Citations

Abstract Introduction: In a multiple myeloma mouse model (MM), we determined that subcutaneous (SC) continuous lenalidomide (Len) delivery demonstrated superior tolerability and efficacy to the active control Len given by daily i.p. over a 28 day cycle. Healthy volunteer studies showed that at a daily dose of 9.6 mg a day (400 mcg/h) the Len AUC0-24 was ∼60% less than that observed with an oral 25 mg Len dose. We hypothesized that this modality could improve Len’s therapeutic index by lowering the hematologic toxicity while maintaining or improving the efficacy. Methods: A phase 1b study in 2nd line or greater relapsed/refractory MM was performed to confirm the animal findings and determine if continuous Len can improve its therapeutic index with no negative impact on the cellular immune system. In brief, an RVd regimen was utilized wherein SC Len 9.6 mg/day was administered with an FDA registered ambulatory pump in a continuous fashion using a 28/28 day cycle. Patients were either trained to operate their pump and change the pre-filled cassettes at home or were managed in the clinic on M-W-F. All patients were seen in the clinic to receive weekly bortezomib 1.3mg/m2 and dexamethasone dosed weekly at 40/20mg, according to age. Patients who received bortezomib in a prior cycle were required to demonstrate sensitivity defined as durability for 6 months after discontinuation of the bortezomib. Results: Between September 2023 and November 2024, 6 relapsed/refractory MM patients were enrolled from 2 US community-based investigational sites in the phase 1b study. Median age was 73, male to female ratio 1/1, Caucasian 100%, and median lines of previous therapy were 2 (range 1-7). Two patients were refractory and 4 were relapsed to their prior treatment. Four patients were previously exposed to Len, one of which was discontinued from a prior regimen because of severe fatigue, and 6 had received prior bortezomib. Patients had received 3-12 cycles of study therapy. No drug-related grade 3/4 hematologic or non-hematologic toxicity occurred within cycle 1. No patients experienced drug-related anemia, neutropenia, leukopenia, or thrombocytopenia greater than grade 2 in up to 12 cycles of therapy. All 6 patients achieved an objective response (CR=1 / PR=5). One patient who achieved a partial response experienced grade 2 skin reaction during cycle 3 and withdrew from the study. Five patients are continuing treatment per protocol with a median PFS of > 10 mo. Len pharmacokinetics produced median steady-state blood levels (Cmax) of 39 ng/mL (range 26-94) (N=6) and were above the minimum target of 25 ng/mL. The Len regimen produced a median AUC0-24 of 921-1h*ng/ml (range 630-1503). Immune profiling did not show significant increases in immune checkpoint expression associated with T-cell exhaustion while CD19+ B cells were significantly depleted. Conclusion: Continuous delivery of low dose Len provides meaningful efficacy and improved tolerability with no grade >3 drug-related hematologic toxicity. Further studies in MM and chronic lymphocytic leukemia are planned. Citation Format: Nash Gabrail, Keith Lerro, Mohamad A. Hussein, Asher A. Chanan-Khan, Jamie C. Oliver. Continuous subcutaneous lenalidomide delivery improves the therapeutic index and avoids drug-related grade 3/4 hematologic toxicity in patients with relapsed/refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB207.

ObjectiveTo identify characteristics of patients who have poor improvement in symptoms following surgical management of Zenker Diverticulum (ZD).MethodsProspective, multicenter cohort study of all individuals enrolled in the Prospective OUtcomes of Cricopharyngeus Hypertonicity (POUCH) Collaborative who underwent surgical repair of ZD between August 2017 and January 2024. Patient demographics, esophagrams, and the 10‐item Eating Assessment Tool (EAT‐10) pre‐ and post‐procedure were obtained from a REDCap database. t‐tests, Wilcoxon rank sum tests, Chi‐square or Fisher's exact tests were used to compare the characteristics. Patients with <50% improvement in their EAT‐10 scores were deemed surgical nonresponders (SNRs). Those with ≥50% improvement in their EAT‐10 scores were deemed surgical responders (SRs).ResultsA total of 184 patients were prospectively followed after undergoing either open or endoscopic surgical management. Twenty‐two patients (12%) were deemed SNRs. Preoperative presence of a hiatal hernia was statistically significant characteristic between the SNRs (63.6%) and SRs (32.1%) (p = 0.004). Size of the ZD and history of previous ZD surgery was not a significant characteristic. The length of stay and complication rate were not statistically different between the groups.ConclusionCoexistent esophageal pathology may lead to poor symptomatic improvement following ZD surgery. Preoperative workup of other esophageal disorders is recommended to detect likely SNRs. For SNRs, further esophageal workup may be necessary to evaluate for other esophageal causes related to poor symptomatic improvement following ZD surgery.Level of Evidence3 Laryngoscope, 134:4897–4902, 2024

