Mobile robots for isolation-room hospital settings: A scenario-based preliminary study.

Isolated patients pose physical challenges to medical staff owing to the need for protective gear. Additionally, communication issues arise within isolation rooms, hampering patient care. Mobile robots offer potential solutions, allowing for contactless communication and efficient task delegation, thereby reducing the risk of cross-contamination and minimizing staff workload. This preliminary study assessed the usability, acceptability, and potential for improvement of mobile robots in clinical nursing scenarios, focusing on nurses' perspectives. A preliminary test was conducted using mobile robots in a simulated hospital environment with 30 experienced nurses responsible for isolated patient care. Data were collected through interviews, surveys, and scenario-based tasks. Two scenarios were designed to evaluate the usability and effectiveness of mobile robots in real-world nursing situations. Nurses regarded mobile robots as highly usable and useful in healthcare settings. Robots efficiently handled tasks like remote supply delivery and medication distribution. Nurses recognized the potential for improved communication and efficiency with mobile robots; however, concerns were raised about the robots' limitations in providing emotional support and potential safety issues during emergencies. This research emphasizes the promising role of mobile robots in enhancing healthcare delivery within isolation rooms. While these findings indicate the potential for mobile robots, careful planning, training, and scenario development are crucial for their safe and effective integration into clinical settings. Further research, tailored scenarios, and a reevaluation of the evolving role of nurses in a technology-augmented healthcare environment are necessary, emphasizing the importance of understanding the capabilities and limitations of robotic assistance in patient care.

Comparison of Glioblastoma Cell Culture Platforms Based on Transcriptional Similarity with Paired Tissue.

No standardized in vitro cell culture models for glioblastoma (GBM) have yet been established, excluding the traditional two-dimensional culture. GBM tumorspheres (TSs) have been highlighted as a good model platform for testing drug effects and characterizing specific features of GBM, but a detailed evaluation of their suitability and comparative performance is lacking. Here, we isolated GBM TSs and extracellular matrices (ECM) from tissues obtained from newly diagnosed IDH1 wild-type GBM patients and cultured GBM TSs on five different culture platforms: (1) ordinary TS culture liquid media (LM), (2) collagen-based three-dimensional (3D) matrix, (3) patient typical ECM-based 3D matrix, (4) patient tumor ECM-based 3D matrix, and (5) mouse brain. For evaluation, we obtained transcriptome data from all cultured GBM TSs using microarrays. The LM platform exhibited the most similar transcriptional program to paired tissues based on GBM genes, stemness- and invasiveness-related genes, transcription factor activity, and canonical signaling pathways. GBM TSs can be cultured via an easy-to-handle and cost- and time-efficient LM platform while preserving the transcriptional program of the originating tissues without supplementing the ECM or embedding it into the mouse brain. In addition to applications in basic cancer research, GBM TSs cultured in LM may also serve as patient avatars in drug screening and pre-clinical evaluation of targeted therapy and as standardized and clinically relevant models for precision medicine.

A Prospective, Multicenter, Observational Study of Surgical vs Nonsurgical Management for Pituitary Apoplexy.

CONTEXT: Pituitary apoplexy (PA) has been traditionally considered a neurosurgical emergency, yet retrospective single-institution studies suggest similar outcomes among patients managed medically. OBJECTIVE: We established a multicenter, international prospective registry to compare presentation and outcomes in PA patients treated with surgery or medical management alone. METHODS: A centralized database captured demographics, comorbidities, clinical presentation, visual findings, hormonal status, and imaging features at admission. Treatment was determined independently by each site. Key outcomes included visual, oculomotor, and hormonal recovery, complications, and hospital length of stay. Outcomes were also compared based on time from symptom onset to surgery, and from admission or transfer to the treating center. Statistical testing compared treatment groups based on 2-sided hypotheses and P less than .05. RESULTS: A total of 100 consecutive PA patients from 12 hospitals were enrolled, and 97 (67 surgical and 30 medical) were evaluable. Demographics, clinical features, presenting symptoms, hormonal deficits, and imaging findings were similar between groups. Severe temporal visual field deficit was more common in surgical patients. At 3 and 6 months, hormonal, visual, and oculomotor outcomes were similar. Stratifying based on severity of visual fields demonstrated no difference in any outcome at 3 months. Timing of surgery did not affect outcomes. CONCLUSION: We found that medical and surgical management of PA yield similar 3-month outcomes. Although patients undergoing surgery had more severe visual field deficits, we could not clearly demonstrate that surgery led to better outcomes. Even without surgery, apoplectic tumor volumes regress substantially within 2 to 3 months, indicating that surgery is not always needed to reduce mass effect.

