Citations

Dominant-inactivating mutations in the colony stimulating factor-1 receptor ( CSF1R ) cause CSF-1R–related leukoencephalopathy (CRL), an adult-onset neurodegenerative disease that is modeled in the Csf1r +/– mouse. CRL is caused by microglial dysfunction. However, the primary microglial deficit is unknown. To address this question, we employed single-nucleus RNA sequencing of brains from young Csf1r +/– mice without pathological or behavioral alterations. Reduction of CSF-1R signaling caused metal ion accumulation in brain macrophages, with concomitant activation of cell death and stress response pathways in oligodendrocytes and neuronal subpopulations. Reduction of metallothionein 1 ( Mt1 ) and 3 ( Mt3 ) gene expression was a common feature in glial and neuronal cells of Csf1r +/– mice. Overexpression of Mt1 restored metal ion homeostasis, normalized ROS production in microglia, and prevented the development of behavioral deficits, while Mt3 deletion had disease-enhancing effects. These findings demonstrate CSF-1R regulation of metal ion homeostasis via metallothioneins in the brain.

Importance Total thyroidectomy is the established surgical standard for hereditary and sporadic medullary thyroid cancer (sMTC). However, for unilateral sporadic tumors, its benefit over lobectomy remains uncertain. Objective To compare oncologic outcomes between total thyroidectomy and lobectomy in patients with sMTC. Data Sources and Study Selection MEDLINE, Embase, Scopus, and Cochrane Central Register of Controlled Trials were searched from inception to December 2025 to identify comparative studies on patients with sMTC who underwent total thyroidectomy or lobectomy. Data Extraction and Synthesis Reviewers working independently and in duplicate screened titles, abstracts, and full-text articles for eligibility using standardized instructions. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses ( PRISMA ) and Meta-Analysis of Observational Studies in Epidemiology ( MOOSE ) guidelines were used for reporting. Main Outcomes and Measures Primary outcomes were mortality, overall survival, structural recurrence, biochemical cure, and distant metastasis development. The secondary outcome was postoperative complications. Effect measures were calculated as odds ratios (ORs) or relative risks (RRs) with 95% CIs using a random-effects model. The risk of bias was assessed using the Newcastle-Ottawa Scale. Results Nine retrospective studies met inclusion criteria and comprised 1371 patients (295 of 397 patients [74.3%] with documented sex were female, and median age ranged from 45.0 to 58.2 years). A total of 531 patients (38.7%) underwent lobectomy and 840 (61.3%) underwent total thyroidectomy. Of 341 tumors, 280 (82.1%) lacked extrathyroidal extension, 284 of 401 tumors (70.8%) measured smaller than 2 cm (70.8%), and 197 of 343 tumors (57.4%) were node negative; central neck dissection was performed in 445 of 492 patients (90.4%). Multifocal disease was uncommon and reported in 30 of 330 patients (9.1%). Mortality did not differ at 5 years (RR, 0.30; 95% CI, 0.07-1.35) or beyond (RR, 1.00; 95% CI, 0.40-2.47). Overall survival at 5 years was similar (RR, 1.02; 95% CI, 0.94-1.11). Total thyroidectomy was not associated with lower structural recurrence rates at 5 years (OR, 0.45; 95% CI, 0.14-1.49), but it was associated beyond 5 years (OR, 7.26; 95% CI, 1.07-49.21). No differences were observed for biochemical cure at 5 years (OR, 0.86; 95% CI, 0.47-1.56) or beyond 5 years (OR, 0.87; 95% CI, 0.26-2.89). Distant metastasis development did not differ at 5 years (OR, 1.64; 95% CI, 0.09-31.52). Sensitivity analyses revealed no differences across any outcomes. Postoperative complications were more common in total thyroidectomy. Risk of bias was high in 4 studies, moderate in 4, and low in 1. Conclusions and Relevance Findings in this systematic review and meta-analysis, based on data from retrospective studies, suggest that thyroid lobectomy may be associated with oncologic outcomes comparable to total thyroidectomy in selected patients with sMTC.

Abstract Objective: Subjective cognitive complaints (SCC) can precede cognitive decline and are associated with demographic, exposure, lifestyle, and psychological factors. Prevalences of SCC and their correlates in individuals with repetitive head impacts (RHI) are poorly understood. This study characterized SCC in former elite American football players by frequency, mood and behavioral correlates, concordance with informant reports, and associations with neuropsychological test performance, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) markers of neurodegeneration. Method: Former American football players ( n = 180) completed measures of global and domain-specific SCC, neuropsychiatric symptom questionnaires, neuropsychological testing, lumbar puncture, and MRI. Elastic net regression evaluated the relative importance of potential SCC correlates. Intraclass correlation coefficients measured concordance between self and informant reports. Multiple linear regressions tested associations between SCC and verbal memory and executive functioning scores. CSF Aβ 1-42 , p-tau 181 , t-tau, neurofilament light (NfL), hippocampal volume, and regional cortical thickness were examined for their potential associations with SCC. Results: Rates of SCC ranged from 43 to 77% depending on the domain. Symptoms of depression, impulsivity, and anxiety were strongly associated with SCC. Self- and informant-reported SCC showed moderate inter-rater agreement. Adjusting for age, race, education, APOE ϵ4 carrier status, and depressive symptoms, SCC were associated with lower objective verbal memory and executive functioning performance. SCC were associated with lower parahippocampal cortical thickness but not with hippocampal volume or any of the measured CSF tests. Conclusions: SCC are strongly associated with neuropsychiatric factors in former American football players. SCC may also be a marker of cognitive decline and neurodegeneration.

