Long-term outcomes of CNS WHO grade 2 oligodendroglioma in adult patients: a single-institution experience.

PURPOSE: Oligodendrogliomas (ODGs) are a subtype of diffuse lower-grade gliomas with overall survival of > 10 years. This study aims to analyze long-term outcomes and identify prognostic factors in patients with WHO grade 2 ODG. METHODS: We retrospectively reviewed 138 adult patients diagnosed with 1p/19q co-deleted ODG who underwent surgical resection or biopsy between 1994 and 2021, analyzing clinical data, treatment details, and outcomes. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were utilized to identify significant prognostic factors. RESULTS: In the gross total resection (GTR) group, 63 (45.7%) underwent observation and 5 (3.6%) received postoperative treatment; in the non-GTR group, 37 (26.8%) were observed and 33 (23.9%) received postoperative treatment. The median PFS and OS were 6.8 and 18.4 years, respectively. Between adjuvant treatment and observation, there was no significant difference in PFS or OS. However, GTR or STR with less than 10% residual tumor exhibited significantly better PFS and OS compared to PR or biopsy (p = 0.022 and 0.032, respectively). Multivariate analysis revealed that contrast enhancement on MRI was associated with worse PFS (HR = 2.36, p < 0.001) and OS (HR = 5.89, p = 0.001). And the presence of seizures at presentation was associated with improved OS (HR = 0.28, p = 0.006). CONCLUSION: This study underscores favorable long-term outcomes for patients with 1p/19q co-deleted ODG WHO grade 2. Our findings indicate that the EOR plays a crucial role as a significant prognostic factor in enhancing PFS and OS outcomes in WHO grade 2 ODG.

Surgical Strategy for Petroclival Meningioma-Related Trigeminal Neuralgia: The Role of Porus Trigeminus Opening.

OBJECTIVE: Petroclival meningiomas invade Meckel's cave through the porus trigeminus, leading to secondary trigeminal neuralgia. Microsurgery and stereotactic radiosurgery (SRS) are the typical treatment options. This study investigated symptom control, outcomes, and surgical strategies for PC meningioma-induced TN. METHODS: We retrospectively analyzed 28 TN patients with PC meningiomas who underwent microsurgical nerve decompression between January 2021 and February 2023. In all patients undergoing a transpetrosal approach, the porus trigeminus was opened to enable the removal of the entire tumor within Meckel's cave. Clinical outcomes were assessed using the Barrow Neurologic Institute (BNI) pain intensity scale. Risk factors for poor TN outcomes and poor facial numbness were analyzed. RESULTS: Among 28 patients, 21 (75%) underwent the transpetrosal approach, 5 (17.9%) underwent the retrosigmoid approach, and 2 (7.1%) underwent the Dolenc approach. Following microsurgery, 23 patients (82.1%) experienced TN relief without further medication (BNI I or II). TN recurrence occurred in 2 patients (7.1%), and 3 patients (10.7%) did not achieve TN relief. Cavernous sinus invasion was significantly correlated with poor TN outcomes (P = 0.047). A history of previous SRS (P = 0.011) and upper clivus type tumor (P = 0.018) were significantly associated with poor facial numbness. CONCLUSIONS: Microsurgical nerve decompression is effective in improving BNI scores in patients with TN associated with PC meningiomas. Considering the results of our study, the opening of the porus trigeminus can be considered as a suggested procedure in the treatment of PC meningiomas, especially in cases accompanied by TN.

Exploring prognostic factors and treatment strategies for long-term survival in pleomorphic xanthoastrocytoma patients.

Pleomorphic xanthoastrocytomas (PXA) are rare, accounting for < 1% of all astrocytomas. Literature on the clinical course and treatment outcomes of PXAs is limited. The study aimed to determine prognosis and treatment strategies for PXAs. Patients who had PXAs surgery between 2000-2021 were retrospectively analyzed for demographics and radiological characteristics. Initial and salvage treatment outcomes were recorded. Overall, 40 and 9 patients had grade 2 and 3 PXAs; their 5-year progression-free survival (PFS) rates were 75.8% and 37.0%, respectively (p = 0.003). Univariate analysis revealed that strong T1 enhancement (p = 0.036), infiltrative tumor margins (p < 0.001), peritumoral edema (p = 0.003), WHO grade (p = 0.005), and gross total resection (p = 0.005) affected the PFS. Multivariate analysis revealed that the WHO grade (p = 0.010) and infiltrative tumor margins (p = 0.008) influenced the PFS. The WHO grade (p = 0.027) and infiltrative tumor margins (p = 0.027) also affected the overall survival (OS). Subgroup analysis for grade 2 PXAs revealed no significant associations between adjuvant radiation therapy and the PFS and OS. This study highlighted the heterogeneous nature of PXAs and its impact on patient prognosis. Infiltrative tumor margins emerged as a key prognostic factor. Our findings have emphasized the prognostic relevance of radiological features and the need for larger studies on comprehensive management.

