Citations

Background Headache is a common symptom following mild traumatic brain injury (mTBI). Post-traumatic headache (PTH), a secondary headache disorder that develops after mTBI, often persists for months or years. To identify potential recovery mechanisms and prognostic biomarkers, the present study investigated whether longitudinal changes in pain-induced brain activation differ between healthy controls (HC) and PTH participants showing headache improvement and those without improvement. Methods Thirty-three participants who met International Classification of Headache Disorders, 3rd edition, criteria for acute PTH within 59 days post-mTBI and 33 HC participants were included with no significant differences in demographics. All participants underwent functional magnetic resonance imaging scans at baseline, four weeks, and 16 weeks post-enrollment using a thermal stimulation paradigm with noxious and non-painful heat stimuli. ‘Painful vs. Non-Painful Heat’ contrasts were generated using SPM12. PTH improvement was assessed at three months post-enrollment via electronic headache diaries. Two-sample t -tests compared the brain activation between HC and PTH at baseline. Linear mixed-effects models examined longitudinal changes for HC, PTH improvement and non-improvement groups across visits. Generalized linear models compared these groups within visits. Results Baseline analysis revealed several regions with significantly higher activation in acute PTH compared to HC, including bilateral postcentral gyrus, right superior temporal gyrus, right middle temporal gyrus, left inferior parietal gyrus, right superior parietal gyrus, left ventral striatum, left olfactory cortex, left gyrus rectus, and left middle occipital gyrus. Over time, the PTH improvement group demonstrated progressive normalization across all identified brain regions, whereas the non-improvement group showed only partial normalization in left ventral striatum, left olfactory cortex, and left gyrus rectus. Sustained elevated activation in specific regions distinguished PTH participants without headache improvement from those with headache improvement, suggesting potential biomarkers for persistent PTH. Conclusions Our findings demonstrate significantly altered pain-induced brain activations in participants with acute PTH compared to HC. Longitudinal analysis revealed distinct recovery trajectories: progressive normalization in the improvement group versus persistent alterations in the non-improvement group. These neuroimaging patterns may serve as biomarkers for identifying individuals at risk for persistent PTH, with implications for early intervention and personalized treatment approaches.

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons and the accumulation of Lewy bodies, leading to motor and nonmotor symptoms. While both genetic and environmental factors contribute to PD, recent studies highlight the crucial role of lipid metabolism disturbances in disease progression. Altered lipid homeostasis promotes protein aggregation and oxidative stress, with significant changes in lipid classes such as sphingolipids and glycerolipids observed in patients with PD. These disturbances are involved in key pathological processes, such as α-synuclein aggregation, organelle dysfunction, lipid-mediated neuroinflammation, and impaired lipid homeostasis. This review examines the relationship between lipid species and PD progression, focusing on the physiological roles of lipids in the central nervous system. It explores the mechanistic links between lipid metabolism and PD pathology, along with lipid-related genetic risk factors. Furthermore, this review discusses lipid-targeting therapeutic strategies to mitigate PD progression, emphasizing the potential of lipid modulation for effective treatment development.

With their unique therapeutic properties and amenability to engineering modifications, exosomes are considered a promising tool for treating peripheral nerve injuries. Through genetic engineering or physicochemical modifications, the targeting ability and functionality of exosomes can be further enhanced, enabling efficient delivery of therapeutic molecules and significantly boosting their therapeutic potential. This review aims to explore exosome-based therapies in peripheral nerve repair and their mechanisms and summarizes recent advances in the roles of exosomes in neuroprotection, axonal regeneration, vascular regeneration, and inflammatory modulation. Exosomes act as natural messengers between cells, carrying genetic materials, cytokines, and growth factors that can modulate the local microenvironment and foster peripheral nerve regeneration. Studies have shown that exosomes derived from Schwann cells, macrophages, neurons, and mesenchymal stem cells can all promote axonal regeneration and modulate inflammatory responses through various mechanisms. Compared with cell therapy, exosome therapy offers greater stability and safety, with the ability to traverse biological barriers, presenting new possibilities for regenerative medicine and precision therapy. However, challenges such as the heterogeneity and complexity of exosomes, uncertainty of in vivo distribution and metabolic pathways, and the limitations of targeting remain to be addressed. Future research will focus on the engineering modifications of exosomes to enhance their therapeutic efficiency and targeting precision.

