Alex S. Baras

Pathologic response in patients receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer: Is therapeutic effect owing to chemotherapy or TURBT?

PURPOSEnWe estimated the proportion of patients who received neoadjuvant chemotherapy for muscle-invasive bladder cancer whose tumors were downstaged by transurethral resection.nnnMATERIALS AND METHODSnWe identified patients with cT2 N0 urothelial carcinoma who underwent cystectomy at our institution from 2005 to 2014-overall, 139 underwent transurethral resection without chemotherapy, and 146 underwent transurethral resection with chemotherapy. Pathologic response was defined as<pT2 N0. We used a Poisson regression model to determine relative risk (RR) of pathologic response in nonneoadjuvant vs. neoadjuvant patients, adjusting for demographic and clinical covariates. This RR was used to estimate the response attributable to transurethral resection.nnnRESULTSnNeoadjuvant patients were younger than nonneoadjuvant patients (64.4 vs. 71.4 years, P<0.01), with higher median body mass index (28.4 vs. 26.6kg/m2, P<0.01), lower prevalence of Charlson score≥3 (13.7% vs. 30.2%, P<0.01), and lower prevalence of prior non-muscle-invasive cancer (7.5% vs. 20.9%, P<0.01). More neoadjuvant patients achieved response compared with nonneoadjuvant patients (62.3% vs. 20.1%, RR = 3.10, P<0.01). Adjustment resulted in a RR of pathologic response in neoadjuvant vs. nonneoadjuvant patients of 2.60 (95% CI: 1.81-3.74, P<0.01). This adjusted RR indicates that among patients who receive neoadjuvant chemotherapy and undergo transurethral resection, 38% (95% CI: 27%-55%) of pathologic response can be attributed to transurethral resection.nnnCONCLUSIONSnWe estimate that in a cohort of patients who receive chemotherapy and undergo transurethral resection before cystectomy, 38% of pathologic response can be attributed to transurethral resection. Understanding who responds to chemotherapy and who responds to transurethral resection is needed to measure the effectiveness of both interventions.

Intravesical BCG Induces CD4+ T-cell expansion in an immune competent model of bladder cancer

Intravesical bacillus Calmette–Guéerin (BCG) instillations are standard of care for early stage bladder cancer. BCG was found to recruit T cells to the bladder, but their phenotype was unchanged, implying that combining T cell–activating agents with BCG might improve clinical activity. Intravesical bacillus Calmette–Guérin (BCG) immunotherapy is the standard of care in treating non–muscle-invasive bladder cancer, yet its mechanism of action remains elusive. Both innate and adaptive immune responses have been implicated in BCG activity. Although prior research has indirectly demonstrated the importance of T cells and shown a rise in CD4+ T cells in bladder tissue after BCG, T-cell subpopulations have not been fully characterized. We investigated the relationship between effector and regulatory T cells in an immune competent, clinically relevant rodent model of bladder cancer. Our data demonstrate that cancer progression in the N-methyl-N-nitrosourea (MNU) rat model of bladder cancer was characterized by a decline in the CD8/FoxP3 ratio, consistent with decreased adaptive immunity. In contrast, treatment with intravesical BCG led to a large, transient rise in the CD4+ T-cell population in the urothelium and was both more effective and immunogenic compared with intravesical chemotherapy. Whole-transcriptome expression profiling of posttreatment intravesical CD4+ and CD8+ T cells revealed minimal differences in gene expression after BCG treatment. Together, our results suggest that although BCG induces T-cell recruitment to the bladder, the T-cell phenotype does not markedly change, implying that combining T-cell–activating agents with BCG might improve clinical activity. Cancer Immunol Res; 5(7); 594–603. ©2017 AACR.

Defining the Added Value of 99mTc-MIBI SPECT/CT to Conventional Cross-Sectional Imaging in the Characterization of Enhancing Solid Renal Masses.

