Po-Hsuan Lee

Background: Brain metastasis (BrM) from non-small cell lung cancer (NSCLC) is driven by a profoundly immunosuppressive tumor microenvironment (TME) characterized by M2-polarized tumor-associated macrophages (TAMs) and microglia, T-cell exhaustion, and programmed cell death (PD) signaling, which jointly limit the efficacy of current therapies. Transcranial electric field stimulation (EFS) has emerged as a potential neuromodulatory strategy to regulate the TME of brain cancers. Nonetheless, its impact on the BrM TME, optimal stimulation parameters, and functional mechanisms remain unclear. Materials and methods: This preclinical investigation utilized an integrated translational platform comprising patient-derived NSCLC BrM tumor organoids ( n = 8), an immunocompetent syngeneic Lewis lung cancer (LLC) BrM mouse model, and in vitro organotypic brain slice cultures. Low-frequency EFS at 2–15 and 75 Hz was applied, and its efficacy was compared with tumor-treating fields (TTF; 150 kHz) and sham treatment. TME phenotypes were characterized by immunofluorescence, flow cytometry, Western blotting, and enzyme-linked immunosorbent assay (ELISA). Mechanistic studies were conducted in TAMs using calcium chelation, ion channel blockade, and protein kinase C (PKC) inhibition. Results: Among all EFS regimens tested, 75 Hz EFS significantly reduced BrM bioluminescence, tumor cross-sectional area (a 56% reduction vs. controls), and Ki-67 proliferation index, and prolonged survival in LLC BrM mice, whereas 2–15 Hz EFS had minimal effect and TTF showed only modest tumor control. 75 Hz EFS shifted TAMs from an M2-like CD206 ⁺ phenotype to an M1-like inducible nitric oxide synthase (iNOS)⁺/CD86⁺ phenotype, increased IL-1β and tumor necrosis factor (TNF)-α, and suppressed Janus kinase (JAK)2–signal transducer and activator of transcription (STAT3), IL-6, IL-10, and transforming growth factor (TGF)-β. It also reduced PD-1⁺ CD8⁺ exhausted T cells and PD-L1 expression in the BrM TME. These effects were recapitulated in patient-derived BrM tumor organoids and BrM-conditioned macrophage and microglia cultures, and were abrogated by calcium chelation, PKCα/β inhibition, or systemic dexamethasone. Conclusion: In this preclinical investigation, low-frequency transcranial EFS at 75 Hz represents a promising neuro-immunomodulatory strategy that reprograms the NSCLC BrM TME, restores anti-tumor immunity, and restrains tumor progression. Further clinical trials are required to validate the efficacy of low-frequency transcranial EFS in NSCLC BrM.

Cigarette smoking and nicotine dependence are prevalent in the general population and can negatively impact surgical outcomes. However, the effect of preoperative smoking status on the outcomes of endonasal transsphenoidal surgery (ETS) for pituitary adenomas (PA) remains unknown. This study aims to investigate the impact of preoperative smoking status on the outcomes following endonasal transsphenoidal surgery. A retrospective, international, multi-center, propensity score matched (PSM), cohort study was conducted using the TriNetX database. Adult patients diagnosed with PA who underwent endoscopic transsphenoidal excision between 2005 and 2024 were identified. Patients with documented cigarette smoking or nicotine dependence within six months prior to ETS were classified as the smoker cohort, while those without either were classified as the non-smoker (control) cohort. Propensity score matching was performed based on key covariates, including age, sex, race, comorbidities, and preoperative neuroendocrine function. The crude cohort included a total of 11,472 patients. After PSM, 1623 patients were included in both the smoker and non-smoker groups. The mean age at ETS was 50.9 years. Compared to the non-smoker group, smoker patients were associated with a higher incidence of postoperative cerebrospinal fluid (CSF) leakage (OR:1.31; 95%CI:1.05-1.62; p = 0.027), meningitis (OR:1.59; 95%CI:1.02-2.50; p = 0.047), postoperative diabetes insipidus (DI) (OR:1.22; 95%CI:1.04-1.43; p = 0.018), desmopressin use (OR:1.29; 95%CI:1.07-1.56; p = 0.009), hypopituitarism (OR:1.06; 95%CI:1.01-1.33; p = 0.048), and steroid use (OR:1.19; 95%CI:1.01-1.40; p = 0.035). Sensitivity analysis demonstrated consistent results across the different PSM models. Among patients undergoing ETS for PA, preoperative smoking status was associated with higher risks of postoperative CSF leakage, meningitis, DI, desmopressin use, hypopituitarism, and steroid use.