ABSTRACTBackgroundDeep learning (DL) models for accurate renal tumor characterization may benefit from multi‐center datasets for improved generalizability; however, data‐sharing constraints necessitate privacy‐preserving solutions like federated learning (FL).PurposeTo assess the performance and reliability of FL for renal tumor segmentation and classification in multi‐institutional MRI datasets.Study TypeRetrospective multi‐center study.PopulationA total of 987 patients (403 female) from six hospitals were included for analysis. 73% (723/987) had malignant renal tumors, primarily clear cell carcinoma (n = 509). Patients were split into training (n = 785), validation (n = 104), and test (n = 99) sets, stratified across three simulated institutions.Field Strength/SequenceMRI was performed at 1.5 T and 3 T using T2‐weighted imaging (T2WI) and contrast‐enhanced T1‐weighted imaging (CE‐T1WI) sequences.AssessmentFL and non‐FL approaches used nnU‐Net for tumor segmentation and ResNet for its classification. FL‐trained models across three simulated institutional clients with central weight aggregation, while the non‐FL approach used centralized training on the full dataset.Statistical TestsSegmentation was evaluated using Dice coefficients, and classification between malignant and benign lesions was assessed using accuracy, sensitivity, specificity, and area under the curves (AUCs). FL and non‐FL performance was compared using the Wilcoxon test for segmentation Dice and Delong's test for AUC (p < 0.05).ResultsNo significant difference was observed between FL and non‐FL models in segmentation (Dice: 0.43 vs. 0.45, p = 0.202) or classification (AUC: 0.69 vs. 0.64, p = 0.959) on the test set. For classification, no significant difference was observed between the models in accuracy (p = 0.912), sensitivity (p = 0.862), or specificity (p = 0.847) on the test set.Data ConclusionFL demonstrated comparable performance to non‐FL approaches in renal tumor segmentation and classification, supporting its potential as a privacy‐preserving alternative for multi‐institutional DL models.Evidence Level4.Technical EfficacyStage 2.

ABSTRACT The stromal tumor environment (STE) plays a vital yet often underrecognized role in cancer progression, shaping tumor development. It influences complex interactions among stromal cells, immune cells, extracellular matrix (ECM) components, and signaling molecules. Stromal cells regulate integrin signaling and are involved in remodeling the tumor microenvironment, driving critical processes such as cell migration, survival, angiogenesis, and proliferation. Advances in understanding the STE are creating new opportunities for early cancer detection and treatment. Innovations in molecular imaging, particularly for melanoma, are transforming cancer diagnostics by providing deeper insights into tumor biology, cellular interactions, and angiogenesis, paving the way for more personalized and timely therapeutic interventions. Among these advancements, in vivo skin fluorescent imaging (SFI) stands out as a powerful tool, offering real‐time molecular insights at the point of care with the ability to improve patient management.

