Citations

Abstract Purpose: Tumor-infiltrating lymphocytes are associated with a decreased risk of recurrence in human papillomavirus–associated oropharyngeal squamous cell carcinoma. The composition and spatial distribution of tumor-infiltrating lymphocytes and tumor-infiltrating immune cells are not well characterized. Experimental Design: Formalin-fixed, paraffin-embedded primary and lymph node (LN) tumor tissues from 10 progressors (cases) and 10 matched nonprogressors (controls) were interrogated by imaging mass cytometry. Immune, stromal, and tumor cells were quantified from selected regions of interest using machine learning. Nearest neighbors, cell–cell interactions, and niche analyses were performed. Results: In primary regions of interest, immune cell, lymphocyte, T cell, CD8+ T cell, and innate cell prevalence was significantly greater in controls. High prevalence of immune cells, lymphocytes, innate cells, and CD4+ T cells in primary tissues was significantly associated with increased time to event (TTE). Although primary and LN prevalence of T cells, CD4+ T cells, CD8+ T cells, macrophages, and tumor cells were significantly correlated, differences in LNs were neither significant nor associated with TTE. Average distances between T cells and the nearest B cells and between lymphocytes and the nearest tumor cells were decreased in control primary tissues. Interactions between B and T cells were less organized in primary tissues from cases. A niche predominantly comprising lymphocytes was associated with longer TTE. Conclusions: In human papillomavirus–associated oropharyngeal squamous cell carcinoma, immune cell subset prevalence in primary tumors differs with outcome and is associated with TTE. Interactions between B cells and both T-cell subsets are associated with longer TTE, underscoring the importance of active intratumoral immune responses in outcomes.

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 <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

ImportanceAmyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.ObjectiveTo determine the effects of pridopidine, a σ1-receptor agonist, in ALS.Design, Settings, and ParticipantsPridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.InterventionsEligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.ResultsAmong 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).Conclusions and RelevanceIn this 24-week study, pridopidine did not impact the progression of ALS.Trial RegistrationClinicalTrials.gov Identifiers: NCT04297683, NCT04615923

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; <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

Importance Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD + , resulting in an increase of cellular adenosine triphosphate production. Objective To determine the effects of CNM-Au8 on ALS disease progression. Design, Setting, and Participants CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. Interventions Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. Main Outcomes and Measures The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. Results Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]). Conclusions and Relevance No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. Trial Registration ClinicalTrials.gov Identifiers: NCT04297683 , NCT04414345

Abstract Aims To describe the baseline characteristics of the participants in the VICTOR (Vericiguat Global Study in Patients with Chronic Heart Failure; NCT05093933) trial and compare them to recent trials in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results Baseline characteristics were evaluated in 6105 patients randomized to vericiguat or placebo. The mean age of the participants was 67 ± 11 years, 23.6% were women, 64.4% were White, and 10.7% were self-identified Black. Overall, 29.1% of participants were enrolled in Latin and South America, 27.8% and 18.5% in Eastern and Western Europe, 14.0% in Asia-Pacific and 10.6% in North America. The mean left ventricular ejection fraction was 30 ± 7% and 79% had New York Heart Association class II symptoms. Mean estimated glomerular filtration rate was 70.9 ± 24.0 ml/min/1.73 m2. Median N-terminal pro-B-type natriuretic peptide level was 1476 (970–2495) pg/ml and 47.5% of participants had no prior hospitalization for heart failure. Baseline therapy included 94.4% beta-blockers, 94.3% renin–angiotensin system modulation (including 56.0% on an angiotensin receptor–neprilysin inhibitor), 77.7% mineralocorticoid receptor antagonists, 59.1% sodium–glucose cotransporter 2 inhibitors, and 32.9% implantable cardioverter-defibrillators. Overall characteristics were relatively similar to other recent HFrEF trials but the VICTOR trial enrolled a higher proportion of participants receiving contemporary drug and device therapy. Conclusion The VICTOR trial enrolled the most optimally treated population in a phase III heart failure trial. These features will facilitate assessment of the benefit of vericiguat and elucidate the outcomes of patients on up-to-date medical therapy.

