Citations

Abstract Bispecific T-cell engagers (TCEs) targeting B-cell maturation antigen (BCMA) and CD3, induce deep hematologic responses in ∼60% of heavily pretreated patients with multiple myeloma (MM). We and others found that high tumor burden leads to resistance to TCE and novel strategies are urgently needed to improve responses in this setting. Ikaros degraders, including immunomodulatory drugs (IMiDs) and cereblon E3 ligase modulatory drugs (CELMoDs), represent logical partners for TCEs due to their direct anti-MM effects and additional immune-stimulatory activity; however, it is unclear how to optimally combine them with TCEs. Taking advantage of the immunocompetent IMiD-sensitive Vk∗MYChCRBN murine model of MM, we optimized strategies to overcome primary resistance to BCMA-TCEs and achieve sustained remission, while maintaining a manageable safety profile. The addition of anti–programmed cell death protein 1 (PD1) and pomalidomide reduced the T-cell exhaustion that occurs in response to TCEs in high tumor burden settings. This allowed for a higher degree of T-cell activation and significant improvement in response rates but also increased risk of lethal cytokine release syndrome (CRS). To moderate the response and prevent CRS, we evaluated Ikaros degraders and dexamethasone (DEX) with step-up–dosed TCEs. Pretreatment with iberdomide and DEX reshaped the bone marrow T-cell compartment, promoted infiltration of naïve T cells, and generated 100% response rates and the longest survival in subjects with high tumor burden. This was accompanied by more favorable T-cell profiling, with limited expansion of regulatory T cells and exhaustion. Overall, administering a TCE after DEX and iberdomide treatments provided deeper and more durable responses with a reduced risk of CRS.

Increasing evidence strongly links neuroinflammation to Alzheimer’s disease (AD) pathogenesis. Peripheral monocytes are crucial components of the human immune system, but their contribution to AD pathogenesis is still largely understudied partially due to limited human models. Here, we introduce human cortical organoid microphysiological systems (hCO-MPSs) to study AD monocyte-mediated neuroinflammation. By culturing doughnut-shape organoids on 3D-printed devices within standard 96-well plates, we generate hCO-MPSs with reduced necrosis, minimized hypoxia, and improved viability. Using these models, we found that monocytes from AD patients exhibit increased infiltration ability, decreased amyloid-β clearance capacity, and stronger inflammatory response than monocytes from age-matched control donors. Moreover, we observed that AD monocytes induce pro-inflammatory effects such as elevated astrocyte activation and neuronal apoptosis. Furthermore, the marked increase in IL1B and CCL3 expression underscores their pivotal role in AD monocyte-mediated neuroinflammation. Our findings provide insight into understanding monocytes’ role in AD pathogenesis, and our lab-compatible MPS models may offer a promising way for studying various neuroinflammatory diseases.

This cross-sectional study analyzes patient-reported outcome findings from the Enhanced, Electronic Health Record–Facilitated Cancer Symptom Control (E2C2) trial to investigate level of symptom burden in adolescents and young adults with cancer.

Abstract Parkinson’s disease (PD) is the fastest growing neurodegenerative disease in the world1. Gastrointestinal (GI) dysfunction can occur decades before motor impairments and in up to 80% of individuals living with PD2,3,4. We investigated peripheral relationships that may underlie environmental contributions to mechanisms along the gut-blood axis that contribute to PD pathogenesis. Single-cell multiomic spatial molecular imaging (SMI) of colonic tissue localized inflammatory injury within epithelial cells that appear to be associated with iron mishandling in both inflammatory bowel disease (IBD) and PD biosamples. We found that both the single-cell SMI of RNA and protein revealed parallel cross-modal dysregulation in the gut epithelium, in both IBD and PD biosamples. These data are accompanied by plasma (PD) and stool (IBD) protein depletion of CCL22. Our findings suggest iron mishandling along the gut barrier likely contributes to systemic inflammation, which may be the catalyst that primes circulating immune cells to body-first PD pathogenesis.

SummaryIn individuals with high‐count monoclonal B‐cell lymphocytosis (MBL), we investigated if lymphadenopathy or splenomegaly found by imaging was associated with shorter time to first chronic lymphocytic leukaemia (CLL) therapy (TTFT) and overall survival (OS). Individuals with MBL seen at Mayo Clinic (2002–2019) were retrospectively divided into three cohorts based on imaging studies within 1 year of diagnosis: no imaging studies (Cohort A); imaging with no evidence of lymphadenopathy/splenomegaly (Cohort B); imaging with evidence of lymphadenopathy/splenomegaly (Cohort C). We compared baseline characteristics, TTFT and OS across the MBL cohorts to a cohort of individuals with small lymphocytic lymphoma (SLL). A total of 1078 patients were included: 640 with MBL and 438 with SLL. Compared to Cohort B, individuals in Cohort C were more likely to have unmutated immunoglobulin heavy chain variable region (IGHV) (43% vs. 25% p = 0.016), high‐risk fluorescence in situ hybridization (FISH) (del17p and del11q in 15% vs. 4%, p = 0.038) and higher expression of CD38 (31% vs. 16%; p = 0.011). After adjusting for sex and CLL‐International Prognostic Index (IPI), lymphadenopathy/splenomegaly was associated with a shorter TTFT (hazard ratio [HR] = 2.04, 95% confidence interval [CI]: 1.02–4.04, p = 0.042) but not OS (HR = 1.09, 95% CI: 0.62–1.92, p = 0.775). Lymphadenopathy/splenomegaly on imaging in individuals with high‐count MBL is associated with a more unfavourable risk profile and shorter time to first CLL‐directed therapy.

