Unresponsive Disease Research Articles

OP17 IBD ulcers are characterized by bioactive interleukin-1 and transcriptomic hallmarks of stromal cell state reprogramming

Abstract Background The programs that perpetuate the inflammation and prevent epithelial repair in Inflammatory Bowel Disease (IBD) remain unclear. Interleukin (IL)-1 plays a role in the maintenance of mucosal homeostasis but also in IBD. Expansion of IL-1 expressing myeloid cells is a hallmark of IBD tissue, including severe and anti-TNF unresponsive disease, and IL-1 expression is highly localized to ulcer beds. However, little is known about the presence of bioactive IL-1 proteins in the cell-free mucosal environment of IBD, nor whether IL-1-driven programs affect epithelial regeneration in IBD ulcers. Methods We established a highly sensitive assay (~500-fold greater than ELISA) to assess bioactive extracellular IL-1 from previously cryopreserved IBD biopsies. We assessed a cohort of Crohn’s Disease (CD, n=23), Ulcerative Colitis (UC, n=18) and non-IBD (n=17) patients, with biopsies from paired inflamed/uninflamed regions (primarily colon but also ileal). We assessed IL-1 bioactivity, including IL-1α vs IL-1β contributions, and performed RNA-seq of samples’ matched cellular compartments. An ulcer-associated gene signature was interrogated in a single-cell (sc)RNA-seq cohort (n=42) of very early onset (VEO)IBD including monogenic disorders, as well as publicly available IBD bulk RNA-seq datasets and scRNA-seq of mouse models of colitis. Results IL-1α and IL-1β bioactivity corresponded with disease and ulcer severity in CD and UC. The most extreme signals were seen in select CD patients with deep ulceration. IL-1α was the predominant contributor to total IL-1 bioactivity in most patients although several with ulcers displayed IL-1β predominance. IL-1 bioactivity correlated with IL-1 transcripts in matched RNA-seq, and weighted gene co-expression network analysis revealed a compelling ulcer-specific module. This module contained transcription factors and genes related to cell state, validated in publicly available datasets (e.g. RISK cohort of ileal CD and scRNA-seq of murine DSS colitis), that when interrogated in a scRNA-seq dataset of VEOIBD (including patients with IL-10RA mutations characterized by deep ulcers), suggests an orchestrated IL-1-driven myeloid/stromal response to epithelial ulceration involving cell state reprogramming and loss of key myofibroblast populations. Conclusion Mucosal ulceration in IBD is associated with bioactive IL-1α and IL-1β proteins, and transcriptomic evaluation of the same correlates with bioactive signal. An ulcer-associated gene module, validated in other datasets, sheds light on IL-1 biology in intestinal epithelial repair. Results strongly suggest the IL-1 signaling pathway being an attractive and precision-based therapeutic target in subsets of IBD patients.

Not Every Anosmia is COVID, a Case of Nasal Mass

Smell and test problems especially anosmia is a frequent symptom for COVID infection. Anosmia was experienced by almost 53% of those affected, in some cases persisting for longer periods after resolution of respiratory symptoms. Nasal blockage is another common symptom for emergency department patients and frequently associated with allergic rhinitis. A 25-year-old male patient presented with persistent bilateral nasal blockage, blood-stained nasal discharge, anosmia, and headache since last 1 year. During the peak of the pandemic, he was diagnosed with COVID. He was complaining of anosmia and nasal blockage and was treated with antihistaminic medicine for allergic rhinitis, but his symptoms persisted. He had breathing, bleeding and smelling problems in the last 2 years and started complaining of left sided proptosis for 3-4 weeks before being admitted to our department and had computerized tomography (CT) imaging at another facility. He was referred by an ophthalmologist to our hospital for advanced imaging with magnetic resonance (MRI) with contrast. He was investigated for exophthalmos in his left eye. He denied any other prior disease or medication. On examination he has nasal voice, left side exophthalmos, no diplopia or vision problem. The right tympanic membrane (TM) was intact, left sided dull TM with effusion. Other system evaluations were unremarkable. The patient was referred to Ear Nose and Throat consultant for further examination. Nasal endoscopy revealed fungating mass with covered blood clots and engorged vessels filling both the nasal cavities. MRI report described soft tissue mass, infiltrating the nasal cavity, paranasal sinuses and clivus with intracranial extension, to involve the left sub frontal region. Also noted associated destruction of the left lamina papyracea, showing orbital extension, compressing the orbital muscle cone, and compressing the medial rectus, with consequent left sided unilateral proptosis. In addition, there was nasopharyngeal extension. The epicenter of the mass was likely to be the ethmoid sinuses. His MRI revealed complete obstruction of the osteomeatal complexes, complete obliteration of the maxillary, ethmoids and frontal sinuses, due to retention of secretions and mass infiltration. Biopsy was taken and patient was followed up for surgical intervention. The differential diagnosis included vascular tumor, meningothelial tumor, undifferentiated carcinoma, and neuroendocrine carcinoma. Smell and taste disorders emerge during COVID infection, seem to be more common than other upper respiratory tract infections. Allergic rhinitis is also common amongst emergency department patients and frequently associated with nasal blockage. Rhinitis can be differentiated from sinus problems by the increased response of nasal obstruction to treatment, clear nasal discharge, and absence of pain or fever. Rhinitis does not lead to ostial obstruction, and patients do not complain of facial pain or headache. For suspected rhinitis or acute sinusitis, routine radiographic examination is not recommended and should be limited to the diagnosis of chronic or recurrent admissions, cases of questionable diagnoses, patients with unresponsive disease, or investigation of complications. Axial and coronal CT is the imaging modality of choice. In this case the patient was investigated for sinusitis complications and additional further imaging was necessary like MRI with contrast for proper diagnosis and management of the patient. Nasal blockage and upper respiratory system findings may be overseen by the patients or even the healthcare workers. Especially repeated admissions and persistence of these symptoms should be suspicious for the emergency physicians. Additional imaging and thorough examination are crucial for differential diagnosis and proper management of these patients. Emergency physicians should be careful on their diagnoses for common symptoms like nasal blockage especially for the patient