Purpose This study investigates whether the addition of preoperative 99mTc-MIBI SPECT/CT can increase the degree of diagnostic confidence in the differentiation of benign from malignant enhancing renal masses. Patients and Methods Patients were recruited as part of an institutional review board–approved prospective clinical trial. Forty-eight patients with clinical stage T1 solid renal masses who underwent a 99mTc-MIBI SPECT/CT before partial or radical nephrectomy were evaluated. Conventional CT and MRI, which were approximately performed within 8 weeks before 99mTc-MIBI, were retrospectively retrieved. Based on a 5-point scale (1 = definitely benign, 5 = definitely malignant), 2 blinded readers recorded their degree of confidence for each lesion using conventional imaging before and after reviewing the 99mTc-MIBI uptake ratios. Surgical pathology was considered as the reference standard. Results Additional review of 99mTc-MIBI SPECT/CT uptake ratios increased diagnostic confidence in the differentiation of solid renal masses in 14/48 lesions (29.2%). In 9 lesions, the addition of 99mTc-MIBI changed the initial confidence levels of malignancy toward benign diagnosis. Postsurgical pathology confirmed the diagnosis of benign histology (oncocytoma/hybrid oncocytic-chromophobe tumors) in 7 and chromophobe renal cell carcinoma (behave as indolent) in 2 of these lesions. 99mTc-MIBI increased the confidence level toward malignancy in 5 cases; all were confirmed as RCC on surgical pathology. The area under the receiver operative characteristic curve was 0.60 for conventional imaging alone and 0.85 after reviewing 99mTc-MIBI (P for difference = 0.03). Conclusions Preoperative 99mTc-MIBI SPECT/CT enhances the performance of conventional imaging, improving the characterization of benign histologies and lowering the possibility of misclassification.

Neoadjuvant Dose Dense MVAC versus Gemcitabine and Cisplatin in Patients with cT3-4aN0M0 Bladder Cancer Treated with Radical Cystectomy

Purpose: Level I evidence supports the usefulness of neoadjuvant cisplatin based chemotherapy for muscle invasive bladder cancer. Since dose dense MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) has mostly replaced traditional MVAC, we compared pathological response and survival rates in patients with locally advanced bladder cancer who received neoadjuvant chemotherapy with dose dense MVAC vs gemcitabine and cisplatin. Materials and Methods: We retrospectively reviewed the records of patients with urothelial cancer who received neoadjuvant chemotherapy and underwent cystectomy at a total of 20 contributing institutions from 2000 to 2015. Patients with cT3‐4aN0M0 disease were selected for this analysis. The rates of ypT0N0 and ypT1N0 or less were compared between the gemcitabine and cisplatin, and dose dense MVAC regimens. Two multivariable Cox proportional hazards regression models of overall mortality were generated using preoperative and postoperative data. Results: Of the patients who underwent neoadjuvant chemotherapy and radical cystectomy during the study period 319 met our inclusion criteria. A significantly lower rate of ypT0N0 was observed in the gemcitabine and cisplatin arm than in the dose dense MVAC arm (14.6% vs 28.0%, p = 0.005). The rate of ypT1N0 or less was 30.1% for gemcitabine and cisplatin compared to 41.0% for dose dense MVAC (p = 0.07). The mean Kaplan‐Meier estimates of overall survival in the gemcitabine and cisplatin, and dose dense MVAC groups were 4.2 and 7.0 years, respectively (p = 0.001). On multivariable cox regression analysis based on preoperative data patients who received gemcitabine and cisplatin were at higher risk for death than patients who received dose dense MVAC (HR 2.07, 95% CI 1.25–3.42, p = 0.003). Lymph node invasion (HR 1.97, 95% CI 1.15–3.36, p = 0.01) and hydronephrosis (HR 2.18, 95% CI 1.43–3.30, p <0.001) were also associated with higher risk of death. Conclusions: In our retrospective cohort of patients with locally advanced bladder cancer dose dense MVAC was associated with higher complete pathological response and improved survival rates compared to gemcitabine and cisplatin. A clinical trial is warranted to validate these hypothesis generating results to test the superiority of neoadjuvant dose dense MVAC in patients with locally advanced bladder cancer.

