Papillary Disease Research Articles

SunRISe-1: Phase 2b study of TAR-200 plus cetrelimab, TAR-200 alone, or cetrelimab alone in participants with high-risk nonmuscle-invasive bladder cancer unresponsive to Bacillus Calmette-Guérin who are ineligible for or decline radical cystectomy.

TPS593 Background: Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) unresponsive to intravesical bacillus Calmette–Guérin (BCG). TAR-200 is an intravesical drug delivery system for local continuous release of gemcitabine within the bladder. The current study will assess the rate of complete response (CR) upon treatment with TAR-200 + systemic cetrelimab (CET [anti–PD-1 antibody]), TAR-200, and CET in BCG-unresponsive participants with HR-NMIBC who are ineligible for or decline radical cystectomy (RC). Methods: SunRISe-1 (NCT04640623) is an open-label, parallel-group, multicenter phase 2b study designed to assess the efficacy and safety of TAR-200 + CET, TAR-200 alone, and CET alone in participants with BCG-unresponsive HR-NMIBC. Eligible participants are aged ≥ 18 years with ECOG PS 0, 1, or 2 and recurrent or persistent histologically confirmed HR-NMIBC (carcinoma in situ) with or without papillary disease (T1, high-grade Ta), who have been diagnosed within 12 months of last BCG treatment and are ineligible for or declined RC. Participants (N≈200) are randomized 2:1:1 to receive TAR-200 + CET (Cohort 1, n≈100), TAR-200 (Cohort 2, n≈50), or CET (Cohort 3, n≈50). In Cohorts 1 and 2, participants receive intravesical TAR-200 every 3 weeks through Week 24, and every 12 weeks thereafter until Week 96. In Cohorts 1 and 3, participants receive CET until Week 78. Primary disease assessments (cystoscopy, urine cytology, transurethral resection of bladder tumor [TURBT], and magnetic resonance imaging/computed tomography) are made at baseline; subsequent cystoscopy and centrally read urine cytology are performed every 12 weeks through Year 2, every 24 weeks until end of Year 3, and in Year 4 and Year 5 in accordance with institutional standards of care. TURBT is conducted at 24 and 48 weeks. The primary end point for the 3 cohorts is overall CR rate at any time point. Secondary end points include duration of response (ie, from time of first CR achieved to first evidence of recurrence, progression, or death [whichever is earlier] for participants who achieve a CR), overall survival, PK immunogenicity of cetrelimab, safety and tolerability, and patient-reported outcomes. Exploratory end points include incidence and time to cystectomy (measured from randomization to date of cystectomy), biomarkers, and health care resource utilization. This study opened in January 2021 and is enrolling participants at ≈165 study sites worldwide. Currently, the study is active in 13 countries with 12 participants enrolled as of September 12, 2021. Clinical trial information: NCT04640623.

Biomechanical engineering analysis of an acute papillary muscle rupture disease model using an innovative 3D-printed left heart simulator.

OBJECTIVESThe severity of acute papillary muscle (PM) rupture varies according to the extent and site of the rupture. However, the haemodynamic effects of different rupture variations are still poorly understood. Using a novel ex vivo model, we sought to study acute PM rupture to improve clinical management.METHODSUsing porcine mitral valves (n = 32) mounted within an ex vivo left heart simulator, PM rupture was simulated. The mitral valve was divided into quadrants for analysis according to the PM heads. Acute PM rupture was simulated by incrementally cutting from 1/3 to the total number of chordae arising from 1 PM head of interest. Haemodynamic parameters were measured.RESULTSRupture >2/3 of the chordae from 1 given PM head or regurgitation fraction >60% led to markedly deteriorated haemodynamics. Rupture at the anterolateral PM had a stronger negative effect on haemodynamics than rupture at the posteromedial PM. Rupture occurring at the anterior head of the anterolateral PM led to more marked haemodynamic instability than rupture occurring at the other PM heads.CONCLUSIONSThe haemodynamic effects of acute PM rupture vary considerably according to the site and extent of the rupture. Rupture of ≤2/3 of chordae from 1 PM head or rupture at the posteromedial PM lead to less marked haemodynamics effects, suggesting a higher likelihood of tolerating surgery. Rupture at the anterolateral PM, specifically the anterior head, rupture of >2/3 of chordae from 1 PM head or regurgitation fraction >60% led to marked haemodynamic instability, suggesting the potential benefit from bridging strategies prior to surgery.