Objective The superficial cerebral venous system demonstrates considerable anatomical variability. The inferior anastomotic vein, or vein of Labbé (VOL), is a key anastomotic channel between the superficial middle cerebral veins and the transverse sinus. However, the morphological characteristics of the VOL remain inadequately defined, particularly in East Asian populations. This study aimed to systematically analyze the angioarchitecture of the VOL. Methods The VOL was evaluated using three-dimensional (3D) reconstructions derived from gadolinium-enhanced 3D T1-weighted turbo spin-echo sequences and validated against digital subtraction angiography (DSA). Key anatomical parameters – including number, diameter, lateralization, drainage entry points, and the relationship with the superior anastomotic vein – were assessed in 200 cerebral hemispheres from 100 healthy individuals (50 males, 50 females). Results In the validation cohort (n = 20 hemispheres), 3D MRA demonstrated high concordance with DSA in identifying VOL anatomy and diameter. Among all 200 hemispheres analyzed, VOL duplication was identified in 2% and complete absence in 0.5%. The VOL drained into the transverse sinus in 61.3% of cases, into the SDA in 32.7%, and into the superior petrosal sinus in 4%. A lateralized drainage pattern was observed, with the VOL being more prominent than the superior anastomotic vein on the left hemisphere, whereas the superior anastomotic vein predominated on the right hemispheres (p = 0.022). Conclusions This study represents the largest imaging-based analysis of VOL anatomy in an East Asian population. The VOL exhibits substantial interindividual variability in number, drainage pattern, and lateralization. Detailed knowledge of these anatomical nuances is crucial to minimize risk of venous infarction and enhance neurosurgical outcomes.

Background: Unplanned reoperation after craniotomy is a complication that can significantly affect patient outcomes. However, the incidence, causes, predictors, and outcomes of unplanned reoperation after craniotomy for brain metastases (BM) remain unclear. Materials and Methods: This retrospective, single-center study analyzed 500 consecutive patients who underwent elective craniotomy for BM between January 2014 and June 2024. Patients who required an unplanned surgical intervention within 30 days of the initial craniotomy were identified. Predictors and outcomes of unplanned reoperations were evaluated. Results: The incidence of major unplanned reoperation was 8.4% (42/500). The most common causes for major unplanned reoperations were postoperative hemorrhage (40.5%) and hydrocephalus (26.2%). Factors associated with unplanned reoperation included uncontrolled primary tumors [adjusted odds ratio (aOR): 2.53, 95% CI: 1.24–5.16, P = 0.011], 100 000 < platelet count ≤ 150 000 (aOR: 2.29, 95% CI: 1.35–3.89, P = 0.002), platelet count ≤ 100 000 (aOR: 16.10, 95% CI: 2.46–102.2, P = 0.001), multiple BM (aOR: 4.06, 95% CI: 1.94–8.45, P < 0.001), and deep tumor location (aOR: 2.42, 95% CI: 1.19–4.87, P = 0.014). Major unplanned reoperation was associated with a higher rate of nonhome discharge [23.8 vs. 11.8%, absolute risks difference (ARD): 0.12, 95% CI: 0.01–0.23, P = 0.026] and greater functional decline at 6 months measured by Karnofsky Performance Scale (64.3 vs. 27.3%, ARD 0.37, 95% CI: 0.22–0.52, P < 0.001). In the Kaplan–Meier analysis, unplanned reoperation was associated with reduced median overall survival (15.6 vs. 17.1 months, P = 0.017). Conclusions: Uncontrolled primary cancer, lower platelet count, multiple BM lesions, and deep tumor location were associated with unplanned reoperation after BM surgery. Patients with unplanned reoperations were associated with worse functional outcomes.

Brain metastases (BM) among elderly patients with cancer are increasing, and decision‐making for treatment is complicated by comorbidities. This study aimed to identify prognostic factors that can help make informed decisions regarding surgical resection in elderly patients with BM. We retrospectively included elderly patients (65 years or older) with newly diagnosed BM who underwent surgery. We conducted survival analyses and Cox regression analyses to identify potential independent predictors of poor survival. A total of 124 elderly patients with BM undergoing surgical resection were enrolled. In the multivariate analysis, male sex (HR: 1.96, 95% CI: 1.22–3.13), ECM (HR: 2.97, 95% CI: 1.82–4.85), BM in eloquent locations (HR: 1.64, 95% CI: 1.02–2.64), KPS deterioration (HR: 1.93, 95% CI: 1.20–3.10), and mFI‐5 equal to or greater than 2 (HR: 2.10, 95% CI: 1.12–3.95) were associated with poor overall survival. Conversely, receiving systemic treatment after the diagnosis of BM showed a significant overall survival benefit (HR: 0.45, 95% CI: 0.28–0.70). Elevated SII (HR: 1.99, 95% CI: 1.02–3.90) was significantly associated with poor survival, while elevated PNI (HR: 0.56, 95% CI: 0.33–0.94) indicated better survival. Clinicians should adopt a personalized approach when selecting treatment options for elderly patients with BM, considering BM location, the presence of ECM, comorbidities, and suitability for postoperative systemic treatment. Evaluating preoperative nutritional and inflammatory status and monitoring performance status pre‐ and postoperatively are needed, as these factors may affect prognosis.

