Improving medical students recognizing surgery of glioblastoma removal/decompressive craniectomy via physical lifelike brain simulator training.

BACKGROUND: This study aims to investigate the benefits of employing a Physical Lifelike Brain (PLB) simulator for training medical students in performing craniotomy for glioblastoma removal and decompressive craniectomy. METHODS: This prospective study included 30 medical clerks (fifth and sixth years in medical school) at a medical university. Before participating in the innovative lesson, all students had completed a standard gross anatomy course as part of their curriculum. The innovative lesson involved PLB Simulator training, after which participants completed the Learning Satisfaction/Confidence Perception Questionnaire and some received qualitative interviews. RESULTS: The average score of students' overall satisfaction with the innovative lesson was 4.71 out of a maximum of 5 (SD = 0.34). After the lesson, students' confidence perception level improved significantly (t = 9.38, p < 0.001, effect size = 1.48), and the average score improved from 2,15 (SD = 1.02) to 3.59 (SD = 0.93). 60% of the students thought that the innovative lesson extremely helped them understand the knowledge of surgical neuroanatomy more, 70% believed it extremely helped them improve their skills in burr hole, and 63% thought it was extremely helpful in improving the patient complications of craniotomy with the removal of glioblastoma and decompressive craniectomy after completing the gross anatomy course. CONCLUSION: This innovative lesson with the PLB simulator successfully improved students' craniotomy knowledge and skills.

PCTAIRE Protein Kinase 1 (PCTK1) Suppresses Proliferation, Stemness, and Chemoresistance in Colorectal Cancer through the BMPR1B-Smad1/5/8 Signaling Pathway.

Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer-related mortality worldwide. Even with advances in therapy, CRC mortality remains high. Therefore, there is an urgent need to develop effective therapeutics for CRC. PCTAIRE protein kinase 1 (PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family, and the function of PCTK1 in CRC is poorly understood. In this study, we found that patients with elevated PCTK1 levels had a better overall survival rate in CRC based on the TCGA dataset. Functional analysis also showed that PCTK1 suppressed cancer stemness and cell proliferation by using PCTK1 knockdown (PCTK1-KD) or knockout (PCTK1-KO) and PCTK1 overexpression (PCTK1-over) CRC cell lines. Furthermore, overexpression of PCTK1 decreased xenograft tumor growth and knockout of PCTK1 significantly increased in vivo tumor growth. Moreover, knockout of PCTK1 was observed to increase the resistance of CRC cells to both irinotecan (CPT-11) alone and in combination with 5-fluorouracil (5-FU). Additionally, the fold change of the anti-apoptotic molecules (Bcl-2 and Bcl-xL) and the proapoptotic molecules (Bax, c-PARP, p53, and c-caspase3) was reflected in the chemoresistance of PCTK1-KO CRC cells. PCTK1 signaling in the regulation of cancer progression and chemoresponse was analyzed using RNA sequencing and gene set enrichment analysis (GSEA). Furthermore, PCTK1 and Bone Morphogenetic Protein Receptor Type 1B (BMPR1B) in CRC tumors were negatively correlated in CRC patients from the Timer2.0 and cBioPortal database. We also found that BMPR1B was negatively correlated with PCTK1 in CRC cells, and BMPR1B expression was upregulated in PCTK1-KO cells and xenograft tumor tissues. Finally, BMPR1B-KD partially reversed cell proliferation, cancer stemness, and chemoresistance in PCTK1-KO cells. Moreover, the nuclear translocation of Smad1/5/8, a downstream molecule of BMPR1B, was increased in PCTK1-KO cells. Pharmacological inhibition of Smad1/5/8 also suppressed the malignant progression of CRC. Taken together, our results indicated that PCTK1 suppresses proliferation and cancer stemness and increases the chemoresponse of CRC through the BMPR1B-Smad1/5/8 signaling pathway.

Human α-defensin 6 (HD6) suppresses CRC proliferation and metastasis through abolished EGF/EGFR signaling pathway.