Generative AI in glioma: Ensuring diversity in training image phenotypes to improve diagnostic performance for IDH mutation prediction.

BACKGROUND: This study evaluated whether generative artificial intelligence (AI)-based augmentation (GAA) can provide diverse and realistic imaging phenotypes and improve deep learning-based classification of isocitrate dehydrogenase (IDH) type in glioma compared with neuroradiologists. METHODS: For model development, 565 patients (346 IDH-wildtype, 219 IDH-mutant) with paired contrast-enhanced T1 and FLAIR MRI scans were collected from tertiary hospitals and The Cancer Imaging Archive. Performance was tested on internal (119, 78 IDH-wildtype, 41 IDH-mutant [IDH1 and 2]) and external test sets (108, 72 IDH-wildtype, 36 IDH-mutant). GAA was developed using a score-based diffusion model and ResNet50 classifier. The optimal GAA was selected in comparison with the null model. Two neuroradiologists (R1, R2) assessed realism, diversity of imaging phenotypes, and predicted IDH mutation. The performance of a classifier trained with optimal GAA was compared with that of neuroradiologists using the area under the receiver operating characteristics curve (AUC). The effect of tumor size and contrast enhancement on GAA performance was tested. RESULTS: Generated images demonstrated realism (Turing's test: 47.5-50.5%) and diversity indicating IDH type. Optimal GAA was achieved with augmentation with 110 000 generated slices (AUC: 0.938). The classifier trained with optimal GAA demonstrated significantly higher AUC values than neuroradiologists in both the internal (R1, P = .003; R2, P < .001) and external test sets (R1, P < .01; R2, P < .001). GAA with large-sized tumors or predominant enhancement showed comparable performance to optimal GAA (internal test: AUC 0.956 and 0.922; external test: 0.810 and 0.749). CONCLUSIONS: The application of generative AI with realistic and diverse images provided better diagnostic performance than neuroradiologists for predicting IDH type in glioma.

Design of hypoxia responsive CRISPR-Cas9 for target gene regulation.

The CRISPR-Cas9 system is a widely used gene-editing tool, offering unprecedented opportunities for treating various diseases. Controlling Cas9/dCas9 activity at specific location and time to avoid undesirable effects is very important. Here, we report a conditionally active CRISPR-Cas9 system that regulates target gene expression upon sensing cellular environmental change. We conjugated the oxygen-sensing transcription activation domain (TAD) of hypoxia-inducing factor (HIF-1α) with the Cas9/dCas9 protein. The Cas9-TAD conjugate significantly increased endogenous target gene cleavage under hypoxic conditions compared with that under normoxic conditions, whereas the dCas9-TAD conjugate upregulated endogenous gene transcription. Furthermore, the conjugate system effectively downregulated the expression of SNAIL, an essential gene in cancer metastasis, and upregulated the expression of the tumour-related genes HNF4 and NEUROD1 under hypoxic conditions. Since hypoxia is closely associated with cancer, the hypoxia-dependent Cas9/dCas9 system is a novel addition to the molecular tool kit that functions in response to cellular signals and has potential application for gene therapeutics.

Prediction of pseudoprogression in post-treatment glioblastoma using dynamic susceptibility contrast-derived oxygenation and microvascular transit time heterogeneity measures.