Rethinking extent of resection of contrast-enhancing and non-enhancing tumor: different survival impacts on adult-type diffuse gliomas in 2021 World Health Organization classification.

OBJECTIVES: Extent of resection (EOR) of contrast-enhancing (CE) and non-enhancing (NE) tumors may have different impacts on survival according to types of adult-type diffuse gliomas in the molecular era. This study aimed to evaluate the impact of EOR of CE and NE tumors in glioma according to the 2021 World Health Organization classification. METHODS: This retrospective study included 1193 adult-type diffuse glioma patients diagnosed between 2001 and 2021 (183 oligodendroglioma, 211 isocitrate dehydrogenase [IDH]-mutant astrocytoma, and 799 IDH-wildtype glioblastoma patients) from a single institution. Patients had complete information on IDH mutation, 1p/19q codeletion, and O6-methylguanine-methyltransferase (MGMT) status. Cox survival analyses were performed within each glioma type to assess predictors of overall survival, including clinical, imaging data, histological grade, MGMT status, adjuvant treatment, and EOR of CE and NE tumors. Subgroup analyses were performed in patients with CE tumor. RESULTS: Among 1193 patients, 935 (78.4%) patients had CE tumors. In entire oligodendrogliomas, gross total resection (GTR) of NE tumor was not associated with survival (HR = 0.56, p = 0.223). In 86 (47.0%) oligodendroglioma patients with CE tumor, GTR of CE tumor was the only independent predictor of survival (HR = 0.16, p = 0.004) in multivariable analysis. GTR of CE and NE tumors was independently associated with better survival in IDH-mutant astrocytoma and IDH-wildtype glioblastoma (all ps < 0.05). CONCLUSIONS: GTR of both CE and NE tumors may significantly improve survival within IDH-mutant astrocytomas and IDH-wildtype glioblastomas. In oligodendrogliomas, the EOR of CE tumor may be crucial in survival; aggressive GTR of NE tumor may be unnecessary, whereas GTR of the CE tumor is recommended. CLINICAL RELEVANCE STATEMENT: Surgical strategies on contrast-enhancing (CE) and non-enhancing (NE) tumors should be reassessed considering the different survival outcomes after gross total resection depending on CE and NE tumors in the 2021 World Health Organization classification of adult-type diffuse gliomas. KEY POINTS: The survival impact of extent of resection of contrast-enhancing (CE) and non-enhancing (NE) tumors was evaluated in adult-type diffuse gliomas. Gross total resection of both CE and NE tumors may improve survival in isocitrate dehydrogenase (IDH)-mutant astrocytomas and IDH-wildtype glioblastomas, while only gross total resection of the CE tumor improves survival in oligodendrogliomas. Surgical strategies should be reconsidered according to types in adult-type diffuse gliomas.

Increased Risk of Hip Fracture in Patients with Acromegaly: A Nationwide Cohort Study in Korea.

