Citations

Abstract Purpose: KRAS G12C inhibitors can treat KRASG12C-mutant advanced colorectal cancers and pancreatic ductal adenocarcinomas (PDAC), but alterations in Kirsten rat sarcoma (KRAS), EGFR, BRAF, MAP2K1, and other genes bypass KRAS inhibition and reduce therapy efficacy. Our study evaluates the genetic landscape of candidate primary resistance alterations relevant to KRAS targeting in KRASG12C-mutant colorectal cancer and PDAC. Experimental Design: We analyzed two cohorts (national database and Mayo) of patients with advanced colorectal cancer or PDAC tested with next-generation sequencing of ctDNA via Guardant360. Cohorts were divided into three groups: KRASG12C alone (KRASG12C without a resistance gene), KRASG12C with resistance (KRASG12C and ≥1 candidate resistance gene), and KRAS not detected. Candidate resistance mutations were inferred from the reported literature. Results: Among the national (13,603 colorectal cancer and 5,016 PDAC cases) and Mayo (741 colorectal cancer and 422 PDAC cases) cohorts, resistance alterations were identified in a considerable number of KRASG12C cases (46.5% of national colorectal cancer, 16.4% of national PDAC, 53.8% of Mayo colorectal cancer, and 36.4% of Mayo PDAC). The presence of resistance alterations was associated with a trend toward worse overall survival in KRASG12C colorectal cancer (P = 0.05). Conclusions: Putative resistance alterations are prevalent in PDAC and colorectal cancer and may limit monotherapy efficacy. Identifying these alterations has potential implications in optimal patient selection for targeted therapies and the development of combination therapy strategies to overcome primary resistance.

202 Background: While several PARP inhibitors are approved in combination with hormonal therapies for metastatic castrate resistant prostate cancer (CRPC), their use in castrate sensitive prostate cancer (CSPC) is understudied. We previously reported that olaparib monotherapy (without ADT) shows significant clinical activity in BRCA2 -altered patients with biochemically recurrent (BCR) prostate cancer. Here, we explored prognostic and predictive PARP-related mRNA biomarkers derived from primary prostate tumors. Methods: We characterized the expression of 16 PARP transcripts using a cohort of 52,266 radical prostatectomy (RP) specimens (2016-2024) undergoing Decipher prostate genomic classifier testing (Veracyte Inc). Transcriptome-wide mRNA expression data as well as baseline clinical/pathologic factors were retrieved from the Decipher GRID database (NCT02609269). Associations between high PARP expression (top 25%), baseline factors, and gene signatures were examined using logistic regression. We assessed the association between PARP expression and distant metastases in 3 retrospective cohorts (n= 545, 855, and 325). Finally, we evaluated PARP expression in our prior phase II trial (NCT03047135, n=39) of olaparib monotherapy in the setting of BCR following RP. Results: Higher mRNA levels of PARP1 , 2 , 8 and 14 showed strong associations (all P <0.001) with known adverse prognostic factors such as very-high Decipher score (>0.85), high Gleason grade (GG5) and non-organ confined disease (EPE, SVI and LNI), while higher PARP6 and 7 expression were associated with more favorable disease characteristics. High PARP1 expression was positively correlated with DNA-repair deficiency (r=0.77) and tumor immune microenvironment (r=0.62) signatures. In 3 independent retrospective cohorts of intermediate-high risk PCa patients, higher PARP1 expression was strongly associated with development of distant metastases after RP (HR 1.70, 1.81, and 1.67 respectively; all P <0.05). Finally, in our phase II trial of patients with BCR who received olaparib monotherapy, PARP1 (but not PARP2 ) expression from RP was 1.5-fold higher in samples with BRCA2 mutations (median 0.416 vs 0.276, P =0.01) and was associated with overall improved PSA progression-free survival (continuous variable, HR 0.55, P =0.01) and longer time to next systemic treatment (continuous variable, HR 0.66, P =0.02). Conclusions: High PARP1 mRNA expression, measured at RP, is associated with aggressive disease biology and greater risk of metastasis. However, high PARP1 (but not PARP2 ) levels are associated with improved response to PARP inhibition in the setting of BCR prostate cancer. Future trials testing PARP (including PARP1-selective) inhibitors in the CSPC space should consider measuring PARP1 mRNA levels in addition to BRCA1/2 mutation status. Clinical trial information: NCT02609269 , NCT03047135 .

