p27 Cell Cycle Inhibitor and Survival in Luminal-Type Breast Cancer: Gene Ontology, Machine Learning, and Drug Screening Analysis.

PURPOSE: A widely distributed cell cycle inhibitor, p27, regulates cyclin-dependent kinase-cyclin complexes. Although the prognostic value of p27 has been established for various types of carcinomas, its role in luminal breast cancer remains poorly understood. This study aimed to explore the functional enrichment of p27 and identify potential drug targets in patients with luminal-type breast cancer. METHODS: Clinicopathological data were collected from 868 patients with luminal-type breast cancer. Additionally, publicly available data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset (1,500 patients) and the Gene Expression Omnibus database (855 patients) were included in the analysis. Immunohistochemical staining for p27, differential gene expression analysis, disease ontology analysis, survival prediction modeling using machine learning (ML), and in vitro drug screening were also performed. RESULTS: Low p27 expression correlated with younger age, advanced tumor stage, estrogen receptor/progesterone receptor negativity, decreased cluster of differentiation 8+ T cell count, and poorer survival outcomes in luminal-type breast cancer. The METABRIC data revealed that reduced cyclin-dependent kinase inhibitor 1B (CDKN1B) expression (encoding p27) was associated with cell proliferation-related pathways and epigenetic polycomb repressive complex 2. Using ML, p27 emerged as the second most significant survival factor after N stage, thereby enhancing survival model performance. Additionally, luminal-type breast cancer cell lines with low CDKN1B expression demonstrated increased sensitivity to specific anticancer drugs such as voxtalisib and serdemetan, implying a potential therapeutic synergy between CDKN1B-targeted approaches and these drugs. CONCLUSION: The integration of ML and bioinformatic analyses of p27 has the potential to enhance risk stratification and facilitate personalized treatment strategies for patients with breast cancer.

Association between osteoporosis and the rate of telomere shortening.

A shorter leukocyte telomere length (LTL) is reported to be associated with age-related diseases, including osteoporosis. Many studies have tried identifying the association between LTL and osteoporosis, although it remains controversial. This study aimed to determine whether osteoporosis is independently associated with LTL shortening in a prospective longitudinal cohort. The KBASE study is an independent multicenter prospective cohort in South Korea, which began in 2014. We compared the LTL values for each participant at baseline and over a 2-year follow-up period. Boxplots were used to demonstrate the differences in the change in LTL over a 2-year follow-up according to osteoporosis. Multivariable linear regression was conducted to identify whether osteoporosis is independently associated with the rate of telomere shortening. A total of 233 subjects (from 55 to 88 years) from the KBASE cohort were finally enrolled in the study. We observed that the LTL decreased by approximately 1.2 kbp over 2 years. While the LTL decreased as age increased, the rate of LTL shortening did not increase with age. Multivariable linear regression analysis indicated that only osteoporosis was independently associated with rapid LTL shortening over 2 years (B, -8.08; p = 0.038). We sought to identify an association between osteoporosis and LTL shortening in an independent prospective cohort. We found that participants with osteoporosis had significantly faster LTL shortening over 2 years than those without osteoporosis. We hope this study will help elucidate the underlying mechanisms in the relationship between LTL and osteoporosis in the future.

Coil embolization of the middle cerebral artery bifurcation aneurysms: Feasibility and durability.