The incidence of colorectal cancer (CRC) has increased significantly in the past decade. Early diagnosis and new therapeutics are still urgently needed for CRC in clinical practice. Human α-defensin 6 (HD6) plays a defense role against microbes in the gastrointestinal tract. However, the role and mechanism of HD6 in CRC is still unresolved. Specimens from CRC patients with higher HD6 showed better outcomes. Overexpressed HD6 in CRC cells caused a reduction of cell proliferative, migratory, and invasive ability in vitro and in vivo. HD6-overexpressed caused S phase arrest through changes in cyclin-A and B and CDK2 levels. In addition, serpine-1 may be negatively regulated by HD6 altering the translocation of c-Jun N-terminal kinases (JNK), extracellular regulated protein kinases (ERK), and p38. Higher HD6 and lower serpine-1 levels in CRC patients reflected better outcomes. Finally, we found that HD6 interacts directly with epidermal growth factor receptor (EGFR) by co-immunoprecipitated assay. EGF treatment caused an increase of the level of serpine-1 and pEGFR levels and then increased growth activity in HD6 overexpressing cells. Together, our study shows that HD6 may compete with EGF to bind to EGFR and interrupt cancer progression in CRC. We believe these findings may give new insights for HD6 in CRC therapy.

Effect of the simulated half leaf width of a multileaf collimator on volumetric modulated arc therapy plan quality in hippocampal avoidance whole-brain radiotherapy.

PURPOSE: Whole-brain radiotherapy (WBRT) is commonly used in patients with multiple brain metastases. Compared with conventional WBRT, hippocampal avoidance WBRT (HA-WBRT) more favorably preserves cognitive function and the quality of life. The hippocampal volume is considerably small (approximately 3.3 cm3 ). Therefore, downsizing the leaf width of a multileaf collimator (MLC) may provide higher spatial resolution and better plan quality. Volumetric modulated arc therapy (VMAT) could simulate the half MLC leaf width through couch shifting between arcs. This study investigated changes in VMAT quality for HA-WBRT with a simulated fine MLC leaf width. METHODS: We included 18 patients with brain metastasis. All target and avoidance structures were contoured by an experienced radiation oncologist. The prescribed dose was 30 Gy in 10 fractions. For each patient, three different treatment plans were generated for comparison: VMAT with couch-shift, VMAT without couch-shift, and TomoTherapy. All treatment plans fulfilled Radiation Therapy Oncology Group (RTOG) 0933 criteria for HA-WBRT. The Wilcoxon paired signed-rank test was used to compare different treatment plans. RESULTS: VMAT with couch-shift had the better average conformity index (0.823) with statistically significant difference compared to VMAT without couch-shift (0.810). VMAT with couch-shift (0.219) had a more favorable average homogeneity index (HI) than did VMAT without couch-shift (0.230), although the difference was not significant. TomoTherapy had an optimal average HI of 0.070. In terms of the hippocampus, all three treatment plans met the RTOG 0933 criteria. VMAT with couch-shift had a lower average Dmax (15.2 Gy) than did VMAT without couch-shift (15.3 Gy, p = 0.071) and TomoTherapy (15.5 Gy, p = 0.133). The average D100% of hippocampus was the same for both VMAT with and without couch-shift (8.5 Gy); however, TomoTherapy had a lower average D100% value of 7.9 Gy. The treatment delivery time was similar between VMAT with and without couch-shift (average, 375.0 and 369.6 s, respectively). TomoTherapy required a long average delivery time of 1489.9 s. CONCLUSION: The plan quality of VMAT for HA-WBRT was improved by using the couch-shift technique to simulate the half MLC leaf width. However, the improvement was not statistically significant except conformity index. The downsizing effect decreased with the use of the sophisticated grade of VMAT. TomoTherapy offered superior plan quality but required the longest delivery time.

Variations in dosimetric distribution and plan complexity with collimator angles in hypofractionated volumetric arc radiotherapy for treating prostate cancer.

