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5-Aminolevulinic acid (5-ALA) is a naturally occurring heme precursor with a favorable safety profile and is widely used for fluorescence-guided resection of malignant gliomas. Exogenous administration of 5-ALA results in the selective intracellular accumulation of protoporphyrin IX (PpIX), predominantly within tumor cell mitochondria, reflecting tumor-specific alterations in cellular metabolism and heme biosynthetic pathways. Historically, the radiosensitizing potential of 5-ALA was considered limited, as 5-ALA itself is not a porphyrin and intracellular PpIX levels are lower than those achieved with classical porphyrin-based agents, such as hematoporphyrin derivatives or porfimer sodium. Recent experimental and translational studies have challenged this view by demonstrating that the interactions between 5-ALA-induced PpIX and ionizing irradiation elicit biologically significant antitumor effects. This emerging concept has been termed radiodynamic therapy (RDT) and represents a therapeutic paradigm distinct from conventional DNA-centered radiosensitization. Accumulating evidence suggests that 5-ALA-based RDT induces mitochondria-centered oxidative stress through both immediate and delayed reactive oxygen species generation, thereby linking metabolic vulnerability to the radiation response. In this review, we summarize the current mechanistic insights into 5-ALA-based RDT, particularly mitochondrial dysfunction and oxidative stress amplification. We also discuss the translational implications and future perspectives for integrating 5-ALA-based RDT into multimodal treatment strategies for malignant gliomas.

To facilitate return to work (RTW) in patients with stroke, a health and employment support (HES) program was started at Rosai hospitals in Japan. This study aimed to determine the rate of RTW in patients with stroke under this support program. We collected demographic and clinical data of patients with stroke from the implementation reports of the HES program. The program provided coordinated dual support, such as acute medical treatments, and stroke and vocational rehabilitation on the medical side, and management and support on the workplace side. The primary endpoint was RTW. Successful and unsuccessful RTW were examined using the χ 2 test. The RTW rate curves were analyzed using the Kaplan–Meier method. We enrolled 483 patients; 355 (73%) and 128 (27%) patients had successful and unsuccessful RTW, respectively. Stroke types, neurological findings, and activities of daily living were significant factors for RTW. The Kaplan–Meier method revealed that left hemiplegia, right hemiplegia, and neuropsychological deficits, except for combined disability (hemiplegia with neuropsychological deficits), had similar RTW curves with an RTW rate of > 70%.

Purpose In this retrospective study, we aimed to evaluate the efficacy and incidence of radiation-induced brain necrosis (RBN) after volumetric modulated arc therapy-based stereotactic irradiation ( VMAT-STI ) for brain metastases. Methods In the 220 brain metastatic lesions included between January 2020 and June 2022, there were 1–9 concurrently treated lesions (median 1). A biologically effective dose (BED)10 of 80 Gy and a reduced BED10 of 50 Gy were prescribed to the gross tumor volume (GTV) and planning target volume (PTV) (PTV = GTV + 3 mm) margins, respectively. The number of fractions was adjusted from 3 to 15 to accommodate different GTV sizes; for larger tumor volumes, this was increased while maintaining the BED10 values comparable to those for GTV and PTV margins. Results Of the total patients, 16 (7%) exhibited locally progressive lesions; local tumor recurrence was observed in 2 (1%) patients, while RBN was noted in 14 (6%) patients. RBN was significantly more prevalent in the deep white matter around the lateral ventricles (DWM-LV) than in other sites, occurring in 9/22 (41%) lesions of metastases in the DWM-LV. The 2-year actuarial incidence risk of developing RBN was significantly higher in the DWM-LV (69%) than at other sites (5%). Conclusion The recurrence rate of brain metastases was low, and the incidence of RBN was lower in tumor sites other than the DWM-LV. However, the frequency of RBN was significantly higher in the DWM-LV region. Additional VMAT-STI-prescribed dose protocols are necessary to reduce RBN incidence in DWM-LVs.