OBJECTIVE It is not clear whether smoking impacts patient-reported outcomes (PROs) in patients with cervical spondylotic myelopathy (CSM). The aim of this study was to explore the impact of smoking status on baseline symptom severity and the rate of achieving satisfaction and the minimal clinically important differences (MCIDs) for PROs in patients with CSM. METHODS This study was an analysis of the prospective Quality Outcomes Database CSM module. Patients aged ≥ 18 years diagnosed with primary CSM who underwent elective surgery were included. PROs (visual analog scale [VAS] neck and arm pain, Neck Disability Index [NDI], modified Japanese Orthopaedic Association [mJOA], and EQ-5D scores and North American Spine Society [NASS] patient satisfaction) were collected at baseline and 24 months of follow-up. RESULTS Of the 1141 patients with CSM, 202 (17.7%) were smokers and 939 (82.3%) were nonsmokers. Compared with the nonsmokers, smokers were younger (56.3 ± 11.3 years vs 61.5 ± 11.7 years, p < 0.01) and had a lower BMI (29.3 ± 6.8 vs 30.3 ± 6.3, p = 0.04). A higher proportion of smokers had depression, anxiety, and chronic obstructive pulmonary disease (all p < 0.01). At baseline, smokers had worse pain (VAS neck pain score: 6.0 ± 3.2 vs 5.1 ± 3.3; VAS arm pain score: 5.7 ± 3.2 vs 4.7 ± 3.5), disability (NDI score: 45.2 ± 20.0 vs 37.1 ± 20.6), myelopathy (mJOA score: 11.5 ± 2.9 vs 12.2 ± 2.8), and quality of life (EQ-5D score: 0.51 ± 0.23 vs 0.57 ± 0.22) (all p < 0.01). At the 24-month follow-up, a higher proportion of smokers achieved the MCID in mJOA (69.4% vs 56.6%, p < 0.01) compared with nonsmokers. However, after accounting for significant covariates, there was no significant difference in the baseline disease severity. There was also no difference between the PROs at the 24-month follow-up. The two groups also achieved similar MCIDs for most PROs and were similarly satisfied (NASS score of 1 or 2: smoker 81.2% vs nonsmoker 84.6%, p = 0.29) 24 months after surgery. CONCLUSIONS Smokers and nonsmokers with CSM had similar baseline disease severity and 24-month PROs. They also achieved similar rates of MCIDs for PROs and satisfaction after surgery. Numerous previous studies have documented the association between tobacco usage and inferior clinical outcomes after spine surgery. However, in the context of severe and debilitating spinal disorders such as cervical myelopathy, meaningful and impactful improvements are still seen in properly selected patients.

Using 32 immune cell surface markers, we identified 23 monocyte clusters in murine blood. Diabetic gastroparesis was associated with a significant decrease in two circulating classical monocyte-like clusters and an upregulation of the Ccr2-Ccl2 axis in the gastric muscularis propria, suggesting increased tissue monocyte migration. This study offers new targets by pointing to a possible role for two classical monocyte subsets connected to the Ccr2- Ccl2 axis.

Abstract Background Multi‐energy CT (MECT) enables quantification of material concentrations by measuring linear attenuation coefficient line integrals with multiple x‐ray spectra. Photon counting detector (PCD)‐CT utilizes a detector‐based approach for MECT that can suffer from substantial spectral overlap, resulting in amplified material quantification noise. Dual‐source dual‐kV approaches for MECT are currently utilized in some energy‐integrating detector (EID)‐CT systems and can potentially be utilized with PCD‐CT for improved spectral separation. Purpose To evaluate the iodine quantification performance of a novel dual‐source (DS)‐PCD‐CT scan mode and compare to single‐source (SS)‐PCD‐CT and DS‐EID‐CT. Materials and Methods A 30 cm × 40 cm solid water phantom with four iodine inserts (2, 5, 10, and 15 mg/mL) was scanned with the three spectral modalities: SS‐PCD‐CT with two energy thresholds, DS‐PCD‐CT (90/Sn150 kV), and DS‐EID‐CT (90/Sn150 kV). For each modality, full‐dose (12 mGy) and half‐dose scans were acquired, and images were reconstructed with filtered back‐projection using a quantitative (Qr40) kernel. When scanning in a DS configuration, the total radiation dose budget is split between two detectors, increasing the strength of a signal‐dependent filter compared to a SS acquisition. To account for this effect, the modulation transfer function (MTF) for each modality was measured from a 0.05 mm tungsten wire. A linear spatial filter was applied to the SS images to match their MTF to that of the DS images. The resulting high‐ and low‐energy images were input into an image‐domain least squares material decomposition algorithm with iodine and water as the two basis materials. Iodine quantification accuracy and noise measured from the iodine basis images were used as figures of merit, and t‐tests used to compare between modalities. Results The 10% MTF cutoffs were 0.56, 0.57, 0.60, and 0.57 lp/mm for DS‐EID‐CT, DS‐PCD‐CT, SS‐PCD‐CT, and SS‐PCD‐CT after MTF‐matching, respectively, with the SS‐PCD‐CT MTF cutoff dropping to 0.58 lp/mm at half‐dose. Without accounting for the signal‐dependent filter by matching the MTFs, the noise in iodine material basis images from SS‐PCD‐CT was 10% higher than that of DS‐EID‐CT. After matching the MTFs, the noise in the SS‐PCD‐CT iodine image was 9%–22% lower than that of the DS‐EID‐CT. The lowest iodine image noise was from the DS‐PCD‐CT, which was 39%–41% lower than the DS‐EID‐CT. The DS‐PCD‐CT noise magnitude was significantly different from the other modalities. Mean iodine quantification accuracy across all measured concentrations was within 5% for all modalities at full dose, but was only below 5% for the DS‐PCD‐CT at half‐dose. Conclusions SS‐PCD‐CT with two energy thresholds outperformed DS‐EID‐CT in terms of image noise in iodine basis images when spatial resolution was matched. DS‐PCD‐CT gave the lowest noise due to the combination of PCD technology and improved spectral separation from the different x‐ray spectra.