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PurposeThe KNOG-1101 study showed improved 2-year PFS with temozolomide during and after radiotherapy compared to radiotherapy alone for patients with anaplastic gliomas. This trial investigates the effect of concurrent and adjuvant temozolomide on health-related quality of life (HRQoL).Materials and MethodsIn this randomized, open-label, phase II trial, 90 patients with World Health Organization grade III glioma were enrolled across multiple centers in South Korea between March 2012 to February 2015 and followed up through 2017. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) and 20-item EORTC QLQ-Brain Neoplasm (QLQ-BN20) were used to compare HRQoL between patients assigned to concurrent chemoradiotherapy with temozolomide followed by 6 cycles of adjuvant temozolomide (arm A) and radiotherapy (RT) alone (arm B).ResultsOf the 90 patients in the study, 84 patients (93.3%) completed the baseline HRQoL questionnaire. Emotional functioning, fatigue, nausea and vomiting, dyspnea, constipation, appetite loss, diarrhea, seizures, itchy skin, drowsiness, hair loss, and bladder control were not affected by the addition of temozolomide. All other items did not differ significantly between arm A and arm B throughout treatment. Global health status particularly stayed consistent at the end of adjuvant temozolomide (p=0.47) and at the end of RT (p=0.33).ConclusionThe addition of concurrent and adjuvant temozolomide did not show negative influence on HRQoL with improvement of progression-free survival for patients with anaplastic gliomas. The absence of systematic and clinically relevant changes in HRQoL suggests that an overall long-term net clinical benefit exists for concurrent and adjuvant temozolomide.

Objective To analyze radiological characteristics, treatment strategy, and treatment outcomes of posterior fossa giant solid hemangioblastomas (GSHBs; ≥ 4 cm in maximum diameter). Methods We performed a retrospective study on 13 consecutive patients (9 male and 4 female patients [mean age 57.5 ± 13.3 years; range 24-76 years]) with GSHB who underwent surgical resection at a single institution between 2002 and 2018. The median follow-up was 33 months (range 12-120 months). For each patient, neuroimaging findings, operative record, and treatment outcome were reviewed. Results Seven tumors (53.8%) were located within cerebellar hemispheres, 4 (30.8%) in proximity to the brainstem, 1 (7.7%) within the cerebellar vermis, and 1 (7.7%) in the cerebellopontine angle. The mean maximum diameter was 4.8 ± 0.8 cm (range 4.0-6.7 cm). Gross total resection was achieved in 11 patients (84.6%), and near-total resection (NTR) in 2 patients (15.4%). Surgical complications occurred in 5 patients (38.5%); persistent neurological deficits occurred in 2 patients (15.4%). Estimated progression-free survival rates after surgery were 92.3%, 80.8%, and 80.8% at 1, 5, and 10 years, respectively, while the estimated 1-, 5- and 10-year overall survival rates were 100%, 90% and 90%, respectively. Conclusions GSHBs are surgically challenging. The current study shows that favorable outcome can be achieved for GSHBs in the cerebellar hemispheres and vermis. For those involving the brainstem, planned NTR or STR in a piecemeal fashion can be attempted if en bloc resection is judged to be infeasible, and further intervention can be considered as needed.

OBJECTIVE The petrous apex (PA) is one of the most challenging areas in skull base surgery because it is surrounded by numerous critical neurovascular structures. The authors analyzed the clinical outcomes of patients who underwent endoscopic endonasal approach (EEA) and transorbital approach (TOA) procedures for lesions involving PA to determine the perspectives and proper applications of these two approaches. METHODS The authors included patients younger than 80 years with lesions involving PA who were treated between May 2015 and December 2019 and had regular follow-up MR images available for analysis. Patients with meningioma involving petroclival regions were excluded. The authors classified PA into three regions: superior to the petrous segment of the internal carotid artery (p-ICA) (zone 1); posterior to p-ICA (zone 2); and inferior to p-ICA (zone 3). Demographic data, preoperative clinical and radiological findings, surgical outcomes, and morbidities were reviewed. RESULTS A total of 19 patients with lesions involving PA were included. Ten patients had malignant tumor (chondrosarcoma, chordoma, and osteosarcoma), and 6 had benign tumor (schwannoma, Cushing’s disease, teratoma, etc.). Three patients had PA cephalocele (PAC). Thirteen patients underwent EEA, and 5 underwent TOA. Simultaneous combined EEA and TOA was performed on 1 patient. Thirteen of 16 patients (81.3%) had gross- or near-total resection. Tumors within PA were completely resected from 13 of 16 patients using a view limited to only the PA. Complete obliteration of PAC was achieved in all patients. Postoperative complications included 2 cases of CSF leak, 1 case of injury to ICA, 1 fatality due to sudden herniation of the brainstem, and 1 case of postoperative diplopia. CONCLUSIONS EEA is a versatile surgical approach for lesions involving all three zones of PA. Clival tumor spreading to PA in a medial-to-lateral direction is a good indication for EEA. TOA provided a direct surgical corridor to the superior portion of PA (zone 1). Patients with disease with cystic nature are good candidates for TOA. TOA may be a reasonable alternative surgical treatment for select pathologies involving PA.

