and received a second course of treatment. One patient remained without evidence of recurrence after a second course (total 24 weeks). One patient experienced a non-treatment-associated adverse event. Despite a transient rise in IFNα levels, sustained production was not demonstrated. Conclusion Previously, Ad-IFNα intravesical therapy has shown promising drug efficacy. A prior phase 1 trial with a single instillation compared similarly with the current study, suggesting that a second instillation is not necessary to achieve sufficient urinary IFNα levels.
    Article · Jul 2016 · Annals of Surgical Oncology
  • H. Barton Grossman · Donald L. Lamm · Ashish M. Kamat · [...] · Molly A. Ingersoll
    [Show abstract] [Hide abstract] ABSTRACT: Bladder cancer is understudied despite its high prevalence and its remarkable response to immunotherapy. Indeed, funding for studies to explore mechanisms of tumor immunity and novel new therapeutics is disproportionately lower for bladder cancer in comparison with malignancies of the breast, prostate, or lung. However, the recent successes of checkpoint blockade therapy suggest that new therapeutic strategies are on the horizon for bladder cancer. Here, we give a perspective into the evolution of bladder cancer therapy, focusing on strategies to treat high-risk nonmuscle invasive disease, followed by a discussion of recent advances in the treatment of muscle invasive bladder cancer and their potential applicability to lower stage disease. Finally, we explore immunotherapeutic strategies, which have been demonstrated to be successful in the treatment of other malignancies, for their potential to treat and cure patients with nonmuscle and muscle invasive bladder cancer.
    Article · Jul 2016 · Journla of Immunotherapy
  • [Show abstract] [Hide abstract] ABSTRACT: Objective: Non-muscle-invasive bladder cancer (NMIBC) comprises a wide spectrum of tumors with different behaviors and prognoses. It follows that the surveillance for these tumors should be adapted according to the risks of recurrence and progression and should be dynamic in design. Methods and materials: Medline search was conducted from 1980 to 2016 using a combination of MeSH and keyword terms. The highest available evidence was reviewed to define different risk groups in NMIBC. The performance of different follow-up tools such as urine cytology, cystoscopy, and upper tract imaging in detecting bladder carcinoma was assessed. Different commercially available urinary markers were investigated to determine whether such markers would contribute to the surveillance of patients with NMIBC. A follow-up scheme based on the early evidence is proposed. Results: A risk-based approach is paramount. Cystoscopy and cytology are recommended to be done at 3 months following transurethral resection of bladder tumor. For low-risk tumors, annual cystoscopy alone is sufficient; no upper tract evaluations or cytology is needed except at diagnosis. High-risk tumors should be followed up with a more intense schedule: cystoscopy every 3 months for 2 years, 6 months for 2 years, and then annually, with cytology at frequent intervals, and imaging for upper tract evaluation at 1 year and then every 2 years. Intermediate-risk tumors should be subclassified as per the International Bladder Cancer Group recommendations and when associated with 3 or more of the following findings (multiple tumors, size≥3cm, early recurrence<1 year, frequent recurrences>1 per year) then a surveillance strategy similar to that of high risk should be followed. Several urine markers were more sensitive than cytology in the detection of NMIBC; however, these tests are still costly, require specialized laboratories, and do not replace cystoscopy. Until better and cheaper markers are available, their routine use has not been integrated in the follow-up recommendation of current guidelines. Conclusions: Surveillance of NMIBC should follow a risk-adapted approach, with a combination of cystoscopy, cytology, and upper tract imaging. The aim of this approach is to minimize the therapeutic burden of a disease with high recurrence rates without missing progressing tumors. When designing a diagnostic pathway, first-line diagnostic imaging tests should have high sensitivity to ensure disease positives are included in the test population for further investigation. Second-line investigations should be highly specific, to ensure false-positives are minimized.
    Article · Jun 2016 · Urologic Oncology
  • Source
    Ashish M. Kamat · Michael Cookson · J. Alfred Witjes · [...] · H. Barton Grossman
    [Show abstract] [Hide abstract] ABSTRACT: Background: The International Bladder Cancer Group (IBCG) recently proposed a new definition of disease progression in non-muscle invasive bladder cancer (NMIBC), including change in T-stage, change to T2 or higher or change from low to high grade. Objective: To establish whether blue light cystoscopy with hexaminolevulinate (HAL) impacts the rate of progression and time to progression using the revised definition. Methods: An earlier long-term follow-up of a controlled Phase III study reported outcomes following blue light cystoscopy with HAL (255 patients) or white light (WL) cystoscopy (261 patients) in NMIBC patients. The data was re-analysed according to the new definition. Results: In the original analysis, after 4.5 years (median), eight HAL and 16 WL patients were deemed to have progressed (transition from NMIBC to muscle invasive bladder cancer, (T2-4)). According to the new definition, additional patients in both groups were found to have progressed: 31 (12.2%) HAL vs 46 (17.6%) WL (p = 0.085) with four (1.6%) HAL and 11 (4.2%) WL patients progressing from Ta to CIS. Time to progression was longer in the HAL group (p = 0.05). Conclusions: Applying the new IBCG definition there was a trend towards a lower rate of progression in HAL patients, particularly in those progressing from Ta to CIS. Time to progression was significantly prolonged. This suggests that patients should receive blue light cystoscopy with HAL rather than WL at resection. Adoption of the new definition could allow more patients at risk of progression to be treated appropriately earlier.
