BACKGROUND Neuropathic pain is a persistent, treatment-resistant condition driven not only by peripheral nerve injury but also by maladaptive neuroplasticity in central pain-regulatory networks. Evidence increasingly points to dysfunction in the prefrontal cortex (PFC), a vital area for top-down control of pain, emotions, and autonomic functions, as a key factor in maintaining pain hypersensitivity. AIM To examine the combined effects of Kalanchoe pinnata (KP), treadmill exercise, and vagus nerve stimulation (VNS) on neuroinflammation, redox homeostasis, and neuropathic pain in a rat model. METHODS Neuropathic pain was induced via partial sciatic nerve ligation. KP was administered orally at an effective dose of 100 mg/kg. Rats were assigned to 7 groups: (1) Sham; (2) Partial sciatic nerve ligation-neuropathic pain-induced; (3) Gabapentin; (4) KP alone; (5) KP + exercise; (6) KP + VNS; and (7) KP + exercise + VNS. Pain behaviors were assessed using mechanical allodynia and thermal hyperalgesia tests. Biochemical analysis of the PFC measured oxidative stress markers, pro-inflammatory cytokines [nuclear factor-kappa B, tumor necrosis factor alpha, interleukin (IL)-1β, IL-6], anti-inflammatory cytokine (IL-10), nitric oxide, monoaminergic and cholinergic biomarkers. Molecular analysis measured nuclear factor erythroid 2-related factor 2, heme-oxygenase 1, Kelch-like ECH-associated protein 1, B-cell lymphoma 2 associated X-protein, B-cell lymphoma 2, caspase-3, brain-derived neurotrophic factor, and cAMP response element-binding protein in the PFC. RESULTS Results showed that treatments significantly (P < 0.05) reduced pain behaviors compared to untreated controls. Treatments also significantly (P < 0.05) decreased lipid peroxidation, lowered pro-inflammatory cytokine levels, increased antioxidant activity, and restored the balance between neuronal and apoptotic processes. The combination therapies produced greater biochemical normalization than KP monotherapy, suggesting enhanced therapeutic responses through multimodal intervention. The triple treatment produced the most notable effects, significantly normalizing multiple inflammatory and redox parameters. CONCLUSION KP alleviated neuropathic pain, and the enhancement with exercise and VNS highlights the potential of multimodal strategies targeting cortical pain-control networks. This therapeutic approach demonstrates potential as a multimodal preclinical strategy for neuropathic pain management and warrants further investigation.
Small-fiber neuropathy is a common complication of metabolic, neurodegenerative, and treatment-related disorders. Early detection can be challenging because established diagnostic approaches may be invasive, resource-intensive, or relatively insensitive to early small-fiber injury. Corneal confocal microscopy (CCM) is a rapid, noninvasive imaging technique that enables quantitative assessment of the corneal subbasal nerve plexus and has been proposed as a biomarker of peripheral small-fiber damage. This minireview critically evaluates the role of CCM for early detection, diagnostic testing, prognostic stratification, longitudinal follow-up, and treatment response assessment in systemic neuropathies, particularly diabetic peripheral neuropathy (DPN). Evidence is strongest in DPN, in which CCM consistently demonstrates group-level corneal nerve loss; however, individual diagnostic performance is only moderate and varies according to patient spectrum, reference standard, sampling protocol, analysis method, and diagnostic threshold. Evidence in other neurologic diseases, including Parkinson’s disease, multiple sclerosis, and chemotherapy-induced peripheral neuropathy, is less robust. Advancements in automated image analysis and artificial intelligence have improved reproducibility and efficiency of corneal nerve quantification in recent years. Nevertheless, widespread implementation in the clinics is still hampered by methodological heterogeneity, lack of full standardization, and absence of universally validated diagnostic and prognostic cut-off points. CCM is therefore a promising tool for translational research and precision medicine, but population-level differences in corneal nerve parameters should not be interpreted as establishing an individual diagnosis. At present, CCM should complement rather than replace established clinical, neurophysiological, functional, and pathological assessments, including quantitative sensory testing and skin biopsy when clinically indicated. Before integration into clinical practice can be recommended, multi-center prospective studies utilizing standardized acquisition and analysis protocols, validated thresholds, and clinically meaningful patient outcomes are required.