Safety and efficacy of a new high-dose regimen of panobinostat, gemcitabine, busulfan, and melphalan for 1st or 2nd salvage ASCT for refractory/relapsed or high-risk myeloma: Matched-pair comparisons with concurrent control cohorts.

Improvement of autologous stem-cell transplantation (ASCT) for myeloma is needed. Building on our prior work, we prospectively evaluated panobinostat and gemcitabine/busulfan/melphalan (GemBuMel) with ASCT in this population. Patients aged 18-65 years with relapsed/refractory or high-risk myeloma and adequate end-organ function were eligible. Treatment included panobinostat (20 mg/day, days -9 to -2) and GemBuMel (days -8 to -2). Patients were enrolled in 1st (ASCT-1) or 2nd ASCT (ASCT-2) cohorts. We compared their outcomes with all our other concurrent ASCT patients who met eligibility criteria but received melphalan or BuMel off study, matched for age, prior therapy lines, high-risk cytogenetics, and response at ASCT. We enrolled 80 patients, 48 and 32 in the ASCT-1 and ASCT-2 cohorts, respectively; in these two cohorts, high-risk cytogenetics were noted in 33 and 15 patients, respectively; unresponsive disease in 12 and 11 patients, respectively, after a median of 2 and 3 therapy lines, respectively. Transplant-related mortality (TRM) occurred in two ASCT-2 patients. One-year PFS rates were 69% (ASCT-1) and 72% (ASCT-2); 1-year OS rates were 79% (ASCT-1) and 84% (ASCT-2). Minimal residual disease negativity improved after ASCT-1 (8.5%-23%, p < .0001) and ASCT-2 (34%-55%, p = .02), which correlated with improved outcomes. Trial patients and controls (N = 371) had similar TRM and post-ASCT maintenance. Trial patients had better PFS after either a 1st (p = .02) or a 2nd ASCT (p = .04) than matched-paired control patients. In conclusion, panobinostat/GemBuMel is effective for relapsed/refractory or high-risk myeloma patients, with better PFS than concurrent matched controls receiving melphalan or BuMel.

Treatment of Pediatric Eosinophilic Esophagitis: Traditional and Novel Therapies.

This review presents and summarizes the existing studies on the treatment goals and options for pediatric eosinophilic esophagitis utilizing rigorous peer-reviewed literature. In addition to traditional treatments, emerging biologic therapies continue to evolve the approach to treating pediatric eosinophilic esophagitis. Well defined treatment goals will aid the continued development of new therapies. Further, innovative assessment tools have changed how the clinician is able to assess the effectiveness of therapies with a trend toward less invasive options. The management of pediatric eosinophilic esophagitis continues to evolve with the advent of both novel treatment options and assessment tools. Treatment choices, with benefits and risks involved, should be presented to families upon diagnosis and tailored towards the individual patient and likelihood of adherence and success. Biologic therapy for EoE presents an exciting option for both first line therapy and escalation for those with severe or unresponsive disease.

Phase 2 trial of intravesical cabazitaxel, gemcitabine, and cisplatin (CGC) for the treatment of non-muscle invasive BCG unresponsive urothelial carcinoma of the bladder.

TPS4616 Background: For patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacille Calmette-Guerin (BCG), multi-agent intravesical trials have been limited. The goal of this Phase 2 study is to investigate the efficacy of intravesical chemotherapy consisting of sequential cabazitaxel, gemcitabine, and cisplatin (CGC) in the salvage setting. Phase 1 results reporting on 18 subjects demonstrated adverse events limited to local Grade 1 and 2 toxicities. Partial funding support for the trial was provided by a pharmaceutical company. Methods: This is a Phase 2 trial (NCT02202772) presently enrolling patients with BCG unresponsive NMIBC as defined by the FDA who refuse or are ineligible for radical cystectomy. All patients undergo pre-treatment transurethral resection of bladder tumor (TURBT) and a 6-week regimen of intravesical cisplatin (100mg), gemcitabine (2gm), and cabazitaxel (5mg). Each drug is instilled weekly except for cisplatin, which is given every other week. Complete response is defined as having no evidence of cancer on post-induction biopsy and negative urine cytology at 3 months. Complete responders proceed with monthly and bimonthly maintenance therapy without cisplatin in the first and second years, respectively, for a total of 24 months. Results: To date thirty-one patients have been enrolled (with target accrual of 33), of whom seven are female. One patient withdrew consent before first evaluation cystoscopy. Mean age thus far is 72 years. All patients have previously received at least two prior induction cycles of BCG, and meet FDA criteria for BCG unresponsive disease. All patients have biopsy proven high grade disease at enrollment; 8 (27%) have high grade T1 disease; and 20 (67%) patients have CIS. Conclusions: Salvage options for BCG unresponsive NMIBC are limited. The CGC protocol has been demonstrated to be safe in a previous Phase 1 study, and accrual for this Phase 2 is near completion. Clinical trial information: NCT02202772 .

