Citations

Introduction: The Mindfulness-Based Stress Reduction (MBSR) Program for breast cancer survivors (BCS) is designed to enhance cognitive training through formal and informal meditational practices. This randomized clinical trial (RCT) aimed to evaluate if BCS assigned to either the MBSR(BC), Breast Cancer Education Support (BCES), or Usual Care (UC) regimens experienced greater improvements at 6, 12, and 26 weeks on objective and subjective cognitive performance. Methods: BCS ( n = 212) randomized to a three-group RCT: MBSR(BC) ( n = 91), BCES ( n = 90), or UC ( n = 31) were assessed on cognitive performance and symptoms at baseline, 6, 12, and 26 weeks. Linear mixed models were fit to evaluate the effects of the MBSR(BC) program, hypothesizing ordered effect improvements: (MBSR[BC] highest, BCES intermediate, UC lowest) along with baseline characteristics evaluated as moderators. Results: Of the BCS (mean age of 57), 73% were White, and non-Hispanic, and 77% received both chemotherapy (CT) and radiation. Cognitive performance improved in all groups. Although there were no statistically significant between-group differences in cognitive outcomes, significant symptom reductions occurred for the MBSR(BC) group ( p = 0.003). Within-group effect size analysis at 26 weeks showed substantial improvements in all three groups (effect sizes >0.50) in subjective impairments and quality of life (effect size >0.50) and objective measures of cognitive performance. MBSR(BC) showed the largest within-group effect size in the reduction of fatigue (effect size = 0.81). Effect sizes occurred in the hypothesized direction for 10 of the 18 outcomes. Discussion: Although the MBSR(BC) program did not show significant differences in cognitive performance compared with BCES and UC, all groups improved and reductions in fatigue were beneficial for MBSR(BC). Results suggest that cognitive performance may improve after CT over time considering one’s natural history. Furthermore, BCS enrolled in RCTs may be more motivated to improve their health status (NCT02786797).

Importance While the typical onset of multiple sclerosis (MS) occurs in early adulthood, 2% to 10% of cases initially present prior to age 18 years, and approximately 5% after age 50 years. Guidance on approaches to differential diagnosis in suspected MS specific to these 2 age groups is needed. Observations There are unique biological factors in children younger than 18 years and in adults older than age 50 years compared to typical adult-onset MS. These biological differences, particularly immunological and hormonal, may influence the clinical presentation of MS, resilience to neuronal injury, and differential diagnosis. While mimics of MS at the typical age at onset have been described, a comprehensive approach focused on the younger and older ends of the age spectrum has not been previously published. Conclusions and Relevance An international committee of MS experts in pediatric and adult MS was formed to provide consensus guidance on diagnostic approaches and key clinical and paraclinical red flags for non-MS diagnosis in children and older adults.

ABSTRACTAimsThis study aimed to determine the efficacy and safety of iltamiocel investigational autologous muscle cell therapy in females with stress urinary incontinence (SUI).MethodsAdult females were randomized 2:1 to iltamiocel (150 × 106 cells) or placebo and stratified by severity and prior SUI surgery. The primary objective was efficacy based on the frequency of stress incontinence episodes (SIE) recorded in a 3‐day diary at 12 months posttreatment. After 12 months, placebo participants could elect to receive open‐label iltamiocel. Efficacy and safety analyses were performed using all patients as treated populations.ResultsThe study enrolled 311 patients, 297 were randomized to either iltamiocel (n = 199) or placebo (n = 98). Of the 295 participants that completed 12 months blinded follow‐up, the proportion achieving the primary endpoint of ≥ 50% SIE reduction was not statistically different between treatment groups (52% vs. 53.6%; p = 0.798). A significantly greater proportion of iltamiocel participants in the prior SUI surgery stratum group achieved ≥ 75% SIE reduction compared with placebo, (40% vs. 16%; p = 0.037). Treatment response was maintained at 24 months in 78.4% and 64.9% of iltamiocel participants who achieved ≥ 50% and ≥ 75% SIE reduction, respectively, at Month 12. Adverse events related to the treatment were reported in 19 (9.5%) iltamiocel participants and 6 (6.1%) placebo participants.ConclusionThe study did not meet its primary endpoint however, iltamiocel cell therapy is safe and may be ideally suited to female patients who have undergone prior surgery for SUI. Additional study in this group of patients with high unmet medical needs is warranted.Trial RegistrationClinicalTrials.gov identifier: NCT01893138; EudraCT number: 2014‐002919‐41.