OBJECTIVES: To evaluate the added value of MR dynamic susceptibility contrast (DSC)-perfusion-weighted imaging (PWI)-derived tumour microvascular and oxygenation information with cerebral blood volume (CBV) to distinguish pseudoprogression from true progression (TP) in post-treatment glioblastoma. METHODS: This retrospective single-institution study included patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and a newly developed or enlarging measurable contrast-enhancing mass within 12 weeks after concurrent chemoradiotherapy. CBV, capillary transit time heterogeneity (CTH), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) were obtained from DSC-PWI. Predictors were selected using univariable logistic regression, and performance was measured with adjusted diagnostic odds with tumour volume and area under the curve (AUC) of receiver operating characteristics analysis. RESULTS: A total of 103 patients were included (mean age, 59.6 years; 59 women), with 67 cases of TP and 36 cases of pseudoprogression. Pseudoprogression exhibited higher CTH (4.0 vs. 3.4, p = .019) and higher OEF (12.7 vs. 10.7, p = .014) than TP, but a similar CBV (1.48 vs. 1.53, p = .13) and CMRO2 (7.7 vs. 7.3s, p = .598). Independent of tumour volume, both high CTH (adjusted odds ratio [OR] 1.52; 95% confidence interval [CI]: 1.11-2.09, p = .009) and high OEF (adjusted OR 1.17; 95% CI:1.03-1.33, p = .016) were predictors of pseudoprogression. The combination of CTH, OEF, and CBV yielded higher diagnostic performance (AUC 0.71) than CBV alone (AUC 0.65). CONCLUSION: High intratumoural capillary transit heterogeneity and high oxygen extraction fraction derived from DSC-PWI have enhanced the diagnostic value of CBV in pseudoprogression of post-treatment IDH-wild type glioblastoma. CLINICAL RELEVANCE STATEMENT: In the early post-treatment stage of glioblastoma, pseudoprogression exhibited both high oxygen extraction fraction and high capillary transit heterogeneity and these dynamic susceptibility contrast-perfusion weighted imaging derived parameters have added value in cerebral blood volume-based noninvasive differentiation of pseudoprogression from true progression. KEY POINTS: • Capillary transit time heterogeneity and oxygen extraction fraction can be measured noninvasively through processing of dynamic susceptibility contrast imaging. • Pseudoprogression exhibited higher capillary transit time heterogeneity and higher oxygen extraction fraction than true progression. • A combination of cerebral blood volume, capillary transit time heterogeneity, and oxygen extraction fraction yielded the highest diagnostic performance (area under the curve 0.71).

Hypoxia stabilizes SETDB1 to maintain genome stability.

Von Hippel-Lindau (VHL) is a tumor suppressor that functions as the substrate recognition subunit of the CRL2VHL E3 complex. While substrates of VHL have been identified, its tumor suppressive role remains to be fully understood. For further determination of VHL substrates, we analyzed the physical interactome of VHL and identified the histone H3K9 methyltransferase SETBD1 as a novel target. SETDB1 undergoes oxygen-dependent hydroxylation by prolyl hydroxylase domain proteins and the CRL2VHL complex recognizes hydroxylated SETDB1 for ubiquitin-mediated degradation. Under hypoxic conditions, SETDB1 accumulates by escaping CRL2VHL activity. Loss of SETDB1 in hypoxia compared with that in normoxia escalates the production of transposable element-derived double-stranded RNAs, thereby hyperactivating the immune-inflammatory response. In addition, strong derepression of TEs in hypoxic cells lacking SETDB1 triggers DNA damage-induced death. Our collective results support a molecular mechanism of oxygen-dependent SETDB1 degradation by the CRL2VHL E3 complex and reveal a role of SETDB1 in genome stability under hypoxia.

Mechanistic insights into the dual role of CCAR2/DBC1 in cancer.

Cell cycle and apoptosis regulator 2 (CCAR2), also known as deleted in breast cancer 1 (DBC1), has been recently identified as a master regulator of transcriptional processes and plays diverse roles in physiology and pathophysiology, including as a regulator of apoptosis, DNA repair, metabolism, and tumorigenesis. CCAR2 functions as a coregulator of various transcription factors and a critical regulator of numerous epigenetic modifiers. Based on its ability to stimulate apoptosis by activating and stabilizing p53, CCAR2 was initially considered to be a tumor suppressor. However, an increasing number of studies have shown that CCAR2 also functions as a tumor-promoting coregulator by activating oncogenic transcription factors and regulating the enzymatic activity of epigenetic modifiers, indicating that CCAR2 may play a dual role in cancer progression by acting as a tumor suppressor and tumor promoter. Here, we review recent progress in understanding the dual tumor-suppressing and oncogenic roles of CCAR2 in cancer. We discuss CCAR2 domain structures, its interaction partners, and the molecular mechanisms by which it regulates the activities of transcription factors and epigenetic modifiers.

Imaging-Based Versus Pathologic Survival Stratifications of Diffuse Glioma According to the 2021 WHO Classification System.