PD13-12 BLADDER SPARING TREATMENT IN PATIENTS WITH BCG UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER: AN ANALYSIS OF LONG-TERM SURVIVAL OUTCOMES

You have accessJournal of UrologyCME1 Apr 2023PD13-12 BLADDER SPARING TREATMENT IN PATIENTS WITH BCG UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER: AN ANALYSIS OF LONG-TERM SURVIVAL OUTCOMES Wei Shen Tan, Valentina Grajales, Roberto Contieri, Patrick Hensley, Kelly Bree, Pavlos Msaouel, Charles Guo, Neema Navai, Colin Dinney, and Ashish Kamat Wei Shen TanWei Shen Tan More articles by this author , Valentina GrajalesValentina Grajales More articles by this author , Roberto ContieriRoberto Contieri More articles by this author , Patrick HensleyPatrick Hensley More articles by this author , Kelly BreeKelly Bree More articles by this author , Pavlos MsaouelPavlos Msaouel More articles by this author , Charles GuoCharles Guo More articles by this author , Neema NavaiNeema Navai More articles by this author , Colin DinneyColin Dinney More articles by this author , and Ashish KamatAshish Kamat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003260.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In recent years, more patients are selecting to forgo radical cystectomy (RC) and select bladder sparing treatment (BST) for Bacillus Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC). Herein, we assessed long-term survival outcomes of BCG unresponsive NMIBC patients treated with BST versus early RC. METHODS: We performed an IRB approved retrospective study analyzing patients with BCG unresponsive NMIBC diagnosed between April 2001 and September 2021 at our institution. Survival outcomes between the following patient cohorts were compared: 1) Early RC versus BST and 2) Early RC versus delayed RC. Primary endpoint was overall-(OS) and cancer-specific survival (CSS). Cox-regression was used to estimate OS, CSS, high-grade recurrence-free survival (RFS) and progression-free survival (PFS) endpoints. RESULTS: A total 118 patients who met criteria for BCG unresponsive disease were identified (80 BST versus 38 early RC). Patients undergoing early RC were more likely to have higher T1 stage (52.6% vs 35.0%, p=0.048) and lymphovascular invasion (10.5% vs 0%, p=0.003) compared to those treated with BST. Comparative outcomes for OS (HR: 1.34, 95% CI: 0.65-2.76, log-rank p=0.429) and CSS (HR: 0.84, 95% CI: 0.21-3.38, log-rank p=0.803) between early RC and BST were not significant (inconclusive). With a median follow-up of 72.1 months (IQR: 30.1-134.0), at 60 months, BST treated patients had a high-grade RFS rate of: 37%, PFS to muscle-invasive disease/metastasis rate: 84% and avoidance of RC rate: 81%. The risk of high-grade recurrence was higher in current smokers (HR: 6.00, 95% CI: 1.73-20.6, p=0.005). For patients undergoing RC for BCG unresponsive disease, median time to RC were 2.1 months and 15.8 months for early and delayed RC respectively. Comparative outcomes were similar for the early and delayed RC: OS (58% vs 54%) (HR: 1.17, 95% CI: 0.50-2.71, p=0.717) and CSS (81% vs 81%) (HR: 1.07, 95% CI: 0.23-4.92, log-rank p=0.927). CONCLUSIONS: Long-term survival outcomes following BST (with delayed RC when indicated) in patients with BCG unresponsive NMIBC is not inferior compared to early RC. Source of Funding: This research was supported by the Wayne B. Duddlesten Professorship in Cancer Research, the Raymond and Maria Floyd Bladder Cancer Research Foundation Grant, NIH/NCI UTMD Anderson SPORE in Genitourinary Cancer (P50CA091846) and the Cancer Center Support Grant (NCI Grant P30 CA016672) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e410 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Wei Shen Tan More articles by this author Valentina Grajales More articles by this author Roberto Contieri More articles by this author Patrick Hensley More articles by this author Kelly Bree More articles by this author Pavlos Msaouel More articles by this author Charles Guo More articles by this author Neema Navai More articles by this author Colin Dinney More articles by this author Ashish Kamat More articles by this author Expand All Advertisement PDF downloadLoading ...

Interview: Timothy Clinton

Interview: Timothy Clinton

Study EV-104: Phase 1 study of intravesical enfortumab vedotin for treatment of patients with non-muscle invasive bladder cancer (NMIBC)—Trial in progress.

