Hossam M. Ali

Disrupted excitation–inhibition (E/I) balance involving GABA and glutamate (Glu) is implicated in the pathophysiology of depression. Ketamine, an NMDA receptor antagonist with rapid antidepressant properties, may modulate this balance, yet proton magnetic resonance spectroscopy (¹H-MRS) studies report inconsistent findings regarding the direction, magnitude, and timing of neurochemical effects. Static ¹H-MRS metabolite concentrations, however, do not directly index neuronal excitation or inhibition; the E=Glx/Glu and I = GABA framework adopted here, as used commonly in the field, is an assumed convention rather than a validated physiological equivalence. We conducted a systematic review and meta-analysis evaluating ketamine’s influence on GABA, Glu, and Glx levels and their relationship to clinical outcomes in adults with depression. Multiple databases were searched from inception through October 16, 2025; of 1046 identified studies, 11 met inclusion criteria. Included studies demonstrated significant methodological variability across infusion protocols, metabolite selection, MRS acquisition timing, and brain region of interest. Meta-analyses from limited evidence base did not demonstrate statistically significant treatment-related alterations in any metabolite. The anterior cingulate and prefrontal cortices were most frequently examined regions. The quality of included studies was generally good, despite methodological heterogeneity. One RCT found percent reduction in Glx/GABA ratio positively correlated with symptom improvement. Only a few studies examined ketamine blood levels relative to metabolite changes. Current ¹H-MRS evidence does not confirm significant ketamine-related neurochemical alterations, likely reflecting methodological heterogeneity in timing, acquisition techniques, and brain regions examined rather than a true absence of effect. E/I balance shows promise as a treatment response predictor. Rigorous RCTs with standardized protocols, larger sample sizes, uniform dosing, and systematic biomarker investigations are needed to clarify ketamine’s neurochemical mechanism and optimize ketamine’s clinical application in treatment-resistant depression.

Patients with plasma cell leukemia (PCL) are generally excluded from pivotal T-cell redirecting bispecific antibody (BsAb) trials. We evaluated real-world outcomes in a multicenter retrospective study of 122 patients with primary or secondary PCL across 15 academic centers, categorized as 'active' (≥5% circulating plasma cells within 30 days of BsAb initiation) or 'historical'. In a heavily pretreated population, patients received teclistamab (37%), elranatamab (11%), talquetamab as a line of therapy (Tal LOT, 42%), or talquetamab as bridging therapy to CAR-T (Tal Bridge, 11%). Cytokine release syndrome (CRS) was grade 1-2 in 56% and grade 3-4 in 4%, whereas neurotoxicity was grade 1-2 in 16% and grade 3-4 in 5%. Among 110 evaluable patients, the overall response rate (ORR) was 55%, including 61% with Tal LOT, 58% with Tal Bridge, 46% with elranatamab, and 33% with teclistamab. With a median follow-up of 8.3 months, talquetamab demonstrated superior survival. Tal LOT showed a median progression-free survival (mPFS) of 5.5 months and a median overall survival (mOS) of 11.5 months, and both were unreached in the Tal Bridge cohort. In contrast, teclistamab and elranatamab showed a mPFS of 1.2 and 1.6 months and mOS of 8.1 and 3.6 months, respectively (P=0.007, P=0.023). In active PCL, Tal LOT achieved mPFS/mOS of 6.9/12.2 months versus 0.7/1.4 months with teclistamab and 1.0/3.1 months with elranatamab, respectively (P<0.001, P=0.002). Multivariable analysis associated active PCL with worse survival and Tal LOT with improved outcomes. BsAbs were safe in PCL, with talquetamab showing superior outcomes compared with BCMA-directed BsAbs.

Elranatamab, a BCMA-CD3 bispecific antibody, has demonstrated robust activity in relapsed/refractory multiple myeloma (RRMM), but real-world outcomes remain poorly defined. We conducted a multicenter retrospective study of 130 patients treated with commercial elranatamab across nine U.S. academic centers. The cohort was heavily pretreated (91% triple-class refractory, 49% penta-refractory), with 49% previously exposed to BCMA-targeted therapies. Only 22% would have met eligibility for MagnetisMM-3 cohort A. The overall response rate (ORR) was 65%, including ≥CR in 36%. Median progression-free survival (PFS) and overall survival (OS) were 4.3 and 14.6 months, respectively, shorter than MagnetisMM-3. Elevated LDH and low hemoglobin independently predicted poor outcomes and were incorporated into the novel ALPS (Anemia-LDH Prognostic System) score, which stratified patients into distinct risk groups for ORR, OS, PFS, and duration of response. Prior BCMA exposure reduced depth of response, with inferior OS observed in those treated within one year of prior therapy. Infections occurred in 38% of patients. Intravenous immunoglobulin supplementation, modeled as a time-dependent covariate, was associated with improved infection-free survival and PFS. While the incidence of CRS was modestly lower than in MagnetisMM-3, ICANS occurred more frequently in this real-world cohort. These findings highlight the efficacy, limitations, and supportive care needs of elranatamab in a frailer, more heterogeneous real-world RRMM population.

Purpose: We aimed to synthesize and provide an updated meta-analysis of the current data on extended-release naltrexone (XR-NTX) and oral naltrexone (NTX) for alcohol use disorder (AUD). Methods: A comprehensive database search was conducted and updated on October 1, 2025. This meta-analysis encompassed randomized controlled trials (RCTs) and observational studies that compared XR-NTX and oral NTX in adults with AUD. Included studies reported outcomes on treatment persistence and healthcare utilization, specifically ED visits and inpatient hospitalizations during follow-up. Odds ratios (ORs) were computed using the Mantel-Haenszel random-effects model. Results: Out of 101 studies screened, seven studies (N = 42,268; n = 2,103 for XR-NTX, n = 40,165 for NTX) met the inclusion criteria for the meta-analysis. Overall, treatment persistence was significantly higher with XR-NTX compared with oral NTX (OR = 1.94 [95% CI, 1.22–3.10]), with benefits observed at both three months (pooled OR = 2.24 [95% CI, 1.14–4.41], p = 0.019) and six months (OR = 1.59 [95% CI, 1.04–2.43], p = 0.032). No significant differences were observed in healthcare utilization, including all-cause ED visits (OR = 1.33 [95% CI, 0.93–1.90]) or all-cause inpatient admissions (OR = 0.84 [95% CI, 0.49–1.43]). Conclusion: This meta-analysis suggests higher treatment persistence among patients with AUD receiving XR-NTX versus oral NTX, underscoring formulation as a key factor in persistence and retention. However, alcohol-related healthcare utilization metrics, including ED visits and hospitalizations, showed no significant between-group differences. Further pragmatic trials accounting for patient preferences, sex-specific outcomes, and barriers to care accessibility are needed.