OBJECTIVE: To evaluate the feasibility and durability of coil embolization for MCAB aneurysms by analyzing clinical and radiological results. METHODS: From January of 2008 to June of 2018, we treated a total of 1785 aneurysms using coil embolization. The aneurysms were treated by both coiling and stent-assisted coiling. Among these cases, 223 MCAB aneurysms were analyzed retrospectively. Clinical and radiological assessments were conducted at admission, after treatment, at discharge, and at last clinical follow-up. RESULTS: Coil embolization was performed on 223 MCAB aneurysms in 217 patients. Peri-procedural ischemic, hemorrhagic, and other complications within 30 days after coil embolization occurred at rates of 8.0 %, 8.0 %, and 2.0 %, respectively, in the ruptured group and at 2.9 %, 1.2 %, and 0 %, respectively, in the unruptured group. The overall morbidity and mortality rates associated with complications were 2.3 % and 2.0 %. The cumulative major recurrence rates were 5.1 % at 12 months, 7.1 % at 18 months, and 11.9 % at three years after coil embolization. The mean follow-up period was 33.27 ± 25.48 months. Independent risk factors for major recurrence after coil embolization for MCAB aneurysms were a ruptured aneurysm, initial incomplete occlusion, the aneurysm size, and the neck size. CONCLUSION: Coil embolization is a good alternative treatment option for MCAB aneurysms compared to surgical clipping. Considering the risk factors for major recurrence, the follow-up angiography should continue up to three years after coil embolization.

Stroke recurrence and osteoporotic conditions in postmenopausal patients with atherosclerotic ischemic stroke.

Recurrence after stroke is common, and associated with a high mortality rate. Degradation of the elastic tissue in the arterial wall has been shown to aggravate atherosclerosis in blood vessels. Considering that type 1 collagen is present in both bone and vascular smooth muscle cells, we explored whether osteoporotic conditions affect the likelihood of stroke recurrence in postmenopausal women following atherosclerotic ischemic stroke. To determine actual bone mineral density (BMD), the Hounsfield unit values in the frontal skull were evaluated using brain computed tomography (CT) scans taken at admission. A multivariate Cox regression analysis was also performed to examine if osteoporosis could independently predict stroke recurrence in postmenopausal patients with large artery atherosclerosis (LAA) or small vessel occlusion (SVO) stroke. This study included 2130 consecutive patients (both males and females aged 50 and older) with acute LAA or SVO strokes. After adjusting for all covariates, hypothetical osteoporosis was identified as an independent predictor of stroke recurrence in female patients ≥50 years with acute LAA or SVO stroke (hazard ratio, 1.84; 95 % confidence interval, 1.05 to 3.24; p = 0.034). Our findings showed that osteoporosis could potentially affect the recurrence of ischemic stroke in postmenopausal patients with LAA or SVO stroke.

Identification of predictive factors for better outcomes in LINAC-based radiation treatment for cerebral cavernous malformation.

The effectiveness of radiation therapy in the treatment of cerebral cavernous malformations (CCM) remains debatable. However, numerous studies have shown a reduction in hemorrhage risk following radiotherapy for CCM. Therefore, herein, we share our experiences utilizing linear accelerator (LINAC)-based radiation for treating CCMs, with the aim of identifying the key factors influencing the therapeutic outcomes. We conducted a retrospective review of all patients with non-brainstem CCMs who underwent radiation treatment, as recorded in the NOVALIS registry at our institution. T2-weighted MR images were used for volumetric assessments using the iPlan radiotherapy planning software. To determine the independent predictors of nidus volume reduction and perilesional brain edema (PBE), we performed multivariate Cox regression analysis to calculate hazard ratios. Twenty patients with 31 non-brainstem CCMs were enrolled in this study. Analysis revealed age as an independent predictive factor for both nidus volume reduction and PBE after radiation treatment for CCM. Furthermore, a single fraction dose of 17 Gy or more was identified as an independent predictor of nidus volume decrease, while a single fraction dose of 18 Gy or more was found to be an independent risk factor for PBE in patients with CCM following LINAC-based radiation therapy. LINAC-based radiation therapy for non-brainstem CCMs with a single fraction radiation dose between 16.5 and 17.5 Gy, or a biologically equivalent dose of approximately 120 Gy, may be the most effective at reducing nidus volume and limiting side effects, particularly in patients under the age of 55 years. We further observed that the risk of PBE increased as the maximum radiation dose delivered to a 1 cc volume of the surrounding normal brain exceeded approximately 17.3 Gy. Therefore, we believe that calculating the D1cc of the normal brain may help to predict the occurrence of PBE when radiotherapy is administered to non-brainstem CCMs.