TPS582 Background: The majority of patients with bladder cancer present with non-muscle invasive disease (Chang 2016; Woldu 2017; Kates 2020; Li 2020). The standard of care for treatment of high risk NMIBC involves transurethral resection of the bladder tumor (TURBT) followed by intravesical Bacillus Calmette-Guerin (BCG) or chemotherapy. Although the response rate to BCG therapy is high, many patients recur within 1–5 years (Matulay JU 2021). For patients who have BCG unresponsive disease after adequate course of BCG, there are limited options. While radical cystectomy (RC) is still considered the standard of care, most patients are reluctant to undergo RC and their options are limited to intravesical chemotherapy or pembrolizumab. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in bladder tumors. In EV-301, a phase 3 study, EV showed an OS benefit vs chemotherapy in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (Powles NEJM 2021). Based on its demonstrated benefit in la/mUC, EV is currently being evaluated in earlier UC settings. The purpose of this study is to investigate the intravesical administration of EV for patients with NMIBC. Methods: EV-104 (NCT05014139) is a phase 1, open-label, multicenter, dose-escalation and dose-expansion study designed to evaluate the safety, tolerability, PK, and antitumor activity of intravesical EV in adults with high-risk BCG-unresponsive NMIBC (carcinoma in situ with or without papillary disease) who are ineligible for or refuse RC. The dose escalation part of the trial aims to identify the maximum tolerated dose (MTD) and/or recommended dose of intravesical EV. The dose expansion part will evaluate patients at the MTD or recommended dose and further characterize safety and antitumor activity of intravesical EV. The study treatment regimen will include an induction phase, where patients will receive intravesical EV weekly for 6 weeks followed by monthly maintenance for a total of 9 additional EV doses. Patients will be assessed for response every 3 months by cystoscopy and urine cytology, while on study. Safety and antitumor activity endpoints will be summarized using descriptive statistics. The study is currently enrolling in the US with additional sites planned in Canada and the EU. Clinical trial information: NCT05014139 .

Elicitation of Health State Utilities Associated with Progression from Bacillus Calmette-Guerin (BCG) Unresponsive Non-muscle Invasive Bladder Cancer (NMIBC).

The treatments for high-grade non-muscle invasive bladder cancer (NMIBC) vary between bladder preserving intravesical approaches and radical cystectomy. The impact of these treatments on health-related quality of life may vary widely. The purpose of this study was to elicit the general public's perspective on quality of life, measured as utility scores associated with treatment for Bacillus Calmette-Guerin (BCG)-unresponsive NMIBC and disease progression, for supporting economic evaluation of newly developed treatments for NMIBC. Part I involved the development and testing of health states describing NMIBC, which was informed by a rapid review, expert input and a patient advisor. Part II involved elicitation of societal utility values for the different health states. Time trade-off (TTO) interviews were conducted with members of the UK general public. Five health states described different NMIBC scenarios including disease recurrence and progression. Participants ranked each health state, followed by the TTO valuation exercise. Descriptors included NMIBC symptom severity, impact and treatment characteristics. In total, 202 members of the general public participated. The mean age was 46 (standard deviation [SD] 14.6) years. Sample mean (SD) EQ-5D-5L visual analogue scale (VAS) and index scores were 83.2 (12.3) and 0.89 (0.18), respectively. Mean utilities were 0.781 for No High-Grade Recurrence, 0.586 for High-Grade Recurrence, 0.572 for >1-Year Post-cystectomy and 0.283 for metastatic disease. The First Year Post-cystectomy path health state had a mean utility of 0.288. Pairwise comparisons found statistically significant differences between utilities (p < 0.001), except between High-Grade Recurrence and > 1-Year Post-cystectomy (p = 0.524). There were significant differences in utility scores by age and employment status. This study provides utility scores for health states describing living with NMIBC, which is associated with a significant health-related quality-of-life burden. These values address an existing gap in available data and have the potential to be used in models evaluating the cost-effectiveness of both current and newly developed treatments for bladder cancer.

Prediction of refractory gastroesophageal reflux disease in young children.

Many children respond to medical treatment for gastroesophageal reflux disease (GERD). However, some may require invasive intervention for refractory disease. Due to the lack of prognostic tools in children, this study aimed to develop a predictive model for refractory GERD. A retrospective review was performed in children with symptoms of GERD at a university hospital. Refractory GERD was defined as an unresponsive disease after optimal treatment with medication for >8 weeks. The predictive model was constructed based on clinical features and 24-h multichannel intraluminal impedance-pH (MII-pH) monitoring results. A total of 205 children were included with a median (IQR) age of 0.6 (0.3, 2.0) years. Over half of the patients (59.5%) had motor disabilities. Forty-four children (21.5%) were diagnosed with refractory GERD and subsequently underwent fundoplication. Multivariable analysis suggested that the refractory disease was associated with motor disabilities (OR: 5.35; 95% CI: 2.06-13.91), recurrent aspiration pneumonia (OR: 2.78; 95% CI: 1.24-6.26), prematurity with an onset of GERD at a post-conceptual age <40 weeks (OR: 6.76; 95% CI: 1.96-23.33), and abnormal total reflux episodes according to age (OR: 2.78; 95% CI: 1.24-6.19), but not the acid exposure time or symptom association analysis. The predictive model for refractory GERD based on associated factors revealed an area under the ROC curve of 76.8% (95% CI: 69.2%-84.3%) with a sensitivity of 77.3% and a specificity of 64% when applying a cutoff score of ≥2.5. The predictive model, using clinical features and MII-pH, may be an additional tool to predict refractory GERD in young children.

Cap Polyposis: An Elusive Diagnosis in a Pediatric Patient Successfully Managed With Endoscopic Treatment

Cap polyposis is a rare condition of the rectum or sigmoid colon manifested by inflammatory polyps covered by a thick layer of fibrinopurulent mucus. This condition typically presents as mucoid diarrhea and rectal bleeding, and patients are often prescribed antibiotics (such as those for Helicobacter pylori), steroids, infliximab, or aminosalicylates. Surgical management is an option for unresponsive disease, but endoscopic management has been rarely reported. For cases of cap polyposis in which conservative medical management fails, wide-field endoscopic mucosal resection is a viable option.