    Full-text available · Article · Apr 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Recurrence with papillary tumor(s) by 3-mo after induction bacillus Calmette-Guérin (BCG) is historically believed to be a poor prognostic indicator in patients with high-risk non-muscle invasive bladder cancer. However, the impact of a clinical Ta (cTa) papillary recurrence at 3 mo after BCG is often debated. Objective: To evaluate the prognostic implications of cTa papillary recurrence found 3 mo after induction BCG therapy and to evaluate its significance in clinical trial design. Design, setting, and participants: We reviewed our database of 917 patients who underwent transurethral resection and induction of BCG from 1995 to 2012. Clinical characteristics were compared between 3-mo recurrence stages. Intervention: Transurethral resection of bladder tumor and intravesical therapy. Outcome measurements and statistical analysis: Chi-square analysis and Student t test were used to compare clinical characteristics between 3-mo recurrence stages. Kaplan-Meier method was used to determine bladder-preservation time, progression-free survival, and disease-specific survival. Results and limitations: We identified 84 patients who met the study criteria (66 patients with cTa and 18 patients with clinical T1 [cT1]). The median follow-up for the entire cohort was 74 mo. Of the patients with cTa recurrence, 60 continued with bladder-sparing therapy. Patients with a high-grade cTa recurrence who continued bladder-sparing therapy had a 17% incidence of disease progression and a 62% incidence of recurrence within 1 yr. No patients with low-grade cTa recurrence (n=13) developed disease progression or underwent radical cystectomy. Patients with an initial cTa at diagnosis had a higher 5-yr bladder preservation rate than those with an initial cT1 diagnosis (84% vs 61%; p=0.041). Patients with high-grade cTa recurrence and those with cT1 recurrence had similar outcomes with respect to death rates over the entire follow-up period (11% and 15%, respectively), as well as 5-yr progression-free survival (77% vs 83%). Limitations include using a single institution and a retrospective review. Conclusions: Patients with low-grade cTa papillary recurrence 3 mo after induction of BCG can safely continue with bladder-sparing therapy. Patients with high-grade cTa papillary recurrence at that time have risks of recurrence and progression similar to those of patients with cT1 recurrence. These are important factors to consider during clinical trial design. Patient summary: Low-grade clinical Ta papillary recurrence following induction of bacillus Calmette-Guérin therapy can be safely managed conservatively, although a high-grade clinical Ta recurrence should be treated similar to a clinical T1 recurrence due to its comparable progression rates.
    Article · Feb 2016 · European Urology
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: The response of non-muscle-invasive bladder cancer (NMIBC) to intravesical immunotherapy with bacillus Calmette-Guérin (BCG) depends on adequate stimulation of an immune response. Although BCG has been used for decades, we lack tools to accurately predict response in individual patients. To address this deficiency, we initiated a clinical trial in patients with intermediate- and high-risk NMIBC. BCG was administered according to the Southwest Oncology Group protocol. Urine samples were collected for cytokine assay at baseline, immediately before and after BCG instillation at 6 wk, and immediately before and after the third BCG instillation of the first maintenance course. Levels of 12 cytokines were measured, and changes from baseline were calculated after treatment. A total of 130 patients were enrolled. Increases in single cytokines correlated with recurrence, but the best predictor of recurrence was changes in a combination of cytokines. A nomogram (CyPRIT) constructed using urinary levels of nine inducible cytokines (IL-2, IL-8, IL-6, IL-1ra, IL-10, IL-12[p70], IL-12[p40], TRAIL, and TNF-α) predicted the likelihood of recurrence with 85.5% accuracy (95% confidence interval 77.9-93.1%). This cytokine panel and nomogram have potential for identifying patients at risk of tumor recurrence during BCG treatment to guide modification of the dose and duration of BCG immunotherapy. Clinicaltrials.gov NCT01007058. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    Full-text available · Article · Jun 2015 · European Urology