BACKGRUOUND: Acromegaly leads to various skeletal complications, and fragility fractures are emerging as a new concern in patients with acromegaly. Therefore, this study investigated the risk of fractures in Korean patients with acromegaly. METHODS: We used the Korean nationwide claims database from 2009 to 2019. A total of 931 patients with acromegaly who had never used an osteoporosis drug before and were treated with surgery alone were selected as study participants, and a 1:29 ratio of 26,999 age- and sex-matched osteoporosis drug-naïve controls without acromegaly were randomly selected from the database. RESULTS: The mean age was 46.2 years, and 50.0% were male. During a median follow-up of 54.1 months, there was no difference in the risks of all, vertebral, and non-vertebral fractures between the acromegaly and control groups. However, hip fracture risk was significantly higher (hazard ratio [HR], 2.73; 95% confidence interval [CI], 1.32 to 5.65), and non-hip and non-vertebral fractures risk was significantly lower (HR, 0.40; 95% CI, 0.17 to 0.98) in patients with acromegaly than in controls; these results remained robust even after adjustment for socioeconomic status and baseline comorbidities. Age, type 2 diabetes mellitus, cardio-cerebrovascular disease, fracture history, recent use of acid-suppressant medication, psychotropic medication, and opioids were risk factors for all fractures in patients with acromegaly (all P<0.05). CONCLUSION: Compared with controls, patients surgically treated for acromegaly had a higher risk of hip fractures. The risk factors for fracture in patients with acromegaly were consistent with widely accepted risk factors in the general population.

Dexamethasone suppression for 18F-FDG PET/CT to localize ACTH-secreting pituitary tumors.

BACKGROUND: 18Fluorine-Fluoro-deoxy-glucose (18F-FDG) positron emission tomography (PET) is widely used for diagnosing various malignant tumors and evaluating metabolic activities. Although the usefulness of 18F-FDG PET has been reported in several endocrine diseases, studies on pituitary disease are extremely limited. To evaluate whether dexamethasone (DEX) suppression can improve 18F-FDG PET for the localization of adrenocorticotropic hormone-secreting adenomas in the pituitary gland in Cushing's disease (CD). METHODS: We included 22 patients with CD who underwent PET imaging before and after DEX administration. We compared the success rates of PET before and after DEX suppression, magnetic resonance imaging (MRI), and bilateral inferior petrosal sinus sampling (BIPSS). We determined the final locations of adenomas based on intraoperative multiple-staged resection and tumor tissue identification using frozen sections. Standardized uptake value (SUV) were analyzed to confirm the change of intensity of adenomas on PET. RESULTS: Twenty-two patients were included (age at diagnosis: 37 [13-56] years), and most were women (90.91%). Pituitary adenomas compared to normal pituitaries showed increased maximum SUV after DEX suppression but without statistical significance (1.13 versus. 1.21, z=-0.765, P = 0.444). After DEX suppression, the mean and maximum SUV of adenomas showed a positive correlation with nadir cortisol levels in high-dose DEX suppression test (Rho = 0.554, P = 0.007 and Rho = 0.503, P = 0.017, respectively). In reference sites, mean SUV of cerebellum was significantly decreased (7.65 vs. 6.40, P = 0.006*), but those of the thalamus and gray matter was increased after DEX suppression (thalamus, 8.70 vs. 11.20, P = 0.010*; gray matter, 6.25 vs. 7.95, P = 0.010*). CONCLUSION: DEX suppression did not improve 18F-FDG PET/CT localization in patients with CD.

Clinically conserved genomic subtypes of gastric adenocarcinoma.

Gastric adenocarcinoma (GAC) is a lethal disease characterized by genomic and clinical heterogeneity. By integrating 8 previously established genomic signatures for GAC subtypes, we identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs). CGS1 have the poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 is enriched with canonical epithelial gene expression. CGS3 and CGS4 have high copy number alterations and low immune reactivity. However, CGS3 and CGS4 differ in that CGS3 has high HER2 activation, while CGS4 has high SALL4 and KRAS activation. CGS5 has the high mutation burden and moderately high immune reactivity that are characteristic of microsatellite instable tumors. Most CGS6 tumors are positive for Epstein Barr virus and show extremely high levels of methylation and high immune reactivity. In a systematic analysis of genomic and proteomic data, we estimated the potential response rate of each consensus subtype to standard and experimental treatments such as radiation therapy, targeted therapy, and immunotherapy. Interestingly, CGS3 was significantly associated with a benefit from chemoradiation therapy owing to its high basal level of ferroptosis. In addition, we also identified potential therapeutic targets for each consensus subtype. Thus, the consensus subtypes produced a robust classification and provide for additional characterizations for subtype-based customized interventions.