410 Background: Inflammasomes are multiprotein complexes that regulate inflammation-associated signaling pathways. Although inflammation plays a crucial role in cancer cell proliferation, the specific role of inflammasomes in prostate cancer (PCa) remains underexplored. This study aims to elucidate the expression of inflammasome-related genes in PCa and assess their association with clinical outcomes. Methods: De-identified transcriptome data from a cohort of 52,266 radical prostatectomy (RP) samples tested (2016-2024) with the Decipher prostate genomic classifier (Veracyte, San Diego, CA) were retrieved from the GRID registry (NCT02609269). Expression analysis focused on 33 genes involved in inflammatory pathways. Outcomes analysis was conducted on a retrospective cohort of 855 patients treated with RP (META855), using Cox regression analysis, adjusting for baseline pathological characteristics. Results: Analysis of baseline gene expression in the GRID RP cohort revealed that most genes exhibit low baseline expression, whereas HSP90AB1, APP, TXN, and TXNIP demonstrate strong expression signals. Higher expression of most genes was associated with higher rate of Gleason grade group 4 or 5 in the GRID RP cohort. On survival analysis of the META855 cohort, higher expression (top 25%) of AIM2 and HSP90AB1 were associated with worse metastasis-free survival (p<0.05 for both). Conversely, both high and low expression levels of NLRP3 were associated with better metastasis-free survival outcomes following RP compared to average expression (p<0.05). On multivariable Cox regression analysis, adjusting for grade group, seminal vesicle involvement, lymph node involvement, and margin status, higher expression of AIM1 (HR 1.75) and HSP90AB1 (HR 1.60) were significantly associated with shorter time to metastasis following RP (p<0.05 for both). Conclusions: There is a molecular heterogeneity within pro-inflammatory genes among patients with PCa.Our findings showed thathigher expression of HSP90AB1 is linked to poorer oncological outcomes, whereas both high and low expression levels of NLRP3 are associated with better outcomes following RP.Further refinement is required to build a robust signature, along with external validation of these findings in other cohorts.

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR &amp;lt;1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510

Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; &amp;lt;1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683

Abstract Background Accurate low‐dose CT simulation is required to efficiently assess reconstruction and dose reduction techniques. Projection domain noise insertion requires proprietary information from manufacturers. Analytic image domain noise insertion methods are successful for linear reconstruction algorithms, however extending them to non‐linear algorithms remains challenging. Emerging, deep‐learning‐based image domain noise insertion methods have potential, but few approaches have explicitly incorporated physics information and a texture‐synthesis model to guide the generation of locally and globally correlated noise texture. Purpose We proposed a p hysics‐informed model‐based gener a tive neura l network for simulating scann e r‐ and algori t hm‐specific low‐dose C T e xams (PALETTE). It is expected to provide an alternative to projection domain noise insertion methods in the absence of manufacturers’ proprietary information and tools. Methods PALETTE integrated a physics‐based noise prior generation process, a Noise2Noisier sub‐network, and a noise texture synthesis sub‐network. The Noise2Noisier sub‐network provided a bias prior, which, combined with the noise prior, served as the inputs to noise texture synthesis sub‐network. Explicit regularizations in spatial and frequency domains were developed to account for noise spatial correlation and frequency characteristics. For proof‐of‐concept, PALETTE was trained and validated for a commercial iterative reconstruction algorithm (SAFIRE, Siemens Healthineers), using the paired routine and 25% dose images from CT phantoms (lateral size 30–40 cm; three training and four testing phantoms) and open‐access patient cases (10 training and 20 testing cases). In phantom validation, noise power spectra (NPS) were compared in water background and tissue‐mimicking inserts, using peak frequency and mean‐absolute‐error (MAE). In patient case evaluation, visual inspection and quantitative assessment were conducted on axial, coronal, and sagittal planes. Local and global noise texture were visually inspected in low‐dose CT images and the difference images between routine and low dose. Noise levels in liver and fat were measured. Local and global 2D Fourier magnitude spectra of the difference images and the corresponding radial mean profiles were used to assess similarity in noise frequency components within tissues and entire field‐of‐view, using spectral correlation mapper (SCM) and spectral angle mapper (SAM). Several baseline neural network models (e.g., GAN) were included in the evaluation. Statistical significance was tested using a t ‐test for related samples. Results PALETTE‐derived NPS showed accurate noise peak frequency (PALETTE/reference: water 1.40/1.40 lp/cm; inserts 1.7/1.7lp/cm) and small MAE (≤0.65 HU 2 cm 2 ). PALETTE created anatomy‐dependent noise texture, showing realistic local and global granularity and streaks. No statistically significant difference was observed in noise levels ( p > 0.05). Noise range was comparable across 3D image volume (PALETTE / reference):liver – [18.0, 53.4] / [19.3, 50.0] HU; fat – [11.7, 42.4] / [12.1, 41.3] HU. Percent absolute difference of local noise was small (mean ± standard deviation): liver 4.1%±3.1%, fat 4.6%±3.1%. Noise frequency distribution was close to the reference (mean per case): SCM ≥ 0.92, SAM ≤ 0.22. Additionally, PALETTE outperformed all baseline models in visual inspection and quantitative comparison. Conclusion PALETTE can provide high‐quality image domain noise insertion for simulating accurate low‐dose CT images created with a commercial non‐linear reconstruction algorithm.

