Citations

Abstract Systemic light chain amyloidosis (AL) arises from monoclonal immunoglobulin light chains, but determinants of progression from precursor states remain poorly defined. In a cross-sectional cohort comprising 1950 systemic AL patients diagnosed 2010-2024, 258 (13.2%) patients with a previously diagnosed plasma cell disorder (PCD) were compared to patients with no prior PCD diagnosis. Patients with monoclonal gammopathy of undetermined signficance (MGUS) and smoldering multiple myeloma (SMM) in the former group had lower difference between involved and uninvolved FLCs (dFLC), higher M-protein, and lower rates of t(11;14) at AL diagnosis. Patients developing AL from SMM had a shorter time to AL (median 34.2 versus 61.3 months) and higher dFLC (median 28.9 versus 11.0 mg/dl) compared to those from MGUS. Patients developing AL after known multiple myeloma (MM) or lymphoplasmacytic lymphoma (LPL) commonly lacked deep hematologic response before AL (≤ very good partial response in 78% of MM, 100% of LPL patients). We additionally studied longitudinally followed cohorts of 3,966 MGUS and 426 (SMM) patients with longitudinal FLC measurements and matched follow-up, in which 1.8% of MGUS and 7.2% of SMM patients developed AL. Those patients who developed AL showed markedly higher dFLC at MGUS/SMM diagnosis and more frequent λ restriction and rates of t(11;14). Higher dFLC was associated with progressively earlier AL development; a 10% cumulative risk occurred at 20 months for patients with a dFLC >80 mg/dL but was not reached if dFLC <10 mg/dL at an estimated median follow-up of 86 months. In multivariable analysis, dFLC >6.4 mg/dL (HR 11.3) and λ isotype (HR 3.6) independently predicted AL, whereas heavy chain secretion was associated with lower risk (HR 0.2 for IgG). These findings indicate that AL risk is primarily driven by cumulative light chain exposure, refining our knowledge of AL pathophysiology and providing guidance for follow-up of patients with elevated dFLC.

Background Psychiatric disorders are increasingly contributing to global disability. Despite advances in conservative management, the prevalence of treatment-resistant cases remains high. Meanwhile, neurosurgery for psychiatric disorders (NPD) remains underused, largely due to strict regulations and historical concerns, particularly those related to neuropsychological side effects (NPSE). Objective To address this issue, we conducted a systematic review with meta-analysis to compare NPSE associated with radiofrequency ablative NPD to those observed in neuro-oncological, neurovascular and epilepsy surgeries. Methods PubMed, Embase and LILACS databases were searched in April 2024 for articles published in English/Spanish from 1990 to 2022, following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Results A total of 48 articles with 2678 participants were included. The frequency of transient and permanent NPSE in the NPD group ranged from 0.94% to 11.50% and 0.94% to 2.03%, respectively, comparable to the other surgical groups (epilepsy: 0.31–11.70%; vascular: 0.52–22.90%; oncology: 0.94–17.60% for transient NPSE; epilepsy: 0.31–12%; vascular: 0.40–1.96% and oncology: 0.84–1.48% for permanent NPSE). Regarding permanent NPSE, arguably the most critical consideration, the NPD group showed better outcomes in memory, language and social cognition than the epilepsy group, but worse outcomes in executive and perceptual-motor functions. Compared with the vascular group, the NPD group had better executive function but worse complex attention. Finally, the NPD group had fewer permanent deficits than the oncology group in executive function, complex attention and perceptual-motor domains, although language performance was lower. Conclusions Contemporary NPD apparently carries a similar risk of NPSE as other conventional neurosurgical procedures, challenging misconceptions and this unjustified barrier to its broader use.

Abstract Purpose: In RET-rearranged non–small cell lung cancer (NSCLC), treatment options after first-generation selective RET inhibitors (SRI) are limited, and the value of SRI retreatment remains unclear. This study evaluates outcomes of SRI retreatment. Experimental Design: This multicenter retrospective study included patients with advanced RET-rearranged NSCLC who received ≥2 SRI-based therapy lines. Of 411 SRI-treated patients, 41 (10%) underwent SRI retreatment. Outcomes included objective response rate (ORR), progression-free survival (PFS), 6-month PFS, time to treatment failure, adverse events (AE). Results: Among 41 patients, 14 (34%) discontinued the initial SRI because of toxicity and 27 (66%) because of progression. After discontinuation for toxicity, all switched to an alternate SRI, achieving an ORR of 67%, median PFS of 9.9 months, and 6-month PFS of 80.3%. AEs reoccurred in nine patients (64%), with grade ≥3 AEs in 3 (21%) who switched at full dose. Among patients who discontinued because of progression, SRI monotherapy (n = 13) achieved an ORR of 23%, median PFS of 7 months, and 6-month PFS of 61.5%. Benefit was observed in patients with brain-only or oligoprogressive disease or dose reduction on first SRI. Combination therapy (n = 14; targeted agents, n = 11; chemotherapy, n = 3) achieved an ORR of 39%, median PFS of 4 months, and 6-month PFS of 27.3%. Conclusions: Same-class SRI switch after toxicity is feasible and clinically active but warrants cautious, dose-adjusted switching to mitigate toxicities. The efficacy of SRI rechallenge after progression seems limited overall. However, selected patients, such as those with brain-only or oligoprogressive disease, may derive benefit.