PCN349 Healthcare Resource Use (HCRU) of NON-Muscle Invasive Bladder Cancer (NMIBC) Patients Post Bacillus Calmette-Guérin (BCG)-Unresponsive Status in Multiple Countries

BCG is the standard-of-care treatment for NMIBC patients. However, many patients become BCG unresponsive with few options for subsequent treatment other than cystectomy. We evaluated HCRU in these patients, as little evidence is available. A retrospective chart review was conducted in five European countries, US, China, and Japan from January to May 2019. Urologists and medical/clinical oncologists abstracted data for BCG-unresponsive patients. BCG-unresponsive status was defined as having at least one of: persistent or recurrent carcinoma in situ (CIS) alone or with recurrent Ta/T1 disease within 12 months of completion of adequate BCG therapy; recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG therapy; T1 high-grade disease at the first evaluation following an induction BCG course. HCRU data included physician visits, tests, procedures, and hospitalisations from the time patients were classified as BCG-unresponsive. 508 physicians abstracted data for 2,554 patients. Mean patient age was 72 years and 77% were male. 60% had a current ECOG of 0-1, and staging at diagnosis were CIS alone (34%), papillary disease only (34%), and papillary with CIS (32%). Since BCG-unresponsive status, patients visited their treating physician and PCP most frequently (mean 4.6 and 1.6 visits, respectively) and most patients (92%) underwent tests/procedures related to NMIBC. Most commonly, 75% of patients received CT scans, 50% underwent urine cytology tests and 41% TURBT. 43% were hospitalised, with 59% of these requiring ≥3 nights in hospital. The most common reasons for hospitalisation were standard procedure (49%), intractable gross haematuria (23%) and treating a complication (22%). 34% of patients were admitted through ER. Current management approaches resulted in considerable HCRU demand post BCG-unresponsive status. Most patients required multiple tests/procedures and a high proportion required overnight hospitalisations, which highlights the need for effective treatment and management strategies.

Second-Line Conservative Device-Assisted Intravesical Treatment in Selected Patients With Recurrent High-Risk Non-Muscle-Invasive Bladder Cancer.

In cases of recurrent high-risk non-muscle-invasive bladder cancer, radical cystectomy (RC) is recommended. We compared oncologic and treatment-related outcomes of second-line conservative device-assisted therapy to RC. In a retrospective cohort study, we analyzed 209 consecutive patients with recurrent bacillus Calmette-Guérin-unresponsive high-risk non-muscle-invasive bladder cancer; 107 subjects refused RC and were offered electromotive drug administration (n= 44) or chemohyperthermia (n= 63) (group A), and 102 patients underwent RC (group B). In group A, patients who did not benefit from device-assisted treatment underwent RC. The endpoints were high-grade disease-free survival, progression-free survival, cancer-specific survival, overall survival, and treatment-related complications. Follow-up was based on international guideline recommendations. Analyses were performed with log-rank and Fisher exact tests. The median follow-up was 59 months (SD ± 5.3). When comparing group A to B, overall survival rates were 91.6% and 90.2%, respectively (P > .05); cancer-specific survival was 94.4% and 96.1%, respectively (P > .05); high-grade disease-free survival was 43% and 74.5%, respectively (P< .05); and progression-free survival was 59.8% and 75.5%, respectively (P< .05). Patients with carcinoma-in-situ had worse oncologic outcomes compared to patients with papillary disease. In the multivariate analysis, multifocality, disease recurrence, and progression risk group were independently associated with device treatment failure. The 90-day RC-related overall complications rates were 63.9% in group A and 66.6% in group B (P= .63); grade 3 to 5 complications were 9.8% in group A and 9.8% in group B(P= .99). Complications within group A were comparable (P > .05). Device-assisted treatment may a represent a valid second-line conservative tool in selected patients with recurrent high-risk non-muscle-invasive bladder cancer.

Abstract IA21: Intravesical gene therapy for NMIBC

Abstract BCG is our most effective therapy for treating NMIBC, but over time, most patients will eventually recur. Alternative therapies to avoid cystectomy are needed as to date, only valrubicin, with a CR approaching 10% at 12 months in BCG-refractory CIS, has been FDA approved. Significant unmet need thus remains for an effective second-line therapy for patients facing cystectomy. The elucidation of a pathway for registration of new agents for BCG-unresponsive NMIBC has drawn the attention of pharma, and a variety of new approaches are under evaluation. Gene therapy is a promising approach for the management of BCG-unresponsive NMIBC. Effective gene transfer across the urothelium has been accomplished, and several agents are being evaluated in ongoing clinical trials. Coldgenesys reported a 47% CR at 6 months for BCG-unresponsive NMIBC using a replication-competent oncolytic adenovirus. The SUO CTC reported a 35% RFS at 12 months for patients treated with rAd-IFNα2b/Syn3 gene therapy in a phase II trial. The RFS for patients with papillary disease was 50% and the CR for patients with CIS was 30%. The SUO-CTC have recently completed recruitment for the phase III trial and further preclinical work has progressed to elucidate rAd-IFN/Syn3 treatment efficacy via predictive efficacy biomarkers for patient selection, vectors that might improve transduction efficiency and the design of novel therapeutic combination strategies to take advantage of rAd-IFN's immunologic activity. Citation Format: Sharada Mokkapati, Jon Duplisea, Michael Metcalfe, Amy Lim, Vikram Narayan, Devin Plote, Debashish Sundi, James E. Furguson III, Nigel R. Parker, Seppo Yla-Herttuala, David McConkey, Kimberly S. Shluns, Colin P.N. Dinney. Intravesical gene therapy for NMIBC [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA21.

