Citations

Abstract Background Standardizing beam modeling in the treatment planning system is challenging due to machine‐specific configuration variations. Because of the proton therapy system (PTS) complexity and continuous development, there is no vendor's representative (“golden”) beam data like in LINACs at this stage. Purpose The primary goal of this study is to create a PTS‐specific repository of source model parameters and beam commissioning data for scanning proton therapy treatment planning systems and establish a set of reference values with associated bands of variations for this data. Methods We conducted a survey of 31 PTSs at 27 proton therapy centers to gather beam commissioning source model parameters used in their treatment planning system, ensuring a diverse selection of PTSs from major vendors: Hitachi, IBA, Varian, and Mevion. For each proton therapy center, we collected (i) beam meterset calibration in protons per MU, (ii) in‐air spot size at isocenter in terms of standard deviation in x‐ (crossline, σ x ) and y‐ (inline, σ y ) directions, (iii) in‐air angular spread at isocenter in x‐direction (θ x ) and y‐direction (θ y ) and (iv) distal falloff. For each PTS, we plotted each parameter as a function of nominal energy and performed polynomial regression analysis with optimal model selection based on Akaike Information Criterion. We calculated intraclass correlation coefficients (ICC) to quantify inter‐PTS variability and generated uncertainty bands representing standard deviations across PTSs for each parameter. Additionally, we computed percentage deviations of each individual PTS from the overall multi‐vendor mean to identify systematic vendor‐specific patterns and outliers across the 31 total PTSs analyzed. Results Multi‐vendor beam parameter analysis across 31 PTSs revealed systematic vendor‐specific patterns in inter‐PTS consistency and energy dependencies. Beam meterset calibration demonstrated excellent inter‐PTS consistency across most vendors (ICC: Varian ProBeam ≈ 0, IBA Proteus ONE = 0.006, Mevion S250i with HYPERSCAN = 0.015), with IBA Proteus PLUS systems showing moderate variation (ICC = 0.156 for the dedicated nozzle, ICC = 0.248, for the universal nozzle). Spot size and angular spread variability were highly vendor‐dependent, ranging from excellent consistency in IBA Proteus ONE to substantial variation in IBA Proteus PLUS with the universal nozzle (angular spread ICC = 0.566). Distal falloff maintained excellent consistency across all vendors (ICC < 0.023), indicating reliable energy spread characteristics. Uncertainty band analysis revealed characteristic energy‐dependent patterns, with most systems showing larger uncertainties at lower energies for spot size and angular spread, while IBA Proteus PLUS with the universal nozzle exhibited the largest uncertainty bands overall. Percentage deviation analysis demonstrated vendor‐specific clustering patterns, with some systems showing systematic positive or negative deviations from the multi‐vendor mean. Conclusions The reference data provided in this work will help to cross‐check the beam model during treatment planning system commissioning. Furthermore, this information is useful for Monte Carlo applications and research, where beam characteristics are required to set up phase space parameters, thereby avoiding the need to model the entire PTS. Finally, the results of this study will have indispensable educational value by providing valuable insights into the characteristics and capabilities of different PTSs.

Abstract The benefit of rituximab maintenance after first-line (1L) bendamustine-rituximab (BR) in patients with mantle cell lymphoma (MCL) remains uncertain, with inconsistent results from the phase 2 MAINTAIN trial and several retrospective studies. We conducted a large retrospective study at 27 US and Canadian academic centers to examine the benefit of rituximab maintenance after BR. A total of 911 patients received 1L BR between 2010 and 2020, and 703 had an objective response and no evidence of disease progression at the 3-month post-BR landmark. Among those, 394 (56%) received rituximab maintenance and 309 (44%) did not, with largely similar baseline patient and disease characteristics. In the landmark analysis, rituximab maintenance was associated with improved event-free survival (EFS; median, 49.9 vs 29.7 months; P&lt; .001) as well as overall survival (OS; median, 109.5 vs 74.2 months; P&lt; .001). The EFS and OS benefits were observed across most of the subgroups. EFS and OS differences were statistically significant in those who achieved a complete response to 1L BR (n = 590; median EFS, 62.7 vs 31.1 months [P&lt; .001]; median OS, 136.1 vs 75.3 months [P&lt; .001]), but the analysis among those who achieved a partial response to 1L BR was limited by the small sample size. These results provide additional evidence for the survival benefit of rituximab maintenance after BR in MCL and support its use in clinical trial design and routine practice.