PURPOSE: Hypofractionated radiotherapy can reduce treatment durations and produce effects identical to those of conventionally fractionated radiotherapy for treating prostate cancer. Volumetric arc radiotherapy (VMAT) can decrease the treatment machine monitor units (MUs). Previous studies have shown that VMAT with multileaf collimator (MLC) rotation exhibits better target dose distribution. Thus, VMAT with MLC rotation warrants further investigation. METHODS AND MATERIALS: Ten patients with prostate cancer were included in this study. The prostate gland and seminal vesicle received 68.75 and 55 Gy, respectively, in 25 fractions. A dual-arc VMAT plan with a collimator angle of 0° was generated and the same constraints were used to reoptimize VMAT plans with different collimator angles. The conformity index (CI), homogeneity index (HI), gradient index (GI), normalized dose contrast (NDC), MU, and modulation complexity score (MCSV ) of the target were analyzed. The dose-volume histogram of the adjacent organs was analyzed. A Wilcoxon signed-rank test was used to compare different collimator angles. RESULTS: Optimum values of CI, HI, and MCSV were obtained with a collimator angle of 45°. The optimum values of GI, and NDC were observed with a collimator angle of 0°. In the rectum, the highest values of maximum dose and volume receiving 60 Gy (V60 Gy ) were obtained with a collimator angle of 0°, and the lowest value of mean dose (Dmean ) was obtained with a collimator angle of 45°. In the bladder, high values of Dmean were obtained with collimator angles of 75° and 90°. In the rectum and bladder, the values of V60 Gy obtained with the other tested angles were not significantly higher than those obtained with an angle of 0°. CONCLUSION: This study found that MLC rotation affects VMAT plan complexity and dosimetric distribution. A collimator angle of 45° exhibited the optimal values of CI, HI, and MCSv among all the tested collimator angles. Late side effects of the rectum and bladder are associated with high-dose volumes by previous studies. MLC rotation did not have statistically significantly higher values of V60 Gy in the rectum and bladder than did the 0° angle. We thought a collimator angle of 45° was an optimal angle for the prostate VMAT treatment plan. The findings can serve as a guide for collimator angle selection in prostate hypofractionated VMAT planning.

Predictive Value of the Interaction between CEA and Hemoglobin in Neoadjuvant CCRT Outcomes in Rectal Cancer Patients.

The adoption of neoadjuvant concurrent chemoradiotherapy (CCRT) has reshaped the therapeutic landscape, but response prediction remains challenging. This study investigates the interaction between pre-CCRT carcinoembryonic antigen (CEA) and post-CCRT hemoglobin (Hb) levels in predicting the response of locally advanced rectal cancer (LARC) to CCRT. Retrospective data from 93 rectal cancer patients receiving neoadjuvant CCRT were analyzed. Univariate analyses assessed clinical factors associated with tumor regression grade (TRG) and T-stage outcomes. Machine learning identified predictive biomarkers. Interaction effects between CEA and Hb were explored through subgroup analyses. Post-CCRT Hb varied between pre-CCRT CEA groups. The interaction between pre-CCRT CEA and post-CCRT Hb influenced TRG. Males with normal pre-CCRT CEA and anemia showed better treatment responses. Females with elevated pre-CCRT CEA and post-CCRT anemia exhibited poorer responses. The interaction effect between them was significant, indicating that their relationship with TRG was not additive. Inflammatory biomarkers, WBC, neutrophil count, and post-CCRT platelet level correlated with CCRT response. Contrasting with previous findings, anemia was a predictor of better treatment response in males with normal pre-CCRT CEA. The interaction between pre-CCRT CEA and post-CCRT Hb levels predicts the response of LARC to CCRT. CEA, Hb, and sex should be considered when assessing treatment response. Inflammatory biomarkers contribute to response prediction. Understanding these complex relationships can enhance personalized treatment approaches in rectal cancer patients.

Advanced Manufacturing in the Fabrication of a Lifelike Brain Glioblastoma Simulator for the Training of Neurosurgeons.