Stress causes depression and cognitive decline. With limitations in pharmacotherapy, sciatic nerve stimulation (SNS) offers a promising nondrug alternative. This study aimed to explore the therapeutic efficacy of SNS in mitigating stress‐induced depressive behaviors and memory deficits by focusing on astrocytic dysfunction and cellular senescence in the hippocampus. C57BL/6 mice were subjected to the water immersion restraint stress (WIRS) paradigm to induce stress‐related behavioral deficits. Behavioral tests assessed locomotion, anxiety, depression‐like behavior, and memory. Astrocytic disruption and cellular senescence in the hippocampus were assessed using glial fibrillary acidic protein (GFAP) immunostaining and senescence‐associated β‐galactosidase (SA‐β‐gal) staining. SNS at 20 Hz significantly improved cognitive function and reduced depression‐like behavior in WIRS‐treated mice. It also restored hippocampal GFAP expression and decreased both SA‐β‐gal‐positive cell accumulation and the expression of senescence markers p16 and p21, suggesting an attenuation of cellular senescence. To further explore the link between cellular senescence and SNS‐mediated effects, we administered the anti‐senescence agent vitamin C to WIRS mice. While vitamin C alleviated stress‐induced hippocampal senescence and depressive behavior, it failed to reverse memory deficits or restore GFAP expression, indicating that the benefits of SNS extend beyond its anti‐senescent actions. In summary, SNS effectively counteracts the neurobehavioral consequences of chronic stress by targeting astrocytic dysfunction and cellular senescence. These findings support SNS as a promising, nonpharmacological strategy for treating stress‐related depression and cognitive decline. Future studies should explore its clinical translation and broader therapeutic potential.

Background: Mitochondria are essential for cellular energy production and cell survival. Mitochondrial dysfunction has been implicated in various neurological disorders, prompting the development of novel therapeutic approaches targeting these organelles. Among these, mitochondrial transplantation (MT), which replaces dysfunctional mitochondria with healthy counterparts from donor tissues, has emerged as a promising strategy. While skeletal muscle is a rich source of mitochondria, the optimal muscle tissue for MT remains unidentified, and the potential functional differences among mitochondria from various muscle types are not fully understood. This study investigates the quantity, size, respiratory function, energy production, and anti-inflammatory effects of mitochondria isolated from red skeletal muscle (RSM), mixed skeletal muscle (MSM), and white skeletal muscle (WSM). Methods: Mitochondria were extracted from the soleus muscle (RSM), pectoralis major and rectus abdominis (MSM), and biceps brachii and gastrocnemius (WSM) of healthy 8-week-old male Sprague Dawley rats. Nanoparticle tracking analysis was employed to determine mitochondrial quantity and size. The activities of mitochondrial complexes I, II, and IV and adenosine triphosphate (ATP) content were assessed. The protective effects of mitochondria (100 μg/mL) from each muscle type against lipopolysaccharide (LPS, 5 μg/mL)-induced cell death and mitochondrial membrane potential disruption were evaluated in PC-12 neuronal cells. Results: RSM-derived mitochondria exhibited a smaller average size and significantly higher mitochondrial content compared to those from MSM (mean size: p = 0.0056, vs. pectoralis major; p = 0.0056, vs. rectus abdominis; count of mitochondria: p < 0.0001, vs. pectoralis major; p < 0.0001, vs. rectus abdominis) and WSM (mean size: p = 0.0006, vs. biceps brachii; p < 0.0001, vs. gastrocnemius; count of mitochondria: p < 0.0001, vs. biceps brachii; p < 0.0001, vs. gastrocnemius). Additionally, RSM mitochondria demonstrated the highest activity of mitochondrial complex I among the three muscle types (p = 0.0001, vs. pectoralis major; p = 0.0095, vs. rectus abdominis; p < 0.0001, vs. biceps brachii; p < 0.0001, vs. gastrocnemius). WSM-derived mitochondria showed relatively lower complex II activity (p = 0.0006, biceps brachii vs. soleus; p = 0.0218, biceps brachii vs. rectus abdominis), while complex IV activity and ATP content were comparable across all groups. Supplementation with mitochondria isolated from RSM and WSM, but not MSM, effectively mitigated LPS-induced cell death (mitochondria isolated from soleus: p = 0.0031; biceps brachii: p = 0.0046; gastrocnemius: p = 0.0169) and preserved mitochondrial membrane potential (mitochondria isolated from soleus: p = 0.0204; biceps brachii: p = 0.0086; gastrocnemius: p = 0.0001) in PC-12 cells. Conclusions: RSM emerges as the optimal source for mitochondrial extraction, demonstrating superior respiratory activity and significant protective effects against LPS-induced cell death and mitochondrial dysfunction. These findings provide critical insights into optimizing MT outcomes through the strategic selection of mitochondrial sources.