Abstract Background These recommendations provide guidance on the optimal timing for transitioning from intravenous to oral antibiotics in patients with complicated urinary tract infection (cUTI), especially in presence of associated Gram-negative bacteremia. Methods The panel's recommendations are based upon evidence derived from systematic literature reviews which focused on comparative benefits and harms of transitioning to oral therapy versus continuing parenteral therapy of the total duration of treatment, including publications since 2000. These recommendations adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Results The guidelines panel suggests transitioning to oral antibiotics in patients with cUTI who are clinically improving, able to take medication, and for whom an effective oral option is available, rather than continuing parenteral therapy for the remaining treatment duration, regardless of the presence of associated Gram-negative bacteremia. An effective oral option needs to be active against the causative pathogen and achieve therapeutic levels in the urine and relevant tissue. Conclusions Parenteral and oral antibiotics used to complete treatment courses for cUTI provide similar efficacy and adverse events, especially in the context of shorter duration of therapy. This recommendation places a high value on reducing avoidable intravenous catheter-related adverse events, costs, and resources, as well as taking into account practical aspects of antibiotic administration.

Abstract Background These recommendations provide guidance on the optimal duration of antibiotics in patients with complicated urinary tract infection (cUTI), especially in presence of associated Gram-negative bacteremia. Methods The panel's recommendations are based upon evidence derived from systematic literature reviews which focused on comparative benefits and harms of shorter (5–7 days) vs prolonged (10–14 days) duration of antibiotics, including publications since 2000. These recommendations adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Results The guidelines panel suggests that patients with cUTI who are improving on effective therapy can be treated with shorter duration of antimicrobials (either 5–7 days of a fluoroquinolone or 7 days of a non-fluoroquinolone) rather than longer courses of antibiotics, regardless of the presence of associated Gram-negative bacteremia. An effective antimicrobial agent achieves therapeutic levels in the urine and relevant tissue and is active against the causative pathogen. However, men with febrile UTI in whom acute bacterial prostatitis is suspected may benefit from a longer treatment duration (10–14 days), and a short courses of oral beta lactams may require higher doses for efficacy. Conclusions Shorter durations of antibiotics for cUTI provide similar efficacy as longer courses, except in men with febrile UTI in whom acute bacterial prostatitis is suspected. This recommendation places a high value on antibiotic stewardship considerations as well as reducing the burden of antimicrobial administration from a healthcare perspective and reducing the burden of taking antibiotics from a patient perspective.

Abstract Background These recommendations address the empiric choice of antibiotics in suspected complicated urinary tract infection (cUTI). Issues to balance include the need for appropriate initial empiric antimicrobial therapy, the patient's severity of illness, and antimicrobial stewardship concerns. Methods The panel's recommendations are based upon evidence derived from systematic literature reviews that focused on comparative benefits and harms of classes of antibiotics approved for cUTI, starting with publications from 2008 onwards, and our review of predictors of resistance in uropathogens included references identified since 2000. These recommendations adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Results The guidelines panel suggests initially selecting among preferred empiric antibiotic choices rather than alternative options, stratified for the patient's severity of illness and antimicrobial stewardship considerations. When choosing among these antibiotics for a specific patient, the guideline panel suggests a 4-step process to account for changing resistance patterns and individualized patient needs. The steps are: (1) assess the severity of illness (for initial prioritization of antibiotics), (2) consider patient-specific risk factors for resistant uropathogens (for optimization of coverage), (3) evaluate other patient-specific considerations (to reduce the risk of adverse events), and (4) for patients with sepsis, consult a relevant local antibiogram if available (to further improve the likelihood of giving appropriate empiric therapy). Lastly, the guideline panel suggests selecting definitive effective therapy with a targeted spectrum based on the result of the urine culture. Conclusions Many of the classes of antibiotics approved to treat cUTI demonstrate similar efficacy as other classes of antibiotics in randomized controlled trials. Bacterial resistance prevalence is always changing, and new antibiotics will be developed. In this context, the guidelines panel provides recommendations for choosing empiric antibiotic therapy for cUTI that will help clinicians decide among available antibiotic options at the point of care.

Abstract Multiple myeloma is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment (IME). To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T-cell memory after autologous stem cell transplant, whereas naïve B-cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48; P = 2.3e−4). At disease progression, multiple myeloma cells upregulated cancer–testis antigens (CTAg) and immune effector genes, with concurrent B-cell depletion, enrichment of myeloid-derived suppressor cell expression, and phenotypic T-cell exhaustion. These findings highlight dynamic immune–tumor interactions, identifying naïve B-cell reconstitution as a biomarker of durable response and CTAgs as potential targets for high-risk disease at progression. Significance: Longitudinal profiling of multiple myeloma and the IME revealed dynamic immune–tumor interactions across the disease course. Altered expression in CD8+ T cells limited memory phenotype after transplant, whereas naïve B-cell recovery associated with sustained treatment response. At progression, CTAg expression associated with immunosuppression, revealing novel mechanisms of immune dysregulation.