Neurosurgeons require considerable expertise and practical experience to deal with the critical situations commonly encountered in complex surgical operations such as cerebral cancer; however, trainees in neurosurgery seldom have the opportunity to develop these skills in the operating room. Physical simulators can give trainees the experience they require. In this study, we adopted advanced molding and replication techniques in the fabrication of a physical simulator for use in practicing the removal of cerebral tumors. Our combination of additive manufacturing and molding technology with elastic material casting made it possible to create a simulator that realistically mimics the skull, brain stem, soft brain lobes, and cerebral cancer with cerebral tumors located precisely where they are likely to appear. Multiple and systematic experiments were conducted to prove that the elastic material used herein was appropriated for building professional medical physical simulator. One neurosurgical trainee reported that under the guidance of a senior neurosurgeon, the physical simulator helped to elucidate the overall process of cerebral cancer removal and provided a realistic impression of the tactile feelings involved in craniotomy. The trainee also learned how to make decisions when facing the infiltration of a cerebral tumor into normal brain lobes. Our results demonstrate the efficacy of the proposed physical simulator in preparing trainees for the rigors involved in performing highly delicate surgical operations.

To Optimize Radiotherapeutic Plans for Superior Tumor Coverage Predicts Malignant Glioma Prognosis and Normal Tissue Complication Probability.

Background: Radiotherapy (RT) provides a modern treatment to enhance the malignant glioma control rate. The purpose of our study was to determine the effect of tumor coverage on disease prognosis and to predict optimal RT plans to achieve a lower normal tissue complication probability (NTCP). Methods: Ten malignant-glioma patients with tumors adjacent to organs at risk (OARs) were collected. The patients were divided into two groups according to adequate coverage or not, and prognosis was analyzed. Then, using intensity-modulated radiation therapy (IMRT), volume-modulated arc therapy (VMAT), and helical tomotherapy (TOMO) to simulate new treatment plans for 10 patients, the advantages of these planning systems were revealed for subsequent prediction of NTCP. Results: The results of clinical analysis indicated that overall survival (p = 0.078) between the adequate and inadequate groups showed no differences, while the adequate group had better recurrence-free survival (p = 0.018) and progression-free survival (p = 0.009). TOMO had better CI (p < 0.001) and also predicted a lower total-irradiated dose to the normal brain (p = 0.001) and a lower NTCP (p = 0.027). Conclusions: The TOMO system provided optimal therapeutic planning, reducing NTCP and achieving better coverage. Combined with the clinical results, our findings suggest that TOMO can make malignant glioma patients close to OARs achieve better disease control.

Genome-Wide Association Study Identifies Multiple Susceptibility Loci for Malignant Neoplasms of the Brain in Taiwan.

Primary brain malignancy is a rare tumor with a global incidence of less than 10 per 100,000 people. Hence, there is limited power for identifying risk loci in individual studies, especially for Han Chinese. We performed a genome-wide association study (GWAS) in Taiwan, including 195 cases and 195 controls. We identified five new genes for malignant neoplasms of the brain: EDARADD (rs645507, 1p31.3, p = 7.71 × 10-5, odds ratio (OR) = 1.893), RBFOX1 (rs8044700, p = 2.35 × 10-5, OR = 2.36), LMF1 (rs3751667, p = 7.24 × 10-7, OR = 2.17), DPP6 (rs67433368, p = 8.32 × 10-5, OR = 3.94), and NDUFB9 (rs7827791, p = 9.73 × 10-6, OR = 4.42). These data support that genetic susceptibility toward GBM or non-GBM tumors is highly distinct, likely reflecting different etiologies. Combined with signaling analysis, we found that RNA modification may be related to major risk factors in primary malignant neoplasms of the brain.

Risk factors of postoperative hydrocephalus following decompressive craniectomy for spontaneous intracranial hemorrhages and intraventricular hemorrhage.