Sex differences in mortality in patients with acromegaly: a nationwide cohort study in Korea.

OBJECTIVE: The results of previous studies on sex differences in mortality and comorbidities among patients with acromegaly are diverse. We assessed sex differences in mortality and the risk of complications in patients with acromegaly. METHODS: We included 1884 patients with acromegaly with 1:50 age- and sex-matched 94 200 controls using the Korean nationwide claims database from 2009 to 2019. RESULTS: During the median 5.51 years of follow-up, the acromegaly group had higher all-cause mortality than the control group (hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.38-2.19), with higher risk in women than men (HR 2.17 vs 1.36). The most common cause of death was malignancy. Women with acromegaly aged ≥50 years exhibited significantly higher mortality than men with acromegaly aged ≥50 years (HR 1.74 vs 0.96). In a treatment subgroup other than surgery alone, women had a higher risk of mortality than men (HR 2.82 vs 1.58). Sex differences in mortality among patients with acromegaly remained equal after adjustment for the Charlson Comorbidity Index (CCI), socioeconomic status (SES), body mass index (BMI), alcohol consumption, smoking, fasting plasma glucose, creatinine, and total cholesterol. Patients with acromegaly had elevated risks of developing major adverse cardiovascular events (MACE), atrial fibrillation, obstructive sleep apnea (OSA), diabetes mellitus (DM), end-stage renal disease (ESRD), Parkinson's disease (PD), depression, and malignancy than age- and sex-matched controls, with a higher risk of OSA and DM in women than men. CONCLUSIONS: The risk of mortality and complications in patients with acromegaly compared to age- and sex-matched controls was higher in women than in men.

Classification of IDH wild-type glioblastoma tumorspheres into low- and high-invasion groups based on their transcriptional program.

BACKGROUND: Glioblastoma (GBM), one of the most lethal tumors, exhibits a highly infiltrative phenotype. Here, we identified transcription factors (TFs) that collectively modulate invasion-related genes in GBM. METHODS: The invasiveness of tumorspheres (TSs) were quantified using collagen-based 3D invasion assays. TF activities were quantified by enrichment analysis using GBM transcriptome, and confirmed by cell-magnified analysis of proteome imaging. Invasion-associated TFs were knocked down using siRNA or shRNA, and TSs were orthotopically implanted into mice. RESULTS: After classifying 23 patient-derived GBM TSs into low- and high-invasion groups, we identified active TFs in each group-PCBP1 for low invasion, and STAT3 and SRF for high invasion. Knockdown of these TFs reversed the phenotype and invasion-associated-marker expression of GBM TSs. Notably, MRI revealed consistent patterns of invasiveness between TSs and the originating tumors, with an association between high invasiveness and poor prognosis. Compared to controls, mice implanted with STAT3- or SRF-downregulated GBM TSs showed reduced normal tissue infiltration and tumor growth, and prolonged survival, indicating a therapeutic response. CONCLUSIONS: Our integrative transcriptome analysis revealed three invasion-associated TFs in GBM. Based on the relationship among the transcriptional program, invasive phenotype, and prognosis, we suggest these TFs as potential targets for GBM therapy.

Role of Immediate Postoperative Prolactin Measurement in Female Prolactinoma Patients: Predicting Long-Term Remission After Complete Tumor Removal.