OBJECTIVE: Imaging-based survival stratification of patients with gliomas is important for their management, and the 2021 WHO classification system must be clinically tested. The aim of this study was to compare integrative imaging- and pathology-based methods for survival stratification of patients with diffuse glioma. MATERIALS AND METHODS: This study included diffuse glioma cases from The Cancer Genome Atlas (training set: 141 patients) and Asan Medical Center (validation set: 131 patients). Two neuroradiologists analyzed presurgical CT and MRI to assign gliomas to five imaging-based risk subgroups (1 to 5) according to well-known imaging phenotypes (e.g., T2/FLAIR mismatch) and recategorized them into three imaging-based risk groups, according to the 2021 WHO classification: group 1 (corresponding to risk subgroup 1, indicating oligodendroglioma, isocitrate dehydrogenase [IDH]-mutant, and 1p19q-co-deleted), group 2 (risk subgroups 2 and 3, indicating astrocytoma, IDH-mutant), and group 3 (risk subgroups 4 and 5, indicating glioblastoma, IDHwt). The progression-free survival (PFS) and overall survival (OS) were estimated for each imaging risk group, subgroup, and pathological diagnosis. Time-dependent area-under-the receiver operating characteristic analysis (AUC) was used to compare the performance between imaging-based and pathology-based survival model. RESULTS: Both OS and PFS were stratified according to the five imaging-based risk subgroups (P < 0.001) and three imaging-based risk groups (P < 0.001). The three imaging-based groups showed high performance in predicting PFS at one-year (AUC, 0.787) and five-years (AUC, 0.823), which was similar to that of the pathology-based prediction of PFS (AUC of 0.785 and 0.837). Combined with clinical predictors, the performance of the imaging-based survival model for 1- and 3-year PFS (AUC 0.813 and 0.921) was similar to that of the pathology-based survival model (AUC 0.839 and 0.889). CONCLUSION: Imaging-based survival stratification according to the 2021 WHO classification demonstrated a performance similar to that of pathology-based survival stratification, especially in predicting PFS.

Efficacy and safety of metformin plus low-dose temozolomide in patients with recurrent or refractory glioblastoma: a randomized, prospective, multicenter, double-blind, controlled, phase 2 trial (KNOG-1501 study).

PURPOSE: Glioblastoma (GBM) has a poor prognosis after standard treatment. Recently, metformin has been shown to have an antitumor effect on glioma cells. We performed the first randomized prospective phase II clinical trial to investigate the clinical efficacy and safety of metformin in patients with recurrent or refractory GBM treated with low-dose temozolomide. METHODS: Included patients were randomly assigned to a control group [placebo plus low-dose temozolomide (50 mg/m2, daily)] or an experimental group [metformin (1000 mg, 1500 mg, and 2000 mg per day during the 1st, 2nd, and 3rd week until disease progression, respectively) plus low-dose temozolomide]. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, overall response rate, health-related quality of life, and safety. RESULTS: Among the 92 patients screened, 81 were randomly assigned to the control group (43 patients) or the experimental group (38 patients). Although the control group showed a longer median PFS, the difference between the two groups was not statistically significant (2.66 versus 2.3 months, p = 0.679). The median OS was 17.22 months (95% CI 12.19-21.68 months) in the experimental group and 7.69 months (95% CI 5.16-22.67 months) in the control group, showing no significant difference by the log-rank test (HR: 0.78; 95% CI 0.39-1.58; p = 0.473). The overall response rate and disease control rate were 9.3% and 46.5% in the control group and 5.3% and 47.4% in the experimental group, respectively. CONCLUSIONS: Although the metformin plus temozolomide regimen was well tolerated, it did not confer a clinical benefit in patients with recurrent or refractory GBM. Trial registration NCT03243851, registered August 4, 2017.

Defining subventricular zone involvement to predict the survival of patients in isocitrate dehydrogenase-wild type glioblastoma: validation in a prospective registry.

OBJECTIVES: The prognostic value of subventricular zone distance (SVD) is unclear because of different definitions and lack of evaluation of clinical survival models. The aim of this study was to define SVD and evaluate its prognostic value in a survival nomogram for glioblastoma. METHODS: This retrospective study included 158 (SVD biomarker) from historical glioblastoma patients and 187 (survival modeling) with IDH-wild type glioblastoma from a prospective registry (NCT02619890). SVD was assessed by two radiologists: definition 1, the distance between the tumor edge to subventricular zone (SVZ); definition 2, the distance between the tumor centroid to SVZ; definition 3, enhancement at the ventricular wall. The associations between SVD and overall survival (OS) were evaluated using multivariable Cox proportional hazards regression analysis. Performance of an updated SVD survival model was compared with that of the Radiation Therapy Oncology Group (RTOG) 0525 nomogram. RESULTS: SVD according to both definition 1 (hazard ratio [HR]: 0.97, 95% CI: 0.94-0.99; p = .011) and definition 2 (HR: 0.96, 0.94-0.98, p < .001) was adversely associated with OS. Definition 1 was adversely associated with PFS (HR: 0.96, 0.94-0.99, p = .008) and showed the highest reproducibility (intraclass correlation coefficient, 0.90). The SVD-updated model showed similar to better performance than the RTOG model for predicting OS of up to 3 years (AUC: 0.735-0.738 vs. 0.687-0.708), with higher time-dependent specificity for 1-year (89.9% vs. 70.6%) and 3-year OS (93.3% vs. 80.0%). CONCLUSION: SVZ distance is an independent adverse prognostic factor in patients with IDH-wild type glioblastoma. Updating the survival model with SVZ provides better time-dependent specificity and reproducibility. KEY POINTS: • Subventricular zone distance (SVD) measurement from tumor edge showed high reproducibility. • Longer SVD was independently associated with longer overall survival. • Adding SVD improved time-dependent specificity for survival model in a prospective registry.