According to the current WHO classification, noninvasive germ cell neoplasia of the testis comprises germ cell neoplasia in situ (GCNIS), specific forms of intratubular germ cell neoplasia, and gonadoblastoma. Because type II germ cell tumors (GCT, type II) arise from GCNIS, accurate detection of precursor lesions is diagnostically important. In preparation for the 2024 International Society of Urological Pathology (ISUP) Consensus Conference on genitourinary precursor lesions, which took place in Florence, Italy, an anonymous survey was distributed to ISUP members to assess current diagnostic practices regarding testicular precursor lesions. The literature and current WHO classification affirm the significance of precursor lesions in testicular tumours. Working Group 4—Precursor Lesions of the Testis—focused on their practical application by individual pathologists rather than establishing consensus from scientific data. There is strong agreement that GCNIS is the preferred and appropriate term for GCT precursor lesions and that its presence should be reported in cases of invasive GCT. Respondents also agree that “seminoma with intratubular nonseminoma” is the appropriate terminology for seminoma with an associated noninvasive nonseminomatous (embryonal carcinoma, yolk sac tumor, trophoblasts, or teratoma) component. Most pathologists prefer to use OCT3/4 as the primary immunohistochemical marker, and a panel was generally not considered necessary. No consensus is reached regarding the requirement for immunohistochemistry to confirm GCT precursor lesions in the testis. Three questions remain open: the value of subtyping intratubular lesions, the immunohistochemical approach to gonadoblastoma, and the criteria distinguishing Sertoli cell nodules from Sertoli cell tumors.

Abstract Tau pathology emerges early in Alzheimer’s disease within entorhinal cortex layer II (ECII) and reaches hippocampal CA1, but how this circuit-level spread translates into sex-dependent vulnerability remains unclear. Using a circuit-defined model in which P301L human tau is expressed selectively in Wolframin-1 (Wfs1 + ) ECII neurons and propagates to CA1, we found that the extent and proximal–distal distribution of tau-positive CA1 neurons were comparable in males and females. Despite similar propagation, females exhibited broad hippocampal-dependent cognitive impairment (working memory, object recognition, fear acquisition, trace associative memory, and contextual fear memory), whereas males showed a selective deficit in trace associative memory. Consistent with these behavioral outcomes, CA1 pyramidal neurons in tau-propagated females displayed reduced excitability (slower action potential kinetics, reduced firing during depolarizing steps) and reduced spontaneous excitatory postsynaptic current (EPSC) amplitude, while males showed subtler intrinsic changes with altered EPSC kinetics. Bulk RNA sequencing of entorhinal cortex and CA1 revealed robust immune pathway engagement after tau propagation, with males showing a stronger Th1/Th2 and neuroinflammatory signature and CTLA4-associated signaling changes, whereas females showed prominent complement–phagosome pathway enrichment and a female-specific increase in Clec7a + microglia density in CA1. CD4 + T-cell infiltration into CA1 was detected in both sexes. Together, these results indicate that sex-specific neuroimmune programs, rather than differences in tau propagation load, shape CA1 electrophysiological dysfunction and the breadth of memory impairment following early entorhinal-to-hippocampal tau spread.