PD12-07 A PHASE III STUDY TO EVALUATE THE SAFETY AND EFFICACY OF INTRAVESICAL NADOFARAGENE FIRADENOVEC FOR PATIENTS WITH HIGH-GRADE, BCG UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER

INTRODUCTION AND OBJECTIVE: A subset of patients (pts) with high-grade non-muscle invasive bladder cancer (NMIBC) who are treated with BCG will have BCG unresponsive disease, and are at considerable risk for tumor recurrence and progression. The development of effective intravesical therapies represents an important unmet need in this population. Nadofaragene firadenovec is a novel intravesical gene-mediated therapy that delivers the human IFNα2b gene resulting in sustained IFNα2b expression, and provided durable responses in a previous Phase 2 trial. Herein, we report results from the papillary disease (PD) cohort of the Phase 3 trial. METHODS: This multicenter, open-label Phase 3 study investigated nadofaragene for high-grade NMIBC (carcinoma in situ [CIS ± Ta/T1], or PD [Ta/T1 alone]) unresponsive to BCG. Nadofaragene (3X1011 vp/mL [75 mL]) was administered intravesically once every 3 months for up 4 doses in the initial 12 months. Pts with no evidence of high-grade disease at month 12 were offered continued treatment at the investigator’s discretion. The primary endpoint was complete response (CR) rate at any time in the CIS cohort (results presented in a prior abstract). Secondary end points included rate and durability of high-grade-recurrence-free (HGRF) survival as well as safety in PD pts, reported herein. RESULTS: A total of 157 pts were enrolled, of whom 50 were in the PD cohort (safety population n=50; efficacy population n=48). At study entry, all pts were BCG-unresponsive. Of the 48 pts in the efficacy population, 35 (72.9%), 30 (62.5%), 28 (58.3%), and 21 (43.8%) achieved HGRF survival at months 3, 6, 9, and 12, respectively. Within this PD cohort, the most common treatment-emergent adverse events (TEAEs) were transient in nature; specifically, instillation site discharge 30%; bladder spasm 18%; micturition urgency 18%; urinary tract infection 18%. The most common drug-related TEAEs were instillation site discharge 26%; bladder spasm 14%; micturition urgency 14%; dysuria 14%. Grade 3 TEAEs were reported in 9 pts (3 study drug-related), with a single Grade 4 (not related to study drug). No pt had an adverse event leading to death. CONCLUSIONS: Nadofaregene firadenovec was well tolerated and achieved an encouraging, durable HGRF survival in high-grade BCG-unresponsive NMIBC pts with PD. This demonstrates a clinically meaningful benefit in a pt population for whom to date non-surgical treatment options have remained limited. Clinical trial information: NCT02773849. Source of Funding: FKD

A randomized phase II study of erdafitinib (ERDA) versus intravesical chemotherapy (IC) in patients with high-risk nonmuscle invasive bladder cancer (HR-NMIBC) with FGFR mutations or fusions, who recurred after Bacillus Calmette-Guérin (BCG) therapy.