Abstract Background: Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) to pancreatic ductal adenocarcinoma (PDAC) risk at over 20 genomic loci. The Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium are currently expanding on previous GWAS studies for PDAC from ∼9,000 cases and ∼12,000 controls to ∼36,000 cases and ∼800,000 controls in individuals of European and Asian ancestry. This ongoing GWAS phase is estimated to detect up to 50 new risk signals. Post-GWAS studies aim to fine-map and functionally assess risk variants in disease-relevant cell types and contexts to identify target genes and underlying mechanisms of risk. Massively parallel reporter assays (MPRAs) are a powerful method of assessing allele-specific gene regulatory effects. Integrating sequences into the genome using lentiviruses (Lenti-MPRA) enables the capture of variant function in the context of the native cellular chromatin. An added benefit is that Lenti-MPRAs can be used for difficult to transfect cells such as primary cells, that often reflect the disease relevant cell types. Methods: We have used a lentiviral MPRA to test 228 fine-mapped SNPs at the chr5p15.33 multi-cancer risk locus in PDAC cell lines (MIA PaCa-2, PANC-1) and the normal-derived ductal pancreas (HPDE) cell line. Additionally, we have optimized the transduction of large MPRA libraries into primary pancreas cells. Tunicamycin was used to induce ER stress in cell lines and primary cells, assessing downstream gene expression using RT-qPCR. Results: Our pilot MPRA demonstrated high reproducibility in PDAC cell lines (r2=0.93-0.97, MIA PaCa-2, PANC-1 cells) and normal-derived pancreatic ductal cells (r2=0.68-0.86, HPDE cells). We identified 33 SNPs out of 228 with significant allele-specific transcriptional activity in PDAC cell lines and 5 in HPDE cells (FDR ≤0.05). An additional 6-15% of variants exhibited significant allele-specific transcriptional activity when in the frames of the SNP-centered tested oligos were shifted left or right. We demonstrate the inducibility of ER-stress with tunicamycin treatment over 24 hours in cells lines and primary pancreatic cells. Additionally, we observed increased expression of CLPTM1IL at the chr5p15.33 locus after tunicamycin treatment over 24 hours in cell lines and primary pancreatic cells, suggesting ER-stress and inflammation may influence gene expression at this locus. Conclusions: Lentiviral MPRA assays in commonly used PDAC cell lines have demonstrated good reproducibility. The optimization studies and preliminary work in primary pancreatic cells provide a solid foundation for the next steps of assessing all GWAS loci in ER stress, an important disease relevant condition. Citation Format: Minal B Patel, Aidan O'Brien, Jun Zhong, Irene Collins, Jason W Hoskins, Stephen J Chanock, Samuel O Antwi, Rachel Z Stolzenberg-Solomon, Alison P Klein, Brian M Wolpin, Sara Lindström, H. Efsun Arda, Kevin M Brown, Katelyn E Connelly, Laufey T Amundadottir, Meagan Jezek. The functional characterization of pancreatic ductal adenocarcinoma GWAS risk variants in primary pancreatic cells – A pilot study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A018.

