Genetic factors account for up to 80% of the liability for schizophrenia (SCZ) and bipolar disorder (BD). Genome-wide association studies have successfully identified several genes associated with ...increased risk for both disorders. This has allowed researchers to model the aggregate effect of genes associated with disease status and create a polygenic risk score (PGRS) for each individual. The interest in imaging genetics using PGRS has grown in recent years, with several studies now published. We have conducted a systematic review to examine the effects of PGRS of SCZ, BD and cross psychiatric disorders on brain function and connectivity using fMRI data. Results indicate that the effect of genetic load for SCZ and BD on brain function affects task-related recruitment, with frontal areas having a more prominent role, independent of task. Additionally, the results suggest that the polygenic architecture of psychotic disorders is not regionally confined but impacts on the task-dependent recruitment of multiple brain regions. Future imaging genetics studies with large samples, especially population studies, would be uniquely informative in mapping the spatial distribution of the genetic risk to psychiatric disorders on brain processes during various cognitive tasks and may lead to the discovery of biological pathways that could be crucial in mediating the link between genetic factors and alterations in brain networks.
Multiple myeloma (MM) is the second most common hematologic malignancy in adults worldwide. Over the past few years, major therapeutic advances have improved progression-free and overall survival, as ...well as quality of life. Despite this recent progress, MM remains incurable in the vast majority of cases. Patients eventually relapse and become refractory to multiple drug classes, making long-term management challenging. In this review, we will focus on the treatment paradigm of relapsed/refractory MM (RRMM) in the era of advanced therapies emphasizing the available novel modalities that have recently been incorporated into routine practice, such as chimeric antigen receptor T-cell therapy, bispecific antibodies, and other promising approaches. We will also discuss major factors that influence the selection of appropriate drug combinations or cellular therapies, such as relapse characteristics, and other disease and patient related parameters. Our goal is to provide insight into the currently available and experimental therapies for RRMM in an effort to guide the therapeutic decision-making process.
Schizophrenia, a debilitating disorder with typical manifestation of clinical symptoms in early adulthood, is characterized by cognitive impairments in executive processes such as in working memory ...(WM). However, there is a rare case of individuals with early-onset schizophrenia (EOS) starting before their 18th birthday, while WM and its neural substrates are still undergoing maturation. Using the WM n-back task with functional magnetic resonance imaging, we assessed the functional neurodevelopment of WM in adolescents with EOS and age- and gender-matched typically developing controls. Participants underwent neuroimaging in the same scanner twice, once at age 17 and at 21 (mean interscan interval = 4.3 years). General linear model analysis was performed to explore WM neurodevelopmental changes within and between groups. Psychopathological scores were entered in multiple regressions to detect brain regions whose longitudinal functional change was predicted by baseline symptoms in EOS. WM neurodevelopment was characterized by widespread functional reductions in frontotemporal and cingulate brain areas in patients and controls. No between-group differences were found in the trajectory of WM change. Baseline symptom scores predicted functional neurodevelopmental changes in frontal, cingulate, parietal, occipital, and cerebellar areas. The adolescent brain undergoes developmental processes such as synaptic pruning, which may underlie the refinement WM of network. Prefrontal and parietooccipital activity reduction is affected by clinical presentation of symptoms. Using longitudinal neuroimaging methods in a rare diagnostic sample of patients with EOS may help the advancement of neurodevelopmental biomarkers intended as pharmacological targets to tackle WM impairment.