TPS603 Background: ERDA, an oral pan-FGFR inhibitor, is approved by the US FDA for metastatic urothelial carcinoma (mUC) with susceptible FGFR3 or FGFR2 gene alterations and progressed on/ or after at least 1 line of prior platinum-containing chemotherapy (PCC) including within 12 months of neoadjuvant/adjuvant PCC.1 Around 40% of patients with bladder cancer present with HR-NMIBC. First-line BCG therapy fails in 30-40% of patients and subsequent treatment options are limited. This study is designed to evaluate recurrence-free survival (RFS) following treatment with ERDA vs IC in patients with FGFR positive HR-NMIBC who recurred after BCG therapy. Methods: This is an open-label, multicenter, randomized, phase 2, safety and efficacy study of ERDA in adults with histologically confirmed HR-NMIBC and FGFR mutations or fusions. Inclusion criteria: ECOG status ≤1, adequate bone marrow, liver, renal function, and ineligibility for or declining cystectomy, with no history of prior FGFR inhibitors. Patients will be enrolled into 1 of 3 cohorts. Cohort 1 (n=240): high-grade disease Ta/T1 lesion (papillary only) with disease recurrence after BCG therapy will be randomized to ERDA or IC (investigator choice: gemcitabine or mitomycin C); Cohort 2 (n=20): carcinoma in situ (CIS) with/without papillary disease to receive ERDA monotherapy; Cohort 3 (n=20): marker lesion study in patients with intermediate-risk papillary disease only to receive ERDA monotherapy. Dose will be maintained at 8 mg, up-titrated to 9 mg, or withheld based on phosphate levels. Primary endpoint: Cohort 1- RFS; Secondary endpoints: Cohort 1 - time to progression and disease worsening, disease-specific survival (invasive bladder cancer), overall survival, RFS rate at 6, 12, 24 months, and RFS on subsequent anticancer therapy (RFS2). An IDMC will be commissioned for Cohort 1. Exploratory endpoints: Cohort 2- complete response (CR) rate at 6 months; Cohort 3- CR in marker lesion. Patients will be enrolled at sites in ~14 countries. EudraCT: 2019-002449-39. Loriot Y et al. N Engl J Med. 2019;381:338-48. Clinical trial information: 2019-002449-39.

Papillary thyroid carcinoma and Graves disease: a case report

Papillary thyroid carcinoma and Graves disease: a case report

Keynote 057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG).

350 Background: The PD-1 inhibitor pembro has durable antitumor activity in pts with metastatic urothelial carcinoma. Upregulation of the PD-1 pathway has been observed in BCG-resistant NMIBC, suggesting pembro may benefit. Efficacy and safety of pembro in pts with HR, BCG-unresponsive NMIBC was evaluated in the single-arm phase 2 KEYNOTE-057 study; updated results for pts with carcinoma in situ (CIS) with or without papillary tumor (cohort A) are reported. Methods: Pts with histologically confirmed HR, BCG-unresponsive CIS with or without papillary disease, who received adequate BCG therapy and were unable/unwilling to undergo radical cystectomy received pembro 200 mg Q3W for 24 mo or until recurrence, progression, or unacceptable toxicity. Pts with HR NMIBC or progressive disease during treatment were required to discontinue. Primary end point: complete response rate (CRR); key secondary end points: duration of response and safety. Results: 103 pts (median age 73 years; CIS alone 71.8%; median number of prior BCG instillations 12) have enrolled in cohort A. 3-mo CRR rate was 38.8% (95% CI 29.4%-48.9%) by central assessment. Among 40 pts who achieved CR at 3 mo, 72.5% maintained CR at last follow-up (median 14.0 mo; range 4.0-26.3) and median CR duration has not been reached (range 0+ to 14.1+ mo). 80.2% of pts had a CR duration of ≥6 mo (Kaplan-Meier method). 10 (25.0%) experienced recurrent NMIBC after CR; at the time of analysis, none progressed to muscle invasive or metastatic disease. Treatment-related adverse events (AEs) occurred in 65 (63.1%) pts; most frequent were pruritus (10.7%), fatigue (9.7%), diarrhea (8.7%), hypothyroidism (5.8%), and maculopapular rash (5.8%). Grade 3/4 treatment-related AEs occurred in 13 (12.6%) pts; 1 death was considered treatment-related (colitis in patient inadequately treated with steroids). Immune-mediated AEs occurred in 19 (18.4%) pts. Conclusions: Pembro had encouraging activity in pts with HR, BCG-unresponsive CIS with or without papillary tumors and a safety profile consistent with that of previous experience. Updated data using additional follow-up will be presented. Clinical trial. Clinical trial information: NCT02625961.

A phase III, randomized, open-label, multicenter, global study of durvalumab and bacillus calmette-guérin (BCG) versus BCG alone in high-risk, BCG-naïve non-muscle-invasive bladder cancer (NMIBC) patients (POTOMAC).