OBJECTIVE The long-term effects of increased body mass index (BMI) on surgical outcomes are unknown for patients who undergo surgery for low-grade lumbar spondylolisthesis. The goal of this study was to assess long-term outcomes in obese versus nonobese patients after surgery for grade 1 spondylolisthesis. METHODS Patients who underwent surgery for grade 1 spondylolisthesis at the Quality Outcomes Database’s 12 highest enrolling sites (SpineCORe group) were identified. Long-term (5-year) outcomes were compared for patients with BMI ≥ 35 versus BMI < 35. RESULTS In total, 608 patients (57.6% female) were included. Follow-up was 81% (excluding patients who had died) at 5 years. The BMI ≥ 35 cohort (130 patients, 21.4%) was compared to the BMI < 35 cohort (478 patients, 78.6%). At baseline, patients with BMI ≥ 35 were more likely to be younger (58.5 ± 11.4 vs 63.2 ± 12.0 years old, p < 0.001), to present with both back and leg pain (53.8% vs 37.0%, p = 0.002), and to require ambulation assistance (20.8% vs 9.2%, p < 0.001). Furthermore, the cohort with BMI ≥ 35 had worse baseline patient-reported outcomes including visual analog scale (VAS) back (7.6 ± 2.3 vs 6.5 ± 2.8, p < 0.001) and leg (7.1 ± 2.6 vs 6.4 ± 2.9, p = 0.031) pain, disability measured by the Oswestry Disability Index (ODI) (53.7 ± 15.7 vs 44.8 ± 17.0, p < 0.001), and quality of life on EuroQol-5D (EQ-5D) questionnaire (0.47 ± 0.22 vs 0.56 ± 0.22, p < 0.001). Patients with BMI ≥ 35 were more likely to undergo fusion (85.4% vs 74.7%, p = 0.01). There were no significant differences in 30- and 90-day readmission rates (p > 0.05). Five years postoperatively, there were no differences in reoperation rates or the development of adjacent-segment disease for patients in either BMI < 35 or ≥ 35 cohorts who underwent fusion (p > 0.05). On multivariate analysis, BMI ≥ 35 was a significant risk factor for not achieving minimal clinically important differences (MCIDs) for VAS leg pain (OR 0.429, 95% CI 0.209–0.876, p = 0.020), but BMI ≥ 35 was not a predictor for achieving MCID for VAS back pain, ODI, or EQ-5D at 5 years postoperatively. CONCLUSIONS Both obese and nonobese patients benefit from surgery for grade 1 spondylolisthesis. At the 5-year time point, patients with BMI ≥ 35 have similarly low reoperation rates and achieve rates of satisfaction and MCID for back pain (but not leg pain), disability (ODI), and quality of life (EQ-5D) that are similar to those in patients with a BMI < 35.

OBJECTIVE The aim of this study was to compare the rate of achievement of the minimal clinically important difference (MCID) in patient-reported outcomes (PROs) and satisfaction between cervical spondylotic myelopathy (CSM) patients with and without class III obesity who underwent surgery. METHODS The authors analyzed patients from the 14 highest-enrolling sites in the prospective Quality Outcomes Database CSM cohort. Patients were dichotomized based on whether or not they were obese (class III, BMI ≥ 35 kg/m 2 ). PROs including visual analog scale (VAS) neck and arm pain, Neck Disability Index (NDI), modified Japanese Orthopaedic Association (mJOA), EQ-5D, and North American Spine Society patient satisfaction scores were collected at baseline and 24 months after cervical spine surgery. RESULTS Of the 1141 patients with CSM who underwent surgery, 230 (20.2%) were obese and 911 (79.8%) were not. The 24-month follow-up rate was 87.4% for PROs. Patients who were obese were younger (58.1 ± 12.1 years vs 61.2 ± 11.6 years, p = 0.001), more frequently female (57.4% vs 44.9%, p = 0.001), and African American (22.6% vs 13.4%, p = 0.002) and had a lower education level (high school or less: 49.1% vs 40.8%, p = 0.002) and a higher American Society of Anesthesiologists grade (2.7 ± 0.5 vs 2.5 ± 0.6, p < 0.001). Clinically at baseline, the obese group had worse neck pain (VAS score: 5.7 ± 3.2 vs 5.1 ± 3.3), arm pain (VAS score: 5.4 ± 3.5 vs 4.8 ± 3.5), disability (NDI score: 42.7 ± 20.4 vs 37.4 ± 20.7), quality of life (EQ-5D score: 0.54 ± 0.22 vs 0.56 ± 0.22), and function (mJOA score: 11.6 ± 2.8 vs 12.2 ± 2.8) (all p < 0.05). At the 24-month follow-up, however, there was no difference in the change in PROs between the two groups. Even after accounting for relevant covariates, no significant difference in achievement of MCID and satisfaction was observed between the two groups at 24 months. CONCLUSIONS Despite the class III obese group having worse baseline clinical presentations, the two cohorts achieved similar rates of satisfaction and MCID in PROs. Class III obesity should not preclude and/or delay surgical management for patients who would otherwise benefit from surgery for CSM.