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: Objectives To present a (molecular) definition of BCG failure which incorporates fluorescence in situ hybridization (FISH) testing to predict BCG failure before it becomes clinically evident.This will help in trial designs for patients with non-muscle invasive bladder cancer (NMIBC) who fail BCG and thus lack an adequate control arm other than radical cystectomy.Patients and Methods We used data from 143 patients were followed prospectively for 2 years during intravesical BCG therapy during which time FISH assays were collected and correlated to clinical outcomes.ResultsOf the 95 patients with no evidence of tumor at 3-month cystoscopy, 23 developed tumor recurrence, and 17 developed disease progression by 2 years.Patients with a positive FISH at both 6-weeks and 3-months were more likely to develop tumor recurrence (17/37, 46% and 16/28, 57%, respectively) compared to patients with a negative FISH (6/58, 10% and 3/39, 8%, respectively) (both: p<0.001).Using hazard ratios for recurrence with positive 6-week and 3-month FISH results, we constructed clinical trial scenarios whereby patients with a negative 3-month cystoscopy and positive FISH result could be considered to have “molecular BCG failure” and enrolled in prospective, randomized clinical trials comparing BCG therapy (control) with an experimental intravesical therapy.Conclusions Patients with positive early FISH and negative 3-month cystoscopy results can be considered to have molecular BCG failure based on their high rates of recurrence and progression.This is intended for use in designing clinical trials, thus potentially allowing continued use of BCG as an ethical comparator arm.This article is protected by copyright. All rights reserved.
    Full-text available · Article · Jun 2015 · BJU International
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: Urothelial bladder cancer is a highly heterogeneous disease. Cancer cell lines are useful tools for its study. This is a comprehensive genomic characterization of 40 urothelial bladder carcinoma (UBC) cell lines including information on origin, mutation status of genes implicated in bladder cancer (FGFR3, PIK3CA, TP53, and RAS), copy number alterations assessed using high density SNP arrays, uniparental disomy (UPD) events, and gene expression. Based on gene mutation patterns and genomic changes we identify lines representative of the FGFR3-driven tumor pathway and of the TP53/RB tumor suppressor-driven pathway. High-density array copy number analysis identified significant focal gains (1q32, 5p13.1-12, 7q11, and 7q33) and losses (i.e. 6p22.1) in regions altered in tumors but not previously described as affected in bladder cell lines. We also identify new evidence for frequent regions of UPD, often coinciding with regions reported to be lost in tumors. Previously undescribed chromosome X losses found in UBC lines also point to potential tumor suppressor genes. Cell lines representative of the FGFR3-driven pathway showed a lower number of UPD events. Overall, there is a predominance of more aggressive tumor subtypes among the cell lines. We provide a cell line classification that establishes their relatedness to the major molecularly-defined bladder tumor subtypes. The compiled information should serve as a useful reference to the bladder cancer research community and should help to select cell lines appropriate for the functional analysis of bladder cancer genes, for example those being identified through massive parallel sequencing.
    Full-text available · Article · May 2015 · BMC Genomics
  • Source
    Full-text available · Article · Apr 2015 · The Journal of Urology
  • Source
    Mario I. Fernandez · Stephen B. Williams · Daniel L. Willis · [...] · Ashish M. Kamat
    Full-text available · Article · Apr 2015 · The Journal of Urology
  • Source
    Full-text available · Article · Apr 2015 · The Journal of Urology
  • Ashish M Kamat · Thomas W Flaig · H Barton Grossman · [...] · John A Taylor
    [Show abstract] [Hide abstract] ABSTRACT: Multiple clinical trials have demonstrated that intravesical Bacillus Calmette-Guérin (BCG) treatment reduces recurrences and progression in patients with non-muscle-invasive bladder cancer (NMIBC). However, although BCG has been in use for almost 40 years, this agent is often underutilized and practice patterns of administration vary. This neglect is most likely caused by uncertainties about the optimal use of BCG, including unawareness of optimal treatment schedules and about patient populations that most benefit from BCG treatment. To address this deficit, a focus group of specialized urologic oncologists (urologists, medical oncologists and radiation oncologists) reviewed the current guidelines and clinical evidence, discussed their experiences and formed a consensus regarding the optimal use of BCG in the management of patients with NIMBC. The experts concluded that continuing therapy with 3-week BCG maintenance is superior to induction treatment only and is the single most important factor in improving outcomes in patients with NMIBC. They also concluded that a reliable alternative to radical cystectomy in truly BCG-refractory disease remains the subject of clinical trials. In addition, definitions for common terms of BCG failure, such as BCG-refractory and BCG-intolerant, have been formulated.
