Browsing by Author "Guzzo, Thomas J"

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    ItemOpen Access
    30-day readmission after radical cystectomy: Identifying targets for improvement using the phases of surgical care
    (Canadian Urological Association Journal) Berger, Ian; Xia, Leilei; Wirtalla, Christopher; Dowzicky, Phillip; Guzzo, Thomas J; Kelz, Rachel R
    Introduction: Postoperative readmissions following radical cystectomy (RC) have gained attention in the past decade. Postoperative and post-discharge complications play a role in readmission rates; however, our ability to predict readmissions remains poor.Methods: Using the National Surgical Quality Improvement Program database, we identified patients with bladder cancer undergoing RC from 2013–2015. Complications were defined as postoperative and post-discharge. Outcomes were 30-day readmission, post-discharge complications, and post-discharge major complications. Patient, operative, and complication factors were assessed using multivariable logistic regression.Results: We identified 4457 patients who underwent RC; 9.2% of patients experienced a postoperative complication, 18.8% experienced a post-discharge complication, and 20.3% were readmitted. Overweight and obese body mass index (BMI), dependent functional status, chronic obstructive pulmonary disease (COPD), a continent diversion, and duration of operation were associated with post-discharge complications. Postoperative complications were not associated with post-discharge complications. Readmission was associated with Black race (odds ratio [OR] 1.5; 95% confidence interval [CI] 1.0–2.1), overweight (OR 1.5; 95% CI 1.2–1.8) and obese BMI (OR 1.5; 95% CI 1.2–1.9), diabetes (OR 1.2; 95% CI 1.0–1.5), COPD (OR 1.4; 95% CI 1.0–1.8), steroid use (OR 1.5; 95% CI 1.0–2.2), a continent diversion (OR 1.4; 95% CI 1.1–1.7), duration of operation (OR 1.1; 95% CI 1.1–1.2), and postoperative complications (OR 1.5; 95% CI 1.2–2.0). The majority of readmissions experienced a post-discharge complication.Conclusions: Factors that span the preoperative, intraoperative, postoperative, and post-discharge phases of care were identified to increase readmission risk. To improve readmission rates, interventions will have to target factors across the surgical experience.
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    Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.
    (European urology, 2021-12-18) Mitra, Anirban P; Narayan, Vikram M; Mokkapati, Sharada; Miest, Tanner; Boorjian, Stephen A; Alemozaffar, Mehrdad; Konety, Badrinath R; Shore, Neal D; Gomella, Leonard G; Kamat, Ashish M; Bivalacqua, Trinity J; Montgomery, Jeffrey S; Lerner, Seth P; Busby, J Erik; Poch, Michael; Crispen, Paul L; Steinberg, Gary D; Schuckman, Anne K; Downs, Tracy M; Svatek, Robert S; Mashni, Joseph; Lane, Brian R; Guzzo, Thomas J; Bratslavsky, Gennady; Karsh, Lawrence I; Woods, Michael E; Brown, Gordon A; Canter, Daniel; Luchey, Adam; Lotan, Yair; Krupski, Tracey; Inman, Brant A; Williams, Michael B; Cookson, Michael S; Keegan, Kirk A; Andriole, Gerald L; Sankin, Alexander I; Boyd, Alan; O'Donnell, Michael A; Philipson, Richard; Ylä-Herttuala, Seppo; Sawutz, David; Parker, Nigel R; McConkey, David J; Dinney, Colin PN
    A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.
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    Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.
    (The Lancet. Oncology, 2020-11-27) Boorjian, Stephen A; Alemozaffar, Mehrdad; Konety, Badrinath R; Shore, Neal D; Gomella, Leonard G; Kamat, Ashish M; Bivalacqua, Trinity J; Montgomery, Jeffrey S; Lerner, Seth P; Busby, Joseph E; Poch, Michael; Crispen, Paul L; Steinberg, Gary D; Schuckman, Anne K; Downs, Tracy M; Svatek, Robert S; Mashni, Joseph; Lane, Brian R; Guzzo, Thomas J; Bratslavsky, Gennady; Karsh, Lawrence I; Woods, Michael E; Brown, Gordon; Canter, Daniel; Luchey, Adam; Lotan, Yair; Krupski, Tracey; Inman, Brant A; Williams, Michael B; Cookson, Michael S; Keegan, Kirk A; Andriole, Gerald L; Sankin, Alexander I; Boyd, Alan; O'Donnell, Michael A; Sawutz, David; Philipson, Richard; Coll, Ruth; Narayan, Vikram M; Treasure, F Peter; Yla-Herttuala, Seppo; Parker, Nigel R; Dinney, Colin PN

    Background

    BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer.

    Methods

    In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849.

    Findings

    Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths.

    Interpretation

    Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state.

    Funding

    FKD Therapies Oy.
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    Next-day discharge after minimally invasive partial nephrectomy: an analysis of the US National Surgical Quality Improvement Program
    (World Journal of Urology, 2019-05) Berger, Ian; Xia, Leilei; Sperling, Colin; Chelluri, Raju; Taylor, Benjamin; Pulido, Jose; Guzzo, Thomas J