ABSTRACTBackground/AimsMany patients with digestive symptoms describe underlying urinary or gynecologic symptoms, which may increase visceral sensitivity in the abdominopelvic region and amplify distress around digestive symptoms. The aim of this study was to describe the prevalence of urinary and gynecologic symptoms in patients with disorders of gut–brain interaction (DGBI).MethodsConsecutive adult patients with a female reproductive tract who were referred for GI behavioral medicine evaluation for DGBI at a tertiary care center between 2022 and 2023 were prospectively evaluated for symptoms associated with urinary and gynecologic dysfunction. Descriptive statistics were conducted to assess the prevalence of these symptoms within this population by anatomic region affected (esophagus, stomach, and bowel).ResultsA total of 432 patients were included in our cohort with a mean (SD) age of 40.0 years [Q1;Q3 29.0–52.0], with a predominantly White population (86.1%). Dysmenorrhea (61.0%) and menorrhagia (58.6%) were commonly reported among women with digestive symptoms. Urinary symptoms were less common, with 18.7% reporting pain with urination, 33.0% reporting difficulty voiding urine, and 26.1% reporting a history of frequent UTIs. 23% of women experienced ≥ 4 urinary/gynecologic symptoms. There were no significant differences in the type of urogynecologic symptoms reported based on the affected area of the GI tract.ConclusionUrogynecologic symptoms are common among patients with DGBIs affecting the entirety of the GI tract. We presume the presence of these comorbid symptoms is likely to impact symptom severity, quality of life, and could affect treatment response. Future studies are necessary to understand the mechanisms behind these shared conditions as well as develop effective treatments that address their overlap.

Abstract Immune checkpoint inhibitor (ICI) therapy has significantly advanced cancer treatment, particularly for metastatic melanoma, but it is associated with severe, life-threatening adverse effects. A rare but critical complication is the overlap syndrome of Myositis, Myocarditis, and Myasthenia Gravis (MMM), affecting approximately 0.21% of ICI-treated solid tumor patients with an in-hospital mortality rate of up to 60%. Early recognition and management are crucial for improving outcomes. Case Presentation: A 76-year-old male with metastatic melanoma, coronary artery disease, ischemic cardiomyopathy (EF 35%), chronic kidney disease, diabetes, and chronic respiratory failure (baseline oxygen requirement of 2L) presented two weeks after starting Nivolumab and Relatlimab. He developed worsening exertional dyspnea, orthopnea, diplopia, dysarthria, and progressive proximal muscle weakness. On presentation, he was hemodynamically stable, with elevated troponin T (1241 ng/L) and NT-proBNP (2698 pg/mL). Initial investigations, including EKG and chest X-ray, were unremarkable with no thymoma. Left heart catheterization revealed severe multivessel coronary artery disease but no treatable lesions. He was noted to have fatigable ptosis and he subsequently developed bulbar symptoms, including hypophonia and dysphagia. A diagnosis of Myasthenia Gravis was suspected. Further evaluation showed respiratory muscle weakness (NIF -12 cm H2O, vital capacity 2L, mild hypercarbia on ABG) and progressive weakness, leading to intubation. Elevated creatine kinase (1527 U/L), persistent troponin elevation, and global hypokinesis on repeat echocardiography pointed to a likely diagnosis of myocarditis/myositis. Electromyography revealed neuropathy without acute findings, and serological testing for acetylcholine receptor antibodies, HMG-CoA reductase antibodies, and myositis was negative. ICI-induced MMM was diagnosed, and the patient was treated with methylprednisolone, IVIG, pyridostigmine, and ICI discontinuation. Despite plasmapheresis, his condition deteriorated. He developed septic shock from multiple infections (E-Coli bacteremia, Stenotrophomonas pneumonia) and progressed to cardiogenic shock, requiring vasopressors. Subsequent imaging revealed pneumoperitoneum concerning bowel perforation, but further diagnostic workup was declined by the family. Comfort care was initiated, and the patient passed away. Discussion: ICI use has grown rapidly, with agents like Nivolumab expanding treatment options for metastatic melanoma. However, MMM, a rare but severe complication, demands prompt recognition. Presentation often occurs within 21 days of ICI initiation, and patients may display elevated CPK and stable or rising troponin levels. Myasthenia gravis within MMM can cause rapid respiratory failure, with significant morbidity. Management includes corticosteroids, IVIG and immediate ICI discontinuation. Treatment should begin without waiting for confirmatory tests, given the syndrome's high mortality. Early, multidisciplinary intervention is essential in managing this fatal condition effectively.