    Article · Mar 2015 · Nature Reviews Urology
  • Source
    File available · Dataset · Jan 2015
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 × 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (Ptrend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. Cancer Res; 74(20); 5808-18. ©2014 AACR.
    Full-text available · Article · Oct 2014 · Cancer Research
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: Objective: Diagnosis and surveillance of high risk non muscle-invasive bladder cancer (NMIBC) represent specific challenges to urologists. In contrast to low/intermediate risk tumors, these tumors recur more frequently. A significant number will eventually progress to muscle-invasive bladder cancer, a life threatening disease requiring extensive therapeutic efforts. Although clinical risk factors have been identified that may predict tumor recurrence and progression, additional biomarkers are desperately needed to improve tumor diagnosis and guide clinical management of these patients. In this article, the role of molecular urine markers in the management of high risk NMIBC is analyzed. Methods: In this context, several potential indications (diagnostic, prognostic, predictive) were identified and the requirements for molecular markers were defined. In addition, current knowledge within the different indications was summarized. Results: Significant progress has been made in the last decade studying the impact of molecular urine markers in patients with high risk NMIBC. Conclusions: Although we may not be ready for the inclusion of molecular markers in clinical decision-making, and many questions remain unanswered, recent studies have identified situations in which the use of molecular markers in particular in high grade tumors may prove beneficial for patient diagnosis and surveillance.
    Full-text available · Article · Oct 2014 · Urologic Oncology
  • Article · Oct 2014 · Cancer Research
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: Hexaminolevulinate (HAL) is a tumour photosensitizer that is used in combination with blue-light cystoscopy (BLC) as an adjunct to white-light cystoscopy (WLC) in the diagnosis and management of non-muscle-invasive bladder cancer (NMIBC). Since being licensed in Europe in 2005, HAL has been used in >200,000 procedures, with consistent evidence that it improves detection compared with WLC alone. Current data support an additional role in the reduction of recurrence of NMIBC. Since the approval of HAL by the FDA in 2010, experience of HAL-BLC in the USA continues to expand. To define areas of need and to identify the benefits of HAL-BLC in clinical practice, a focus group of expert urologists specializing in the management of patients with bladder cancer convened to review the clinical evidence, share their experiences and reach a consensus regarding the optimal use of HAL-BLC in the USA. The focus group concluded that HAL-BLC should be considered for initial assessment of NMIBC, surveillance for recurrent tumours, diagnosis in patients with positive urine cytology but negative WLC findings, and for tumour staging.
    Full-text available · Article · Sep 2014 · Nature Reviews Urology
  • Source
    Daniel L. Willis · Mario I. Fernandez · Rian J. Dickstein · [...] · Ashish M. Kamat
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: While many urologists recommend radical cystectomy for micropapillary bladder cancer invading the lamina propria (cT1), contradictory small reports exist on the efficacy of conservative management with intravesical bacillus Calmette-Guérin for this disease. We report our updated experience in what to our knowledge is the largest series of patients with cT1 micropapillary bladder cancer. Materials and methods: An institutional review board approved review of our cancer database identified 283 patients with micropapillary bladder cancer, including 72 staged with cT1N0M0 disease at diagnosis and initiation of therapy. Survival analysis was performed using the Kaplan-Meier estimator and compared using the log rank test. Results: In this cohort of 72 patients 40 received primary intravesical bacillus Calmette-Guérin and 26 underwent up-front radical cystectomy. Of patients who received bacillus Calmette-Guérin 75%, 45% and 35% experienced disease recurrence, progression and lymph node metastasis, respectively. Patients treated with up-front cystectomy had improved survival compared to patients treated with primary bacillus Calmette-Guérin (5-year disease specific survival 100% vs 60% p = 0.006) and patients who underwent delayed cystectomy after recurrence (5-year disease specific survival 62%, p = 0.015). Prognosis was especially poor in patients who waited for progression before undergoing radical cystectomy with an estimated 5-year disease specific survival of only 24% and a median survival of 35 months. In patients treated with up-front cystectomy pathological up-staging was found in 27%, including 20% with lymph node metastasis. Conclusions: While certain patients with T1 micropapillary bladder cancer may respond to intravesical bacillus Calmette-Guérin, survival is improved in those who undergo early radical cystectomy. Further molecular studies are needed to identify subsets of patients in whom the bladder can be safely spared.
    Full-text available · Article · Sep 2014 · The Journal of Urology

Publication Stats

15k Citations


  • 2007
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2003-2004
    • University of Texas MD Anderson Cancer Center
      • • Department of Epidemiology
      • • Department of Urology
      Houston, TX, United States
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1997
    • University of Rochester
      Rochester, New York, United States
  • 1993
    • University of Michigan
      • Department of Surgery
      Ann Arbor, Michigan, United States