Publications

BACKGROUND: Anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS1) rearranged non-small cell lung cancers (NSCLC) develop bypass resistance mechanisms that activate mitogen-activated protein kinase (MAPK) pathway signaling. We conducted a study to evaluate the ALK/ROS1 inhibitor lorlatinib combined with MAPK pathway inhibitors: binimetinib (MEK inhibitor) or TNO155 (SHP2 inhibitor).

PATIENTS AND METHODS: This phase IB study employed a 3 + 3 design. Patients who had disease progression on ALK or ROS1 inhibitors received lorlatinib (50 mg or 75 mg daily) with binimetinib (30 mg or 45 mg BID) or TNO155 (40 mg or 50 mg daily). The primary objective of phase 1 was determining the recommended phase 2 dose for the combinations. The primary objective of the phase 2 portion was determining the objective response rate (ORR) of each combination. Secondary endpoints included safety and tolerability and progression-free survival.

RESULTS: In this phase IB clinical trial, 17 patients received lorlatinib and binimetinib; two patients received lorlatinib with TNO155. All patients with ALK + NSCLC had received prior lorlatinib. Among 15 evaluable patients in the lorlatinib-binimetinib cohort, one (6.7%) had a partial response (duration of response: 114 days), eight (53.3%) had stable disease, and six (40%) experienced primary progression. Median progression-free survival on lorlatinib-binimetinib was 51 days (95% CI 39-107). Treatment-related adverse events associated with lorlatinib-binimetinib were primarily grade 1-2, including rash (65%), edema (47%), and lipid abnormalities (47%). One patient discontinued treatment for grade 2 retinopathy. In the lorlatinib-TNO155 arm, both patients stopped treatment due to rapid disease progression and pleural effusions, limiting efficacy evaluation. The study was terminated due to slow accrual before advancing to the phase 2 component.

CONCLUSIONS: Regimens co-targeting the MAPK pathway and ALK or ROS1 had limited efficacy in unselected patients with lorlatinib-resistant NSCLC, underscoring the need for more effective and biomarker-informed treatment strategies.

A previously espoused notion that the brain is an immune-privileged organ has been challenged by evidence of bidirectional communication between the central nervous system and the periphery. A well-described "glymphatic" system in the brain and the meningeal lymphatic system serve as conduits through which antigens, immune cells, and metabolic waste travel from the brain to the deep cervical lymph nodes. These nodes, which are more than passive drainage points, serve as locales where dendritic cells, T cells, and B cells interact with central nervous system-derived signals and modulate immune responses that can influence the brain itself. Disruption of clearance mechanisms to deep cervical nodes-due to intracranial vascular disease, aging, poor sleep, chronic inflammation, or other etiologies-may lead to immune dysregulation. Abnormalities in lymphatic drainage can also alter the presentation of antigens from the central nervous system, affect lymphocyte trafficking, and contribute to the aggregation of proteins like β-amyloid, tau, and α-synuclein. This review synthesizes current knowledge on glymphatic and meningeal lymphatic anatomy and function, highlights how impaired drainage contributes to disorders including multiple sclerosis, Alzheimer disease, and Parkinson disease, and discusses the emerging role of deep cervical lymph node imaging and immunophenotyping in assessing neuroinflammation. Finally, we consider how modulation of meningeal lymphatic and nodal function, through pharmacologic or physical interventions, may impair or restore drainage and alter the course of disease in various ways. The integration of advanced imaging with immunological analysis ultimately may enhance the diagnosis, monitoring, and treatment of neuroinflammatory and neurodegenerative diseases. We propose that deep cervical lymph nodes represent an understudied locale, and, potentially, a therapeutic target for peripheral interventions to influence brain disease trajectories.

IntroductionLong-acting injectable cabotegravir (CAB-LA) for preexposure prophylaxis (PrEP) is a promising HIV prevention tool for people who inject drugs (PWID), who face elevated HIV risk and barriers to care. While acceptable to PWID, CAB-LA implementation in low-barrier syringe services programs (SSPs) has not been examined.MethodsFrom August 2023 to July 2025, we conducted semistructured interviews with 12 SSP staff involved in CAB-LA delivery. Interviews were transcribed and analyzed using thematic analysis guided by the Consolidated Framework for Implementation Research.ResultsFacilitators included CAB-LA's relative advantage over oral PrEP, external technical support, 340B pharmacy revenue, alignment with SSP mission and workflows, motivated staff, and financial incentives. Barriers included lack of FDA approval for PWID, complex logistics, performance pressures, infrastructure constraints, competing priorities, staff workload, and client outreach and engagement.ConclusionIntegrating CAB-LA into SSPs is promising, but successful implementation requires targeted strategies, including additional resources, workflow adaptations, and enhanced outreach.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry. Prim Care Companion CNS Disord 2026;28(1):25f04082. Author affiliations are listed at the end of this article.

BACKGROUND: Meningiomas are the most common adult brain tumors. While homozygous deletions of CDKN2A/B are linked to early recurrence and hence serve as CNS WHO grade 3 criterion, the clinical impact of hemizygous deletions remains unclear-especially since distinguishing between hemi- and homozygous losses can be technically challenging.