10-year follow-up study on medical expenses and medical care use according to biological age: National Health Insurance Service Health Screening Cohort (NHIS-HealS 2002~2019).

OBJECTIVES: The world is witnessing a sharp increase in its elderly population, accelerated by longer life expectancy and lower birth rates, which in turn imposes enormous medical burden on society. Although numerous studies have predicted medical expenses based on region, gender, and chronological age (CA), any attempt has rarely been made to utilize biological age (BA)-an indicator of health and aging-to ascertain and predict factors related to medical expenses and medical care use. Thus, this study employs BA to predict factors that affect medical expenses and medical care use. MATERIALS AND METHODS: Referring to the health screening cohort database of the National Health Insurance Service (NHIS), this study targeted 276,723 adults who underwent health check-ups in 2009-2010 and kept track of the data on their medical expenses and medical care use up to 2019. The average follow-up period is 9.12 years. Twelve clinical indicators were used to measure BA, while the total annual medical expenses, total annual number of outpatient days, total annual number of days in hospital, and average annual increases in medical expenses were used as the variables for medical expenses and medical care use. For statistical analysis, this study employed Pearson correlation analysis and multiple regression analysis. RESULTS: Regression analysis of the differences between corrected biological age (cBA) and CA exhibited statistically significant increases (p<0.05) in all the variables of the total annual medical expenses, total annual number of outpatient days, total annual number of days in hospital, and average annual increases in medical expenses. CONCLUSIONS: This study quantified decreases in the variables for medical expenses and medical care use based on improved BA, thereby motivating people to become more health-conscious. In particular, this study is significant in that it is the first of its kind to predict medical expenses and medical care use through BA.

Proteomic analysis predicts anti-angiogenic resistance in recurred glioblastoma.

BACKGROUND: Recurrence is common in glioblastoma multiforme (GBM) because of the infiltrative, residual cells in the tumor margin. Standard therapy for GBM consists of surgical resection followed by chemotherapy and radiotherapy, but the median survival of GBM patients remains poor (~ 1.5 years). For recurrent GBM, anti-angiogenic treatment is one of the common treatment approaches. However, current anti-angiogenic treatment modalities are not satisfactory because of the resistance to anti-angiogenic agents in some patients. Therefore, we sought to identify novel prognostic biomarkers that can predict the therapeutic response to anti-angiogenic agents in patients with recurrent glioblastoma. METHODS: We selected patients with recurrent GBM who were treated with anti-angiogenic agents and classified them into responders and non-responders to anti-angiogenic therapy. Then, we performed proteomic analysis using liquid-chromatography mass spectrometry (LC-MS) with formalin-fixed paraffin-embedded (FFPE) tissues obtained from surgical specimens. We conducted a gene-ontology (GO) analysis based on protein abundance in the responder and non-responder groups. Based on the LC-MS and GO analysis results, we identified potential predictive biomarkers for anti-angiogenic therapy and validated them in recurrent glioblastoma patients. RESULTS: In the mass spectrometry-based approach, 4957 unique proteins were quantified with high confidence across clinical parameters. Unsupervised clustering analysis highlighted distinct proteomic patterns (n = 269 proteins) between responders and non-responders. The GO term enrichment analysis revealed a cluster of genes related to immune cell-related pathways (e.g., TMEM173, FADD, CD99) in the responder group, whereas the non-responder group had a high expression of genes related to nuclear replisome (POLD) and damaged DNA binding (ERCC2). Immunohistochemistry of these biomarkers showed that the expression levels of TMEM173 and FADD were significantly associated with the overall survival and progression-free survival of patients with recurrent GBM. CONCLUSIONS: The candidate biomarkers identified in our protein analysis may be useful for predicting the clinical response to anti-angiogenic agents in patients with recurred GBM.

