Citations

ABSTRACT The optimal phage susceptibility testing (PST) method is unclear. Here, two PST methods were compared using Pseudomonas aeruginosa isolates recovered from patients with cystic fibrosis enrolled in a placebo-controlled clinical trial of a single intravenous dose of a four-phage cocktail (WRAIR-PAM-CF1). In total, 508 P. aeruginosa sputum isolates were evaluated, including isolates collected before or after phage or placebo treatment, isolates from the same trial participants over time, and isolates of different colony morphologies from the same participants at the same time point. Susceptibility to phages PaWRA01Φ11, PaWRA01Φ39, PaWRA02Φ83, and PaWRA02Φ87 and a cocktail of all four phages was assessed using a plaque assay (PA) and a Biolog Omnilog-based liquid assay (LA) with the same bacterial inoculum. A total of 170/508 isolates (33%) and 195/508 isolates (38%) were identified as susceptible to the cocktail by PA and LA, respectively. Among the susceptible isolates, 169/170 (99%; PA) and 187/195 (96%; LA) also tested susceptible to at least one of the four phages in the cocktail. Susceptible percent agreement between the PA and LA ranged from 76% to 100% and non-susceptible percent agreement ranged from 89% to 100% for all phages studied and the cocktail. Phage PaWRA02Φ83 demonstrated the greatest individual activity, with 164/508 (32%) and 188/508 (37%) isolates testing susceptible by PA and LA, respectively. The four-phage cocktail provided numerically broader coverage of P. aeruginosa (i.e., had the highest susceptibility rate) than did any single phage. There was high concordance between PST results by PA and LA. IMPORTANCE Standardization of phage susceptibility testing (PST) methods is essential to support phage therapy trials and any future clinical implementation. There are no standardized PST methods or interpretive criteria for PST. In this study, PST was performed by a plaque assay and a Biolog Omnilog-based liquid assay on Pseudomonas aeruginosa isolates recovered from cystic fibrosis patients enrolled in a clinical trial. Susceptibility of 508 isolates to four phages and a cocktail of all four was evaluated. There was high concordance between susceptibility assessed by plaque and liquid assays and numerically broader coverage of P. aeruginosa by the cocktail compared to any single phage. This manuscript should be of interest to those performing PST.

Abstract Tumors of neuroendocrine origin are a heterogenous group of related neoplasms which can arise from anywhere in the body. Neuroendocrine neoplasms (NENs) are categorized by site of origin, differentiation status and grade (Ki‐67 expression and/or mitotic rate), with significant prognostic variability accordingly. Historically, the prevalence of bone metastasis is reported to be 6%–12% based on “first generation” (i.e., 111 Indium pentetreotide [Octreoscan®]) somatostatin receptor imaging (SSRI). We conducted a retrospective cohort study including patients with well‐differentiated NENs to determine the clinical and imaging characteristics of osseous metastases when evaluated with higher‐sensitivity 68 Gallium‐DOTATATE positron emission tomography (PET) scans, as well as determining fracture prevalence in selected sub‐cohorts. We also developed a risk score analysis to assess risk of fracture in this cohort. Four hundred twenty‐four patients were identified for inclusion. The median age was 61 years. Most patients were asymptomatic (64%), had sclerotic lesions (77%), Krenning 4 (71%), and had >3 sites (69%) of osseous disease. A high proportion of patients had osseous metastases at sites with high risk for fracture, including vertebra (82%), pelvis (63%), and peri‐trochanteric femur (34%). Fifty‐seven patients (13%) in the entire cohort suffered a fracture. Fracture prevalence was significantly lower in small bowel neuroendocrine tumors (NETs, 7%) and Grades 1 and 2 disease (8% and 9%, respectively), with higher prevalence in pancreatic NETs, paragangliomas/pheochromocytomas, lung carcinoid, and Grade 3 disease (≥20% for each; p ‐values <.05). Our study showed that the rate of osseous metastatic disease approximates 20% in well‐differentiated NENs. Most bone metastases are asymptomatic and the risk of fracture is variable based on the primary site of disease and tumor grade. Our novel risk score analysis for fracture was designed to assist clinician decision making as to management of bone metastasis in this patient population.