Although reconstruction techniques after endoscopic skull base surgery have been improved, there are difficulties in reconstructing the skull base with a nasoseptal flap (NSF), especially in the case of high-flow cerebrospinal fluid (CSF) leak. The aim of this study was to analyze risk factors for the development of postoperative CSF leaks in terms of less experienced surgeon practices. Retrospective review of medical records was performed for 125 patients who underwent endoscopic skull base surgery for intradural pathology with intraoperative high-flow CSF leakage between Oct 2012 and Apr 2017. Basic demographic data were collected, including body mass index (BMI), tumor pathology, comorbidities, and outcomes. To assess the learning curve effect, patients were divided into early cohort (n = 30) and late cohort (n = 95) groups. Overall postoperative CSF leakage was 10.4% (13/125) in this series. There were no significant risk factors for postoperative CSF leakage among the demographic data including BMI, comorbidities, or radiation history. Postoperative CSF leakage was most prevalent in the transclival approach than in other approaches, but the difference was not statistically significant (20.8%, p = 0.351). When dividing the results by timetable, the patients who underwent skull base reconstruction in the early cohort experienced more postoperative CSF leakage (23.3%, 7 cases out of 30) than in the late cohort (6.3%, 6 cases out of 95, p = 0.014). The learning curve was steeper in the early cohort (30 early cases 23.3%, 31–60 10%, 61–90 6.7%, 91–125 2.9%). To improve the success rate of endoscopic skull base reconstruction, surgeons have to keep the basic technical details in mind to reduce the learning curve.

The role of transsphenoidal surgery in the recovery of preexisting hormone dysfunction from pituitary tumors remains controversial. This study aimed to investigate the incidence of hormone dysfunction among asymptomatic non-functioning pituitary adenomas and their recovery following endoscopic transsphenoidal surgery. Eligibility criteria included age under 80 years, presence of a non-functioning pituitary adenoma compressing the normal gland resulting in deviation of the stalk, absence of visual symptoms, and availability for regular follow-up using MRI and pre- and post-operative endocrinological assessments. 182 patients with silent non-functioning pituitary adenomas were included in this study between March 2014 and December 2018. All patients underwent endoscopic transsphenoidal surgery and complete hormonal evaluation, with basal hormone assays and a combined pituitary function test before and after surgery until the end of last follow-up. Preoperative assessment of hormonal function revealed that 124 of 182 patients (68.1%) had at least a single hormone dysfunction preoperatively. Among these, 61 of 124 (49.2%) had a dysfunction in a single axis, and 63 (50.8%) had a hormone dysfunction in two or more axes. Overall, the median endocrinological follow-up duration was 15.0 months (6–57 months). At 1 month following surgery, 91 patients (73.4%) with hormone dysfunction experienced improvement in at least a single hormone axis. Prolactin was the most common hormone among those that recovered at the last follow up (92.8% improvement) followed by growth hormone (GH, 50.0%), thyroid stimulating hormone (TSH, 50.0%), gonadotropin (Gn, 46.9%), and adrenocorticotropic hormone (ACTH, 45.0%). Time to recovery varied from 1.1 months (for prolactin) to 2.2 months (for gonadotropin, and ACTH). In patients with preoperative deficiency in GH, and ACTH, postoperative transient diabetes insipidus was associated with poor recovery (GH: HR = 0.50, p = 0.048; ACTH: HR = 0.39, p = 0.023). Non-functioning pituitary adenomas with silent hormone dysfunction are often overlooked by clinicians and patients. We suggest that even silent hormone dysfunction in patients with non-functioning pituitary adenomas can be improved with effective surgical decompression and these tumors may be potential indications of endoscopic transsphenoidal surgery.