Tumor Habitat Analysis Using Longitudinal Physiological MRI to Predict Tumor Recurrence After Stereotactic Radiosurgery for Brain Metastasis.

OBJECTIVE: It is difficult to predict the treatment response of tissue after stereotactic radiosurgery (SRS) because radiation necrosis (RN) and tumor recurrence can coexist. Our study aimed to predict tumor recurrence, including the recurrence site, after SRS of brain metastasis by performing a longitudinal tumor habitat analysis. MATERIALS AND METHODS: Two consecutive multiparametric MRI examinations were performed for 83 adults (mean age, 59.0 years; range, 27-82 years; 44 male and 39 female) with 103 SRS-treated brain metastases. Tumor habitats based on contrast-enhanced T1- and T2-weighted images (structural habitats) and those based on the apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) images (physiological habitats) were defined using k-means voxel-wise clustering. The reference standard was based on the pathology or Response Assessment in Neuro-Oncologycriteria for brain metastases (RANO-BM). The association between parameters of single-time or longitudinal tumor habitat and the time to recurrence and the site of recurrence were evaluated using the Cox proportional hazards regression analysis and Dice similarity coefficient, respectively. RESULTS: The mean interval between the two MRI examinations was 99 days. The longitudinal analysis showed that an increase in the hypovascular cellular habitat (low ADC and low CBV) was associated with the risk of recurrence (hazard ratio [HR], 2.68; 95% confidence interval [CI], 1.46-4.91; P = 0.001). During the single-time analysis, a solid low-enhancing habitat (low T2 and low contrast-enhanced T1 signal) was associated with the risk of recurrence (HR, 1.54; 95% CI, 1.01-2.35; P = 0.045). A hypovascular cellular habitat was indicative of the future recurrence site (Dice similarity coefficient = 0.423). CONCLUSION: After SRS of brain metastases, an increased hypovascular cellular habitat observed using a longitudinal MRI analysis was associated with the risk of recurrence (i.e., treatment resistance) and was indicative of recurrence site. A tumor habitat analysis may help guide future treatments for patients with brain metastases.

Combination of metformin/efavirenz/fluoxetine exhibits profound anticancer activity via a cancer cell-specific ROS amplification.

The possible anticancer activity of combination (M + E + F) of metformin (M), efavirenz (E), and fluoxetine (F) was investigated in normal HDF cells and HCT116 human colon cancer cells. Metformin increased cellular FOXO3a, p-FOXO3a, AMPK, p-AMPK, and MnSOD levels in HDFs but not in HCT116 cells. Cellular ATP level was decreased only in HDFs by metformin. Metformin increased ROS level only in HCT116 cells. Transfection of si-FOXO3a into HCT116 reversed the metformin-induced cellular ROS induction, indicating that FOXO3a/MnSOD is the key regulator for cellular ROS level. Viability readout with M, E, and F alone decreased slightly, but the combination of three drugs dramatically decreased cell survival in HCT116, A549, and SK-Hep-1 cancer cells but not in HDF cells. ROS levels in HCT116 cells were massively increased by M + E + F combination, but not in HDF cells. Cell cycle analysis showed that of M + E + F combination caused cell death only in HCT116 cells. The combination of M + E + F reduced synergistically mitochondrial membrane potential and mitochondrial electron transport chain complex I and III activities in HCT116 cells when compared with individual treatments. Western blot analysis indicated that DNA damage, apoptosis, autophagy, and necroptosis-realated factors increased in M + E + F-treated HCT116 cells. Oral administration with M + E + F combination for 3 weeks caused dramatic reductions in tumor volume and weight in HCT116 xenograft model of nude mice when compared with untreated ones. Our results suggest that M + E + F have profound anticancer activity both in vitro and in vivo via a cancer cell-specific ROS amplification (CASRA) through ROS-induced DNA damage, apoptosis, autophagy, and necroptosis.

CDK9 inhibitors downregulate DKK1 expression to suppress the metastatic potential of HCC cells.