Most patients with multiple myeloma experience disease relapse after treatment with a B-cell maturation antigen-targeted therapy (BCMA-TT), and data describing outcomes for patients treated with ...sequential BCMA-TT are limited. We analyzed clinical outcomes for patients infused with standard-of-care idecabtagene vicleucel, an anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, at 11 US medical centers. A total of 50 patients with prior BCMA-TT exposure (38 antibody-drug conjugate, 7 bispecific, 5 CAR T) and 153 patients with no prior BCMA-TT were infused with ide-cel, with a median follow-up duration of 4.5 and 6.0 months, respectively. Safety outcomes between cohorts were comparable. The prior BCMA-TT cohort had a lower overall response rate (74% versus 88%; p = 0.021), median duration of response (7.4 versus 9.6 months; p = 0.03), and median progression-free survival (3.2 months versus 9.0 months; p = 0.0002) compared to the cohort without prior BCMA-TT. All five patients who received a prior anti-BCMA CAR T responded to ide-cel, and survival outcomes were best for this subgroup. In conclusion, treatment with ide-cel yielded meaningful clinical responses in real-world patients exposed to a prior BCMA-TT, though response rates and durability were suboptimal compared to those not treated with a prior BCMA-TT.
Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the ...existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.
Background
Both immunotherapy (IO) and targeted therapy (TT) are used as adjuvant (adj) treatment for stage III melanoma, however, data describing real‐world outcomes are limited. In addition, a ...significant proportion of patients relapse, for whom best management is unclear. The aim of our study was to assess the efficacy, and safety of adj anti‐PD1 IO and TT in a real‐world cohort of patients with resected stage III melanoma, and further delineate patterns of recurrence and treatment strategies.
Methods
We retrospectively analyzed 130 patients who received adj therapy (100 anti‐PD1 IO and 30 TT).
Results
At a median follow‐up of 30 months, median relapse‐free survival (RFS) was 24.6 (95% CI, 17–not reached NR) versus 64 (95% CI, 29.5–NR) months for the TT and IO groups, respectively (p = 0.26). Median overall survival (OS) was NR for either subgroup. At data cutoff, 77% and 82% of patients in TT and IO arms were alive. A higher number of grade ≥3 treatment‐related adverse events (AEs) were noted in the IO group (11% vs. 3%), however, a higher proportion of patients permanently discontinued adj therapy in the TT group (43% vs. 11%) due to toxicity. Strategies at relapse and outcomes were variable based on location and timing of recurrence. A significant number of patients who relapsed after adj IO received a second round of IO. Among them, patients who were off adj IO at relapse had superior second median RFS (mRFS2), compared to those who relapsed while on adj IO; mRFS2 was NR versus 5.1 months (95% CI, 2.5–NR), respectively, p = 0.02.
Conclusion
In summary, both TT and IO yielded prolonged RFS in a real‐world setting, however, longer follow‐up is needed to determine any potential OS benefit. Adj therapy, particularly TT, may not be as well tolerated as suggested in clinical trials, with lower completion rates (59% vs. 74%) in a real‐life setting. Overall, patients who relapse during adj therapy have poor outcomes, while patients who relapse after discontinuation of adj IO therapy appear to benefit from IO re‐treatment.
Both immunotherapy and targeted therapy are used as adjuvant treatment modalities for stage III melanoma. However, data describing real‐world outcomes are limited. Our study aimed to assess the efficacy and safety of adjuvant anti‐PD‐1 immunotherapy and targeted therapy in a real‐world cohort of 130 patients with resected stage III melanoma, and further delineate patterns of recurrence and treatment strategies.
Therapeutic plasma exchange (TPE) is an extracorporeal technique where patient's plasma containing pathogenic substances is separated and removed from the whole blood, while the cellular component is ...returned to the patient mixed with replacement solution via an apheresis machine. Due to its ability to remove pathogenic substances from plasma including immunoglobulins, TPE has proven efficacious in the management of various disorders across different medical disciplines, including plasma cell dyscrasias, which are characterized by the abundant secretion of non-functional immunoglobulins produced by an abnormally proliferating plasma cell clone. This review summarizes the current indications of TPE in plasma cell-related disorders and discusses its application, safety, and therapeutic effects.