Significant Genes Associated with Mortality and Disease Progression in Grade II and III Glioma.

BACKGROUND: The Wnt/ß-catenin pathway plays a critical role in the tumorigenesis and maintenance of glioma stem cells. This study aimed to evaluate significant genes associated with the Wnt/ß-catenin pathway involved in mortality and disease progression in patients with grade II and III glioma, using the Cancer Genome Atlas (TCGA) database. METHODS: We obtained clinicopathological information and mRNA expression data from 515 patients with grade II and III gliomas from the TCGA database. We performed a multivariate Cox regression analysis to identify genes independently associated with glioma prognosis. RESULTS: The analysis of 34 genes involved in Wnt/ß-catenin signaling demonstrated that four genes (CER1, FRAT1, FSTL1, and RPSA) related to the Wnt/ß-catenin pathway were significantly associated with mortality and disease progression in patients with grade II and III glioma. We also identified additional genes related to the four significant genes of the Wnt/ß-catenin pathway mentioned above. The higher expression of BMP2, RPL18A, RPL19, and RPS12 is associated with better outcomes in patients with glioma. CONCLUSIONS: Using a large-scale open database, we identified significant genes related to the Wnt/ß-catenin signaling pathway associated with mortality and disease progression in patients with grade II and III gliomas.

GV1001 reduces neurodegeneration and prolongs lifespan in 3xTg-AD mouse model through anti-aging effects.

GV1001, which mimics the activity of human telomerase reverse transcriptase, protects neural cells from amyloid beta (Aß) toxicity and other stressors through extra-telomeric function, as noted in our prior in vitro studies. As per a recent phase II clinical trial, it improves cognitive function in patients with moderate to severe dementia. However, the underlying protective mechanisms remain unclear. This study aimed to investigate the effects of GV1001 on neurodegeneration, senescence, and survival in triple transgenic Alzheimer's disease (3xTg-AD) mice. GV1001 (1 mg/kg) was subcutaneously injected into old 3xTg-AD mice thrice a week until the endpoint for sacrifice, and survival was analysed. Magnetic resonance imaging (MRI) and Prussian blue staining (PBS) were performed to evaluate entry of GV1001 entrance into the brain. Diverse molecular studies were performed to investigate the effect of GV1001 on neurodegeneration and cellular senescence in AD model mice, with a particular focus on BACE, amyloid beta1-42 (Aß1-42), phosphorylated tau, volume of dentate gyrus, ß-galactosidase positive cells, telomere length, telomerase activity, and ageing-associated proteins. GV1001 crossed the blood-brain barrier, as confirmed by assessing the status of ferrocenecarboxylic acid-conjugated GV1001 using magnetic resonance imaging and PBS. GV1001 increased the survival of 3xTg-AD mice. It decreased BACE and Aß1-42 levels, neurodegeneration (i.e., reduced CA1, CA3 and dentate gyrus volume, decreased levels of senescence-associated ß-galactosidase positive cells, and increased telomere length and telomerase activity), and levels of ageing-associated proteins. We suggest that GV1001 exerts anti-ageing effects in 3xTg-AD mice by reducing neurodegeneration and senescence, which contributes to improved survival.

Changes in Disc Height as a Prognostic Factor in Patients Undergoing Microscopic Discectomy.