Dynamic alteration in SULmax predicts early pathological tumor response and short-term prognosis in non-small cell lung cancer treated with neoadjuvant immunochemotherapy.

Introduction: Biomarkers predicting tumor response to neoadjuvant immunochemotherapy in non-small cell lung cancer (NSCLC) are still lacking despite great efforts. We aimed to assess the effectiveness of the immune PET Response Criteria in Solid Tumors via SULmax (iPERCIST-max) in predicting tumor response to neoadjuvant immunochemotherapy and short-term survival in locally advanced NSCLC. Methods: In this prospective cohort study, we calculated SULmax, SULpeak, metabolic tumor volume (MTV), total lesion glycolysis (TLG) and their dynamic percentage changes in a training cohort. We then investigated the correlation between alterations in these parameters and pathological tumor responses. Subsequently, iPERCIST-max defined by the proportional changes in the SULmax response (△SULmax%) was constructed and internally validated using a time-dependent receiver operating characteristic (ROC) curve and the area under the curve (AUC) value. A prospective cohort from the Sun Yat-Sen University Cancer Center (SYSUCC) was also included for external validation. The relationship between the iPERCIST-max responsiveness and event-free survival in the training cohort was also investigated. Results: Fifty-five patients with NSCLC were included in this study from May 2019 to December 2021. Significant alterations in post-treatment SULmax (p < 0.001), SULpeak (p < 0.001), SULmean (p < 0.001), MTV (p < 0.001), TLG (p < 0.001), and tumor size (p < 0.001) were observed compared to baseline values. Significant differences in SULpeak, SULmax, and SULmean between major pathological response (mPR) and non-mPR statuses were observed. The optimal cutoff values of the SULmax response rate were −70.0% and −88.0% using the X-tile software. The univariate and multivariate binary logistic regression showed that iPERCIST-max is the only significant key predictor for mPR status [OR = 84.0, 95% confidence interval (CI): 7.84–900.12, p < 0.001]. The AUC value for iPERCIST-max was 0.896 (95% CI: 0.776–1.000, p < 0.001). Further, external validation showed that the AUC value for iPERCIST-max in the SYSUCC cohort was 0.889 (95% CI: 0.698–1.000, p = 0.05). Significantly better event-free survival (EFS) in iPERCIST-max responsive disease (31.5 months, 95% CI 27.9–35.1) than that in iPERCIST-max unresponsive disease (22.2 months, 95% CI: 17.3–27.1 months, p = 0.024) was observed. Conclusion: iPERCIST-max could better predict both early pathological tumor response and short-term prognosis of NSCLC treated with neoadjuvant immunochemotherapy than commonly used criteria. Furthermore, large-scale prospective studies are required to confirm the generalizability of our findings.

S1987 Cap Polyposis: A Rare Condition in a Pediatric Patient Successfully Treated With Endoscopic Treatment

Introduction: Cap polyposis is a rare condition of the rectum or sigmoid colon manifested by inflammatory polyps covered by a thick layer of fibrinopurulent mucus. This condition typically presents as mucoid diarrhea and rectal bleeding, and patients are often prescribed antibiotics (such as those for Helicobacter pylori), steroids, infliximab, or aminosalicylates. Surgical management is an option for unresponsive disease, but endoscopic management has been rarely reported. Case Description/Methods: A 16-year-old boy had a 10-year history of mucoid diarrhea and occasional rectal bleeding and incontinence. Previous endoscopy revealed pseudopolyps in the rectum that appeared inflammatory with granulation tissue. Initial laboratory evaluation revealed mild iron deficiency, anemia, and hypoalbuminemia. The patient was treated with limited polypectomy, topical steroids, and diphenoxylate-atropine, which did not resolve his symptoms. A full workup for inflammatory bowel disease with an upper endoscopy, colonoscopy, and magnetic resonance enterography showed indications of marked polyposis in the rectum that was suggestive of “cap polyposis”. Tests for H. pylori were negative. There was no improvement with metronidazole or with treatments to reduce straining during bowel movements. Repeat sigmoidoscopy showed diffuse 1–4-cm multilobulated polypoid lesions in the rectum. Initially ESD was considered but deemed unsuitable due to poor lifting of the lesions. Thus, wide field endoscopic mucosal resection (WEMR) was performed, Approximately 40 band ligations with snare endoscopic submucosal resection were performed with near complete removal of all of the lesions. There was no post-procedure bleeding, pain, or other adverse effects. The resected tissue specimen had signs of high-grade dysplasia away from the resection margins. The patient’s symptoms resolved, and a second-look procedure 3.5 months later revealed only a slightly nodular area with no signs of dysplasia or cap polyposis. Discussion: Patients with cap polyposis typically report mucoid stools and rectal bleeding, and evaluations reveal a characteristic pattern on colonoscopy and pathology. For cases of cap polyposis in which conservative medical management fails, wide-field endoscopic mucosal resection is a viable option.

Sequential Intravesical Valrubicin and Docetaxel for the Salvage Treatment of Non-Muscle-Invasive Bladder Cancer.