Abstract Modern radiation therapy (RT) technologies allow for improved sparing of normal tissues, decreasing the risk of both acute and long-term toxicities. Existing RT dose constraints for prospective trials within the National Clinical Trials Network (NCTN) were formulated in the context of solid malignancies. As patients with hematologic malignancies are often treated with lower RT doses and are usually younger with more favorable prognoses, customized dose constraints are needed. The NRG Oncology Hematologic Malignancies Working Group (NRG HEME) commissioned a review of existing organ-at-risk (OAR) constraints from published primary literature, the NRG Center for Innovation in Radiation Oncology (CIRO), and national guidelines. Customized constraints were developed by iterative review by NRG HEME. Final recommendations were approved by radiation oncology representatives from all the lymphoma NCTN groups (NRG Oncology, Children’s Oncology Group, Alliance, ECOG-ACRIN, SWOG, Canadian Cancer Trials Group). For 49 OARs, a strict recommended constraint was determined, of which 20 were not present in CIRO. Of the remaining 29 constraints, 20 were lower, 2 were the same, and 5 used different metrics; 2 were higher than at least 1 CIRO trial constraint. Acceptable variations were determined and unacceptable variations were added for select critical OARs for plan scoring. While doses to OARs without explicit unacceptable variations should not exceed acceptable variations, violations should not be considered for plan quality assessment on trials. This consensus list of standard OAR constraints should be incorporated for all future NCTN trials in hematologic malignancies. Strict dose constraints will minimize long-term toxicities in this patient population.

Abstract INTRODUCTION We examined when Alzheimer's disease biomarkers become informative by identifying age‐related breakpoints with slope‐changing trajectories. METHODS In 2082 Mayo Clinic Study of Aging participants, we modeled plasma amyloid beta (Aβ)42/40, phosphorylated tau (p‐tau)181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), amyloid/tau positron emission tomography (PET), hippocampal volume (HVa), and global cognition. Generalized additive models described age trends; Davies' test and piecewise linear regression estimated breakpoints. A C2N subsample ( n = 462) provided mass‐spectrometry plasma markers (p‐tau181, p‐tau217, their ratios, Aβ42/40). RESULTS In the full cohort, Aβ42/40, HVa, and cognition declined with age; p‐tau181, NfL, GFAP, and amyloid/tau PET increased. We observed single breakpoints (years, 95% CI): GFAP 68.1 (63.5–71.8), NfL 70.7 (65.9–75.6), p‐tau181 67.2 (60.3–70.3), amyloid PET 62.3 (56.2–69.3), HVa 68.1 (63.1–71.9), cognition 59.8 (55.4–66.0); tau PET showed none. In the mass‐spectrometry subset, p‐tau217 and p‐tau181 broke at 72.6; their ratios and Aβ42/40 showed no breakpoints. DISCUSSION Breakpoints cluster near late midlife, suggesting windows for screening and monitoring.