OBJECTIVE: Some patients with disc herniation who underwent discectomy complain of back pain after surgery and are unsatisfied with the surgical results. This study aimed to evaluate the relationship between preoperative disc height (DH), postoperative DH, and pain score 12 months after surgery in patients who underwent microdiscectomy for herniated lumbar disc. METHODS: This study enrolled patients who underwent microdiscectomy at a medical center between January 2012 and December 2020. Patients with X-ray or computed tomography and pain score assessment (visual analog scale score) prior to surgery, immediately post-op, and at 1, 6, and 12 months after surgery were included. The DH index was defined as DH/overlying vertebral width. The DH ratio was defined as the postoperative DH/preoperative DH. Simple linear regression and multivariate linear regression analyses were applied to assess the correlation between DHs and leg pain scores 12 months after surgery. RESULTS: A total of 118 patients who underwent microdiscectomy were included. DH decreased up to 12 months after surgery. The DH ratio at 1, 6, and 12 months after discectomy showed a significant positive correlation with the pain scores at 12 months after discectomy (1 month : p=0.045, B=0.52; 6 months : p=0.008, B=0.78; 12 months : p=0.005, B=0.69). Multivariate linear regression analysis revealed that the level of surgery, sex, age, and body mass index had no significant relationship with back pain scores after 12 months. CONCLUSION: In patients who underwent microdiscectomy, the DH ratios at 1, 6, and 12 months after surgery were prognostic factors for back pain scores at 12 months after surgery. Aggressive discectomy is recommended for lower postoperative DH ratios and Visual analog scale scores, leading to improved patient satisfaction.

GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer's disease mouse model.

GV1001 protects neural cells from amyloid-ß (Aß) toxicity and other stressors in in vitro studies and demonstrates clinically beneficial effects in patients with moderate to severe Alzheimer's disease (AD). Here, we investigated the protective effects and mechanism of action of GV1001 in triple transgenic AD (3xTg-AD) mice. We found that GV1001 improved memory and cognition in middle- and old-aged 3xTg-AD mice. Additionally, it reduced Aß oligomer and phospho-tau (Ser202 and Thr205) levels in the brain, and mitigated neuroinflammation by promoting a neuroprotective microglial and astrocyte phenotype while diminishing the neurotoxic ones. In vitro, GV1001 bound to gonadotropin releasing hormone receptors (GnRHRs) with high affinity. Levels of cyclic adenosine monophosphate, a direct downstream effector of activated GnRHRs, increased after GV1001 treatment. Furthermore, inhibition of GnRHRs blocked GV1001-induced effects. Thus, GV1001 might improve cognitive and memory functions of 3xTg-AD mice by suppressing neuroinflammation and reducing Aß oligomers levels and phospho-tau by activating GnRHRs and their downstream signaling pathways.

The genes significantly associated with an improved prognosis and long-term survival of glioblastoma.

BACKGROUND AND PURPOSE: Glioblastoma multiforme (GBM) is the most devastating brain tumor with less than 5% of patients surviving 5 years following diagnosis. Many studies have focused on the genetics of GBM with the aim of improving the prognosis of GBM patients. We investigated specific genes whose expressions are significantly related to both the length of the overall survival and the progression-free survival in patients with GBM. METHODS: We obtained data for 12,042 gene mRNA expressions in 525 GBM tissues from the Cancer Genome Atlas (TCGA) database. Among those genes, we identified independent genes significantly associated with the prognosis of GBM. Receiver operating characteristic (ROC) curve analysis was performed to determine the genes significant for predicting the long-term survival of patients with GBM. Bioinformatics analysis was also performed for the significant genes. RESULTS: We identified 33 independent genes whose expressions were significantly associated with the prognosis of 525 patients with GBM. Among them, the expressions of five genes were independently associated with an improved prognosis of GBM, and the expressions of 28 genes were independently related to a poorer prognosis of GBM. The expressions of the ADAM22, ATP5C1, RAC3, SHANK1, AEBP1, C1RL, CHL1, CHST2, EFEMP2, and PGCP genes were either positively or negatively related to the long-term survival of GBM patients. CONCLUSIONS: Using a large-scale and open database, we found genes significantly associated with both the prognosis and long-term survival of patients with GBM. We believe that our findings may contribute to improving the understanding of the mechanisms underlying GBM.

Risk Factors for Prevertebral Soft Tissue Swelling Following Single-Level Anterior Cervical Spine Surgery.