TPS500 Background: Standard of care (SoC) for high-risk NMIBC patients is transurethral resection of the bladder tumor followed by BCG. Although several randomized clinical studies have demonstrated the efficacy of BCG in NMIBC, recurrence rates are as high as 50% in the first 3 yrs of follow up and can be even higher for aggressive histologic subtypes. Immunotherapy agents active in the programmed cell death (PD) pathway responsible for suppressing anti-tumor immunity present an emerging treatment opportunity. In trials treating patients with metastatic urothelial cancer who progressed after platinum-based chemotherapy, response rates doubling those with traditional chemotherapy have been reported for immunotherapies targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1). Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with a manageable safety and tolerability profile. PD-L1 inhibition with durvalumab in combination with other immunotherapies, including SoC BCG, may improve response rate and duration of tumor response. Methods: POTOMAC is an open-label, multicenter, global Phase 3 trial enrolling approximately 1,300 patients ≥18 yrs with histologically confirmed high-risk NMIBC who have undergone complete resection of papillary tumors (patients with residual carcinoma in situ [CIS] are eligible) and are BCG-naïve. Of those, approximately 975 patients will be randomized (1:1:1) to durvalumab (1500 mg every 4 wks for 13 cycles) + BCG induction (6x every 1 wk instillation) and 2 yrs of maintenance (3 doses x every 1 wk at 3, 6, 12, 18, and 24 months), durvalumab + BCG (induction only) or BCG (induction and 2 yrs of maintenance). Randomization will be stratified by high-risk papillary disease (Y/N) and CIS (Y/N). The primary endpoint is disease-free survival. Secondary endpoints include proportion of patients alive and disease free at 24 months, overall survival at 5 yrs, pharmacokinetics, immunogenicity, safety and tolerability, and HRQoL. Clinical trial information: NCT03528694.

Bladder sparing surgery in high-grade bladder cancer.

The gold standard for managing muscle-invasive bladder cancer is radical cystectomy (RCE). The RCE is a treatment, which carries high burden of perioperative morbidity and mortality. As biomolecular markers make muscle-invasive high-grade bladder cancer(HGBC) an entity different from non-invasive papillary disease, we tested a hypothesis that alternative bladder preserving surgery(BPS) approaches, such as partial cystectomy and transurethral resection of the bladder would not compromise the oncological results of treating HGBC in selected patients.Aim:To study the cancer specific survival of HGBC patients depending on the mode of surgical treatment- RCE, partial en-block cystectomy, and transurethral resection of the bladder in the practice of the Departments of Urology and Oncology of Bogomolets National Medical University, and to assess the prevalence of bladder sparing surgical management of HGBC in local practice as a part of trimodal treatment approach to bladder preservation.Materials and Methods: Retrospectively we studied the medical records of 3597urothelial bladder cancer patients, of whom 346 (10%) had high-grade disease and who underwent surgical treatment in 2004-2017. All patients were studied with contact computed tomography of the chest, abdomen, pelvis, and biopsy of the tumor. Based on the results of the diagnostic workup the choice of surgical treatment between RCE, partial cystectomy and transurethral resection was made considering the size of the tumor, location of the tumor in the bladder in relation to the bladder neck, and technical and oncological feasibility of performing the bladder sparing surgery. Kaplan- Meier survival curves were built to compare the results of survival per cancer stage and type of surgical treatment. Survival data of the patients were collected from the cancer registry maintained at the Kyiv Municipal Clinical Oncological Center. Results of data analysis were controlled for confounding parameters, such as adjuvant treatment: perioperative radiotherapy, and chemotherapy.Results: Median follow-up was 93months (1-226months). Males were 276 (80%). Average age at diagnosis was 62±4.5years. By the time of the study 61% of patients have died due to the progression of the disease. All patients with stage I disease (7% or 24patients) were managed with bladder-sparing surgery. In muscle-invasive disease (309patients), the RCE was performed in 109 (35.3%) patients, partial cystectomy was performed in 79 (25.6%) patients, and transurethral resection- in 121 (39.1%) patients. The overall 5-year survival of HGBC patients after radical surgical treatment (RCE/BPS) for stage I patients was 0%/83%, for stage II- 43%/58%, for stage III- 37%/42%, and for stage IV- 10%/40%. Atotal of 44patients (12.7% of all treated, and 19.6% of treated with bladder sparing) received postoperative radiotherapy after bladder-sparing surgery. Atotal of 14patients (4% of all treated) received postoperative chemotherapy.Conclusion: Bladder sparing surgery (partial en-block cystectomy, and transurethral resection of the bladder) in selected patients is not inferior to RCE in terms of cancer-specific survival when treating patients with HGBC of all stages. The bladder sparing surgery was performed in 64.7% of patients with high grade bladder cancer. Utilization of adjuvant treatment is low, 12.7% for postoperative radiotherapy, and 4% for perioperative chemotherapy.

Endoscopic Sphincterotomy for Gallbladder Muddy Stones or Sludge in Patients With Papillary Disease: A Retrospective Study.