Objective Assess if velopharyngeal gap size during speech is associated with consonant accuracy and whether hypernasality severity and compensatory misarticulation errors (CMAs) mediate this relationship. Design Cross-sectional. Setting Metropolitan hospital. Participants Eighty-one patients undergoing assessment for velopharyngeal insufficiency (VPI). Assessment(s) Each patient completed a preoperative magnetic resonance imaging protocol during sustained /i/ production and a perceptual speech evaluation. Velopharyngeal gap size was measured in millimeters. Hypernasality was rated using the Cleft Audit Protocol for Speech-Augmented-Americleft Modification. Percent consonants correct (PCC) and percent of CMAs used were derived from transcriptions of the American English sentence or phrase sample. Main Outcome Measure(s) A generalized structural equation model was used to examine whether velopharyngeal gap size is associated with PCC indirectly through hypernasality severity and CMA use. Results Larger velopharyngeal gap sizes were associated with more severe hypernasality ( P < .001), greater hypernasality severity was associated with increased CMA use ( P < .001), and greater CMA use was associated with lower PCC ( P < .001). Velopharyngeal gap size was not directly associated with PCC ( P = .400). However, the full indirect pathway from gap size to PCC through hypernasality severity and CMA use was significant ( P = .001); gap size was significantly associated with PCC when accounting for both direct and indirect pathways combined ( P = .005). Conclusions These findings suggest hypernasality severity is the key mediator between gap size and speech accuracy. Patients with more severe hypernasality may benefit from timely surgical remediation of VPI to increase overall consonant accuracy.

PURPOSE Patients with breast cancer requiring postmastectomy radiation therapy (PMRT) often desire breast reconstruction. Reconstructions can be adversely affected by PMRT, and fear of reconstruction complications has discouraged adoption of short-course radiation therapy used after lumpectomy. To fill the evidence gap, we conducted a noninferiority trial of hypofractionated versus conventional PMRT in patients undergoing breast reconstruction. The primary outcome was reconstruction complication rate, a composite of wound healing, readmission, capsular contracture, unplanned reoperation, and reconstruction failure. METHODS Women with unilateral invasive breast cancer with planned immediate or delayed reconstruction and PMRT were randomly assigned (1:1) to 50 Gy (25 fractions/5 weeks) or 42.56 Gy (16 fractions/3 weeks). This study was designed with a noninferiority margin of 10%, assuming a 2-year reconstruction complication rate of 25% with conventional PMRT. Randomization was stratified by immediate versus delayed and autologous versus implant-only reconstruction. RESULTS Between 2018 and 2021, 898 patients enrolled with a median follow-up of 3.9 years; 825 patients were evaluable for the primary end point. The 24-month reconstruction complication rates were 12.3% (52/422) with hypofractionated PMRT and 10.2% (41/403) with conventional PMRT, corresponding to an estimated difference of -2.1% (95% CI, -6.5 to 2.2). The complication rate was higher (regardless of arm) with implant-only versus autologous reconstruction (odds ratio = 1.65). There was no statistically significant difference in 36-month locoregional recurrence rates: 1.5% (95% CI, 0.7 to 3.2) with hypofractionated and 2.2% (95% CI, 1.1 to 4.3) with conventional PMRT. Acute and late toxicity rates were not statistically different. CONCLUSION A 16-fraction course of hypofractionated PMRT is safe and noninferior to conventional PMRT in women undergoing breast reconstruction after mastectomy.