Background Reductions in blood pressure (BP) control among patients with hypertension were observed early in the COVID‐19 pandemic. The degree to which BP control may have returned to prepandemic levels is unknown. Methods Individuals aged 18 to 85 years with hypertension from 17 health systems participating in the National Patient‐Centered Clinical Research Network were identified using electronic health record data collected as part of routine care. BP control (percentage of patients whose most recent BP measurement was <140/<90 mm Hg) was estimated in a series of 12‐month rolling measurement periods from 2017 through 2022 (January 1, 2017 through December 31, 2017; April 1, 2017 through March 31, 2018; … January 1, 2022 through December 31, 2022). Differences in average BP control between 2022 (January 1, 2022 through December 31, 2022) and 2019 (January 1, 2019 through December 31, 2019) were estimated overall (adjusted for age, sex, and race and ethnicity) and by race and ethnicity (adjusted for age and sex). Results Our sample included 1 193 314 persons with hypertension in 2019 (48.9% aged 65–85 years, 52.9% men, 66.2% non‐Hispanic White) and 1 499 418 individuals in 2022 (50.6% aged 65–85 years, 47.1% men, 62.7% non‐Hispanic White). The weighted average BP control dropped from 65.3% in 2019 to 61.8% in 2020 and then partially recovered to 62.6% in 2022 (adjusted mean difference, −2.6 percentage points [95% CI, −5.0 to −0.2]). Non‐Hispanic Asian individuals experienced the largest temporal drop in BP control, declining from 68.4% in 2019 to 63.9% in 2022. Conclusions BP control was disrupted during the COVID‐19 pandemic and had not fully rebounded to prepandemic levels by the end of 2022. Continued surveillance is needed to determine whether the decline in BP control will persist and will result in future adverse cardiovascular events.

Abstract Background Anti‐M antibodies were described as rarely eliciting hemolytic disease of the fetus and newborn (HDFN) in pregnancy. More recent literature, primarily from Asia, reports severe HDFN attributed to maternal anti‐M. The objective of this study is to determine if there is a difference in the frequency and/or severity of anti‐M HDFN among subjects who self‐report as Asian compared to non‐Asian. Methods Retrospective data were collected from 18 sites. Fetuses/neonates affected by HDFN were categorized as unaffected, mild, moderate, or severe based on clinical management and outcomes. Results Anti‐M was identified in 557 obstetric patients. Among 332 neonates with complete data for analysis, anti‐M was detected in isolation during the pregnancies of 210 (63.3%) neonates; 198 (94.3%) were unaffected by HDFN. The overall frequency of HDFN was 6.5% (2/31) in Asian patients and 5.6% (10/179) in non‐Asian patients. The frequency of severe HDFN was 6.5% (2/31) among Asian patients and 0.6% (1/179) among non‐Asian patients. Among non‐Asian patients, eight (4.5%) were mild and one (0.6%) was moderate. Of 63 pregnancies with anti‐M and ABO incompatibility, 6 (9.5%) were associated with mild HDFN and 57 (90.5%) were unaffected. Of 49 pregnancies with anti‐M and non‐ABO antibody(s), 6 (12.2%) were associated with mild HDFN and 43 (87.8%) were unaffected. One case (10.0%) of HDFN (mild) occurred in the presence of anti‐M, additional antibody(s), and ABO incompatibility. Conclusion In this study, severe anti‐M HDFN was rare in non‐Asian subjects. There is a signal that Asian patients are at greater risk for severe anti‐M HDFN.

Background Immune exclusion inhibits antitumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. In triple-negative breast cancer (TNBC), an aggressive and generally immune-rich subtype, an immune-cold microenvironment predicts poor prognosis due to a limited response to chemotherapy and immune checkpoint inhibitors. This study aimed to identify mechanisms regulating immune infiltration in TNBC. Methods We performed spatial transcriptomic analysis comparing immune-enriched versus immune-cold treatment-naïve TNBCs. Functional analyses, including loss-of-function and reconstitution experiments, were conducted to investigate the role of trophoblast cell-surface antigen 2 (TROP2), a key target of anticancer antibody drug conjugates (ADCs), in promoting TNBC progression. A humanized TROP2 syngeneic TNBC model was used to assess the effects of TROP2-targeting in combination with anti-programmed cell death protein 1 (PD-1) therapy. Additionally, data from patients treated with immune checkpoint blockade were used to test hypotheses from the preclinical findings. Results We reveal that TROP2 controls barrier-mediated immune exclusion in TNBC through claudin 7 association and tight junction regulation. TROP2 expression is inversely correlated with T-cell infiltration and predicts poor outcomes in TNBC. We demonstrate that TROP2 is sufficient to drive tumor progression in vivo in a CD8 T cell-dependent manner, while its loss deregulates expression and localization of multiple tight junction proteins, enabling T-cell infiltration. We show that TROP2 targeting via hRS7, the antibody component of the ADC sacituzumab govitecan, enhances the anti-PD-1 response and improves T-cell accessibility and effector function. Correspondingly, TROP2 expression is highly associated with lack of response to anti-PD-1 therapy in human breast cancer. Conclusions This study defines a new mechanism of barrier-mediated immune exclusion in cancer controlled by TROP2-dependent tight junctions. This mechanism drives tumor progression but can be targeted via TROP2-directed therapy to activate antitumor immunity and enhance immunotherapy response.