The incidence of brain metastasis (BM) from colorectal cancer (CRC) is increasing. This study aims to identify the clinical prognosticators and evaluate the prognostic validity of common comorbidity indices in patients with BM from CRC. This retrospective single-center study analyzed 93 patients with BM from CRC who received surgical excision and/or radiotherapy. The clinical characteristics and prognostic indices including the 5-item modified frailty index (mFI-5) and prognostic nutritional index (PNI) were calculated from the collected patient data and analyzed. In this study, 66 (71.0%), 10 (10.8%), and 17 (18.3%) patients received whole-brain radiotherapy (WBRT) alone, surgery alone, and surgery plus WBRT, respectively. The median survival of all patients was 3.98 months (IQR: 1.74-7.99). The 2- and 3-year survival rates were 7.4% and 3.7%, respectively. Controlled primary tumor (p = 0.048), solitary BM (p = 0.001), surgery + radiation (p < 0.001), and greater PNI (p = 0.001) were independent predictors of favorable survival. In surgically treated patients, uncontrolled primary tumor (p = 0.006), presence of multiple BM (p < 0.001), and MFI-5 ≥ 2 (p = 0.038) were independent prognosticators. For patients who received WBRT, the presence of two (p = 0.004) or multiple (p < 0.001) BM and PNI (p < 0.001) were independent survival predictors MFI-5, multiple BM, and the status of the primary tumor were independent prognosticators for patients who underwent surgery for CRCBM. For patients who received WBRT, the PNI and the number of BM were independent survival predictors.

Oligoprogression is an emerging issue in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, the surgical treatment for central nervous system (CNS) oligoprogression is not widely discussed. We investigated the outcomes of craniotomy with adjuvant whole-brain radiotherapy (WBRT) and subsequent therapies for CNS oligoprogression in patients with EGFR-mutated NSCLC. NSCLC patients with CNS oligoprogression were identified from a tertiary medical center. The outcomes of surgery with adjuvant WBRT or WBRT alone were analyzed, along with other variables. Overall survival and progression-free survival were analyzed using the log-rank test as the primary and secondary endpoints. A COX regression model was used to identify the possible prognostic factors. Thirty-seven patients with CNS oligoprogression who underwent surgery or WBRT were included in the study after reviewing 728 patients. Twenty-one patients underwent surgery with adjuvant WBRT, and 16 received WBRT alone. The median overall survival for surgery and WBRT alone groups was 43 (95% CI 17–69) and 22 (95% CI 15–29) months, respectively. Female sex was a positive prognostic factor for overall survival (OR 0.19, 95% CI 0.06–0.57). Patients who continued previous tyrosine kinase inhibitors (OR 3.48, 95% CI 1.06–11.4) and induced oligoprogression (OR 3.35, 95% CI 1.18–9.52) were associated with worse overall survival. Smoking history (OR 4.27, 95% CI 1.54–11.8) and induced oligoprogression (OR 5.53, 95% CI 2.1–14.7) were associated with worse progression-free survival. Surgery combined with adjuvant WBRT is a feasible treatment modality for CNS oligoprogression in patients with EGFR-mutated NSCLC. Changing the systemic-targeted therapy after local treatments may be associated with improved overall survival.

The clip-induced spinal cord injury (SCI) rat model is pivotal in preclinical SCI research. However, the literature exhibits variability in compression duration and limited attention to clip deformation-related loss of closure force. We aimed to investigate the impact of compression duration on SCI severity and the influence of clip deformation on closure force. Rats received T10-level clip-induced SCI with durations of 1, 5, 10, 20, and 30 s, and a separate group underwent T10 transection. Outcomes included functional, histological, electrophysiological assessments, and inflammatory cytokine analysis. A tactile pressure mapping system quantified clip closure force after open–close cycles. Our results showed a positive correlation between compression duration and the severity of functional, histological, and electrophysiological deficits. Remarkably, even a brief 1-s compression caused significant deficits comparable to moderate-to-severe SCI. SSEP waveforms were abolished with durations over 20 s. Decreased clip closure force appeared after five open–close cycles. This study offers critical insights into regulating SCI severity in rat models, aiding researchers. Understanding compression duration and clip fatigue is essential for experiment design and interpretation using the clip-induced SCI model.