OBJECTIVE: Anterior cervical spine surgery (ACSS) is a common surgical procedure used to treat cervical spinal degenerative diseases. One of the complications associated with ACSS is prevertebral soft tissue swelling (PSTS), which can result in airway obstruction, dysphagia, and other adverse outcomes. This study aims to investigate the correlation between various cervical sagittal parameters and PSTS following single-level ACSS, as well as to identify independent risk factors for PSTS. METHODS: A retrospective study conducted at a single institution. The study population included all patients who underwent single-level ACSS between January 2014 and December 2022. Patients with a history of cervical spine surgery or trauma were excluded from the study. The presence and severity of PSTS was assessed by reviewing pre- and postoperative imaging studies. The potential risk factors for PSTS that were examined include patient age, sex, body mass index, tobacco use, comorbidities, serum albumin levels, operative time, implant type, implanted level, and various cervical spine sagittal parameters. Multivariate linear regression analysis was performed to identify the independent risk factors for PSTS. RESULTS: A total of 62 consecutive patients who underwent single-level ACSS over a 8-year period at a single institution were enrolled in this study. Only preoperative segmental angle showed positive correlation with PSTS among various cervical spine sagittal parameters (r=0.36, p=0.005). Artificial disc replacement showed a negative correlation with PSTS (ß=-0.38, p=0.002), whereas the use of demineralized bone matrix (DBM) had a positive impact on PSTS (ß=0.33, p=0.009). We found that male sex, lower preoperative serum albumin, and implantation of upper cervical level (above C5) were independent predictors for PSTS after single-level ACSS (ß=1.21; 95% confidence interval [CI], 0.27 to 2.15; p=0.012; ß=-1.63; 95% CI, -2.91 to -0.34; p=0.014; ß=1.44; 95% CI, 0.38 to 2.49; p=0.008, respectively). CONCLUSION: Our study identified male sex, lower preoperative serum albumin levels, and upper cervical level involvement as independent risk factors for PSTS after single-level ACSS. These findings can help clinicians monitor high-risk patients and take preventive measures to reduce complications. Further research with larger sample sizes and prospective designs is needed to validate these findings.

DKK3 expression is associated with immunosuppression and poor prognosis in glioblastoma, in contrast to lower-grade gliomas.

PURPOSE: We previously reported that expression of dickkopf-3 (DKK3), which is involved in the Wnt/ß-catenin pathway, is significantly associated with prognosis in patients with glioblastoma multiforme (GBM). The aim of this study was to compare the association of DKK3 with other Wnt/ß-catenin pathway-related genes and immune responses between lower grade glioma (LGG) and GBM. METHODS: We obtained the clinicopathological data of 515 patients with LGG (World Health Organization [WHO] grade II and III glioma) and 525 patients with GBM from the Cancer Genome Atlas (TCGA) database. We performed Pearson's correlation analysis to investigate the relationships between Wnt/ß-catenin-related gene expression in LGG and GBM. Linear regression analysis was performed to identify the association between DKK3 expression and immune cell fractions in all grade II to IV gliomas. RESULTS: A total of 1,040 patients with WHO grade II to IV gliomas were included in the study. As the grade of glioma increased, DKK3 showed a tendency to be more strongly positively correlated with the expression of other Wnt/ß-catenin pathway-related genes. DKK3 was not associated with immunosuppression in LGG but was associated with downregulation of immune responses in GBM. We hypothesized that the role of DKK3 in the Wnt/ß-catenin pathway might be different between LGG and GBM. CONCLUSION: According to our findings, DKK3 expression had a weak effect on LGG but a significant effect on immunosuppression and poor prognosis in GBM. Therefore, DKK3 expression seems to play different roles, through the Wnt/ß-catenin pathway, between LGG and GBM.

Predicting cognitive stage transition using p-tau181, Centiloid, and other measures.