INTRODUCTION: Hydrocephalus is a complication of spontaneous intracerebral hemorrhage; however, its predictive relationship with hydrocephalus in this patient cohort is not understood. Here, we evaluated the incidence and risk factors of hydrocephalus after craniectomy. METHODS: Retrospectively studied data from 39 patients in the same hospital from 2016/01 to 2020/12 and analyzed risk factors for hydrocephalus. The clinical data recorded included patient age, sex, timing of surgery, initial Glasgow Coma Scale score, intracerebral hemorrhage (ICH) score, alcohol consumption, cigarette smoking, medical comorbidity, and blood data. Predictors of patient outcomes were determined using Student t test, chi-square test, and logistic regression. RESULTS: We recruited 39 patients with cerebral herniation who underwent craniectomy for spontaneous supratentorial hemorrhage. Persistent hydrocephalus was observed in 17 patients. The development of hydrocephalus was significantly associated with the timing of operation, cigarette smoking, and alcohol consumption according to the Student t test and chi-square test. Univariate and multivariate analyses suggested that postoperative hydrocephalus was significantly associated with the timing of surgery (P = .031) and cigarette smoking (P = .041). DISCUSSION: The incidence of hydrocephalus in patients who underwent delayed operation (more than 4 hours) was lower than that in patients who underwent an operation after less than 4 hours. nonsmoking groups also have lower incidence of hydrocephalus. Among patients who suffered from spontaneous supratentorial hemorrhage and need to receive emergent craniectomy, physicians should be reminded that postoperative hydrocephalus followed by ventriculoperitoneal shunting may be necessary in the future.

Impact of respiratory motion in dosimetric and clinical advantages for adjuvant left-sided breast radiotherapy.

We investigated the organ-sparing effect of the deep inspiration breath hold (DIBH) technique among different levels of lung expansion for left-side breast radiotherapy. This retrospective study enrolled 30 patients who received adjuvant left breast radiotherapy after breast-conserving surgery (BCS). Simulation scans of both DIBH and deep breathing four-dimensional computed tomography (4DCT) were acquired, and three treatment plans were generated for each patient. One plan was based on the DIBH images, and the other two plans were based on the mid-lung expansion (ME) and initial lung expansion (IE) phases retrieved from 4DCT data sets. Dosimetric comparisons and normal tissue complication probability (NTCP) models were conducted. We used image registration for displacement analysis and sought potential factors related to the dose benefit of DIBH. The DIBH plans resulted significantly lower doses to the heart, left ventricle (LV) and left anterior descending coronary artery (LAD), including the high- to low-dose areas, followed by the ME plans and IE plans (p < 0.05). DIBH reduced the risk of long-term cardiac mortality by 40% and radiation pneumonitis of the left lung by 37.96% compared with the IE plans (p < 0.001). The reduction in the mean dose to the heart and LV significantly correlated with anterior displacement of the left lung. The DIBH technique is a feasible tool to provide dosimetric and clinical advantages for adjuvant left-sided breast radiotherapy. Breathing pattern and the level of lung expansion seem to play an important role.

miR-671-5p Inhibition by MSI1 Promotes Glioblastoma Tumorigenesis via Radioresistance, Tumor Motility and Cancer Stem-like Cell Properties.

MicroRNAs (miRNAs) could be potential biomarkers for glioblastoma multiforme (GBM) prognosis and response to therapeutic agents. We previously demonstrated that the cancer stem cell marker Musashi-1 (MSI1) is an RNA binding protein that promotes radioresistance by increasing downstream RNA stability. To identify that MSI1 interacts with miRNAs and attenuates their function, we also get candidate miRNAs from the mRNA seq by predicting with TargetScan software. miR-671-5p in GBM cells interacts with MSI1 by intersecting the precipitated miRNAs with the predicted miRNAs. Notably, overexpression of MSI1 reversed the inhibitory effect of miR-671-5p. The phenotype of miR-671-5p in GBM cells could affect radiosensitivity by modulating the posttranscriptional activity of STAT3. In addition, miR-671-5p could attenuate tumor migration and cancer stem cell (CSC) characteristics by repressing the posttranscriptional activity of TRAF2. MSI1 may regulate GBM radioresistance, CSCs and tumor motility through miR-671-5p inhibition to increasing STAT3 and TRAF2 presentation. In vivo, the GBM tumor size was inversely correlated with miR-671-5p expression, but tumorigenesis was promoted by STAT3 and TRAF2 activation in the miR-671-5p-positive GBM population. miR-671-5p could be activated as a novel therapeutic target for GBM and has potential application as a predictive biomarker of glioblastoma prognosis.

4-Acetylantrocamol LT3 Inhibits Glioblastoma Cell Growth and Downregulates DNA Repair Enzyme O6-Methylguanine-DNA Methyltransferase.