Objectives The aim of the study was to identify trends in postoperative management of persons undergoing surgery for Zenker diverticula (ZD) by evaluating length of stay (LOS), diet on discharge, and imaging with or without surgical complication. Methods Prospectively enrolled adult patients with cricopharyngeal muscle dysfunction with diverticula undergoing surgery from August 1, 2017 to February 1, 2023 were included. Data were extracted from a multi‐institutional REDCap database, summarizing means, medians, percentages, and frequencies. Fisher's exact or chi squared analyses were utilized, as appropriate, to compare subsets of data. Descriptive analysis assessed differences in clinical course and the relationship to postoperative management. Results There were 298 patients with a mean (standard deviation) age of 71.8 (11.2) years and 60% male. Endoscopic surgery was performed in 79.5% (237/298) of patients versus 20.5% (61/298) open surgery. Sixty patients (20.1%) received postoperative imaging, with four leaks identified. Complications were identified in 9.4% of cases ( n = 29 complications in 28 patients), more commonly in open surgery. Most (81.2%) patients were discharged within 23 h. About half of patients (49%) were discharged from the hospital on a pureed/liquid diet; 36% had been advanced to a soft diet. In patients without complications, LOS was significantly longer following open cases ( p = 0.002); postoperative diet was not different between open and endoscopic ( p = 0.26). Conclusions Overall, most patients are discharged within 23 h without imaging. However, LOS was affected by surgical approach. Postoperative complications are different in endoscopic versus open surgery. Complications with either approach were associated with prolonged LOS, need for imaging, and diet restriction. Level of Evidence Level III Laryngoscope , 134:2678–2683, 2024

ObjectiveTo compare improvement in patient‐reported outcomes (PROM) in persons undergoing endoscopic and open surgical management of Zenker diverticula (ZD).MethodologyProspective, multicenter cohort study of all individuals enrolled in the Prospective OUtcomes of Cricopharyngeus Hypertonicity (POUCH) Collaborative who underwent surgery for ZD. Patient survey, radiography reports, and the 10‐item Eating Assessment Tool (EAT‐10) pre‐ and post‐procedure were abstracted from a REDCap database, which summarized means, medians, percentages, and frequencies of. Outcome based on operative intervention (endoscopic vs. open) was compared using t‐test, Wilcoxon rank sum test or chi‐square test, as appropriate.ResultsOne hundred and forty‐seven persons were prospectively followed. The mean age (SD) of the cohort was 68.7 (11.0). Overall, 66% of patients reported 100% improvement in EAT‐10; 81% of patients had greater than 75% improvement; and 88% had greater than 50% improvement. Endoscopic was used for n = 109 patients, and open surgical intervention was used for n = 38. The median [interquartile range, IQR] EAT‐10 percent improvement for endoscopic treatment was 93.3% [72, 100], and open was 100% [92.3, 100] (p = 0.05). The incidence of intraoperative complications was 3.7% for endoscopic and 7.9% for open surgical management. The median [IQR] in follow‐up was 86 and 97.5 days, respectively.ConclusionBoth endoscopic and open surgical management of ZD provide significant improvement in patient‐reported outcomes. The data suggest that open diverticulectomy may provide a modest advantage in symptomatic improvement compared to endoscopic management. The data suggest that the postoperative complication rate is higher in the open surgical group.Level of Evidence3 Laryngoscope, 134:97–102, 2024