Talaporfin sodium (mono-L-aspartyl chlorin e6; NPe6), a second-generation photosensitizer, is clinically used in photodynamic therapy (PDT). It accumulates preferentially in tumors and exhibits deep tissue penetration, rapid systemic clearance, and minimal photosensitivity. However, treatment of deep-seated malignancies remains challenging. Here, we demonstrate that talaporfin sodium undergoes physicochemical reactions with X-rays to generate reactive oxygen species, a mechanism analogous to that of 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX in radiodynamic therapy (RDT). To evaluate its therapeutic efficacy, we employed a pancreatic cancer xenograft model using MIA PaCa-2 cells in mice. Talaporfin sodium was administered intravenously 2 h before X-ray exposure, followed by fractionated X-ray irradiation (3 Gy daily for 3 consecutive days). Talaporfin-mediated RDT significantly inhibited tumor growth compared with radiation therapy alone. Furthermore, an exploratory RNA-seq analysis of xenografts revealed transcriptional signatures of stress and immune activation, suggesting that talaporfin-mediated RDT enhances oxidative and immunogenic responses within the tumor microenvironment. These findings highlight the potential of talaporfin sodium as a clinically translatable radiosensitizer for RDT, offering a promising strategy for the treatment of deep-seated cancers such as pancreatic carcinoma.

BackgroundAverage female life expectancy in Japan is approximately 90 years. Occasionally, we encounter stroke patients older than 90 years.AimsTo determine the clinical features and outcomes associated with cerebral infarction in patients aged ≥ 90 years.MethodsWe examined 289 consecutive patients (163 males, 129 females; mean age 77.5 years) diagnosed with cerebral infarction. We divided them into four groups according to age in years: middle (< 65), pre-old (65–74), old (75–89), and super old (≥ 90). We divided the super old group into mild symptoms (NIHSS ≤ 5) and severe symptoms (NIHSS > 5) and examined outcomes.ResultsStatistically significant associations were observed between female sex, cardiogenic infarction, and high complication rates and super old age. NIHSS and mRS scores at 30-day post-stroke were higher in the super old group. In some cases, complications led to poor prognoses. Eighty-seven percent of patients with mild symptoms (NIHSS ≤ 5) recovered to mRS 0–2 similar to the younger age group. None of the patients with severe symptoms (NIHSS > 5) recovered to mRS 0–2.DiscussionWe investigated the clinical outcomes following cerebral infarction in patients aged 90 years or older and found that mild symptoms were consistently associated with good prognoses, regardless of patients’ age.ConclusionsPatients in the super old group had more severe symptoms and poorer outcomes than younger age groups. However, patients with mild symptoms tended to have better prognoses and returned to daily life similar to the younger age group.

This study investigated the return-to-work (RTW) rates and associated factors following endoscopic transsphenoidal surgery (eTSS) among patients with pituitary and hypothalamic tumors in Japan. The primary research question aimed to determine the variables affecting early RTW post-surgery. A retrospective analysis was conducted on 44 preoperatively employed patients who underwent eTSS at a single center between April 2018 and January 2025. Clinical data, including demographics, tumor characteristics, comorbidities, and perioperative variables, were extracted from the medical records. The primary outcome was RTW within 3 months of surgery. Statistical analyses were performed using t-tests and Fisher’s exact tests. The median time to RTW was 5 weeks, and the RTW rates were 38.6%, 69.5%, and 75.0% at 1, 3, and 6 months, respectively, with an overall RTW rate of 84.1%. Factors such as a prolonged length of hospital stay (LOS), mental disorders, and the absence of prior TSS were significantly linked to delayed RTW at 3 months. Mental disorders also tended to decrease RTW at 6 months. No significant associations were found between adequate hormone replacement and age, sex, tumor type, or endocrinological dysfunction. Patients receiving multidisciplinary support for RTW tended to experience longer recovery periods, possibly reflecting a greater need. In patients undergoing eTSS for pituitary region tumors, a history of mental disorders, prolonged LOS, and no history of prior TSS were key factors could be associated with delayed RTW. Early identification of these factors may facilitate tailored multidisciplinary RTW support strategies.

Glioblastomas (GBMs) are the most aggressive types of central nervous system tumors. Although certain genomic alterations have been identified as prognostic biomarkers of GBMs, the histomorphological features that predict their prognosis remain elusive. In this study, following an integrative diagnosis of 227 GBMs based on the 2021 World Health Organization classification system, the cases were histologically fractionated by cellular variations and abundance to evaluate the relationship between cellular heterogeneity and prognosis in combination with O -6-methylguanine-DNA methyltransferase gene promoter methylation (m MGMTp ) status. GBMs comprised four major cell types: astrocytic, pleomorphic, gemistocytic, and rhabdoid cells. t -distributed stochastic neighbor embedding analysis using the histological abundance of heterogeneous cell types identified two distinct groups with significantly different prognoses. In individual cell component analysis, the abundance of gemistocytes showed a significantly favorable prognosis but confounding to m MGMTp status . Conversely, the abundance of epithelioid cells was correlated with the unfavorable prognosis. Linear model analysis showed the favorable prognostic utility of quantifying gemistocytic and epithelioid cells, independent of m MGMTp . The evaluation of GBM cell histomorphological heterogeneity is more effective for prognosis prediction in combination with m MGMTp analysis, indicating that histomorphological analysis is a practical and useful prognostication tool in an integrative diagnosis of GBMs.