OBJECTIVE This study was performed to evaluate the role of Gamma Knife radiosurgery (GKRS) as a primary treatment for central neurocytomas (CNs). METHODS The authors retrospectively assessed the treatment outcomes of patients who had undergone primary treatment with GKRS for CNs in the period between December 2001 and December 2018. The diagnosis of CN was based on findings on neuroimaging studies. The electronic medical records were retrospectively reviewed for additional relevant preoperative data, and clinical follow-up data had been obtained during office evaluations of the treated patients. All radiographic data were reviewed by a dedicated neuroradiologist. RESULTS Fourteen patients were treated with GKRS as a primary treatment for CNs in the study period. Seven patients (50.0%) were asymptomatic at initial presentation, and 7 (50.0%) presented with headache. Ten patients (71.4%) were treated with GKRS after the diagnosis of CN based on characteristic MRI findings. Four patients (28.6%) initially underwent either stereotactic or endoscopic biopsy before GKRS. The median tumor volume was 3.9 cm3 (range 0.46–18.1 cm3). The median prescription dose delivered to the tumor margin was 15 Gy (range 5.5–18 Gy). The median maximum dose was 30 Gy (range 11–36 Gy). Two patients were treated with fractionated GKRS, one with a prescription dose of 21 Gy in 3 fractions and another with a dose of 22 Gy in 4 fractions. Control of tumor growth was achieved in all 14 patients. The median volume reduction was 26.4% (range 0%–78.3%). Transient adverse radiation effects were observed in 2 patients but resolved with improvement in symptoms. No recurrences were revealed during the follow-up period, which was a median of 25 months (range 12–89 months). CONCLUSIONS Primary GKRS for CNs resulted in excellent tumor control rates without recurrences. These results suggest that GKRS may be a viable treatment option for patients with small- to medium-sized or incidental CNs.

As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.

Glioblastoma (GBM) is the most lethal primary brain tumor with few treatment options. The survival of glioma-initiating cells (GICs) is one of the major factors contributing to treatment failure. GICs frequently produce and respond to their own growth factors that support cell proliferation and survival. In this study, we aimed to identify critical autocrine factors mediating GIC survival and to evaluate the anti-GBM effect of antagonizing these factors. Proteomic analysis was performed using conditioned media from two different patient-derived GBM tumor spheres under a growth factor-depleted status. Then, the antitumor effects of inhibiting an identified autocrine factor were evaluated by bioinformatic analysis and molecular validation. Proteins secreted by sphere-forming GICs promote cell proliferation/survival and detoxify reactive oxygen species (ROS). Among these proteins, we focused on midkine (MDK) as a clinically significant and pathologically relevant autocrine factor. Antagonizing MDK reduced the survival of GBM tumor spheres through the promotion of cell cycle arrest and the consequent apoptotic cell death caused by oxidative stress-induced DNA damage. We also identified PCBP4, a novel molecular predictor of resistance to anti-MDK treatment. Collectively, our results indicate that MDK inhibition is an important therapeutic option by suppressing GIC survival through the induction of ROS-mediated cell cycle arrest and apoptosis., Brain cancer: a key growth factor Targeting the growth factor midkine (MDK) may offer improved treatment for glioblastoma, the most lethal brain cancer. In glioblastoma, the tumor-initiating cells produce their own growth factors, encouraging themselves to keep multiplying, and making glioblastoma very difficult to treat. Do-Hyun Nam and Hyun Ju Kang at the Samsung Medical Center, Seoul, South Korea and coworkers screened the growth factors produced by two glioblastoma samples, then focused on a single cancer-associated factor, MDK. Antagonizing MDK slowed tumor cell growth, and further investigation showed that suppressing MDK restored the susceptibility of tumor cells to DNA damage and the mechanisms that weed out damaged cells. Noting that treatment efficacy varied between tumor samples, the researchers identified a biomarker for sensitivity to MDK treatment. These results point the way to new treatments for this particularly deadly cancer.