BACKGROUND: Transsphenoidal surgery is one of the important treatment options in the management of prolactinomas; however, complete resection of the tumor does not always lead to endocrinological remission. While many studies have investigated preoperative factors associated with surgical outcome, little has been known about the relationship between postoperative factors and long-term surgical outcomes; moreover, there is no consistency in results. The aim of this study was to demonstrate the reliability of immediate postoperative prolactin levels as predictors of long-term outcomes. METHODS: A total of 105 female patients who underwent complete removal of their histologically confirmed prolactinomas were included, and their medical records were retrospectively reviewed. To evaluate the predictability of immediate postoperative prolactin levels for long-term remission, prolactin levels were measured at 2, 6, 12, 18, 24, 48, and 72 h after surgery. RESULTS: From the 105 included patients, 95 (90.5%) and 10 (9.5%) belonged to the remission and non-remission groups, respectively. A significant difference was observed in the prolactin level measured 6 h after surgery between the remission and non-remission groups, and this difference stayed apparent until 72 h after surgery. We derived a cut-off value for every postoperative time point that showed a significant relationship with disease remission. CONCLUSION: Our study suggests that immediate postoperative measurement of prolactin levels is a reliable predictor of long-term remission and can contribute to early identification of patients who require adjuvant treatment after surgery.

Surgical Treatment of Prolactinomas: Potential Role as a First-Line Treatment Modality.

PURPOSE: Treatment with dopamine agonists (DAs) has been the first-line standard treatment for prolactinoma, and surgery has been reserved for drug intolerance and resistance for several decades. We evaluated whether surgery plays a primary role in prolactinoma management. MATERIALS AND METHODS: We conducted a retrospective study of 210 prolactinoma patients who had received surgical treatment at our institution. We analyzed the treatment outcomes according to tumor extent, sex, and preoperative DA medication. RESULTS: Overall hormonal remission was achieved in 164 patients (78.1%), and complete removal was achieved in 194 patients (92.4%). When the tumors were completely removed, the remission rate increased to 84.5%. Anterior pituitary function was normalized or improved in 94.6% of patients, whereas only 4.1% of patients showed worsening of hormone control. Hormonal remission was higher in patients who had not received DA preoperatively than in those who had received preoperative DA treatment. Smaller tumor size (<1 cm), no invasion into the cavernous sinus, and female sex were predictors of good surgical outcomes. CONCLUSION: Although DAs remain the first-line standard treatment for prolactinomas, surgery can be an excellent option and should be considered as an alternative primary treatment modality when patients are predicted to achieve a good surgical outcome.

MRI-Based Classification of Rathke's Cleft Cyst and Its Clinical Implication.

BACKGROUND: Rathke's cleft cysts (RCCs) are benign tumors of the pituitary gland. Small, asymptomatic RCCs do not require surgical treatment, whereas surgical treatment is required for symptomatic RCCs. METHODS: We retrospectively reviewed medical records of patients with an RCC who were diagnosed and managed in our institution between April 2004 and April 2020 and generated two different cohorts: the observation (n=114) and the surgical group (n=99). Their initial MRI signal characteristics were analyzed. The natural course focusing on cyst size was observed in the observation group and postoperative visual and endocrine outcomes were evaluated in the surgical group. RESULTS: The characterization of MRI signals of cyst contents in both T1-weighted (T1W) and T2-weighted (T2W) images revealed nine combinations for our 213 patients. Among 115 patients with a high T2W signal, the cysts showed hypo-, iso-, and hyper-intensity on T1W images in 72, 39, and 44 patients, respectively; Type S-low, Type S-iso, and Type S-high. One more major group of 35 patients showed RCCs with hyperintensity on the T1W images and hypointensity on the T2W images named as Type M. In the comparison between observation and surgical groups, we identified only two major groups in which the number of patients in the surgical and observation groups was statistically different: more Type S-low in a surgical group (p<0.001) and more Type M in an observation group (p=0.007). In subgroup analysis, the range of change in the cyst size was the highest in Type S-high in the observation group (p=0.028), and intergroup differences in visual and endocrine outcomes were not evident in the surgical group. CONCLUSION: MRI characteristics help to predict the natural course of RCCs. We identified subgroups of RCCs which are more or less likely to require surgical intervention.

Mesenchymal Stem-Like Cells Derived from the Ventricle More Effectively Enhance Invasiveness of Glioblastoma Than Those Derived from the Tumor.