The formation of gallbladder stones is associated with dysfunctional contraction and duodenal papilla diseases. However, endoscopic sphincterotomy can improve the contraction of the gallbladder and resolve duodenal papilla disease. The aim of the study was to assess the feasibility and effectiveness of endoscopic sphincterotomy in the treatment of muddy stones or sludge in the gallbladder during papillary disease. The clinical data of 53 patients with gallbladder muddy stones or sludge undergoing endoscopic sphincterotomy were retrospectively analyzed. A total of 53 patients received successful endoscopic sphincterotomy with no serious complications. Sphincterotomy did not significantly lower resting gallbladder volume from 63.2±10.8 to 50.1±5.9 mL (P>0.05), but significantly increased gallbladder ejection fraction from 0.41±0.13 to 0.63±0.16 (P<0.01), as measured by the lipoid food test. The static liver and gallbladder imaging examination also showed an increase in gallbladder ejection fraction from 0.45±0.08 to 0.68±0.11 (P<0.01). In addition, the choledochus pressure reduced from 21.9±4.0 to 15.6±2.5 mm Hg, and the gallbladder muddy stones or sludge disappeared after endoscopic sphincterotomy. At the end of the follow-up period, there was no relapse of sludge or muddy stones in the gallbladder. The formation of gallbladder muddy stones or sludge is associated with papilla disease. Endoscopic sphincterotomy can resolve papilla disease, decrease gallbladder bile stasis, improve gallbladder evacuation, and prevent the formation of gallbladder stones.

Value of 64-row helical CT in diagnosis of duodenal papillary diseases

Value of 64-row helical CT in diagnosis of duodenal papillary diseases

Endoscopic Evidence That Randall's Plaque is Associated with Surface Erosion of the Renal Papilla.

This study was conducted to assess the reliability and precision of an endoscopic grading scale to identify renal papillary abnormalities across a spectrum of equipment, locations, graders, and patients. Intra- and interobserver reliability of the papillary grading system was assessed using weighted kappa scoring among 4 graders reviewing a single renal papilla from 50 separate patients on 2 occasions. Grading was then applied to a cohort of patients undergoing endoscopic stone removal procedures at two centers. Patient factors were compared with papillary scores on the level of the papilla, kidney, and patient. Graders achieved substantial (kappa >0.6) intra- and inter-rater reliability in scored domains of ductal plugging, surface pitting, and loss of contour. Agreement for Randall's Plaque (RP) was moderate. Papillary scoring was then performed for 76 patients (89 kidneys, 533 papillae). A significant association was discovered between pitting and RP that held both within and across institutions. A general linear model was then created to further assess this association and it was found that RP score was a highly significant independent correlate of pitting score (F = 7.1; p < 0.001). Mean pitting scores increased smoothly and progressively with increasing RP scores. Sums of the scored domains were then calculated as a reflection of gross papillary abnormality. When analyzed in this way, a history of stone recurrence and shockwave lithotripsy were strongly predictive of higher sums. Renal papillary pathology can be reliably assessed between different providers using a newly described endoscopic grading scale. Application of this scale to stone-forming patients suggests that the degree of RP appreciated in the papilla is strongly associated with the presence of pitting. It also suggests that patients with a history of recurrent stones and lithotripsy have greater burdens of gross papillary disease.

Bacillus Calmette-Guérin (BCG) Treatment Failures with Non-Muscle Invasive Bladder Cancer: A Data-Driven Definition for BCG Unresponsive Disease.

Objective: To create the first data-driven definition for those unlikely to benefit from further BCG treatment.Materials and Methods: The database created for the Phase 2 BCG-Interferon-α 2B (IFN) study was queried and BCG failure patients were identified (n = 334). Full study protocols have previously been published. Separate models were constructed for analysis of patients with any CIS (pure or concomitant) and pure papillary disease. Variables considered included age, gender, stage, grade, tumor size and focality (for papillary only), number of prior BCG courses, and prior BCG failure interval.Results: Patients with recurrent CIS within 6 months of their most recent prior BCG course (HR 2.56, p < 0.01) and ≥2 prior BCG failures (HR 1.54, p < 0.01) responded worst to repeat intravesical therapy. Those with CIS recurrence at 6–12 months did not differ from those recurring within 6 months (HR = 0.88, p = 0.71). Patients with recurrent papillary disease within 6 months (HR 1.82, p = 0.02), ≥2 BCG failures (HR 1.54, p = 0.03), and multifocal disease (HR 2.05, p < 0.01) responded worst to therapy. Patients with T1 disease remained disease free in 38% of cases (24–51% 95% CI) at 2 years with low rates of progression.Conclusions: Patients who fail two courses of BCG with either persistent or recurrent multifocal papillary disease within 6 months or CIS within 12 months of their prior BCG should be considered BCG unresponsive. Recurrent T1 disease respond reasonably well to another course with low progression rates but further investigation is warranted.