Abstract 1611: Intravesical BCG induces CD4 T Cell expansion in an immune competent model of bladder cancer

Intravesical BCG Immunotherapy is the standard of care in treating non-muscle invasive bladder cancer (NMIBC), yet its mechanism of action remains elusive. Both innate and adaptive immune responses have been implicated in BCG activity. While prior research has indirectly demonstrated the importance of T cells and shown a rise in CD4+ T cells in bladder tissue after BCG, T cell subpopulations have not been fully characterized. We investigated the relationship between effector and regulatory T cells in an immune competent, clinically relevant rodent model of bladder cancer. Fischer 344 rats aged 7 weeks received 1.5mg/kg N-Nitroso-N-methylurea (MNU) every other week for 6 weeks (4 doses). Bladder dysplasia began by week 8 and by week 16 the majority of rats had a NMIBC phenotype. Beginning week 8 following the first MNU dose, rats were intravesically administered 0.3ml of BCG (Tice), cisplatin (1mg/ml), Mitomycin C (2mg/ml), MMC+ BCG, or saline (n=10 for all groups) weekly for 6 total doses. Animals were sacrificed at week 16, and bladders were processed for histopathology and digested into single cell suspensions for flow cytometry. Whole transcriptome expression profiling was then performed on sorted CD4 and CD8 cells of post-BCG tumors vs untreated tumors to assess T cell differentiation after BCG. Our data demonstrate that cancer progression in the MNU rat model of bladder cancer is characterized by a decline in the CD8/FoxP3 ratio, consistent with decreased adaptive immunity. By contrast, treatment with intravesical BCG leads to a large, transient rise in the CD4+ T cell population in the urothelium, and is both more effective and immunogenic compared to intravesical chemotherapy. Interestingly, whole transcriptome expression profiling of post-treatment intravesical CD4+ and CD8+ T cells revealed minimal differences in gene expression after BCG treatment. Together, our results suggest that while BCG induces T cell recruitment to the bladder, the T cell phenotype does not markedly change, implying that combining T cell activating agents with BCG might improve clinical activity. Citation Format: Max Kates, Thomas Nirschl, Nikolai Sopko, Noah Hahn, David McConkey, Alex Baras, Charles Drake, Trintiy Bivalacqua. Intravesical BCG induces CD4 T Cell expansion in an immune competent model of bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1611. doi:10.1158/1538-7445.AM2017-1611

Accuracy of urethral frozen section during radical cystectomy for bladder cancer.

OBJECTIVEnOur objective was to determine the accuracy of urethral frozen section (FS) by analyzing our clinical experience.nnnMATERIALS AND METHODSnA total of 298 patients undergoing radical cystectomy for bladder cancer with benign or malignant urethral FS were identified between 2000 and 2012. Urethral FS were compared with rereviewed FS to calculate the positive and negative predictive values of the FS. To assess the ability of the positive FS to be cleared with further sampling/resection, FS were then compared with the final urethral margin. The cases of positive urethral FS were then specifically analyzed to assess rates of urethral recurrence and survival.nnnRESULTSnAll negative FS were confirmed to be negative on FS rereview and on final pathology, resulting in a NPV of 100%. Urethral FS were positive in 28 (8.7%) patients, of whom 2 (7%) were negative on FS rereview, yielding a positive predictive value of 93%. Both false positives were because of contamination of detached cancer from the bladder being present in the FS. After additional sampling/resection, the final margin was negative in 13 (46%) patients.nnnCONCLUSIONSnA negative urethral FS reliably identifies individuals for whom urethrectomy is unnecessary and provides robust information for decision-making regarding the safety of orthotopic reconstruction. Nearly half of the patients with a positive FS were ultimately determined to have a negative final margin. Accordingly, we recommend that surgeons and pathologists discuss positive FS findings at the time of surgery and consider whether additional tissue should be analyzed in real time.

Plasmacytoma of the larynx

Amyloid is an extracellular proteinaceous low-molecular-weight fibril. In the larynx, amyloid deposits usually represent a benign localized disease. Although laryngeal amyloidosis is an indolent lesion, amyloid deposition in the larynx may actually result from a lymphoproliferative disorder and not isolated amyloidosis. In this case report, we describe a patient referred for laryngeal amyloidosis who was subsequently diagnosed with extramedullary plasmacytoma of the larynx. The report discusses the presentation, diagnosis, and treatment provided. The importance of systemic workup and accurate tissue diagnosis in differentiating primary amyloidosis and secondary amyloid deposition will be highlighted.