PURPOSE: Glioblastoma (GBM) is one of the most lethal human tumors with a highly infiltrative phenotype. Our previous studies showed that GBM originates in the subventricular zone, and that tumor-derived mesenchymal stem-like cells (tMSLCs) promote the invasiveness of GBM tumorspheres (TSs). Here, we extend these studies in terms of ventricles using several types of GBM patient-derived cells. MATERIALS AND METHODS: The invasiveness of GBM TSs and ventricle spheres (VSs) were quantified via collagen-based 3D invasion assays. Gene expression profiles were obtained from microarray data. A mouse orthotopic xenograft model was used for in vivo experiments. RESULTS: After molecular and functional characterization of ventricle-derived mesenchymal stem-like cells (vMSLCs), we investigated the effects of these cells on the invasiveness of GBM TSs. We found that vMSLC-conditioned media (CM) significantly accelerated the invasiveness of GBM TSs and VSs, compared to the control and even tMSLC-CM. Transcriptome analyses revealed that vMSLC secreted significantly higher levels of several invasiveness-associated cytokines. Moreover, differentially expressed genes between vMSLCs and tMSLCs were enriched for migration, adhesion, and chemotaxis-related gene sets, providing a mechanistic basis for vMSLC-induced invasion of GBM TSs. In vivo experiments using a mouse orthotopic xenograft model confirmed vMSLC-induced increases in the invasiveness of GBM TSs. CONCLUSION: Although vMSLCs are non-tumorigenic, this study adds to our understanding of how GBM cells acquire infiltrative features by vMSLCs, which are present in the region where GBM genesis originates.

Revisiting prognostic factors in glioma with leptomeningeal metastases: a comprehensive analysis of clinical and molecular factors and treatment modalities.

PURPOSE: To comprehensively investigate prognostic factors, including clinical and molecular factors and treatment modalities, in adult glioma patients with leptomeningeal metastases (LM). METHODS: Total 226 patients with LM (from 2001 to 2021 among 1495 grade 2 to 4 glioma patients, 88.5% of LM patients being IDH-wildtype) with complete information on IDH mutation, 1p/19q codeletion, and MGMT promoter methylation status were enrolled. Predictors of overall survival (OS) of entire patients were determined by time-dependent Cox analysis, including clinical, molecular, and treatment data. Subgroup analyses were performed for patients with LM at initial diagnosis and LM diagnosed at recurrence (herein, initial and recurrent LM). Identical analyses were performed in IDH-wildtype glioblastoma patients. RESULTS: Median OS was 17.0 (IQR 9.7-67.1) months, with shorter median OS in initial LM than recurrent LM patients (12.2 vs 20.6 months, P < 0.001). In entire patients, chemotherapy and antiangiogenic therapy were predictors of longer OS, while male sex and initial LM were predictors of shorter OS. In initial LM, higher KPS, chemotherapy, and antiangiogenic therapy were predictors of longer OS, while male sex was a predictor of shorter OS. In recurrent LM, chemotherapy and longer interval between initial glioma and LM diagnoses were predictors of longer OS, while male sex was a predictor of shorter OS. A similar trend was observed in IDH-wildtype glioblastoma. CONCLUSION: Active chemotherapy and antiangiogenic therapy demonstrated survival benefit in glioma patients with LM. There is consistent female survival advantage, whereas longer interval between initial glioma diagnosis and LM development suggests longer OS in recurrent LM.

Leptomeningeal metastases in glioma revisited: incidence and molecular predictors based on postcontrast fluid-attenuated inversion recovery imaging.