BACKGROUND: A combination of plasma phospho-tau (p-tau), amyloid beta (Aß)-positron emission tomography (PET), brain magnetic resonance imaging, cognitive function tests, and other biomarkers might predict future cognitive decline. This study aimed to investigate the efficacy of combining these biomarkers in predicting future cognitive stage transitions within 3 years. METHODS: Among the participants in the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE-V) study, 49 mild cognitive impairment (MCI) and 113 cognitively unimpaired (CU) participants with Aß-PET and brain imaging data were analyzed. RESULTS: Older age, increased plasma p-tau181, Aß-PET positivity, and decreased semantic fluency were independently associated with cognitive stage transitions. Combining age, p-tau181, the Centiloid scale, semantic fluency, and hippocampal volume produced high predictive value in predicting future cognitive stage transition (area under the curve = 0.879). CONCLUSIONS: Plasma p-tau181 and Centiloid scale alone or in combination with other biomarkers, might predict future cognitive stage transition in non-dementia patients. HIGHLIGHTS: -Plasma p-tau181 and Centiloid scale might predict future cognitive stage transition. -Combining them or adding other biomarkers increased the predictive value. -Factors that independently associated with cognitive stage transition were demonstrated.

Relationship between telomere shortening and early subjective depressive symptoms and cognitive complaints in older adults.

Telomere length (TL) has been reported to be associated with depression and cognitive impairment in elderly. Early detection of depression and cognitive impairment is important to delay disease progression. Therefore, we aimed to identify whether TL is associated with early subjective depressive symptoms and cognitive complaints among healthy elderly subjects. This study was a multicenter, outcome assessor-blinded, 24-week, randomized controlled trial (RCT). Measurement of questionnaire and physical activity scores and blood sample analyses were performed at baseline and after six months of follow-up in all study participants. Linear regression analyses were performed to identify whether early subjective depressive symptoms, cognitive complaints, and several blood biomarkers are associated with TL. Altogether, 137 relatively healthy elderly individuals (60-79 years old) were enrolled in this prospective RCT. We observed an approximate decrease of 0.06 and 0.11-0.14 kbps of TL per one point increase in the geriatric depression scale and cognitive complaint interview scores, respectively, at baseline and after six months of follow-up. We also found an approximate decrease of 0.08-0.09 kbps of TL per one point increase in interleukin (IL)-6 levels at baseline and after six months of follow-up. Our study showed that both early subjective depressive symptoms and cognitive complaints were associated with a relatively shorter TL in relatively healthy elderly individuals. In addition, based on our findings, we believe that IL-6 plays an important role in the relationship between shortening TL and early subjective depressive symptoms and cognitive complaints.

Identification of genes from ten oncogenic pathways associated with mortality and disease progression in glioblastoma.

Glioblastoma multiforme (GBM) is the most malignant brain tumor with an extremely poor prognosis. The Cancer Genome Atlas (TCGA) database has been used to confirm the roles played by 10 canonical oncogenic signaling pathways in various cancers. The purpose of this study was to evaluate the expression of genes in these 10 canonical oncogenic signaling pathways, which are significantly related to mortality and disease progression in GBM patients. Clinicopathological information and mRNA expression data of 525 patients with GBM were obtained from TCGA database. Gene sets related to the 10 oncogenic signaling pathways were investigated via Gene Set Enrichment Analysis. Multivariate Cox regression analysis was performed for all the genes significantly associated with mortality and disease progression for each oncogenic signaling pathway in GBM patients. We found 12 independent genes from the 10 oncogenic signaling pathways that were significantly related to mortality and disease progression in GBM patients. Considering the roles of these 12 significant genes in cancer, we suggest possible mechanisms affecting the prognosis of GBM. We also observed that the expression of 6 of the genes significantly associated with a poor prognosis of GBM, showed negative correlations with CD8+ T-cells in GBM tissue. Using a large-scale open database, we identified 12 genes belonging to 10 well-known oncogenic canonical pathways, which were significantly associated with mortality and disease progression in patients with GBM. We believe that our findings will contribute to a better understanding of the mechanisms underlying the pathophysiology of GBM in the future.

High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach.

BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive malignant primary brain tumor. Wnt/ß-catenin is known to be related to GBM stemness. Cancer stem cells induce immunosuppressive and treatment resistance in GBM. We hypothesized that Wnt/ß-catenin-related genes with immunosuppression could be related to the prognosis in patients with GBM. METHODS: We obtained the clinicopathological data of 525 patients with GBM from the brain cancer gene database. The fraction of tumor-infiltrating immune cells was evaluated using in silico flow cytometry. Among gene sets of Wnt/ß-catenin pathway, Dickkopf-3 (DKK3) gene related to the immunosuppressive response was found using machine learning. We performed gene set enrichment analysis (GSEA), network-based analysis, survival analysis and in vitro drug screening assays based on Dickkopf-3 (DKK3) expression. RESULTS: In analyses of 31 genes related to Wnt/ß-catenin signaling, high DKK3 expression was negatively correlated with increased antitumoral immunity, especially CD8 + and CD4 + T cells, in patients with GBM. High DKK3 expression was correlated with poor survival and disease progression in patients with GBM. In pathway-based network analysis, DKK3 was directly linked to the THY1 gene, a tumor suppressor gene. Through in vitro drug screening, we identified navitoclax as an agent with potent activity against GBM cell lines with high DKK3 expression. CONCLUSIONS: These results suggest that high DKK3 expression could be a therapeutic target in GBM. The results of the present study could contribute to the design of future experimental research and drug development programs for GBM.

Efficacy of Cytokine-Induced Killer Cell Immunotherapy for Patients With Pathologically Pure Glioblastoma.

The most common malignant central nervous system tumor is glioblastoma multiforme (GBM). Cytokine-induced killer (CIK) cell therapy is a promising type of adoptive cell immunotherapy for various cancers. We previously conducted a randomized clinical trial on CIK cell therapy in patients with GBM. The aim of this study was to evaluate the efficacy of CIK immunotherapy for patients with pathologically pure GBM, using data from our previous randomized clinical trial. The difference between overall survival (OS) and progression-free survival (PFS) according to CIK immunotherapy was analyzed using the Kaplan-Meier method. Hazard ratios were calculated using univariate and multivariate Cox regression analyses to determine whether CIK cell immunotherapy was independently associated with higher OS and PFS in patients with pure GBM. A total of 156 eligible patients were included in the modified intention-to-treat (mITT) population. We confirmed that 125 (80.1%) GBM samples were pure GBM tumors without the presence of other types of tumors. For patients with pure GBM, Kaplan-Meier analysis showed no significant difference in OS between the CIK cell treatment and control groups. However, multivariate Cox regression demonstrated CIK cell immunotherapy as an independent predictor of greater OS (hazard ratio, 0.59; 95% CI, 0.36-0.97; p = 0.038) and PFS (hazard ratio, 0.55; 95% CI, 0.36-0.84; p = 0.001) in patients with pathologically pure GBM in the mITT population. This study showed that CIK cell immunotherapy combined with conventional temozolomide chemoradiotherapy could prolong OS and PFS in patients with newly diagnosed pathologically pure GBM, with no significant adverse events related to treatment. However, unlike the results of multivariate Cox analysis, no statistical significance of CIK cell immunotherapy in OS in Kaplan-Meier analysis raises a question. Further studies are required to validate these results.

Association between sleep parameters and longitudinal shortening of telomere length.