Abstract Patients with head and neck squamous cell carcinomas (HNSCC) often have poor outcomes due to suboptimal risk management and treatment strategies; yet integrating novel prognostic biomarkers into clinical practice is challenging. Here, we report the presence of multinucleated giant cells (MGC)—a type of macrophages—in tumors from patients with HNSCC, which are associated with a favorable prognosis in treatment-naive and preoperative chemotherapy–treated patients. Importantly, MGC density increased in tumors following preoperative therapy, suggesting a role of these cells in the antitumoral response. To enable clinical translation of MGC density as a prognostic marker, we developed a deep-learning model to automate its quantification on routinely stained pathological whole slide images. Finally, we used spatial transcriptomic and proteomic approaches to describe the MGC-related tumor microenvironment and observed an increase in central memory CD4 T cells. We defined an MGC-specific signature resembling to TREM2-expressing mononuclear tumor-associated macrophages, which colocalized in keratin tumor niches. Significance: Novel individual biomarkers are needed to guide therapeutic decisions for patients with head and neck cancer. We report for the first time, granulomas of TREM2-expressing multinucleated giant macrophages in keratin-rich tumor niches, as a biomarker of favorable prognosis and developed a deep-learning model to automate its quantification on routinely stained pathological slides.

AbstractObjectiveThis study aims to compare the long‐term outcomes of Aquablation for small‐to‐moderate (30–80 cm3) prostates with the outcomes for large (80–150 cm3) prostates at 5‐year follow up.MethodsThe Waterjet Ablation Therapy for Endoscopic Resection of Prostate Tissue (WATER; NCT02505919) is a prospective, double‐blind, international clinical trial encompassing 116 patients, examining Aquablation versus transurethral resection of the prostate (TURP) for LUTS/BPH in prostates sized between 30 and 80 cm3. In parallel, WATER II (W‐II; NCT03123250), a prospective, multicentre, single‐arm international clinical trial, explores Aquablation outcomes in prostates ranging from 80 to 150 cm3. Baseline parameters and 60‐month outcomes were scrutinized using statistical analyses, including Students' t test, Wilcoxon tests for continuous variables, and Fisher's test for binary variables.ResultsThere is a significant improvement in International Prostate Symptom Score (IPSS) from baseline to 60 months in both WATER (22.9 to 7.0) and WATER II (23.2 to 6.8) (P = 0.852). Urinary flow rate (Qmax) increased in both groups from baseline to 60 months (WATER: 9.4 to 17.3 cc/s; WATER II: 8.7 to 17.1 cc/s) (P = 0.933). Immediate and sustained enhancements were observed in IPSS and Qmax. At 5 years, a notable percentage of patients in both groups were BPH medication‐free (WATER: 99%; WATER II: 94%) (P = 0.0517) and free from surgical retreatment (WATER: 95%; WATER II: 97%) (P = 0.508).ConclusionsThe 5‐year follow‐up affirms that Aquablation therapy exhibits sustained outcomes, minimal irreversible complications, and low retreatment rates for treating LUTS/BPH, irrespective of prostate volume ranging from 30 to 150 cm3.