Glioblastoma (GBM) is the most malignant primary brain tumor in adults with substantial genomic alterations. The median survival is approximately 14.6 months, despite aggressive therapeutic intervention, which comprised of surgical resection, radiotherapy, and chemotherapy. Recent studies on cancer genomic have revealed crucial insights into dynamic molecular subgroups within GBM, which govern distinct clinical response and sensitivity of each individual to therapy. In the present study, we analyzed genomic composition of primary GBMs between two ethnic groups [IRCR (Institute of Refractory Cancer Research), and TCGA (The Cancer Genome Atlats)] to explore genomic and molecular features that constitute malignant behavior of glioblastoma based on distinct ethnicity. We identified enrichments of MAPK and p53 pathways in IRCR patients, while aberrant activation of Receptor Tyrosine Kinases (RTKs) were predominant in TCGA cohort. We also discovered differential clinical prognosis between two groups and explored essential features that present such diversity., Glioblastoma (GBM) is the most aggressive primary brain tumor. We analyzed recurrent somatic variants and molecular pathways that are enriched in different subpopulations.

c-Met, as a receptor expressed on the cell membrane, contributes to the growth and metastasis of tumors, as well as angiogenesis, mainly through the hepatocyte growth factor (HGF)/c-Met axis during tumor progression. Although several c-Met inhibitors, including small molecules and monoclonal antibody inhibitors, are currently being investigated, their clinical outcomes have not been promising. Development of an antibody–drug conjugate (ADC) against c-Met could be an attractive therapeutic strategy that would provide superior antitumor efficacy with broad-spectrum c-Met expression levels. In the present study, site-specific drug–conjugate technology was applied to develop an ADC using the human-mouse cross-reactive c-Met antibody and a prodrug pyrrolobenzodiazepine (PBD). The toxin payload was uniformly conjugated to the light-chain C-terminus of the native cIRCR201 antibody (drug-to-antibody ratio = 2), as confirmed using LC–MS. Using a high-throughput screening system, we found that cIRCR201-dPBD exhibited varying sensitivities depending on the expression levels of c-Met, and it induced receptor-mediated endocytosis and toxin-mediated apoptosis in 47 different cancer cell lines. cIRCR201-dPBD also showed significant antitumor activity on the MET-amplified cancer cells using in vivo xenograft models. Therefore, cIRCR201-dPBD could be a promising therapeutic strategy for tumors with c-Met expression.

Background Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages. Results We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCOhigh TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCOhigh TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate the origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments. Conclusions Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.

OBJECTIVEFractionated Gamma Knife surgery (FGKS) has recently been used to treat large brain metastases. However, little is known about specific volume changes of lesions during the course of treatment. The authors investigated short-term volume changes of metastatic lesions during FGKS.METHODSThe authors analyzed 33 patients with 40 lesions who underwent FGKS for intracranial metastases of non–small-cell lung cancer (NSCLC; 25 patients with 32 lesions) and breast cancer (8 patients with 8 lesions). FGKS was performed in 3–5 fractions. Baseline MRI was performed before the first fraction. MRI was repeated after 1 or 2 fractions. Adaptive planning was executed based on new images. The median prescription dose was 8 Gy (range 6–10 Gy) with a 50% isodose line.RESULTSOn follow-up MRI, 18 of 40 lesions (45.0%) showed decreased tumor volumes (TVs). A significant difference was observed between baseline (median 15.8 cm3) and follow-up (median 14.2 cm3) volumes (p < 0.001). A conformity index was significantly decreased when it was assumed that adaptive planning was not implemented, from baseline (mean 0.96) to follow-up (mean 0.90, p < 0.001). The average reduction rate was 1.5% per day. The median follow-up duration was 29.5 weeks (range 9–94 weeks). During the follow-up period, local recurrence occurred in 5 lesions.CONCLUSIONSThe TV showed changes with a high dose of radiation during the course of FGKS. Volumetric change caused a significant difference in the clinical parameters. It is expected that adaptive planning would be helpful in the case of radiosensitive tumors such as NSCLCs or breast cancer to ensure an adequate dose to the target area and reduce unnecessary exposure of normal tissue to radiation.