Abstract P2-12-22: Atypical ductal hyperplasia and breast cancers - A ten year clinical and pathological review on core biopsy, lumpectomy and mastectomy specimens

Abstract Introduction Atypical ductal hyperplasia (ADH) is known to be associated with underlying pre-malignant or malignant breast conditions. Here we report our 10-year data on ADH found in core biopsy, lumpectomy and mastectomy specimens Methods From 1st January 2005 to 31st December 2014, a total of 104 core needle biopsy specimens and 218 lumpectomy / mastectomy specimens were found to contain ADH. Clinical, radiological and pathology data were retrieved and analysed from a prospectively-maintained database. Results Out of the 104 patients with core biopsy showing ADH, 101 patients received excision and 3 refused operation. 34 patients turned out to have ductal carcinoma in-situ (DCIS) on excision, while 6 had invasive ductal carcinoma (IDC), 1 had lobular carcinoma in-situ (LCIS) and 1 had angiosarcoma resulting in an upstaging rate of 40.4% (42/104). The remaining patients had benign lesions including papillary lesions, fibrocystic disease, or ADH alone. Multivariate analysis found that the only correlating factor for the presence of DCIS or IDC was suspicious mammographic features (BIRADS 4 or above) (P = 0.008 and 0.02 respectively) but not other parameters such as extent of micro-calcifications (P = 0.12) or age (P = 0.11). Histopathological diagnosis after excision of lesions containing ADH on core biopsyExcisional Biopsy ResultNumber (%)DCIS34 (32.7%)ADH32 (30.8%)Benign27 (26%)IDC6 (5.8%)LCIS1 (0.9%)Angiosarcoma1 (0.9%)Refuse operation3 (2.9%) 218 lumpectomy or mastectomy specimens were found to harbor ADH. 62 (28.4%) had co-existing pre-malignant or malignant breast diseases. The only determining factor for the presence of malignant or pre-malignant condition was suspicious breast imaging features (BIRADS 4 or above) after multivariate analysis (P = 0.0003). Co-existing conditions in the lumpectomy / mastectomy specimens with ADHCo-existing Patholog(ies)Number (%)Atypical Ductal Hyperplasia alone97 (44.4%)Fibroadenoma / Fibrocystic disease31 (14.2%)Intraductal papilloma22 (10%)Phyllodes tumor6 (2.8%)Ductal carcinoma in-situ36 (16.5%)Invasive ductal carcinoma23 (10.6%)Lobular carcinoma in-situ1 (0.5%)Invasive lobular carcinoma1 (0.5%)Malignant phyllodes tumor1 (0.5%) Conclusion ADH is closely related to the presence of invasive cancer or DCIS especially when suspicious breast imaging features are present. The upstaging rate is still high in patients where initial biopsy was ADH. Citation Format: Co M, Kwong A. Atypical ductal hyperplasia and breast cancers - A ten year clinical and pathological review on core biopsy, lumpectomy and mastectomy specimens. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-12-22.

Glottic Cancer

Conventional wisdom is that the overwhelming majority of glottic cancer patients have a smoking history. However, in recent years observations suggested that an increasing number of glottic cancer patients had never been smokers. Therefore, an investigation was done examining the incidence of having a smoking history in a recent cohort of glottic cancer patients. Retrospective review of 100 patients with glottic cancer to determine those reporting never having smoked. Thirty-one of 100 did not have a smoking history. Clinical observations of those cases revealed that the disease morphology tended to be exophytic, papillary, and very vascular, often resembling recurrent respiratory papillomatosis (RRP). Remarkably, 2 of 31 were initially treated elsewhere assuming they had RRP and underwent 5 cidofovir injections. Both presented with advanced cancer, and the disease growth markedly accelerated coincident with the injections. Observations herein provide new insights that glottic cancer may be an evolving disease in which smoking is less exclusive, not unlike HPV-induced pharynx cancer. Similar to RRP, the angiogenic papillary disease morphology is well suited for voice-preserving angiolytic KTP laser treatment. Given the resemblance of some glottic cancers to RRP, great care should be taken when using cidofovir for papillary glottic neoplasms.