Background and Aims: Severe alcohol-associated hepatitis (AH) is rising in incidence with a high mortality burden. While corticosteroids are recommended for eligible patients with severe AH, no guidance exists for the timing of steroid initiation, tapering regimens, and surveillance of adverse events. We aim to systematically review these variables and provide evidence-based recommendations for the inpatient and outpatient management of severe AH. Approach and Results: We performed a literature search from inception to May 30, 2024, to include clinical trials published in full form and assessed the quality of evidence using the Cochrane Risk of Bias tool. Data were collected on the timing of initiation, rate, and complications following steroid therapy, and taper regimens in the setting of severe AH. Of 28 studies that fulfilled our inclusion criteria, the median time from admission to steroid initiation was 6.5 days. The most common steroid dosing regimen was prednisolone 40 mg daily for 28 days. Twenty-five studies containing 3196 subjects reported adverse events, with exactly 50% in the steroid arm and the other half in the comparison arm. Infections, gastrointestinal bleeds, and renal impairment were the most frequently reported adverse events. Most infections occurred within the first month of the study. A 2-week steroid taper was the most frequently reported regimen. Conclusions: We recommend taking up to a week to systematically and thoroughly evaluate patients before initiating steroids, and vigilant monitoring in the first month of treatment. We also recommend the lowest possible steroid exposure with a 2-week steroid taper and close outpatient follow-up.