Glioblastoma multiforme (GBM) is a deadly malignant brain tumor that is resistant to most clinical treatments. Novel therapeutic agents that are effective against GBM are required. Antrodia cinnamomea has shown antiproliferative effects in GBM cells. However, the exact mechanisms and bioactive components remain unclear. Thus, the present study aimed to investigate the effect and mechanism of 4-acetylantrocamol LT3 (4AALT3), a new ubiquinone from Antrodia cinnamomeamycelium, in vitro. U87 and U251 cell lines were treated with the indicated concentration of 4AALT3. Cell viability, cell colony-forming ability, migration, and the expression of proteins in well-known signaling pathways involved in the malignant properties of glioblastoma were then analyzed by CCK-8, colony formation, wound healing, and western blotting assays, respectively. We found that 4AALT3 significantly decreased cell viability, colony formation, and cell migration in both in vitro models. The epidermal growth factor receptor (EGFR), phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), Hippo/yes-associated protein (YAP), and cAMP-response element binding protein (CREB) pathways were suppressed by 4AALT3. Moreover, 4AALT3 decreased the level of DNA repair enzyme O6-methylguanine-DNA methyltransferase and showed a synergistic effect with temozolomide. Our findings provide the basis for exploring the beneficial effect of 4AALT3 on GBM in vivo.

Engineering Additive Manufacturing and Molding Techniques to Create Lifelike Willis' Circle Simulators with Aneurysms for Training Neurosurgeons.

Neurosurgeons require considerable expertise and practical experience in dealing with the critical situations commonly encountered during difficult surgeries; however, neurosurgical trainees seldom have the opportunity to develop these skills in the operating room. Therefore, physical simulators are used to give trainees the experience they require. In this study, we created a physical simulator to assist in training neurosurgeons in aneurysm clipping and the handling of emergency situations during surgery. Our combination of additive manufacturing with molding technology, elastic material casting, and ultrasonication-assisted dissolution made it possible to create a simulator that realistically mimics the brain stem, soft brain lobes, cerebral arteries, and a hollow transparent Circle of Willis, in which the thickness of vascular walls can be controlled and aneurysms can be fabricated in locations where they are likely to appear. The proposed fabrication process also made it possible to limit the error in overall vascular wall thickness to just 2-5%, while achieving a Young's Modulus closely matching the characteristics of blood vessels (~5%). One neurosurgical trainee reported that the physical simulator helped to elucidate the overall process of aneurysm clipping and provided a realistic impression of the tactile feelings involved in this delicate operation. The trainee also experienced shock and dismay at the appearance of leakage, which could not immediately be arrested using the clip. Overall, these results demonstrate the efficacy of the proposed physical simulator in preparing trainees for the rigors involved in performing highly delicate neurological surgical operations.

Optimal tumor coverage with different beam energies by IMRT, VMAT and TOMO: Effects on patients with proximal gastric cancer.

To compare the effects of different photon energies on radiation planning by intensity-modulated radiotherapy (IMRT), volumetric-modulated arc therapy (VMAT) and helical tomotherapy (TOMO) for proximal gastric cancer (PGC). Network analysis with microarray procession and gene ontology were used to identify the effect of radiotherapy (RT) on PGC. Then, we retrospectively analyzed 8 PGC patients after receiving irradiation with a prescribed dose of 50.4 Gy. The Pinnacle treatment planning system (TPS, V9.8) was used to generate IMRT and VMAT plans by using 6 or 10 MV. TOMO plans were calculated on the Tomotherapy Planning Station Hi-Art Version 4.2.3 workstation (Tomotherapy Incorporated, Madison, WI, USA). PGC is associated with high DNA repair ability. TOMO plan results in higher tumor coverage and a better conformity index than IMRT and VMAT. 10-MV VMAT yields better dosimetric quality of the gradient index than 6-MV VMAT (P = .012). TOMO was associated with a lower irradiation dose in the mean dose to the right kidney (P = .049), left kidney and heart than 6-MV IMRT and 6-MV VMAT. 6-MV IMRT plan presented a higher dose of lung Dmean (P = .017) than 10-MV IMRT. Additionally, VMAT, using a planning energy of 6 MV, was associated with a significantly higher left kidney Dmean (P = .018) and V10 (P = .036) than a planning energy of 10 MV. TOMO is a better RT plan not only for tumor coverage but also for sparing organs at risk. IMRT and VMAT plans with 10 MV beams are more suitable than 6 MV beams for PGC treatment.