Abstract Background: The PALLAS trial (ABCSG-42, AFT-05, BIG-14-03) investigates adjuvant palbociclib plus endocrine therapy (ET) versus ET alone in patients (pts) with HR+/HER2− early breast cancer. While palbociclib improves outcomes in metastatic settings, final analysis from PALLAS did not demonstrate benefit in survival outcomes from the addition of palbociclib to ET. A number of pts discontinued palbociclib before the planned 2 year duration though degree of palbociclib exposure was not associated with clinical outcomes. This analysis explores factors predictive of palbociclib early discontinuation and dose reductions, including baseline characteristics, toxicities, and patient-reported outcomes (PROs). Methods: Using the safety population of 5736 pts (2840 receiving palbociclib + ET), we assessed early palbociclib discontinuation within a competing-risks framework (competing events: progression, death). Cumulative incidence curves (Aalen-Johansen estimates) and cause-specific hazard models were used to explore associations with clinical and demographic factors (age, menopausal status, stage, race, endocrine therapy type), key toxicities (neutropenia, anemia, nausea), and baseline PROs (patient assessed quality of life [QoL], anxiety, fatigue, pain, frailty/ dependency, depression, and low income. financial difficulties). An automated model selection based on the Akaike information criterion (AIC) starting from the cause-specific hazard model incorporating all considered predictors including PROs. Results: Early discontinuation of palbociclib not due to progression or death occurred in 1171 pts (41.3%); an additional 343 pts (12.1%) stopped due to results of a futility analysis. In 108 (3.8%) and 2 (0.1%) pts treatment was discontinued due to progression or death. Median time to early discontinuation was 7.7 months in pts that discontinued treatment (median interquartile range 3.45-13.60). Very early discontinuation (≤3 months) occurred in 261 pts (9.2%). Dose reductions to 100mg and 75mg occurred in 1566 pts (55.2%) and 951 pts (33.6%) of 2840 pts, respectively. In univariable analyses, higher age, lower N-stage, and specific baseline PROs (baseline QoL, fatigue, anxiety, depression, frailty/ dependency and financial difficulties) were linked with increased risk of discontinuation. The best-fitting multivariable model identified age, nodal stage (N-stage), low quality of life (QoL), and low income as key predictors of early treatment discontinuation. Conclusions: In the PALLAS trial, our findings highlight the importance of integrating PROs into risk prediction of early treatment discontinuation. Additionally, when starting pts on oral targeted therapies in the adjuvant setting, symptom control, social work and financial counseling resources may support pts at higher risk of non-adherence. This is in line with findings from the ESMO Breast QoL analysis (Bjelic-Radisic et al.), which emphasized the added value of subjective patient-reported outcomes alongside objective clinical parameters in understanding treatment burden and adherence. Support: AFT, ABCSG, Pfizer, ECOG-ACRIN, NSABP Foundation, GBG, BIG; https://acknowledgments.alliancefound.org; ClinicalTrials.gov Identifier: NCT02513394. Citation Format: M. Vetter, A. Wiencierz, M. Gnant, D. Hlauschek, C. Kurzeder, C. Grasic Kuhar, N. Zdenkowski, E. Shinn, J. Suga, D. Egle, J. Meisel, S. Antolin-Novoa, E. Munzone, T. Haddad, S. Loibl, A. Holynskyj, C. Fesl, A. Dueck, A. DeMichele, E. Mayer, on behalf of the PALLAS groups and investigators (ABCSG, AFT, BIG,PReCOG, GBG, NSABP). Predictors of early discontinuation of adjuvant palbociclib in early HR+/ HER2- breast cancer: final analysis of the PALLAS trial integrating patient-reported outcomes [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-07-14.

Importance Brain metastases are common in patients with cancer, and radiation is often used for management. Among patients with more than 4 brain metastases, the effects of stereotactic radiation targeting only individual tumors, compared with whole brain radiation with hippocampal avoidance, which radiates both tumors and normal brain, remain unknown. Objective To determine whether stereotactic radiation improves symptom severity and interference with daily functioning, compared with whole brain radiation with hippocampal avoidance. Design, Setting, and Participants Phase 3, open-label, randomized clinical trial conducted at 4 United States–based centers. Eligible patients had 5 to 20 brain metastases and no prior brain-directed radiation. Enrollment occurred between April 11, 2017, and May 17, 2024 (final follow-up, March 18, 2025). Intervention Stereotactic radiation, compared with whole brain radiation with hippocampal avoidance. Main Outcomes and Measures Mean weighted patient-reported symptom severity and interference score change over 6 months postbaseline relative to baseline using the MD Anderson Symptom Inventory–Brain Tumor instrument (scale, 0-10; score change range, −10 to 10; −10 = best). A clinically meaningful Δ was defined as 0.98. Results Of 196 randomized patients (mean age, 61 years; 129 [66%] female; 176 [90%] White; median number of brain metastases, 14 [IQR, 11-18]; 49 [25%] with prior neurosurgical resection), 83 (42%) completed the 6-month assessment. For the primary outcome, between baseline and postbaseline assessments through the 6-month follow-up, stereotactic radiation changed the weighted composite MD Anderson Symptom Inventory–Brain Tumor score from 2.69 to 2.37 (mean change, −0.32) and hippocampal-avoidance whole brain radiation changed the score from 2.29 to 3.03 (mean change, 0.74) (mean difference, −1.06 [95% CI, −1.54 to −0.58]; P < .001). Related grade 3-5 adverse events occurred in 12 patients (12%) in the stereotactic radiation group and 13 patients (13%) in the hippocampal-avoidance whole brain radiation group; grade 1-3 fatigue was most frequent (27 [28%] vs 43 [44%], respectively). Conclusions and Relevance In patients with 5 to 20 brain metastases, these findings support stereotactic radiation over hippocampal-avoidance whole brain radiation to improve symptoms and interference with daily functioning, key components of quality of life. Trial Registration ClinicalTrials.gov Identifier: NCT03075072