OBJECTIVE: Leptomeningeal metastases (LMs) in glioma have been underestimated given their low incidence and the lack of reliable imaging. Authors of this study aimed to investigate the real-world incidence of LMs using cerebrospinal fluid (CSF)-sensitive imaging, namely postcontrast fluid-attenuated inversion recovery (FLAIR) imaging, and to analyze molecular predictors for LMs in the molecular era. METHODS: A total of 1405 adult glioma (World Health Organization [WHO] grade 2-4) patients underwent postcontrast FLAIR imaging at initial diagnosis and during treatment monitoring between 2001 and 2021. Collected molecular data included isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion, H3 K27 alteration, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. LM diagnosis was performed with MRI including postcontrast FLAIR sequences. Logistic regression analysis for LM development was performed with molecular, clinical, and imaging data. Overall survival (OS) was compared between patients with and those without LM. RESULTS: LM was identified in 228 patients (16.2%), 110 (7.8%) at the initial diagnosis and 118 (8.4%) at recurrence. Among the molecular diagnostics, IDH-wildtype (OR 3.14, p = 0.001) and MGMT promoter unmethylation (OR 1.43, p = 0.034) were independent predictors of LM. WHO grade 4 (OR 10.52, p < 0.001) and nonlobar location (OR 1.56, p = 0.048) were associated with LM at initial diagnosis, whereas IDH-wildtype (OR 5.04, p < 0.001) and H3 K27 alteration (OR 3.39, p = 0.003) were associated with LM at recurrence. Patients with LM had a worse median OS than those without LM (16.7 vs 32.0 months, p < 0.001, log-rank test), which was confirmed as an independent factor on multivariable Cox analysis (p = 0.004). CONCLUSIONS: CSF-sensitive imaging aids the diagnosis of LM, demonstrating a high incidence of LM in adult gliomas. Furthermore, molecular markers are associated with LM development in glioma, and patients with aggressive molecular markers warrant imaging surveillance for LM.

C5α secreted by tumor mesenchymal stem-like cells mediates resistance to 5-aminolevulinic acid-based photodynamic therapy against glioblastoma tumorspheres.

PURPOSE: Advancements in photodynamic diagnosis (PDD) and photodynamic therapy (PDT) as a standard care in cancer therapy have been limited. This study is aimed to investigate the clinical availability of 5-aminolevulinic acid (5-ALA)-based PDD and PDT in glioblastoma (GBM) patient-derived tumorspheres (TSs) and mouse orthotopic xenograft model. METHODS: PDT was performed using a 635 nm light-emitting diode (LED). Transcriptome profiles were obtained from microarray data. For knockdown of C5α, siRNA was transfected into tumor mesenchymal stem-like cells (tMSLCs). The invasiveness of TSs was quantified using collagen-based 3D invasion assays. RESULTS: Treatment with 1 mM 5 ALA induced distinct protoporphyrin IX (PpIX) fluorescence in GBM TSs, but not in non-tumor cells or tissues, including tMSLCs. These observations were negatively correlated with the expression levels of FECH, which catalyzes the conversion of accumulated PpIX to heme. Furthermore, the 5-ALA-treated GBM TSs were sensitive to PDT, thereby significantly decreasing cell viability and invasiveness. Notably, the effects of PDT were abolished by culturing TSs with tMSLC-conditioned media. Transcriptome analysis revealed diverse tMSLC-secreted chemokines, including C5α, and their correlations with the expression of stemness- or mesenchymal transition-associated genes. By adding or inhibiting C5α, we confirmed that acquired resistance to PDT was induced via tMSLC-secreted C5α. CONCLUSIONS: Our results show substantial therapeutic effects of 5-ALA-based PDT on GBM TSs, suggesting C5α as a key molecule responsible for PDT resistance. These findings could trigger PDT as a standard clinical modality for the treatment of GBM.

Dual inhibition of CPT1A and G6PD suppresses glioblastoma tumorspheres.

PURPOSE: Limited treatment options are currently available for glioblastoma (GBM), an extremely lethal type of brain cancer. For a variety of tumor types, bioenergetic deprivation through inhibition of cancer-specific metabolic pathways has proven to be an effective therapeutic strategy. Here, we evaluated the therapeutic effects and underlying mechanisms of dual inhibition of carnitine palmitoyltransferase 1A (CPT1A) and glucose-6-phosphate dehydrogenase (G6PD) critical for fatty acid oxidation (FAO) and the pentose phosphate pathway (PPP), respectively, against GBM tumorspheres (TSs). METHODS: Therapeutic efficacy against GBM TSs was determined by assessing cell viability, neurosphere formation, and 3D invasion. Liquid chromatography-mass spectrometry (LC-MS) and RNA sequencing were employed for metabolite and gene expression profiling, respectively. Anticancer efficacy in vivo was examined using an orthotopic xenograft model. RESULTS: CPT1A and G6PD were highly expressed in GBM tumor tissues. Notably, siRNA-mediated knockdown of both genes led to reduced viability, ATP levels, and expression of genes associated with stemness and invasiveness. Similar results were obtained upon combined treatment with etomoxir and dehydroepiandrosterone (DHEA). Transcriptome analyses further confirmed these results. Data from LC-MS analysis showed that this treatment regimen induced a considerable reduction in the levels of metabolites associated with the TCA cycle and PPP. Additionally, the combination of etomoxir and DHEA inhibited tumor growth and extended survival in orthotopic xenograft model mice. CONCLUSION: Our collective findings support the utility of dual suppression of CPT1A and G6PD with selective inhibitors, etomoxir and DHEA, as an efficacious therapeutic approach for GBM.