Metastasis is the primary cause of cancer mortality. The primary tumors of colorectal cancer (CRC) often metastasize to the liver. In this study, we have collected 122 samples from 45 CRC patients. Among them, 32 patients have primary tumors, adjacent normal tissues, and matched liver metastases. Thirteen patients have primary tumors without distant metastasis and matched normal tissues. Characterization of these samples was conducted by whole-exome and RNA sequencing and SNP6.0 analysis. Our results revealed no significant difference in genetic alterations including common oncogenic mutations, whole genome mutations and copy number variations between primary and metastatic tumors. We then assembled gene co-expression networks and identified metastasis-correlated gene networks of immune-suppression, epithelial–mesenchymal transition (EMT) and angiogenesis as the key events and potentially synergistic drivers associated with CRC metastasis. Further independent cohort validation using published datasets has verified that these specific gene networks are up regulated throughout the tumor progression. The gene networks of EMT, angiogenesis, immune-suppression and T cell exhaustion are closely correlated with the poor patient outcome and intrinsic anti-PD-1 resistance. These results offer insights of combinational strategy for the treatment of metastatic CRC.

Introduction The clinical benefit of stereotactic radiosurgery (SRS) in the treatment of malignant glioma remains controversial. We analyzed failure patterns of malignant gliomas following SRS to identify the clinical implications of SRS against these malignancies. Materials and methods We retrospectively reviewed 58 consecutive patients who received SRS with a gamma knife for their malignant glioma from January 2013 to December 2018. A total of 51 patients were available for analysis of failure patterns. Failure patterns were defined by the recurrent tumors’ spatial relation to SRS target as follows: in-field local recurrence, remote recurrence, and leptomeningeal seeding. If patients demonstrated several types of failure patterns simultaneously, we categorized them as a combined failure pattern. Results In-field local recurrence was found in 47.1% of patients. Other types of failure patterns were as follows: remote recurrence (19.6%), leptomeningeal seeding (13.7%), and combined failure pattern (19.6%). The majority of patients (52.9%) experienced disease progression beyond the radiation field of SRS, which implies limited efficacy of local therapy against these invasive tumors. The prognosis of patients differed according to failure pattern and patients with local recurrence had better survival outcomes compared to other types of disease progression (p-value = 0.0015, log-rank test). Conclusions This study illustrated that SRS could not improve survival of malignant gliomas significantly even when it had some effect within radiation field. Our findings support utilizing a multidisciplinary treatment strategy to improve the prognosis of malignant gliomas and suggest that SRS is one element of that treatment strategy.

PurposeWe investigated the efficacy of temozolomide during and after radiotherapy in Korean adults with anaplastic gliomas without 1p/19q co-deletion.Materials and MethodsThis was a randomized, open-label, phase 2 study and notably the first multicenter trial for Korean grade III glioma patients. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomized 1:1 to receive radiotherapy alone (60 Gy in 30 fractions of 2 Gy) (control group, n=44) or to receive radiotherapy with concurrent temozolomide (75 mg/m2/day) followed by adjuvant temozolomide (150-200 mg/m2/day for 5 days during six 28-day cycles) (treatment group, n=40). The primary end-point was 2-year progression-free survival (PFS). Seventy patients (83.3%) were available for the analysis of the isocitrate dehydrogenase 1 gene (IDH1) mutation status.ResultsThe two-year PFS was 42.2% in the treatment group and 37.2% in the control group. Overall survival (OS) did not reach to significant difference between the groups. In multivariable analysis, age was a significant risk factor for PFS (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.04 to 4.16). The IDH1 mutation was the only significant prognostic factor for PFS (HR, 0.28; 95% CI, 0.13 to 0.59) and OS (HR, 0.19; 95% CI, 0.07 to 0.50). Adverse events over grade 3 were seen in 16 patients (40.0%) in the treatment group and were reversible.ConclusionConcurrent and adjuvant temozolomide in Korean adults with newly diagnosed non-co- deleted anaplastic gliomas showed improved 2-year PFS. The survival benefit of this regimen needs further analysis with long-term follow-up at least more than 10 years.