BACKGROUND Chimeric antigen receptor T-cell (CAR-T) therapy is highly active in relapsed/refractory multiple myeloma (RRMM), but manufacturing creates an obligatory waiting period between apheresis and infusion. Patients may deteriorate, progress or die during this window. Analyses that begin follow-up at infusion exclude these patients entirely and cannot describe the experience of all patients who enter the CAR-T pathway. AIM To describe, in an intention-to-collect fashion, the outcomes of all RRMM patients who underwent T-cell apheresis for planned CAR-T therapy; to characterise the apheresis-to-infusion interval and the reasons for, and correlates of, failure to reach infusion; and to report progression-free survival (PFS) and overall survival (OS) anchored at the date of apheresis. The study was descriptive; it was not designed to estimate the causal effect of CAR-T infusion on survival. METHODS Retrospective single-centre cohort of all RRMM patients undergoing T-cell apheresis for CAR-T at Hackensack University Medical Center between 1 January 2021 and 30 April 2024. PFS and OS were calculated from apheresis by the Kaplan-Meier method with Greenwood 95% confidence intervals (CIs) and numbers at risk. Groups were compared with the log-rank test; baseline characteristics with the Wilcoxon rank-sum and Fisher exact tests. Because infusion is a post-baseline, time-dependent event, the association between infusion and survival was additionally examined using a Mantel-Byar time-dependent Cox model and a 60-day landmark analysis. Correlates of non-infusion were examined by univariable logistic regression; multivariable modelling was not performed owing to the small number of events. RESULTS Of 99 patients undergoing apheresis, 87 (87.9%, 95%CI: 79.8-93.6) were infused and 12 (12.1%, 95%CI: 6.4-20.2) were not. Median follow-up was 14.0 months [interquartile range (IQR): 8.2-20.7]. Median apheresis-to-infusion interval was 54 days (IQR 46-62; range 37-202; n = 84 evaluable). Contrary to our preliminary report, baseline disease phenotype differed significantly between groups: Extramedullary disease was present in 9/12 (75.0%) non-infused vs 17/87 (19.5%) infused patients (P < 0.001), and plasma cell leukaemia in 3/12 (25.0%) vs 3/87 (3.4%) (P = 0.017). Age, prior lines of therapy (median 5 in both), high-risk cytogenetics (36.4% vs 34.1%) and Revised International Staging System distribution did not differ. The commonest reasons for non-infusion were progressive disease or myeloma-related death (7/12, 58.3%), non-myeloma death (2/12, 16.7%), manufacturing or collection failure (2/12, 16.7%) and infection (1/12, 8.3%). The median time from apheresis to the attrition event was 44 days (IQR 30-72). Median PFS from apheresis was 17.5 months (95%CI: 12.7-21.6) in infused patients vs 1.5 months (95%CI: 0.8-2.3) in non-infused patients; median OS was not reached vs 1.9 months (95%CI: 1.0-6.2) (both log-rank P < 0.001). In the time-dependent Cox model the hazard ratio for death associated with infusion was 0.24 (95%CI: 0.11-0.53), substantially closer to the null than the unadjusted comparison, illustrating how much of the apparent difference reflects the time-dependent nature of the exposure and confounding by disease phenotype. CONCLUSION In this descriptive cohort, roughly one in eight patients who underwent apheresis never received CAR-T, and attrition clustered before the median time to infusion and among patients with extramedullary disease or plasma cell leukaemia. These data support shortening manufacturing turnaround, prioritising patients with aggressive phenotypes for expedited slots and intensified bridging, and reporting outcomes from apheresis using analytic methods that respect the time-dependent nature of infusion.
BACKGROUND Recent studies have shown that the delayed luminescence of erythrosine (DLE) indicators differs between tumor and nontumor breast tissue in patients with breast cancer (BC). AIM To study the features of metabolism of axillary lymph node (ALN) cells and their relationship with regional metastasis in BC patients. METHODS This prospective, single-center, observational cohort study included 69 patients with newly diagnosed BC. DLE indicators were measured for 152 ALNs. DLE decay kinetics were recorded using flash photolysis. A control circuit interfaced the analog measuring devices and digital data processing systems. Eighty-eight and 74 ALN samples were stained with antibodies against vascular cell adhesion molecule-1 (VCAM-1) and C-X-C motif chemokine receptor 4 (CXCR4), respectively. Statistical calculations were performed using Statistica version 12.0 software. RESULTS Singlet oxygen-sensitized delayed fluorescence (SOSDF) indicators were significantly lower, whereas phosphorescence and thermally activated delayed fluorescence indicators were significantly higher in ALNs with metastases than in those without metastases (P < 0.0001). Pronounced VCAM-1 expression in ALNs was significantly more common in patients with tumor grade 3 and human epidermal growth factor receptor 2 (HER2) overexpression and in patients with HER2-positive BC. Pronounced CXCR4 expression in lymph node (LN) follicles was detected significantly more often in patients with metastases in ALNs and with lymphovascular invasion. The intensity of delayed phosphorescence positively correlated with both VCAM-1 and CXCR4 expression in the LN follicles, and VCAM-1 expression in the LN follicles was negatively correlated with SOSDF and positively correlated with the duration of delayed phosphorescence. CONCLUSION These results indicate that metastatic LNs exhibit greater oxygen consumption by tumor cells and that changes in tumor cell metabolism are associated with increased CXCR4 and VCAM-1 expression in ALNs.