BACKGROUND: The relationship between sleep parameters and longitudinal shortening of telomere length is unclear. This study aimed to investigate the relationship between sleep parameters and the shortening of leukocyte telomere length (LTL) over a year. METHODS: Among the participants in the validation cohort of the Korea Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease, participants who measured both baseline and follow-up (two years later) of LTL were analyzed. They were dichotomized according to the degree of LTL attrition over two years. Clinical characteristics were compared between the faster and slower LTL shortening groups (cut-off points: -0.710 kbp, n = 119 each). Multivariable logistic regression analyses were performed to determine independent relationships between faster shortening of LTL length and sleep parameters. RESULTS: A total of 238 participants, aged 55-88 years, were included. Participants with faster LTL shortening had a shorter duration of sleep (P = 0.013) and longer sleep latency (P = 0.007). Among the components of the PSQI, subjective measures of sleep quality, sleep latency, sleep duration, and sleep efficiency were significantly worse in participants with faster LTL shortening. Multivariate logistic regression analysis showed that sleep duration (per hour, OR = 0.831, 95% CI = 0.698-0.989), sleep latency (per minute, OR = 1.013, 95% CI = 1.002-1.024), global PSQI score (OR = 1.134, 95% CI = 1.040-1.236), shortest sleep duration (OR = 5.173, 95% CI = 1.563-17.126), and lowest sleep efficiency (OR = 7.351, 95% CI = 1.943-27.946) were independently associated with faster LTL shortening. CONCLUSIONS: Poor sleep quality, specifically short sleep duration, long sleep latency, and low sleep efficiency were associated with faster longitudinal shortening of LTL.

Current Immunotherapeutic Approaches for Malignant Gliomas.

Glioblastoma is the most common malignant central nervous system (CNS) tumor (48.3%), with a median survival of only about 14.6 months. Although the CNS is an immune-privileged site, activated T cells can cross the blood-brain barrier. The recent successes of several immunotherapies for various cancers have drawn interest in immunotherapy for treatment of malignant glioma. There have been extensive attempts to evaluate the efficiency of immunotherapy against malignant glioma. Passive immunotherapy for malignant glioma includes monoclonal antibody-mediated immunotherapy, cytokine-mediated therapy, and adoptive cell transfer, also known as chimeric antigen receptor T cell treatment. On the other hand, active immunotherapy, which stimulates the patient's adaptive immune system against specific tumor-associated antigens, includes cancer vaccines that are divided into peptide vaccines and cell-based vaccines. In addition, there is immune checkpoint blockade therapy, which increases the efficiency of immunotherapy by reducing the resistance of malignant glioma to immunotherapy. Despite centuries of efforts, immunotherapeutic successes for malignant glioma remain limited. However, many clinical trials of adoptive cell transfer immunotherapy on malignant glioma are ongoing, and the outcomes are eagerly awaited. In addition, although there are still several obstacles, current clinical trials using personalized neoantigen-based dendritic cell vaccines offer new hope to glioblastoma patients. Furthermore, immune checkpoint targeted therapy is expected to decipher the mechanism of immunotherapy resistance in malignant glioma in the near future. More studies are needed to increase the efficacy of immunotherapy in malignant glioma. We hope that immunotherapy will become a new treatment of malignant glioma.

Effect of osteoporotic conditions on the development of peritumoral brain edema after LINAC-based radiation treatment in patients with intracranial meningioma.

PURPOSE: Disruption of the tumor-brain barrier in meningioma is a crucial factor in peritumoral brain edema (PTBE). We previously reported the possible effect of osteoporosis on the integrity of the arachnoid trabeculae because both the bone and the arachnoid trabeculae are composed of type 1 collagen. We hypothesized that osteoporotic conditions may be associated with PTBE occurrence after radiation treatment in patients with meningioma. METHODS: A receiver operating characteristic curve analysis was used to identify the optimal cut-off values of mean skull Hounsfield unit for predicting osteopenia and osteoporosis in patients from our registry. Multivariate Cox regression analysis was used to determine whether possible osteoporosis independently predicted PTBE development in patients with meningioma after radiation. RESULTS: A total of 106 intracranial meningiomas were included for the study. All patients received linear accelerator-based radiation therapy in our hospital over an approximate 6-year period. Multivariate Cox regression analysis identified that hypothetical osteoporosis was an independent predictive factor for the development of PTBE in patients with meningioma after linear accelerator-based radiation treatment (hazard ratio 5.20; 95% confidence interval 1.11-24.46; p = 0.037). CONCLUSIONS: Our study suggests that possible osteoporotic conditions may affect PTBE development after linear accelerator-based radiation treatment for intracranial meningioma. However, due to the study's small number of patients, these findings need to be validated in future studies with larger cohorts, before firm recommendations can be made.