Background: Reverse shoulder arthroplasty (RSA) is increasingly used in the treatment of proximal humerus fractures (PHFs) with reliable clinical improvement. Lateralized RSA implants have conferred superior outcomes compared with the original Grammont design in patients with nontraumatic indications. However, in the setting of a PHF, lateralized components can place increased tension across the tuberosity fracture site and potentially compromise tuberosity healing and outcomes. This systematic review and meta-analysis sought to determine the effect of implant design on clinical outcomes after RSA for PHFs. Methods: A systematic review was performed per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed/MEDLINE, EMBASE, Web of Science, and Cochrane were queried for clinical studies on RSA performed for PHFs that reported implant manufacturer details. Our primary outcomes included postoperative external rotation (ER), forward elevation (FE), abduction, Constant score, rate of greater tuberosity (GT) healing, and the incidence of complications compared between medialized vs. lateralized global implant design. Results: Globally lateralized RSA cohorts (478 RSAs total with cumulative lateral offset achieved through humeral or glenoid lateralization or both humeral and glenoid lateralization) were found to have a greater mean postoperative Constant score compared with globally medialized (medialized glenoid and medialized humerus) RSA cohorts with 1,494 total medialized RSAs (66 vs. 59, p = 0.006), but there was no significant difference regarding mean postoperative ER (30° vs. 22°, p = 0.078), FE (117° vs. 119°, p = 0.708), or abduction (103° vs. 107°, p = 0.377). On meta-regression, neither implant design nor tuberosity status significantly influenced postoperative ER, FE, abduction, or Constant score on meta-regression independent of mean follow-up and age at surgery. The rate of GT healing was greater in lateralized compared with medialized RSAs (88% vs. 72%, p < 0.001). On meta-regression, medialized RSA design was associated with a 73% lower odds of GT healing (odds ratio = 0.27, 95% confidence interval = 0.11-0.68, p = 0.007) independent of mean follow-up and age at surgery. Conclusion: Lateralized RSA implants conferred no significant functional benefit over medialized implants when used in patients with PHFs. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Background A variety of clinically important benchmarks of success (CIBS) have been defined for total shoulder arthroplasty (TSA) to quantify success. However, it is unclear how the preoperative status of the patient influences their likelihood of achieving each CIBS. Questions/purposes (1) What proportion of patients achieve commonly used CIBS after TSA? (2) Is there a relationship between a patients’ preoperative function and their probability of achieving different CIBS? (3) Does there exist preoperative ranges for each outcome measure that are associated with greater achievement of CIBS? Methods We retrospectively queried a multicenter shoulder arthroplasty database for primary anatomic TSA (aTSA) and reverse TSA (rTSA). A total of 2041 aTSAs and 3205 rTSAs were included. The mean ± SD age at time of surgery was 66 ± 9 years for aTSAs and 72 ± 8 years for rTSAs. In all, 51% (1049 of 2041) of aTSAs and 61% (1955 of 3205) of rTSAs were in patients who were women. For aTSAs, osteoarthritis with an intact rotator cuff was the most common preoperative diagnosis (92% [1869 of 2041]). For rTSAs, the most common preoperative diagnoses included rotator cuff tear arthropathy (40% [1280 of 3205]), osteoarthritis with an intact rotator cuff (24% [780 of 3205]), osteoarthritis with a torn rotator cuff (20% [632 of 3205]), and massive rotator cuff tear (10% [309 of 3205]). Outcomes were evaluated at latest follow-up (aTSA 61 ± 36 months, rTSA 47 ± 26 months) and consisted of ROM (abduction, forward elevation, external and internal rotation) as well as the most commonly used outcome scores: the Simple Shoulder Test (SST), Constant score, American Shoulder and Elbow Surgeons (ASES) score, University of California, Los Angeles (UCLA) score, Shoulder Pain and Disability Index (SPADI), and the Shoulder Arthroplasty Smart (SAS) score. The CIBS that we evaluated included the minimum clinically important difference (MCID), substantial clinical benefit (SCB), patient acceptable symptom state (PASS), minimum clinically important percentage of maximal possible improvement (MCI-%MPI), and substantial clinically important percentage of maximal possible improvement (SCI-%MPI). Prosthesis-specific anchor-based CIBS were adopted from prior publications on patients from this database. Multivariable regression was performed to identify the relationship between preoperative outcome measures and achievement of CIBS. Additionally, receiver operating characteristic (ROC) curve analyses were performed to determine whether thresholds in preoperative outcome measures were associated with achieving CIBS. Results For all ROM measures and outcome scores, poorer preoperative ROM was associated with greater odds of achieving the MCID and SCB but lower odds of achieving the PASS. For the SST and the two scores without ceiling effects (the Constant and SAS scores), poorer preoperative outcome scores were associated with greater odds of achieving the MCI-%MPI and SCI-%MPI, but no association was demonstrated for the ASES, SPADI, and UCLA scores. Graphical analysis demonstrated that patients with greater preoperative ROM and outcome scores had a lower probability of achieving the MCID and SCB but a higher probability of achieving the PASS. For outcome scores with known ceiling effects, patients with more favorable preoperative outcome scores were more likely to achieve the MCI-%MPI and SCI-%MPI than the MCID and SCB, respectively. For outcome scores without ceiling effects, patients undergoing aTSA were more likely to achieve the MCID, MCI-%MPI, and the SCI-%MPI than the SCB, but no clear trend was identified for patients undergoing rTSA. On ROC curve analysis, identified thresholds were reasonably accurate (area under the curve > 0.7) for achievement of measures of absolute improvement (the MCID and SCB), but not for absolute postoperative status (the PASS) or relative improvement (the MCI-%MPI and SCI-%MPI). Conclusion While most patients reported being “much better” (aTSA 75%, rTSA 76%) or “better” (aTSA 15%, rTSA 18%) compared with before surgery, 10% of aTSAs and 6% of rTSAs were either “unchanged” or “worse.” Patients’ likelihood of achieving CIBS depends in part on their baseline function and whether success is defined as absolute improvement, absolute postoperative status, or relative improvement. Patients with more favorable preoperative status are more likely to achieve CIBS that evaluate relative improvement (the MCI-%MPI and SCI-%MPI) than absolute improvement (the MCID and SCB). Future studies are needed to determine which individual CIBS or combinations thereof most accurately represent clinically relevant benefit. Level of Evidence Level III, therapeutic study.