Abstract Objective Rare large B-cell lymphomas (LBCLs) present with concurrent or subsequent lymphomatous effusion (solid-effusion LBCL, SE-LBCL), which may have an inferior prognosis compared with their noneffusion counterpart. In addition, the relationship between SE-LBCL and human herpesvirus 8–negative effusion-based LBCL (EB-LBCL) remains unclear. Methods We collected 141 cases of SE-LBCL and a control cohort of 101 cases of stage IV solid-only LBCL. The clinicopathologic features were analyzed and compared between SE-LBCL and solid-only LBCL. Results Patients with SE-LBCL had a median age of 67 years with a male-to-female ratio of 1.3:1. Eighty-six patients had concurrent solid lymphoma and lymphomatous effusion, whereas 55 developed lymphomatous effusion subsequently. Most cases involved the pleural cavities (79%, 112/141), followed by the peritoneal (21%, 29/141) and pericardial (11%, 16/141) cavities. BCL6, CD10, and MUM1 were expressed in 77% (90/117), 46% (60/130), and 61% (58/95) of cases, respectively, and 58% (71/123) were subclassified into the germinal center B-cell (GCB) subtype. Rearrangements of BCL2, BCL6, and MYC were detected in 42% (31/73), 35% (22/63), and 40% (35/88), respectively, and 22% (19/87) had both MYC and BCL2 rearrangements. The patients with SE-LBCL had a dismal prognosis, with a median survival of 5.7 months, which was significantly worse than solid-only LBCL (147.5 months; P &lt; .0001). Conclusions The pathologic features of SE-LBCL were similar to those of solid-only LBCL but distinct from those of EB-LBCL; in particular, lymphomatous effusion was an independently adverse prognostic factor in LBCL. Our study underscores the need for surveillance of lymphomatous effusion during LBCL staging and development of effective therapeutic regimens for SE-LBCL.

Abstract Purpose: Recent advances have seen the development of targeted therapeutics against the receptor tyrosine kinase (RTK)/RAS/MAPK pathway, which, when aberrantly activated, drives the malignant transformation of many cancer indications. However, the efficacy of inhibitors targeting single molecules is dampened by pathway feedback activation and acquired drug resistance. We seek to evaluate the application of JAB-3312 (sitneprotafib), a potent inhibitor of SHP2, in RTK/RAS/MAPK pathway–targeted combination therapies. Furthermore, SHP2 plays a vital role in PD-1–mediated immunosuppression. The rational combination of JAB-3312 with PD-1 blocking therapies is also explored. Experimental Design: Biochemical and cellular assays were applied to evaluate the potency of JAB-3312 in SHP2 inhibition. Tumor cell lines and cell line– and patient-derived xenografts were used to test different combinations of JAB-3312 with KRASG12C, MEK, EGFR, and PD-1 inhibitors. Results: JAB-3312 produced potent in vitro inhibition of SHP2 activity and downstream ERK phosphorylation, with IC50 values of 1.44 nmol/L and 0.68 to 4.84 nmol/L, respectively. When used in combination, JAB-3312 significantly increased the antitumor activity of the KRASG12C inhibitor glecirasib in naïve and resistant models. The combination of JAB-3312 with MEK inhibitors significantly delayed RTK signaling reactivation and enhanced tumor growth inhibition in KRAS-mutated cancer models. The JAB-3312–osimertinib combination exhibited great efficacy in osimertinib-resistant non–small cell lung cancer models. Additionally, JAB-3312 enhanced the efficacy of PD-1 blockade therapies by promoting an antitumor microenvironment. Representative cases of patients who responded to the combination therapies from two ongoing clinical trials (NCT05288205 and NCT04720976) were reported. Conclusions: JAB-3312 in combination with RTK/RAS/MAPK or PD-1 blockade therapies is a promising strategy that warrants further clinical investigation.