Abstract Motivation Compositional data are frequently encountered in many disciplines, such as in next-generation sequencing experiments widely used in biomedical studies. Regression analysis with compositional data as either responses or predictors has been well studied. However, when both responses and predictors are compositional, the inventory of analysis tools is surprisingly limited, especially in the high-dimensional setting. Among the few existing methods, most of them rely on a log-ratio transformation to move compositional data from the simplex to real numbers. Yet, a serious weakness of these methods is their failure to handle the substantial fraction of zeroes observed in data collected from next-generation sequencing experiments. Results To investigate associations between two high-dimensional multi-omics compositions, we propose a composition-on-composition (COC) regression analysis method which does not require log-ratio transformations and hence can handle zeroes in the data. To account for high dimensionality, we estimate regression coefficients using a penalized estimation equation approach. Finally, inference procedures for COC regression are also proposed. Superior performance of COC is demonstrated through both comprehensive numerical simulations and case studies. Availability and implementation Source R codes to implement COC method is available at https://github.com/nrios4/COC.

PURPOSE Stereotactic radiation (SRS/SRT) as opposed to whole-brain radiation (WBRT) represents the standard of care for patients with a limited number of brain metastases given the relatively favorable toxicity profile associated with stereotactic treatment. However, in patients with small cell lung cancer (SCLC), WBRT remains standard because of a lack of prospective data supporting SRS/SRT and concerns related to intracranial progression and neurologic death when WBRT is omitted. We conducted a single-arm, multicenter, phase II trial of SRS/SRT in patients with SCLC and 1-10 brain metastases to assess neurologic death rates relative to historical controls managed with WBRT (ClinicalTrials.gov identifier: NCT03391362 ). METHODS Patients were eligible if they had SCLC or an extrathoracic small cell primary and 1-10 brain metastases. Previous brain-directed radiation including prophylactic cranial irradiation was not permitted. Neurologic death was defined as marked, progressive, radiographic brain progression accompanied by corresponding neurologic symptomatology without systemic disease progression or systemic symptoms of a life-threatening nature. Close imaging-based surveillance of the brain post-SRS/SRT was used. RESULTS Between February 2018 and April 2023, 100 patients were enrolled. The median number of brain metastases was 2 (IQR, 1-4; range, 1-10). The median overall survival was 10.2 months; only 22% of patients required salvage WBRT. In total, 20 neurologic deaths were observed, relative to 64 non-neurologic deaths. The neurologic death rate at 1 year was 11.0% (95% CI, 5.8 to 18.1); the historical rate in patients managed with WBRT was 17.5%. CONCLUSION Our prospective, multi-institutional study demonstrated low rates of neurologic death when SRS/SRT as opposed to WBRT is used in patients with SCLC and 1-10 brain metastases who are surveilled closely post-treatment, supporting the utility of stereotactic approaches in this population.

PURPOSE Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (<50 years, named early-onset CRC [eoCRC]) has been increasing. PATIENTS AND METHODS Individual patient data on 13,365 patients with metastatic CRC enrolled between 2000 and 2012 in 17 first-line randomized trials in the Aide et Recherche en Cancérologie Digestive database were pooled. The distribution of demographics, clinicopathologic features, biomarkers, and outcome data were summarized and compared by age groups. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for potential confounders. Predictive value of age group on clinical outcomes was evaluated by testing interaction effect between treatment and age variables. RESULTS Overall, 2,045 patients with eoCRC (median age, 42.5) and 11,320 patients with average-onset CRC (aoCRC; median age, 63.8) were included in this analysis. Within the eoCRC population, treatment with bevacizumab in addition to chemotherapy improved PFS (9.9 v 6.8 months; hazard ratio [HR], 0.66 [95% CI, 0.54 to 0.80]; P < .0001), which was similar to the findings in aoCRC population (9.4 v 7.3 months; HR, 0.73 [95% CI, 0.67 to 0.80]; P < .001; interaction P = .5415). However, epithelial growth factor receptor inhibitor (EGFRi) did not improve PFS in RAS wild-type (WT) patients with eoCRC who had left-sided primary tumors (8.3 v 8.9 months; HR, 1.20 [95% CI, 0.81 to 1.77]; P = .36), whereas EGFRi significantly improved PFS in the aoCRC population (9.9 v 8.5 months; HR, 0.74 [95% CI, 0.64 to 0.86]; P < .0001; interaction P = .083). CONCLUSION Treatment-naïve patients with metastatic eoCRC appear to derive similar benefit from bevacizumab as patients with aoCRC. However, patients with eoCRC with left-sided RAS/RAF WT tumors did not appear to derive benefit from first-line EGFRi.

A systematic review was conducted of studies published up to 30 August 2024. Studies comparing conventional visual field (VF) indices, ability to detect central visual field defects (CVFDs), structure–function (S-F) concordance, and test characteristics across the HVF 24-2C SITA-Faster, 24-2 SITA-Standard/Faster, and 10-2 SITA-Standard/Fast tests were included. Eight studies with 1239 subjects (49.1% male; mean age, 54.8–66.9 years) were analyzed. The 24-2C produced similar global VF indices compared to the 10-2 and 24-2 (Standard/Faster) (ICC = 0.95 and 0.80, p < 0.001), detected more VF defects and CVFD clusters, and demonstrated greater S-F concordance than the 24-2 (Standard/Faster). Although the 10-2 (Standard/Fast) detected significantly more CVFDs and had a greater S-F concordance, the agreement between the 24-2C and 10-2 grids was substantial (ĸ = 0.488 to 0.708). The 24-2C was also faster compared to the 24-2 Standard and 10-2 (Standard/Fast), with comparable false positives, higher false negatives, and fewer fixation losses than the 24-2 Standard. In conclusion, the HVF 24-2C is quicker and identifies more CVFDs than the 24-2 grid, demonstrates high agreement with the 10-2 grid, and aids in CVFD screening.