METHODS: DNA methylation data, copy-number and mutation data were evaluated on a multicenter cohort of 970 meningiomas. Each sample's CDKN2A/B status was manually classified by visual inspection in relation to whole chromosomal losses and gains in the copy number profile generated from global methylation array in relation to other copy number events. Progression probabilities were determined using the Kaplan-Meier method.

RESULTS: Among 970 meningiomas, n = 30 had homozygous, n = 114 hemizygous (n = 31 segmental; n = 83 focal) and n = 826 CDKN2A/B balanced status. In cases with hemizygous deletions in general, an association with increased progression risk compared to balanced cases was observed, although this did not reach statistical significance (log-rank p = 0.074; HR 1.36, 95% CI [0.97, 1.90]; p = 0.07). However, segmental hemizygous losses were linked to a significantly worse prognosis (log-rank p = 0.0023), but focal hemizygous deletions were not (log-rank p = 0.523). Segmental hemizygous CDKN2A/B deletions were more frequently associated with a higher amount of high-risk copy number variations (CNVs) than focal losses.

CONCLUSION: Our findings suggest that hemizygous CDKN2A/B deletions overall do not confer worse risks for progression in meningiomas. The signal for segmental deletions may not be locus-specific but just one representation of the generally instable genome of aggressive meningiomas.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry. Prim Care Companion CNS Disord 2026;28(1):25f04061. Author affiliations are listed at the end of this article.

PURPOSE: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a unique myeloid malignancy with CD123 interleukin-3 receptor-α overexpression and poor prognosis.

METHODS: This phase I/II, open-label, multicenter study evaluated pivekimab sunirine (PVEK), a novel CD123 antibody-drug conjugate, 0.045 mg/kg once every 3 weeks, in adults with frontline (no previous systemic therapy and de novo BPDCN or coexisting hematologic malignancy) or relapsed/refractory BPDCN (ClinicalTrials.gov identifier: NCT03386513) The primary end point in the primary analysis population (PAP; frontline de novo) was composite complete response (CCR; CR+ clinical CR) rate.

RESULTS: Of 84 patients, 33 had frontline BPDCN (22 de novo [20 in PAP]; 11 with previous or concomitant malignancy) and 51 had relapsed/refractory disease. The median (range) age was 72 (63-76) years. In the PAP (n = 20), the CCR rate was 75% (95% CI, 51 to 91; n = 15; median duration: 10.6 [95% CI, 3.8 to not reached] months) and the median overall survival (OS) was 16.6 (95% CI, 7.2 to not reached) months. Eight of these 15 (53%) patients proceeded to stem-cell transplant (SCT). The corresponding rate for relapsed/refractory disease was 14% (95% CI, 6 to 26; n = 7; median duration: 9.2 [95% CI, 2.4 to not reached] months), and the median OS was 5.8 (95% CI, 3.9 to 8.4) months. Adverse events (AEs) included peripheral edema (54%), fatigue (26%), and infusion-related reactions (26%). Grade ≥3 events included neutropenia (16%), thrombocytopenia (14%), and peripheral edema (12%). Serious AEs included pneumonia (6%) and febrile neutropenia (5%). Two on-treatment cases of reversible veno-occlusive disease (VOD) occurred. Of the total 19 patients who proceeded to SCT, VOD was reported in five patients (four with relapsed/refractory BPDCN).

CONCLUSION: PVEK, with convenient dosing, led to high, durable responses, especially in frontline BPDCN, and a manageable safety profile.

To elucidate the molecular basis underlying differential response and resistance to ibrutinib in Waldenström's macroglobulinemia (WM), we conducted a prospective phase II trial (ClinicalTrials.gov; NCT02604511) of ibrutinib monotherapy in treatment-naïve patients. Seventy-four sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multi-omics. BM cells segregated primarily into B/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B/plasma cells identified three distinct evolutionary patterns: "evolution" (early clone contraction with late clone expansion and increasing genomic complexity), "devolution" (early clone expansion with late clone contraction and genomic simplification), and "no-evolution" (stable clonal architecture). The "evolution" pattern was strongly associated with disease progression, whereas "devolution" correlated with durable clinical response. Transcriptomic profiling of resistant clones enabled development and validation of the Waldenström's Ibrutinib Prediction (WIP) score, which predicted treatment response at baseline. Within the WIP signature, LYN emerged as a key regulator; LYN knockdown or inhibition significantly increased WM cell sensitivity to ibrutinib, suggesting a rational combinatorial strategy. In parallel, GZMB⁺ CD8⁺ effector-memory (TEM) cells expanded post-treatment in progressing patients and co-existed with tumor "evolution". These cells exhibited persistently impaired cytotoxic programs (e.g., GNLY), a de-differentiated memory-like state, elevated PDCD1 expression, and reduced TCR diversity. Together, this study provides the first single-cell framework of tumor clonal evolution and T-cell dysfunction under ibrutinib in WM; introduces the WIP score as a predictive biomarker for treatment response; and identifies actionable tumor-intrinsic and immune mechanisms driving resistance.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry. Prim Care Companion CNS Disord 2026;28(1):25f04058. Author affiliations are listed at the end of this article.