Radiation Therapy for Recurrent or Residual Pituitary Macroadenoma Invading Extrasellar Structures.

PURPOSE: This study aimed to evaluate the efficacy of radiation therapy (RT) for recurrent or residual pituitary macroadenoma (PMA) invading extrasellar regions. MATERIALS AND METHODS: Patients from 2000 to 2020 who received RT with conventional fractionation for recurrent or residual PMA were included. The patients were divided according to the type of tumor [functioning (fx) or non-fx] and the aim of RT (salvage RT alone, immediate postoperative RT, delayed postoperative RT). Local and biochemical failure-free rates (FFR) were calculated using the Kaplan-Meier method. RESULTS: With a median follow up of 82 months (IQR; 42-132 months), 36 patients treated with conventional RT (total 45-54 Gy in 1.8 or 2 Gy per fraction) for recurrent or residual PMA were analyzed. The 10-year local FFRs after RT for non-fx and fx tumor were 100% and 74.4%, respectively (p=0.047). In the immediate postoperative RT group, the 10-year local FFR was 100%, which was higher than the 90% FFR for salvage RT alone or 80% FFR for the delayed postoperative RT group (overall p=0.043, immediate vs. salvage; p=0.312, immediate vs. delayed; p=0.072). The local FFR was compared according to size of tumor with a cut-off value of 4 cm, and there was no significant difference (10-year local FFR 100% vs. 84.7% for >4 cm vs. <4 cm, p=0.320). The extents of extrasellar region invasion were not predictive of local failure after RT. We found no grade ≥3 acute toxicities or newly developed visual impairments as a late toxicity of RT. CONCLUSION: Conventional RT is safe and effective for the local control of recurrent or residual PMA. Our data suggest that immediate postoperative RT can be beneficial in recurrent or residual PMA, although further studies to evaluate risk factors of treatment failure in terms of treatment and disease characteristics are required.

Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres.

INTRODUCTION: The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM. METHODS: The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO. RESULTS: GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group. CONCLUSION: ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM.

The Improvement of Porcine In Vitro Embryo Development through Regulating Autophagy by miRNA-143 Inhibition.

In vitro embryo research is an important stage for the advancement of many reproductive technologies in research and agriculture. For this reason, the improvement of in vitro embryo development is a strategic field worthy of investigation. Relatively little is known about miR-143 and its effects on autophagy associated with embryo development and in vitro embryo culture. In this study, we examined the effect of miR-143 (via mimics and inhibitors) on embryonic development threatened by microinjection after parthenogenetic activation. We evaluated rates of cleavage, blastocyst, and total cell number of blastocyst; additionally, we performed LC3 immunofluorescence analysis and mRNA expression analyses of genes associated with autophagy, endoplasmic reticulum (ER)-phagy, ER stress, embryo quality, and apoptosis. The inhibition of miR-143 positively influenced embryo development by increasing the activity of autophagy and ER-phagy and the expression of embryo quality-related genes, while reducing apoptosis. In contrast, treatment with miR-143 mimics increased ER stress-related gene expression and apoptosis, and reduced embryo development. Together, our findings indicate that miR-143 plays a role in the interplay between autophagy, ER-phagy, and embryo quality during early porcine embryo development.