CD44-associated radioresistance of glioblastoma in irradiated brain areas with optimal tumor coverage.

Glioblastoma multiforme (GBM) requires radiotherapy (RT) as its definitive management. However, GBM still has a high local recurrence rate even after RT. Cancer stem-like cells (CSCs) might enable GBM to evade irradiation damage and cause therapeutic failure. The optimal RT plan should achieve a planning target volume (PTV) coverage of more than 95% but cannot always meet the requirements. Here, we demonstrate that irradiation with different tumor coverage rates to different brain areas has similar effects on GBM. To retrospectively analyze the relationship between PTV coverage and the survival rate in 26 malignant glioblastoma patients, we established primary cell lines from patient-derived malignant glioblastoma cells with the PTV95 (PTV coverage of more than 95%) program (GBM-MG1 cells) and the Non-PTV95 (poor PTV coverage of less than 95%) program (GBM-MG2 cells). The clinical results of PTV95 and Non-PTV95 showed no difference in the overall survival (OS) rate (P = .390) between the two different levels of PTV coverage. GBM-MG1 (PTV95 program) cells exhibited higher radioresistance than GBM-MG2 (Non-PTV95 program) cells. CD44 promotes radioresistance, CSC properties, angiogenesis and cell proliferation in GBM-MG1 (PTV95 program) cells. GBM patients receiving RT with the PTV95 program exhibited higher radioresistance, CSC properties, angiogenesis and cell proliferation than GBM patients receiving RT with the Non-PTV95 program. Moreover, CD44 plays a crucial role in these properties of GBM patients with the PTV95 program.

Musashi-1 Enhances Glioblastoma Migration by Promoting ICAM1 Translation.

Glioblastoma multiforme (GBM) is a lethal brain tumor with a mean survival time of 1 year. One major reason for therapeutic failure is that GBM cells have an extraordinary capacity to invade normal brain tissue beyond the surgical margin, accounting for the lack of treatment efficacy. GBM cells that can infiltrate into the healthy brain possess tumor properties of stemness and invasion, and previous studies demonstrate that Musashi-1 (MSI1), a neural stem cell marker, plays an important role in the maintenance of stem cell status, cellular differentiation, and tumorigenesis in cancers. By analyzing neuronal progenitor cell markers and stemness genes, we predicted that MSI1 might be an important factor in GBM pathogenesis. Because inflammation aids in the proliferation and survival of malignant cells, the inflammatory microenvironment also promotes GBM invasion, and intercellular adhesion molecule-1 (ICAM1), a member of the immunoglobulin superfamily, is involved in inflammation. Our results indicate that the above phenomena are likely due to MSI1 upregulation, which occurred simultaneously with higher expression of ICAM1 in GBM cells. Indeed, MSI1 knockdown effectively suppressed ICAM1 expression and blocked GBM cell motility and invasion, whereas overexpressing ICAM1 reversed these effects. According to RNA immunoprecipitation assays, MSI1-mediated mRNA interactions promote ICAM1 translation. Finally, immunohistochemical analysis showed MSI1 and ICAM-1 to be coexpressed at high levels in GBM tissues. Thus, the MSI1/ICAM1 pathway plays an important role in oncogenic resistance, including increased tumor invasion, and MSI1/ICAM1 may be a target for GBM treatment.

Severe intracranial and intraspinal subarachnoid hemorrhage after lumbar puncture: a rare case report.