Intravesical gemcitabine-docetaxel has emerged as an efficacious and well-tolerated salvage therapy for non-muscle-invasive bladder cancer. However, further rescue therapies are needed for subsequent recurrences or intolerance, particularly when cystectomy is refused or precluded. Valrubicin is a U.S. Food and Drug Administration-approved agent for bacillus Calmette-Guérin unresponsive disease, yet as monotherapy has demonstrated poor efficacy. We report our experience with sequential intravesical valrubicin and docetaxel as a rescue therapy for non-muscle-invasive bladder cancer. We retrospectively identified all patients with recurrent non-muscle-invasive bladder cancer treated with valrubicin and docetaxel between April 2013 and June 2021. Patients received weekly sequential intravesical instillations of 800 mg valrubicin and 37.5 mg docetaxel for 6 weeks. If disease-free at first follow-up, monthly maintenance of 2 years was initiated. The primary outcome was recurrence-free survival, assessed using the Kaplan-Meier method. The analysis included 75 patients with median follow-up of 21 months (IQR: 13-37). Twelve patients with low-grade disease had a 73% recurrence-free survival at 2 years. Sixty-three patients with recurrent high-grade disease had a 38% 2-year high-grade recurrence-free survival. Forty-two (56%) patients had carcinoma in situ present; recurrence-free survival was similar for those with and without carcinoma in situ (P = .63). Two patients died of metastatic bladder cancer while 10 underwent cystectomy. Among patients with high-grade disease, overall, cancer-specific, and cystectomy-free survivals were 87%, 96%, and 84% at 2 years, respectively. Adverse events included bladder spasms (n = 18), urinary frequency (n = 10), and dysuria (n = 8). Two patients could not tolerate valrubicin and docetaxel induction. In a heavily pretreated population, our results suggest valrubicin and docetaxel is an effective rescue treatment for patients with recurrent non-muscle-invasive bladder cancer. Further prospective evaluation is needed.

MP54-17 TIMING OF RADICAL CYSTECTOMY FOR BCG FAILURE

You have accessJournal of UrologyCME1 May 2022MP54-17 TIMING OF RADICAL CYSTECTOMY FOR BCG FAILURE Patrick Hensley, Niyati Lobo, Kelly Bree, Akshay Sood, Neema Navai, Colin Dinney, and Ashish Kamat Patrick HensleyPatrick Hensley More articles by this author , Niyati LoboNiyati Lobo More articles by this author , Kelly BreeKelly Bree More articles by this author , Akshay SoodAkshay Sood More articles by this author , Neema NavaiNeema Navai More articles by this author , Colin DinneyColin Dinney More articles by this author , and Ashish KamatAshish Kamat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002633.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We examine how the timing of radical cystectomy (RC) in a cohort of uniformly treated patients who recur despite intravesical bacillus Calmette-Guérin (BCG) therapy impacts oncologic outcomes. METHODS: An institutional review of patients who underwent radical cystectomy (RC) for ≤cT3N0 urothelial carcinoma of the bladder from 2005-2020 was performed. Patients received at least induction BCG and were categorized as either BCG-nonmuscle-invasive bladder cancer (BCG-NMIBC; ≤cT1 after BCG) vs. BCG-muscle-invasive bladder cancer (BCG-MIBC; progression to ≥cT2 disease after BCG) based on clinical stage prior to RC. Patients who underwent RC for de novo MIBC (D-MIBC) were included as a comparator. Kaplan-Meier analysis estimated median overall survival (OS) and cancer-specific survival (CSS). Comparison of time-to-event endpoints was done using the log-rank test. RESULTS: 78 patients with BCG-NMIBC, 167 with BCG-MIBC, and 637 with D-MIBC were included. Median follow-up after RC was 2.8 years. 446 (55%) MIBC patients received neoadjuvant chemotherapy according to our institutional risk-stratified approach. 69 (88%) NMIBC patients met the FDA definition of ‘BCG unresponsive disease’. Rates of ≥(y)pT3 disease at RC were 12%; 46%; 39% (p <0.001) and for (y)N+ disease were 5%; 27%; 20% (p <0.001) for BCG-NMIBC; BCG-MIBC; D-MIBC, respectively. Median OS was 9.5 years (95% CI 5.3-13.7), 4.1 years (95% CI 2.1-6.2), and 6.9 years (95% CI 5.6-8.3) for BCG-NMIBC; BCG-MIBC; D-MIBC, respectively (Figure). There were no survival differences following RC between patients meeting the following criteria for BCG unresponsive NMIBC: (1) residual/recurrent CIS, (2) recurrent HG Ta/1, or (3) persistent/new HG T1 disease. CONCLUSIONS: Patients who undergo RC for recurrent NMIBC after BCG failure, but prior to progression to MIBC, exhibit favorable pathologic stage and survival outcomes relative to those who progress to MIBC on BCG. Our data emphasize the importance of vigilance, accurate clinical staging and timely intervention in patients who exhibit BCG failure. Source of Funding: This research was supported by the Wayne B. Duddlesten Professorship in Cancer Research, the Raymond and Maria Floyd Bladder Cancer Research Foundation Grant, NIH/NCI UTMD Anderson SPORE in Genitourinary Cancer (P50CA091846), the Cancer Center Support Grant (NCI Grant P30 CA016672), and a Urology Care Foundation Research Scholars Award (IRG 85-001-25) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e933 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Patrick Hensley More articles by this author Niyati Lobo More articles by this author Kelly Bree More articles by this author Akshay Sood More articles by this author Neema Navai More articles by this author Colin Dinney More articles by this author Ashish Kamat More articles by this author Expand All Advertisement PDF DownloadLoading ...