Treatment options for patients with chemotherapy-refractory solid tumors are limited.We conducted an open-label, single-arm, single-center phase II trial to evaluate the efficacy and safety of gefitinib in patients with chemotherapy-refractory solid tumors and EGFR amplification or sensitivity to an EGFR inhibitor identified through a drug-screening platform with patient-derived tumor cells (PDCs).EGFR amplification was detected by targeted sequencing. Sensitivity to an EGFR inhibitor was established in chemical screening using PDCs. Gefitinib (250 mg daily) was administered continuously in 28-day cycles until the occurrence of disease progression, unacceptable toxicity, or death due to any cause. The primary endpoint was the objective response rate (ORR).In total, 15 patients were assigned to the present study. The most common tumor type was glioblastoma multiforme (n = 9, 60%), followed by gastric cancer (n = 3, 20%), anal squamous cancer, rectal cancer, and sarcoma (each n = 1, 6.7%). Among 13 evaluable patients, one patient had a partial response and five had stable disease, with an ORR of 7.7% and a disease control rate of 46.1%. The median progression-free survival was 2.1 months (95% confidence interval [CI] 0.77-3.43). The most common adverse events were diarrhea (26.7%) and skin rash (26.7%).Gefitinib demonstrated modest anti-tumor activity and a manageable safety profile in chemotherapy-refractory solid tumors with EGFR amplification or sensitivity to an EGFR inhibitor identified through a drug-screening platform with PDCs. CLINICALTRIALS.NCT02447419.

Tumor treating fields (TTFields) are anti-mitotic, non-invasive loco-regional cancer therapy comprising low intensity, intermediate frequency alternating electric fields. TTFields plus Temozolomide (TTFields/TMZ) extended survival versus TMZ alone in newly diagnosed glioblastoma (GBM) patients in the EF-14 trial. We report on Korean newly diagnosed GBM patients who participated in the EF-14 trial. Thirty-nine participants of the EF-14 trial were enrolled at 8 sites in South Korea. Patients (24 TTFields/TMZ; 14 TMZ alone) received: TTFields (200 kHz) for > 18 h/day; TMZ at 120–150 mg for 5 days per a 28 day cycle. Safety and efficacy were assessed. Patient baseline characteristics were balanced in the 2 arms and the mean age was 52.1 years, 66.7% were male with a mean KPS of 90. Safety incidence was comparable between the 2 arms. In the TTFields/TMZ arm, 30% suffered from skin irritation versus 52% in the entire study population. No TTFields-related serious adverse events were reported. The median progression-free survival (PFS) in the TTFields/TMZ arm was 6.2 months (95% CI 4.2–12.2) versus 4.2 (95% CI 1.9–11.2) with TMZ alone (p = 0.67). Median overall survival was 27.2 months (95% CI 21-NA) with TTFields/TMZ versus 15.2 months (95% CI 7.5–24.1; HR 0.27, p = 0.01) with TMZ alone. Median OS and 1- and 2-year survival rates were higher with TTFields/TMZ and similar to the entire EF-14 population. About 30% of patients reported skin irritation, a lower rate than seen in the entire EF-14 population. These results demonstrate the efficacy and safety of TTFields in Korean newly diagnosed glioblastoma patients. Clinicaltrials.gov Identifier: NCT00916409.

Preoperative diagnosis of prolactinomas is critical because dopamine agonists have been regarded as a primary treatment. However, serum prolactin level alone is suboptimal for differentiating prolactinomas from hyperprolactinemia-causing non-functioning pituitary adenomas (NFPAs). By using the tumor size, we investigated a more effective parameter for the discrimination.223 patients with pituitary lesions of the histologic diagnosis were retrospectively reviewed. The prolactinoma group (n=48) showed higher serum prolactin (258.6㎍/L) and smaller maximal diameter (16.6mm) than those in the NFPA group (n=175) (44.4㎍/L and 23.9mm; both p-values < 0.001).Using receiver operating curve analyses, we compared diagnostic performances of serum prolactin levels (PRL), a ratio of PRL to maximal tumor diameter (PRL/MD; PDR1), and MD squared (PRL/(MD)2; PDR2) in preoperative diagnosis of prolactinomas. PDR2 exhibited better performance with the cutoff value of 0.83[㎍/L]/ mm2 (area under the curve [AUC] = 0.945), compared to the PDR1 (8.93[㎍/L]/ mm with AUC 0.938) and PRL (99.㎍/L with AUC 0.910). In the external validation study, PDR2 still maintained superiority over PDR1 and PRL (Accuracy of 94.8%, 91.8%, and 75.8%, respectively).In conclusion, PDR2 may be an effective parameter for preoperative discrimination of prolactinomas from NFPAs with hyperprolactinemia, and contribute to select patients who benefit from medical treatment primarily.