Efficacy and Safety of MCNA in Patients with Nonmuscle Invasive Bladder Cancer at High Risk for Recurrence and Progression after Failed Treatment with bacillus Calmette-Guérin

Patients with high risk recurrences after bacillus Calmette-Guérin failure have limited options. We performed an open label study to evaluate the efficacy and safety of intravesical MCNA in this setting. Patients were treated intravesically with 8 mg MCNA weekly for 6 weeks followed by 3 weekly instillations at months 3, 6, 12, 18 and 24. Cystoscopy and cytology were performed every 3 months for 2 years with mandatory biopsy at 6 months and as clinically indicated thereafter. The primary efficacy end point was the disease-free survival rate at 1 year. A total of 129 patients were enrolled in study, including 91 with carcinoma in situ with or without papillary disease and 38 with papillary only tumors. Most patients had high risk disease. A total of 107 cases were bacillus Calmette-Guérin refractory and 2 or more prior bacillus Calmette-Guérin induction courses had been given in 68. Median followup in all patients was 34.7 months. The overall disease-free survival rate was 25.0% at 1 year and 19.0% at 2 years. In patients with papillary only tumors the disease-free survival rate was 35.1% and 32.2% at 1 and 2 years, respectively. The median disease-free duration in the 30 responders was 32.7 months. The progression-free survival rate was 87.3%, 79.8% and 77.7% at 1, 2 and 3 years, respectively, with a progression event in 28 patients. MCNA was well tolerated and few adverse events led to treatment discontinuation. Intravesical MCNA achieved significant activity in patients at high risk with nonmuscle invasive bladder cancer in whom bacillus Calmette-Guérin treatment failed, especially those with papillary only tumors and those with bacillus Calmette-Guérin relapse. A durable response was seen, particularly in patients with a response at 1 year. MCNA offers an option for patients who are not candidates for or who refuse cystectomy.

Optimal treatment of non-muscle invasive urothelial carcinoma including perioperative management revisited.

Non-muscle invasive urothelial carcinoma is a heterogeneous disease that requires the practicing urologist to implement a variety of surgical and non-surgical treatment strategies. The disease course can range from recurrent low grade papillary disease to aggressive disease concerning for progression from initial presentation. Depending on the particular patient and goals of care, treatments similarly span the range from minimally invasive fulgurations to immediate radical cystectomy. For most patients some form of intravesical therapy will bridge the gap between transurethral resections (TUR) and radical surgery. Recent advances in the field continue to emphasize the importance of quality TUR and its strong impact on outcomes. In addition, continued research to optimize intravesical therapies has provided more information about how, when, and in whom these agents should be utilized to enhance their efficacy. This review covers the current state of NMIBC and the standards of care for the management of this disease.

Editorial Comment

For the urologic oncology community, the massive unmet need for therapeutics in bladder cancer throughout the disease spectrum is widely recognized. For patients with non–muscle-invasive bladder cancer (NMIBC), this issue is best illustrated by the following: 3 drug approvals in 30 years, in contrast to 5 new drugs approved for castration-resistant metastatic prostate cancer in the last 3 years. There are many reasons for this dismal performance, including limited interest by big (and little) pharma and a rather poor track record of completion of clinical trials in urothelial cancer. NMIBC is inherently problematic to study in the context of clinical trials in no small part because of a lack of consensus on trial end points both from a clearly clinical and regulatory perspective. The present report summarizes the work at a joint Food and Drug Administration and American Urological Association meeting, whose goal was to reach some consensus on potential trial designs and end points, to “jump start” efforts for the development of novel therapeutics. The focus, appropriately, was on both high-risk NMIBC and BCG-refractory carcinoma in situ (CIS). For the latter setting, there appeared to be broad consensus that there is no standard comparator for a randomized trial, and perhaps of more importance, that an initial complete response rate of 40%-50% at 6 months and a durable response rate of at least 30% for 18-24 months, with the lower bound of the 95% confidence interval excluding 20% could be clinically meaningful – which I interpret to mean as a potentially approvable endpoint. With respect to trial design for patients with high-risk NMIBC, there was consensus that the preferred primary endpoint for these trials should be time to event, using failure to achieve a complete response in patients with CIS and recurrence in patients with CIS or papillary disease as the events. This joint effort of the American Urological Association and Food and Drug Administration is encouraging but requires follow-up action from the urologic oncology community to “encourage” our colleagues in pharma to explore this area of unmet need with renewed enthusiasm, especially given a potential window of opportunity for drug development in trials with end points that are more broadly accepted, which could potentially lead to regulatory approval. Clinical Trial Design for the Development of New Therapies for Nonmuscle-invasive Bladder Cancer: Report of a Food and Drug Administration and American Urological Association Public WorkshopUrologyVol. 83Issue 2PreviewTo summarize the discussion at a public workshop, cosponsored by the U.S. Food and Drug Administration (FDA) and the American Urological Association, reviewing potential trial designs for the development of new therapies for non–muscle-invasive bladder cancer (NMIBC). There have been only 3 drug approvals for NMIBC in the last 30 years, and product development for this disease has been stymied by difficulties in trial design and patient accrual. Full-Text PDF