Off-label use of omalizumab in a 6-year-old child with severe atopic dermatitis.

Background: Atopic dermatitis (AD) is a common chronic inflammatory skin disorder that affects up to 3% of adults and 15%-20% of children across the world. Although the mainstay of treatment is topical corticosteroids and/or calcineurin inhibitors, a majority of patients will not achieve a control of their condition and will need systemic treatment with steroids and immunosuppressants (1). Omalizumab is a humanized anti-IgE antibody licensed by the European Medical Agency for treatment of severe allergic asthma and spontaneous chronic urticaria in children older than 6 and 12 years, respectively; and a promising efficacy of omalizumab in the treatment of severe refractory AD has been shown by the ADAPT randomized clinical trial (2).Case report: A 6-year-old male patient being treated and followed at a pediatric dermatology clinic for a diagnosis of AD since the age of 3 years, showed unresponsive disease to different topical treatment options and non-pharmacological measures. The patient was referred to our clinic for systemic treatment when his SCORAD index was 70/103. At our immunology clinic, we did an extensive workup to unveil a comorbid or underlying disease. His labs showed high IgE levels at 2500 IU/mL, hypereosinophilia, and normal IgA, IgM, and lymphocyte subsets. We started him on different lines of immunosuppressants, including cyclosporine, prednisolone, tacrolimus, and intensive topical treatment; however, the patient did not show any noticeable response for 2 years. We then started him on omalizumab 300 mg twice weekly, and the SCORAD index dropped to 57 at 12 weeks and 55 at 18 weeks. The drug is still well tolerated, and we were able to stop systemic steroids at 15 weeks of treatment.Conclusion: Off-label use of omalizumab in a 6-year-old child with refractory severe AD was effective and safe in controlling the disease even though conventional systemic immunosuppressants proved ineffective.

Adjuvant therapies for non-muscle-invasive bladder cancer: advances during BCG shortage.

Non-muscle-invasive bladder cancer (NMIBC) represents a significant global therapeutic challenge, particularly in the era of Bacillus Calmette-Guérin (BCG) shortage. High-risk NMIBC can progress to muscle invasive or metastatic disease in 25% of patients. Optimal treatment selection, according to risk stratification, is imperative. International guidelines slightly differ in their categorisation of low, intermediate and high-risk NMIBC. Nonetheless, a single post-operative instillation of chemotherapy with Mitomycin C (MMC) or Gemcitabine improves relapse-free survival (RFS) in low-risk NMIBC. Induction and maintenance intravesical BCG remains the historical gold standard for patients with intermediate or high-risk NMIBC. However, clinicians may be forced to consider alternatives given the current BCG shortage. Both intravesical MMC and Gemcitabine have been associated with similar efficacy to BCG, albeit in smaller studies. MMC may also be manipulated using a variety of methods to potentiate its effects. BCG treatment delivery may also be modified without affecting efficacy through dose reduction and abbreviation or omission of maintenance therapy. Preliminary data also highlight that directly proceeding to radical cystectomy may not adversely affect long-term quality of life measures. Access to new systemic and intravesical therapies must be prioritised for patients with BCG recurrent or unresponsive disease. When used in conjunction with molecularly defined biomarkers, these agents herald the potential for improved survival outcomes and alleviation of the current BCG shortage.

Salvage for BCG Unresponsive and Recurrent Disease.

Salvage for BCG Unresponsive and Recurrent Disease.