BACKGROUND: Elevated expression of Dickkopf-1 (DKK1) is frequently observed in hepatocellular carcinoma (HCC) patients with poor clinical outcomes. Several reports indicating the functional involvement of DKK1 in HCC progression have suggested DKK1 as a promising therapeutic target for HCC. OBJECTIVE: In this study, to develop an efficient way to target DKK1, we assessed the effect of CDK9 inhibitors on DKK1 expression linked to metastatic movement of HCC. METHODS: The expression of DKK1 in CDK9 inhibitor-treated HCC cells was measured by western blot, ELISA and quantitative real-time reverse transcription PCR. Wound healing assay, migration assay, invasion assay and western blot were examined to evaluate the functional role of DKK1 in CDK9 inhibitors-treated HCC. RESULTS: Inactivation of CDK9 either by a catalytic inhibitor being clinically evaluated or by a specific CDK9 protein degrader largely downregulated DKK1 expression at the transcript and protein levels. In addition, CDK9 inhibitors suppressed the migration and invasion of HCC cells. We observed that ectopic high expression of DKK1 at least partially reversed the defects in metastatic movement of HCC cells mediated by CDK9 inhibitors. We further discovered that the DKK1-nuclear ß-catenin axis associated with the metastatic potential of HCC cells was impaired by CDK9 inhibitors. CONCLUSION: Taken together, our findings suggest that CDK9 inhibitors are potent tools to target DKK1, which can suppress the metastatic progression of HCC.

Practical answers to frequently asked questions in minimally invasive lumbar spine surgery.

BACKGROUND CONTEXT: Surgical counseling enables shared decision-making (SDM) by improving patients' understanding. PURPOSE: To provide answers to frequently asked questions (FAQs) in minimally invasive lumbar spine surgery. STUDY DESIGN: Retrospective review of prospectively collected data. PATIENT SAMPLE: Patients who underwent primary tubular minimally invasive lumbar spine surgery in form of transforaminal lumbar interbody fusion (MI-TLIF), decompression alone, or microdiscectomy and had a minimum of 1-year follow-up. OUTCOME MEASURES: (1) Surgical (radiation exposure and intraoperative complications) (2)Immediate postoperative (length of stay [LOS] and complications) (3) Clinical outcomes (Visual Analog Scale- back and leg, VAS; Oswestry Disability Index, ODI; 12-Item Short Form Survey Physical Component Score, SF-12 PCS; Patient-Reported Outcomes Measurement Information System Physical Function, PROMIS PF; Global Rating Change, GRC; return to activities; complications/reoperations) METHODS: The outcome measures were analyzed to provide answers to ten FAQs that were compiled based on the authors' experience and a review of literature. Changes in VAS back, VAS leg, ODI, and SF-12 PCS from preoperative values to the early (<6 months) and late (>6 months) postoperative time points were analyzed with Wilcoxon Signed Rank Tests. % of patients achieving minimal clinically important difference (MCID) for these patient-reported outcome measures (PROMs) at the two time points was evaluated. Changes in PROs from preoperative values too early (<6 months) and late (≥6 months) postoperative time points were analyzed within each of the three groups. Percentage of patients achieving MCID was also evaluated. RESULTS: Three hundred sixty-six patients (104 TLIF, 147 decompression, 115 microdiscectomy) were included. The following FAQs were answered: (1) Will my back pain improve? Most patients report improvement by >50%. About 60% of TLIF, decompression, and microdiscectomy patients achieved MCID at ≥6 months. (2) Will my leg pain improve? Most patients report improvement by >50%. 56% of TLIF, 67% of decompression, and 70% of microdiscectomy patients achieved MCID at ≥6 months. (3) Will my activity level improve? Most patients report significant improvement. Sixty-six percent of TLIF, 55% of decompression, and 75% of microdiscectomy patients achieved MCID for SF-12 PCS. (4) Is there a chance I will get worse? Six percent after TLIF, 14% after decompression, and 5% after microdiscectomy. (5) Will I receive a significant amount of radiation? The radiation exposure is likely to be acceptable and nearly insignificant in terms of radiation-related risks. (6) What is the likelihood that I will have a complication? 17.3% (15.4% minor, 1.9% major) for TLIF, 10% (9.3% minor and 0.7% major) for decompression, and 1.7% (all minor) for microdiscectomy (7) Will I need another surgery? Six percent after TLIF, 16.3% after decompression, 13% after microdiscectomy. (8) How long will I stay in the hospital? Most patients get discharged on postoperative day one after TLIF and on the same day after decompression and microdiscectomy. (9) When will I be able to return to work? >80% of patients return to work (average: 25 days after TLIF, 14 days after decompression, 11 days after microdiscectomy). (10) Will I be able to drive again? >90% of patients return to driving (average: 22 days after TLIF, 11 days after decompression, 14 days after microdiscectomy). CONCLUSIONS: These concise answers to the FAQs in minimally invasive lumbar spine surgery can be used by physicians as a reference to enable patient education.

Treatment Outcome of Gamma Knife Radiosurgery for Brain Metastasis from Thyroid Cancer: Favorable Local Control but Poor Survival.