The lumbar puncture is considered as a safe routine procedure in widespread clinical use for nearly a century. To the best of our knowledge, intracranial and intraspinal subarachnoid hemorrhage has never been reported as a complication after a lumbar puncture. We presented a case of a 76-year-old woman who fell in a deep coma after a lumbar puncture with diffuse subarachnoid hemorrhage and acute obstructive hydrocephalus on computed tomographic scans. Magnetic resonance imaging studies of the whole spine showed the hematoma spread along the spinal cord upward to the intracranial subarachnoid space. Remarkably, an extravasation of contrast medium presented at the level of L1 through L2, which was subsequently evaluated using the spinal angiography. There was an ongoing bleeding at the terminus of L1 lumbar segmental artery that lay within the spinal cord. Then a transarterial embolization followed and the hemorrhage stopped immediately. This case reminds us that although lumbar puncture is safe and simple, severe potential complication, such as intracranial and intraspinal subarachnoid hematoma, could occur.

MSI1 associates glioblastoma radioresistance via homologous recombination repair, tumor invasion and cancer stem-like cell properties.

INTRODUCTION: Glioblastoma multiforme (GBM) is the most common brain malignancy in adults, and currently available GBM treatments present several unique challenges. It is known that GBM involves cancer stem-like cells (CSCs) and tumor cells that aggressively invade normal brain tissues, and both cell types may cause resistance to radiotherapy (RT) and are thus responsible for therapeutic failure. The radioresistance of GBM cells relies on the efficient activation of the DNA damage response (DDR), but the mechanisms linking this response with stem-cell status and tumor invasion remain unclear. MATERIALS AND METHODS: We used irradiation to treat patient-derived GBM (Par) cells and then purified radioresistant GBM (R2M2) cells through two rounds of irradiation and an invasion assay. Musashi-1 (MSI1) is a neural stem-cell marker and key oncogenic factor of GBM. We identified MSI1 expression to predict radioresistance through silencing an MSI1-high-expressing R2M2 cell line or inducing overexpression in a Par cell line with low/no MSI1 expression and assessing the subsequent DDR. RESULT: MSI1 enhances tumor invasion via VCAM1 and modulates GBM radioresistance via the hyperactivation of the DDR through increasing homologous recombination repair and evading apoptosis. MSI1 knockdown induces DNA damage accumulation in irradiated GBM cells and promotes their depletion in vitro; MSI1 knockdown also inhibits the formation of GBMs generated by irradiated xeno-transplanted cells. MSI1 inhibition may radiosensitize tumors, prevent CSC-positive selection induced by RT, and reduce tumor invasion. CONCLUSION: MSI1 may involve in regulating GBM radioresistance, invasion, and recurrence and could be a novel target for GBM treatment.

The STAT3/Slug Axis Enhances Radiation-Induced Tumor Invasion and Cancer Stem-like Properties in Radioresistant Glioblastoma.

Glioblastoma multiforme (GBM) requires radiotherapy (RT) as a part of definitive management strategy. RT is highly effective, destroying cancer cells that may exist around the surgical tumor bed. However, GBM still has a poor prognosis and a high local recurrence rate after RT. Accumulating research indicates that GBM contains cancer stem-like cells (CSCs), which are radioresistant and result in therapeutic failure. Additionally, GBM cells can aggressively invade normal brain tissue, inducing therapeutic failure. Using clinical observations, we evaluated the effect of radiation on tumor control. We also explored the biomolecular pathways that connect radioresistance and CSC- and epithelial-mesenchymal transition (EMT)-associated phenotypes in patient-derived GBM cells. Transwell and microarray assay demonstrated that radioresistant GBM cells (GBM-R2I2) exhibit increased invasion and self-renewal abilities compared with parental GBM cells. Finally, to identify potential mechanisms underlying these observations, we used a PCR array to search for molecular markers of cell motility. Signal transducer and activator of transcription 3 (STAT3) directly bound to the Slug promoter in a chromatin immunoprecipitation assay. Reduced STAT3 decreased Slug expression and suppressed cell invasion in GBM-R2I2 cells while increasing Slug reversed these effects. In addition, STAT3 knockdown significantly inhibited CSC properties, synergistically increased the radiotherapeutic effect, and effectively increased the survival rate in vivo. We deciphered a new pathway of GBM radioresistance, invasion, and recurrence via the STAT3/Slug axis that could be a new target of GBM therapy.