Objective: Disruption within the working memory (WM) neural network is considered an integral feature of schizophrenia. The WM network, and the dorsolateral prefrontal cortex (DLPFC) in particular, ...undergo significant remodeling in late adolescence. Potential interactions between developmental changes in the WM network and disease-related processes for schizophrenia remain unclear. The aim of this study was to determine whether DLPFC activation and functional connectivity are impaired during WM in patients with early-onset schizophrenia (EOS; age of onset less than 18 years). Method: We used functional magnetic resonance imaging and psychophysiological interaction analysis to respectively measure blood oxygenation level-dependent signal and to derive functional connectivity estimates in response to the two-back WM task from 25 youths with EOS and 20 matched healthy adolescents. Results: Compared with healthy adolescents, patients with EOS showed reduced engagement of the DLPFC, the anterior cingulate cortex (ACC), and frontal operculum, and had reduced DLPFC connectivity within the WM network. Patients with EOS showed abnormal reduction in the coupling of the DLPFC with the ACC, the inferior parietal lobule, and the middle occipital gyrus. In contrast to healthy adolescents, patients with EOS expressed age-related decrease in the activity of the DLPFC and an increase in its connectivity with the ACC. Conclusions: Patients with EOS show dysfunctional engagement and reduced integration within the WM neural network. The pattern of abnormal age-related correlations in DLPFC activity and connectivity suggests that schizophrenia-related processes have an impact on brain regions that show significant late developmental changes. (Contains 3 figures and 4 tables.)
Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy and durable responses in patients with relapsed/refractory multiple myeloma (RRMM). However, the outcomes with ide-cel in patients ...with extramedullary disease (EMD) remain incompletely characterized. We included patients with RRMM treated with ide-cel between May 2021 and April 2023 across 11 US academic institutions. Visceral or soft tissue lesions non-contiguous from bone was classified as EMD. Time-to-event analyses were performed from date of ide-cel infusion. Among 351 patients, 84 (24%) had EMD prior to infusion. The median follow-up from ide-cel infusion was 18.2 months (95% CI: 17-19.3). The day 90 overall response rates (ORR) were 52% vs. 82% for the EMD and non-EMD cohorts, respectively (p < 0.001). The median progression-free survival (PFS) was 5.3 months (95% CI: 4.1-6.9) for the EMD cohort vs. 11.1 months (95% CI: 9.2-12.6; p < 0.0001) for the non-EMD cohort. In a multivariable analysis, EMD was an independent predictor of inferior PFS hazard ratio 1.5 (1.1-2.2), p = 0.02. The median overall survival was 14.8 months 95% CI: 9-Not reached (NR) vs. 26.9 months (26.3 vs. NR, p = 0.006) for the EMD and non-EMD cohorts, respectively. Extramedullary disease represents an independent predictor of inferior day 90 ORR and PFS among patients treated with ide-cel. Keywords: BCMA CAR-T, Ide-cel, Relapsed/refractory myeloma, Radiation, Immunotherapy
We used the auditory roving oddball to investigate whether individual differences in self-reported anxiety influence event-related potential (ERP) activity related to sensory gating and mismatch ...negativity (MMN). The state-trait anxiety inventory (STAI) was used to assess the effects of anxiety on the ERPs for auditory change detection and information filtering in a sample of thirty-six healthy participants. The roving oddball paradigm involves presentation of stimulus trains of auditory tones with certain frequencies followed by trains of tones with different frequencies. Enhanced negative mid-latency response (130–230 ms post-stimulus) was marked at the deviant (first tone) and the standard (six or more repetitions) tone at Fz, indicating successful mismatch negativity (MMN). In turn, the first and second tone in a stimulus train were subject to sensory gating at the Cz electrode site as a response to the second stimulus was suppressed at an earlier latency (40–80 ms). We used partial correlations and analyses of covariance to investigate the influence of state and trait anxiety on these two processes. Higher trait anxiety exhibited enhanced MMN amplitude (more negative) (F(1,33) = 14.259, p = 6.323 × 10−6, ηp2 = 0.302), whereas state anxiety reduced sensory gating (F(1,30) = 13.117, p = 0.001, ηp2 = 0.304). Our findings suggest that high trait-anxious participants demonstrate hypervigilant change detection to deviant tones that appear more salient, whereas increased state anxiety associates with failure to filter out irrelevant stimuli.
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