To treat malignant glioma, standard fractionated radiotherapy (RT; 60 Gy/30 fractions over 6 weeks) was performed post-surgery in combination with temozolomide to improve overall survival. Malignant glioblastoma recurrence rate is extremely high, and most recurrent tumors originate from the excision cavity in the high-dose irradiation region. In our previous study, protoporphyrin IX physicochemically enhanced reactive oxygen species generation by ionizing radiation and combined treatment with 5-aminolevulinic acid (5-ALA) and ionizing radiation, while radiodynamic therapy (RDT) improved tumor growth suppression in vivo in a melanoma mouse model. We examined the effect of 5-ALA RDT on the standard fractionated RT protocol using U251MG- or U87MG-bearing mice. 5-ALA was orally administered at 60 or 120 mg/kg, 4 h prior to irradiation. In both models, combined treatment with 5-ALA slowed tumor progression and promoted regression compared to treatment with ionizing radiation alone. The standard fractionated RT protocol of 60 Gy in 30 fractions with oral administration of 120 and 240 mg/kg 5-ALA, the human equivalent dose of photodynamic diagnosis, revealed no significant increase in toxicity to normal skin or brain tissue compared to ionizing radiation alone. Thus, RDT is expected to enhance RT treatment of glioblastoma without severe toxicity under clinically feasible conditions.

Atypical teratoid/rhabdoid tumors (AT/RT) are rare, highly malignant neoplasms of the central nervous system that predominantly occur in infants, and are characterized by the presence of rhabdoid cells and inactivation of INI1 or (extremely rarely) BRG1. The vast majority of AT/RT are recognized as primary tumors; however, rare AT/RT or INI1-deficient RT arising from other primary tumors have been reported. To better characterize secondary RT, we performed a histological and molecular analysis of four RT arising from pleomorphic xanthoastrocytoma (PXA), anaplastic PXA, low-grade astrocytoma, or ependymoma. Histologically, although conventional AT/RT are usually not largely composed of rhabdoid cells, three secondary RT were composed mainly of rhabdoid cells, two of which arising from (anaplastic) PXA exhibited marked nuclear pleomorphism reminiscent of that in the precursor lesions. Regarding INI1 alterations, although mutations including small indels are frequent in conventional AT/RT, only in one secondary RT had a mutation. Moreover, together with previously reported cases, biallelic INI1 inactivation in secondary RT was mostly due to biallelic focal and/or broad deletions. Although conventional AT/RT have stable chromosomal profiles, i.e., the frequency of copy number changes involving chromosomes other than chromosome 22 is remarkably low, our array comparative genomic hybridization analysis revealed numerous copy number changes in the secondary RT. In conclusion, secondary RT of the central nervous system are clinicopathologically and molecularly different from conventional pediatric AT/RT, and a nosological issue is whether these secondary RT should be called secondary “AT/RT” as most of the reported cases were.

5-Aminolevulinic acid (5-ALA) can accumulate protoporphyrin IX (PpIX) in tumour cell mitochondria and is well known for its utility in fluorescence-guided resection of malignant gliomas as a live molecular marker. Previously, we and other authors demonstrated that 5-ALA has a radiosensitizing effect for tumours. In the present study, we aimed to investigate the mechanism underlying the radiosensitizing effect of 5-ALA by focusing on glioma cell mitochondria. Using an enhancer (ciprofloxacin) of 5-ALA-induced PpIX accumulation, we evaluated the influence of ionizing irradiation (IR) and delayed reactive oxygen species (ROS) production 12 h after IR by colony-forming assay and flow cytometry (FCM) with different amounts of PpIX accumulation. The mitochondrial mass and mitochondrial electron transport chain (mtETC) activity were evaluated by FCM and western blot analysis. Cell death and delayed ROS production after IR in glioma cells were increased in proportion to 5-ALA-induced PpIX accumulation. Delayed ROS production enhanced by 5-ALA localized to the glioma cell mitochondria. Mitochondrial mass and mitochondrial complex III activity, among mtETC factors, were also increased 12 h after IR in glioma cells in proportion to 5-ALA-induced PpIX accumulation with some variation. These results suggest that 5-ALA enhances IR-induced mitochondrial oxidative stress and leads to increased cell death with mitochondrial changes, thereby acting as a targeting mitochondrial drug, and so-called radiosensitizer in glioma cells.