Background & Aims: We examined treatment patterns and clinical outcomes in a contemporary cohort of children with newly diagnosed inflammatory bowel disease (IBD) in a large, commercially insured U.S. population. Methods: Using the OptumLabs® Data Warehouse, we created an inception cohort of physician-diagnosed IBD in children aged 6–17 years between 2007–23. We examined cumulative incidence of hospitalization, surgery, safety events, and medication use in patients with Crohn's disease (CD) and ulcerative colitis (UC), overall and stratified by diagnostic era, race and ethnicity, sex, and age at diagnosis. Results: Among 787 children with newly diagnosed CD (age at diagnosis, 13.4±2.9y; 57% male; 82% White, 5% Black, 7% Hispanic) followed over mean 4.6±3.0y, 5-year risk of IBD-related hospitalization and major surgery was 30% and 10%, respectively. In children diagnosed in 2019–23, 1-year cumulative use of corticosteroids and advanced therapy was 46% and 75%, respectively; advanced therapy use increased significantly over time (aHR, 3.43 [95% CI, 2.71–4.32] for 2019–23 vs. 2007–12), while corticosteroid use declined (0.67 [0.53–0.84]). Risk of IBD-related hospitalization was lower in children diagnosed between 2019–23 (0.65 [0.43–0.97]) compared with those diagnosed between 2007-12; surgical risk did not decline significantly, with confidence intervals compatible with a clinically meaningful reduction. Among 399 children with newly diagnosed UC (age at diagnosis, 14.0±3.0y; 53% male; 78% White, 5% Black, 7% Hispanic) followed over 4.5±3.0y, 5-year risk of IBD-related hospitalization and colectomy was 36% and 8%, respectively. Advanced therapy use increased significantly over time (4.46 [2.85–6.98] for 2019–23 vs. 2007–12), with no significant change in hospitalization or surgical risk across eras. No consistent racial and ethnic, age, or sex differences in advanced therapy use or clinical outcomes were identified in either CD or UC. Conclusions: In a contemporary cohort of commercially insured children with newly diagnosed IBD, early advanced therapy use has increased markedly over time. Surgical risk did not decline significantly in either disease; however, the study was not powered to exclude a clinically meaningful reduction, and these findings are hypothesis-generating rather than conclusive.

Abstract Everolimus 10 mg daily is the standard dose for advanced neuroendocrine tumors (NETs), but adverse events frequently necessitate dose reduction. As a result, oncologists often adopt a dose‐escalation strategy starting at 5 mg and increasing the dose as tolerated. In this multicenter study, we evaluated the effect of reduced dose (RD) and standard dose (SD) everolimus on survival, progression, and toxicity in patients with advanced NETs. We conducted a multicenter retrospective cohort study of patients with advanced NETs treated with everolimus at Mayo Clinic and University Hospitals (Cleveland, OH). Patients were grouped by starting dose (5 mg vs. 10 mg). Primary endpoints were overall survival (OS), real‐world progression‐free survival (rwPFS), and adverse events. Multivariable Cox models, inverse probability of treatment weighting (IPTW), and time‐varying dose sensitivity analysis were used to account for confounding and dose crossover. Among 170 patients (48 started on 5 mg; 122 on 10 mg), the 5 mg cohort was older, had worse ECOG PS, and was more heavily pretreated. Median OS was 43.7 months (5 mg) versus 81.5 months (10 mg; log‐rank p = .02). However, after multivariable adjustment ( N = 124 G1–G2 patients; 51 events), the association was no longer statistically significant (adjusted HR, 0.59; 95% CI, 0.31–1.12; p = .11). Median rwPFS was 7.0 versus 12.4 months (log‐rank p = .05); the adjusted rwPFS difference was not statistically significant (HR, 0.95; 95% CI, 0.56–1.61; p = .84). Nearly half (46.7%) of 10 mg starters required dose reduction. Any‐grade toxicity was more common with 10 mg (89% vs. 75%; p = .05). The apparent survival advantage of standard‐dose everolimus was substantially attenuated after adjustment. These findings do not establish dose equivalence and should be interpreted in the context of limited statistical power. Given its more favorable observed tolerability profile, RD everolimus warrants prospective evaluation as a starting strategy for patients at increased risk of treatment‐related toxicity who may not tolerate SD.