INTRODUCTIONPreoperative diagnosis of prolactinomas is critical because dopamine agonists have been regarded as a primary treatment modality. However, serum prolactin level alone is suboptimal for differentiating between prolactinomas and hyperprolactinemia-causing non-functioning pituitary adenomas (NFPAs). The authors investigated more effective parameter for differentiating prolactinomas and NFPAs by using the adenoma size. METHODS We performed a retrospective review of patients who underwent trans-sphenoidal surgery for pituitary lesions in a single institute between January 2015 and May 2021. Using the receiver operating curve (ROC) analyses, we compared performances of serum prolactin levels (PRL), a ratio of serum PRL levels to maximal tumor diameter (MD) (PRL/MD; PDR1), and MD squared (PRL/(MD)2; PDR2) in preoperative diagnosis of prolactinomas. RESULTS 223 patients with NFPAs (n=175) and prolactinomas (n=48) were included in the analysis. The prolactinoma group showed higher serum prolactin (258.6 ㎍/L) and smaller MD (16.6 mm) than those in the NFPA group (44.4 ㎍/L and 23.9 mm; both p-values < 0.001). Among diagnostic parameters, PDR2 exhibited the optimal diagnostic performance with the cutoff value of 0.83 [㎍/L]/mm2 (area under the curve [AUC] = 0.945), compared to the PDR1 (8.93 [㎍/L]/mm with AUC 0.938) and PRL (99.4 ㎍/L with AUC 0.910). PDR2 still maintained superior performance in the validation study than PDR1 and PRL (Accuracy of 94.8%, 91.8%, and 75.8%, respectively).CONCLUSIONS PDR2 provided the best performance of three parameters in preoperative discrimination of prolactinomas from NFPAs with hyperprolactinemia, and could contribute to select patients who benefit from medical treatment primarily.

Prediction of visual outcome after endoscopic endonasal tumor resection still remains a challenge. We investigated the prognostic value of the preoperative peripapillary retinal nerve fiber layer (pRNFL) using optical coherence tomography for visual outcome after endoscopic endonasal surgery (EES) for suprasellar tumors.We retrospectively analyzed 122 patients who underwent EES for sellar and suprasellar tumors between January 2016 and January 2018. We retrospectively analyzed the pre- and postoperative relationship between pRNFL thickness and visual outcome based on visual acuity (visual acuity score) and visual field (mean deviation [MD]).Preoperatively, 216 eyes (mean global pRNFL thickness, 94.3 ± 12.4 μm; 88.5%) were included in the normal pRNFL group (≥70 μm) and 28 eyes (mean global pRNFL thickness, 54.3 ± 11.0 μm; 11.5%) were included in the thin pRNFL group (70 μm). There was a very strong correlation between pre- and postoperative pRNFL thickness (r = 0.930). The thin pRNFL group showed a stronger correlation between pre- and postoperative MDs than the normal pRNFL group (r = 0.619 and r = 0.420, respectively; P0.01). Multivariate analyses identified pRNFL thickness as the only significant predictor of postoperative visual acuity (odds ratio [OR], 25.02; 95% confidence interval [CI], 7.68-81.50; P0.01) and visual field (OR, 39.46; 95% CI, 10.39-149.83; P0.01).Preoperative pRNFL thickness plays a prognostic value in postoperative visual outcome after EES for sellar and suprasellar tumors. Patients with pRNFL thickness ≥70 μm before surgery are more likely to improve visual outcome than those with thickness70 μm.