ObjectiveTo assess barium esophagram (BAS) as a diagnostic marker for patients with Killian Jamieson diverticula (KJD).MethodsProspective, multicenter cohort study of individuals enrolled in the Prospective OUtcomes of Cricopharyngeus Hypertonicity (POUCH) Collaborative. Patient demographics, comorbidities, radiographic imaging reports, laryngoscopy findings, patient‐reported outcome measures (PROM), and operative reporting were abstracted from a REDCap database and summarized using means, medians, percentages, frequencies. Paired t‐tests and Wilcoxon Signed Rank test were used to test pre‐ to post‐operative differences in RSI, EAT‐10, and VHI‐10 scores. Diagnostic test evaluation including sensitivity, specificity, positive, and negative predictive value with 95% confidence intervals were calculated comparing BAS findings to operative report.ResultsA total of 287 persons were enrolled; 13 (4%) patients were identified with confirmed KJD on operative reports. 100% underwent open transcervical excision. BAS has a 46.2% (95% confidence interval [CI]: 23.2, 70.9) sensitivity and 97.8% (95% CI: 95.3, 99.0) specificity in detecting a KJD and 50% (95% CI: 25.4, 74.6) positive predictive value but 97.4% (95%CI: 94.8, 98.7) negative predictive value. Preoperatively, patients reported mean (SD) RSI and EAT‐10 of 19.4 (9) and 8.3 (7.5) accordingly. Postoperatively, patients reported mean (SD) RSI and EAT‐10 as 5.4 (6.2) and 2.3 (3.3). Both changes in RSI and EAT‐10 were statistically significant (p = 0.008, p = 0.03).ConclusionKJD are rare and represent <5% of hypopharyngeal diverticula undergoing surgical intervention. Open transcervical surgery significantly improves symptoms of dysphagia. BAS has high specificity but low sensitivity in detecting KJD.Level of Evidence4 Laryngoscope, 133:2110–2115, 2023

ObjectiveTo describe demographics and imaging and compare findings and symptoms at presentation in a large cohort of persons with cricopharyngeus muscle dysfunction (CPMD) with and without hypopharyngeal diverticula.MethodologyProspective, multicenter cohort study of all individuals enrolled in the Prospective OUtcomes of Cricopharyngeal Hypertonicity (POUCH) Collaborative. Patient survey, comorbidities, radiography, laryngoscopy findings, and patient‐reported outcome measures (e.g., Eating Assessment Tool [EAT‐10]) data were abstracted from a REDCap database and summarized using means, medians, percentages, and frequencies. Diagnostic categories were compared using analysis of variance.ResultsA total of 250 persons were included. The mean age (standard deviation [SD]) of the cohort was 69.0 (11.2). Forty‐two percent identified as female. Zenker diverticula (ZD) was diagnosed in 85.2%, 9.2% with CPMD without diverticula, 4.4% with a Killian Jamieson diverticula (KJD), and 1.2% traction‐type diverticula. There were no differences between diagnostic categories in regard to age, gender, and duration of symptoms (p = 0.25, 0.19, 0.45). The mean (SD) EAT‐10 score for each group was 17.1 (10.1) for ZD, 20.2 (9.3) for CPMD, and 10.3 (9.4) for KJD. Patients with isolated CPMD had significantly greater EAT‐10 scores compared to the other diagnostic groups (p = 0.03).ConclusionZD is the most common, followed by CPMD without diverticula, KJD, and traction‐type. Patients with isolated obstructing CPMD may be more symptomatic than persons with ZD or KJD.Level of Evidence4 Laryngoscope, 133:1349–1355, 2023

Significance Our study not only reveals a novel role of peroxisome proliferator-activated receptor δ (PPARδ) in colonic inflammation and colitis-associated tumorigenesis, but also provides some rationale for development of PPARδ antagonists as new therapeutic agents in the treatment of inflammatory bowel disease and colitis-associated colorectal cancer. Moreover, our findings indicate that prostaglandin E 2 generated by chronic inflammation is a crucial mediator connecting chronic inflammation and colorectal carcinogenesis.