BACKGROUND: Brain metastasis from thyroid cancer (TCBM) is extremely rare; thus, despite a good treatment outcome for thyroid cancer, TCBM has shown poor clinical outcomes. Considering the short survival and poor general condition of patients with TCBM, stereotactic radiosurgery may be preferred to achieve local control. METHODS: A total of 25 patients with TCBM who underwent Gamma Knife radiosurgery (GKS) were initially included in this study; however, 3 patients were excluded because of a lack of data. RESULTS: There were 7 men (31.8%) and 15 women (68.2%) and the mean age was 63.7 years. The most common type of thyroid cancer histology was papillary carcinoma. Fourteen patients (63.6%) harbored single brain metastatic tumor and 8 (36.3%) had multiple brain metastatic tumors. The mean duration from thyroid cancer diagnosis to detection of brain metastasis was 7.7 years (range, 0-23 years). The median dose of radiation of GKS was 22 Gy (range, 18-25 Gy). There was no radiation-induced complication after GKS. The median overall survival (OS) was 15 months and the 1-year OS of patients with TCBM was 63%, the 2-year OS was 38%, and the 5-year OS was 28%. The 6-month progression-free survival (PFS) for local recurrence of TCBM was 90.4%, the 1-year PFS was 84%, and the 3-year PFS was 84%. CONCLUSIONS: GKS showed favorable local control for TCBM. However, the rate of distant brain metastasis was high and median survival of patients with TCBM was only 15 months.

Discovery of pan-IAP degraders via a CRBN recruiting mechanism.

Inhibitors of apoptosis proteins (IAPs), defined by the presence of baculovirus IAP repeat (BIR) protein domain, are critical regulators of cell survival and cell death processes. Cellular IAP 1/2 (cIAP1/2) and X-linked IAPs (XIAPs) regulate the innate immune signaling pathway through their E3 ubiquitin ligase activity. Peptidomimetics or small-molecule IAP antagonists have been developed to treat various diseases, such as cancer, infection, and inflammation. In this study, we synthesized and characterized IAP-cereblon (CRBN) heterodimerizing proteolysis-targeting chimera (PROTAC), which induces the degradation of cIAP1/2 and XIAP but not CRBN. We demonstrated that this PROTAC inhibits tumor necrosis factor alpha (TNFα)-induced innate immune response and cancer cell migration and invasion, leading to apoptotic cell death. Our study is the first to demonstrate that both cIAPs and XIAP are degradable when applied to the PROTAC strategy.

Vessel size and perfusion-derived vascular habitat refines prediction of treatment failure to bevacizumab in recurrent glioblastomas: validation in a prospective cohort.

OBJECTIVES: Anti-angiogenic therapy may not benefit all patients with recurrent glioblastomas, and imaging biomarker predicting treatment response to anti-angiogenic therapy is currently limited. We aimed to develop and validate vascular habitats based on perfusion and vessel size to predict time to progression (TTP) in patients with recurrent glioblastomas treated with bevacizumab. METHODS: Sixty-nine patients with recurrent glioblastomas treated with bevacizumab who underwent pretreatment MRI with dynamic susceptibility contrast imaging and vessel architectural imaging were enrolled. Vascular habitats were constructed using vessel size index (VSI) and relative cerebral blood volume (rCBV). Associations with vascular habitats and TTP were analyzed using Cox proportional hazard regression analysis. In a prospectively enrolled validation cohort consisting of 15 patients ( ClinicalTrials.gov identifier; NCT04143425), stratification of TTP was demonstrated by the Kaplan-Meier method (log-rank test) using vascular habitats. RESULTS: Three vascular habitats consisting of high, intermediate, and low angiogenic habitats were identified with rCBV and VSI. Both high angiogenic and intermediate angiogenic habitats were significantly associated with a shorter TTP (hazard ratio [HR], 2.78 and 1.82, respectively; largest p = .003) and so was rCBV (HR, 2.15; p = .02). Concordance probability index of vascular habitat combining high and intermediate angiogenic habitats was 0.74. Vascular habitats stratified patients as good or poor responder in a prospective cohort (p = .059). CONCLUSIONS: Perfusion- and vessel size-derived vascular habitats predicted TTP in recurrent glioblastomas treated with anti-angiogenic therapy and aided patient stratification in a prospective validation cohort. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04143425 KEY POINTS: • High and intermediate angiogenic habitats predicted TTP in recurrent glioblastomas treated with anti-angiogenic therapy. • Vascular habitats combining high and intermediate angiogenic habitats aided patient stratification for anti-angiogenic therapy in recurrent glioblastomas.