Importance The incidence of human papillomavirus type 16 (HPV16–positive) recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is rising. Approved therapies offer a durable response to a minority of patients. Objective To determine the efficacy and safety of a therapeutic HPV16-targeted immunotherapy, PDS0101, in combination with pembrolizumab in participants with HPV16-positive R/M HNSCC, with separate evaluation of immune checkpoint inhibitor (ICI)–naive and ICI-resistant cohorts. Design, Setting, and Participants VERSATILE-002 was a phase 2, open-label, multicenter nonrandomized clinical trial conducted at 26 oncology centers from March 29, 2021, to May 15, 2025, across the US, UK, and Ireland using the Simon 2-stage optimal design. Efficacy analyses were performed on modified intent-to-treat (mITT) population; safety analyses included all participants who received 1 or more doses. Eighty-eight participants with histologically confirmed R/M HPV16-positive HNSCC were enrolled, of whom 87 (98.9%) received treatment and composed the safety population. Seventy five (85.2%) were in the mITT population used for efficacy analyses, of whom 53 (70.7%) were ICI-naive with a programmed cell death ligand 1 combined positive score of 1 or greater and 22 (29.3%) were ICI-resistant. Exposures Pembrolizumab (200 mg, intravenously, every 3 weeks for up to 35 cycles) plus subcutaneous PDS0101 (5 scheduled doses per protocol). Main Outcomes and Measures The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors , version 1.1, by a masked independent central reviewer. Secondary end points included progression-free survival (PFS), median overall survival (mOS), and safety, with exploratory end points of duration of response, disease control rate, and response rates by programmed cell death ligand 1 status. Results Of the 75 patients in the mITT population, the mean (SD) age was 64.0 (8.3) years; 4 individuals (5%) were female and 71 (95%) were male; and 2 individuals (3%) were Asian, 1 (1%) was Black, 5 (7%) were Hispanic, and 71 (95%) were White. Among 53 ICI-naive participants in the mITT cohort, ORR by the central reviewer was 34.0%, median PFS was 5.3 months (95% CI, 2.10-9.00), and mOS was 39.3 months (95% CI, 23.90 to not evaluable). Among 22 ICI-resistant patients in the mITT cohort, no objective responses were observed and the primary end point (ORR by central reviewer) was not met, but mOS was 14.8 months (95% CI, 8.50-26.00). The treatment was well tolerated, with 13.8% experiencing grade 3 or higher treatment-related adverse events. Conclusions and Relevance The results of this nonrandomized clinical trial suggest that PDS0101 plus pembrolizumab showed antitumor activity in ICI-naive HPV16-positive R/M HNSCC, with favorable safety, response rates, and survival outcomes. The findings support further evaluation in a first-line setting. Trial Registration ClinicalTrials.gov Identifier: NCT04260126

Introduction: Laryngopharyngeal symptoms (LPS) refer to aerodigestive complaints that may result from the retrograde flow of gastric contents into the upper aerodigestive tract. These symptoms may be under-recognised in populations exposed to mechanical or environmental stressors. Divers may be at increased risk due to factors such as pressure changes and body positioning. This study characterised the prevalence and severity of LPS among divers and identified associated risk factors. Methods: A cross-sectional, anonymous survey was distributed to members of the Divers Alert Network (DAN). Collected data included demographics, diving-related behaviours, medical history, and LPS burden measured using the Reflux Symptom Index (RSI). Results: Of the 309 survey responses analysed, 47.2% were male with a median age of 50.0 years (IQR: 40.0−60.0). Among 291 divers with complete RSI data, 26.1% (95% CI, 21.4–31.5%) had abnormal RSI scores, representing a +16.0 percentage-point increase (95% CI, 11.3%−21.4%) over non-diving population estimates (P &#x0003C; 0.001). In multivariable analysis, female sex (adjusted prevalence rate [aPR] 1.59, 95% CI 1.07–2.37) and gastroesophageal reflux disease (GERD) history (aPR 1.75, 95% CI 1.16–2.65) were independent predictors. Recreational divers had a lower risk (aPR 0.59, 95% CI 0.39–0.90). Approximately 5% of respondents described their symptoms as life-threatening. Conclusions: Divers may represent an under-recognised population at elevated risk for LPS. Female sex and GERD history were associated with greater symptom burden, while recreational diving appeared less provocative compared to technical diving. These findings may have implications for risk stratification and symptom management in the diving community.