PD63-03 UTILITY OF BLUE LIGHT FLEXIBLE CYSTOSCOPY FOR BLADDER CANCER SURVEILLANCE AFTER INTRAVESICAL THERAPY

You have accessJournal of UrologyBladder Cancer: Non-invasive III (PD63)1 Sep 2021PD63-03 UTILITY OF BLUE LIGHT FLEXIBLE CYSTOSCOPY FOR BLADDER CANCER SURVEILLANCE AFTER INTRAVESICAL THERAPY Sanam Ladi Seyedian, Xiaosong Meng, Sidney Roberts, Hamed Ahmadi, Jeffrey Howard, Iftach Chaplin, Aditya Bagrodia, Vitaly Margulis, Solomon Woldu, Yair Lotan, and Siamak Daneshmand Sanam Ladi SeyedianSanam Ladi Seyedian More articles by this author , Xiaosong MengXiaosong Meng More articles by this author , Sidney RobertsSidney Roberts More articles by this author , Hamed AhmadiHamed Ahmadi More articles by this author , Jeffrey HowardJeffrey Howard More articles by this author , Iftach ChaplinIftach Chaplin More articles by this author , Aditya BagrodiaAditya Bagrodia More articles by this author , Vitaly MargulisVitaly Margulis More articles by this author , Solomon WolduSolomon Woldu More articles by this author , Yair LotanYair Lotan More articles by this author , and Siamak DaneshmandSiamak Daneshmand More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002107.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Previous studies have demonstrated the benefit of blue light flexible cystoscopy (BLFC) in clinical practice though detection of additional cancers missed with white light cystoscopy (WLC) alone. However, the utility of BLFC for surveillance in patients receiving intravesical treatments has not been extensively studied. Identifying early recurrences in these patients can result in better stratification and possibly improved outcomes. Herein, we aim to evaluate the utility of BLFC for surveillance of bladder cancer post intravesical therapy. METHODS: Clinicopathologic information was collected from consecutive patients undergoing office-based BLFC who were enrolled in the Cysview registry between May 2018 and December 2020 at two high volume academic centers. Patients with last intravesical treatment >1 year were excluded. Data were stratified based on the time from last intravesical treatment. RESULTS: A total of 277 BLFC were performed in 136 patients (mean age 73 years). 85% were male, 61% had history of smoking and 30% had ³2 prior bladder cancer recurrences. 74% had high grade (HG) disease and the highest stage prior to BLFC was Ta, T1, carcinoma in situ (CIS), and Ta/T1+CIS in 40%, 34%, 17% and 9%, respectively.Intravesical Bacillus Calmette–Guérin (BCG) and intravesical chemotherapy were used in 83% and 17%, respectively. WLC and BLFC were both normal in 162 (58.5%) procedures. WLC or BLFC was abnormal in 40% of post BCG and 37% of post intravesical chemotherapy cystoscopies.A total of 52 office biopsy were taken, of which, 23/52 (44%) were malignant (Table 1). BLFC was abnormal in all positive biopsies, while only 3/23 had positive or atypical cytology. BLFC was 100% sensitive for detection of cancer in this cohort. WLC was normal and BLFC was abnormal in 23 (8%) procedures. Of these, 16/23 had office-based biopsy and cancer was detected in 9/16. BLFC had the highest false positive rate at <6 weeks post intravesical therapy. CONCLUSIONS: Office-based BLFC helps improve early detection of recurrence in cases with normal WLC. BLFC can help in surveillance of patients receiving intravesical therapy, improve performance of office-based biopsy and increase early detection of BCG unresponsive disease. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1138-e1139 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sanam Ladi Seyedian More articles by this author Xiaosong Meng More articles by this author Sidney Roberts More articles by this author Hamed Ahmadi More articles by this author Jeffrey Howard More articles by this author Iftach Chaplin More articles by this author Aditya Bagrodia More articles by this author Vitaly Margulis More articles by this author Solomon Woldu More articles by this author Yair Lotan More articles by this author Siamak Daneshmand More articles by this author Expand All Advertisement Loading ...

Dilemma-High Response Rates Vs High Toxicity: Autologous Stem Cell Transplantation for Lymphoma

Introduction: Autologous stem cell transplantation (ASCT) is employed successfully at different settings in lymphoma. Most of the patients have been achieving durable remission rates with long term survival. Herein, our aim is to report outcomes of our relapse refractory Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients who underwent ASCT.Methods: We retrospectively evaluated 86 relapse refractory HL, 21 mantle cell lymphoma, 16 low grade lymphoma (n=12 follicular lymphoma, n=4 marginal zone lymphoma) patients who underwent ASCT between 2005-2015. The patients were followed after ASCT for relapse.Results: The baseline characteristics of patients are given in the table. The patients were diagnosed as nodular sclerosing subtype most frequently in HL group (75%). In HL group, 27 patients (32%) had chemo-refractory high risk disease prior to ASCT. On the other hand, all patients in mantle cell and low grade lymphoma groups were in at least partial remission at the time of ASCT. In HL group, at a median time of 28 months after ASCT (range, 1-119), 51 patients (60%) achieved complete remission, 7 patients had partial remission (8%), 28 patients (32%) had stabile disease or progression/relapse. The response was higher in patients with early stage disease (I-II), remission status prior to transplant and BEAM conditioning regimen compared to advance stage (III-IV) (p=0.017), active disease prior to transplant (p=0.008) and other conditioning regimens (p=0.05). Nine patients (10%) died within three months of ASCT due to infection. From 28 patients, 5 patients received brentixumab, 3 patients received nivolumab, 10 patients had GDP, 10 patients had MOPP regimen. Four patient underwent allogeneic stem cell transplantation. Fifty four out of 58 (93%) patients transplanted with responsive disease were alive without disease whereas 4 out of 28 (14%) patients with unresponsive disease were alive in remission within 3 years post ASCT. In low grade lymphoma group, 9 patients (56%) achieved complete remission after ASCT. Interestingly, complete response rate was higher in females (80% vs 43%, p=0.35). Five patients (31%) died within three months of ASCT due to infection. Two patients (13%) relapsed with a median time of 8 months (range, 3-13 months) and received MINE as salvage treatment and followed in complete remission. The 3-year overall survival was 51%, 5-year overall survival was 40%. In mantle cell lymphoma group, 6 patients (29%) achieved complete remission. Four patients (19%) died within three months of ASCT due to infection. Eleven patients (52%) was relapsed with a median time of 39 months (range, 4-123 months). Ten patients received BORID (bortezomib, rituximab, dexamethasone) and 1 patient received lenalidomide as salvage therapy and six of them achieved complete remission. Three patients underwent allogeneic hematopoietic stem cell transplantation as well as two patients received ibrutinib as fourth line therapy and followed in remission. The 3-year overall survival was 71% (Figure).Conclusion: In our experience, ASCT is a feasible option in patients who responded showing long term durable complete remission rates. In Hodgkin lymphoma, patients with BEAM conditioning, remission status prior to ASCT and early stage disease had better response rates. Females achieved higher responses in low grade lymphomas. However, 10% of HL, 31% of low grade lymphoma and 19% of mantle cell lymphoma patients were died because of treatment related toxicity. Candidate patients should be evaluated carefully. Today, novel agents may present a less intensive approach for achieving response. [Display omitted] DisclosuresIlhan:Novartis: Consultancy.