This study aimed to compare the surgical outcomes and morbidities of retrosigmoid and translabyrinthine approaches for large vestibular schwannoma (VS), with a focus on cerebellar injury and morbidities. Eighty-six consecutive patients with large VS, with a maximal extrameatal diameter > 3.0 cm, were reviewed between August 2010 and September 2018. The surgical outcomes, operating time, volume change of perioperative cerebellar edema, and inpatient rehabilitation related to cerebellar morbidities were compared between the two approaches. In total, 53 and 33 patients underwent the retrosigmoid and translabyrinthine approaches, respectively. The median follow-up time was 34.5 months. Surgical outcomes, including the extent of resection, tumor recurrence, and facial nerve preservation, showed no significant differences between the two groups. Patients who underwent the retrosigmoid approach showed a marginal trend for postoperative lower cranial nerve (LCN) dysfunction (P = 0.068). Although the approaching procedure time was longer in the translabyrinthine group, the tumor resection time was significantly longer in the retrosigmoid group (P = 0.001). The median change in the volume of the perioperative cerebellar edema was significantly larger in the retrosigmoid group (P < 0.001) and significantly related to the retrosigmoid approach, solid VS, and tumor resection time. Most cerebellar and LCN deficits were transient; however, the patients in the retrosigmoid group underwent inpatient rehabilitation more than those in the translabyrinthine group (P = 0.018). Both surgical approaches show equivalent surgical outcomes. Notably, the translabyrinthine approach for large VS has advantages in that it reduces cerebellar injury and related morbidities.

Stereotactic radiosurgery (SRS) is feasible for malignant glioma; however, delivering the optimal radiation dose with sufficient large-volume coverage is a major concern. We aimed to investigate the clinical efficacy and safety of fractionated SRS (fSRS) versus single-session SRS (sSRS) for malignant gliomas. We retrospectively reviewed 58 malignant glioma patients who underwent gamma knife SRS from January 2015 to December 2018. Forty-one underwent sSRS, and 17 underwent fSRS. Median dose for fSRS was 28 Gy (range 24–35 Gy), with a median dose of 6 Gy per fraction (range 5–7 Gy). Patients received 4 or 5 fractions on consecutive days. Median dose for sSRS was 18 Gy (range 11–25 Gy), with a median isodose of 50% (range 50–65%). Mean target volumes were 5.9 and 19.3 cc for sSRS and fSRS, respectively (p

The optimal interfraction intervals for fractionated radiosurgery has yet to be established. We investigated the outcome of fractionated gamma knife radiosurgery (FGKRS) for large brain metastases (BMs) according to different interfraction intervals. Between September 2016 and May 2018, a total of 45 patients who underwent FGKRS for BMs were enrolled in this study. They were divided into two groups (standard fractionation over 3 consecutive days with a 24-h interfraction interval versus prolonged fractionation over 4 or 5 days with an interfraction interval of at least 48-h). BMs with ≥ 2 cm in maximum diameter or ≥ 5 cm3 in volume were included in analysis. Among 52 BMs treated with 3-fraction GKRS, 25 (48.1%) were treated with standard fractionation scheme, and 27 (51.9%) with prolonged fractionation scheme. The median follow-up period was 10.5 months (range 5–25). Local tumor control rates of the standard group were 88.9% at 6 months and 77.8% at 12 months, whereas those of the prolonged group were 100% at 6 and 12 months (p = 0.023, log-rank test). In multivariate analysis, fractionation scheme (hazard ratio [HR] 0.294, 95% CI 0.099–0.873; p = 0.027) and tumor volume (HR 0.200, 95% CI 0.051–0.781; p = 0.021) were revealed as the only significant factors affecting the local tumor control after 3-fraction GKRS. Our preliminary tumor control results suggest a promising role of 3-fraction GKRS with an interfraction interval of at least 48-h. This fractionation regimen could be an effective and safe treatment option in the management of large BMs.

Purpose Targeted next-generation sequencing (NGS) panels for solid tumors have been useful in clinical framework for accurate tumor diagnosis and identifying essential molecular aberrations. However, most cancer panels have been designed to address a wide spectrum of pan-cancer models, lacking integral prognostic markers that are highly specific to gliomas. Materials and methods To address such challenges, we have developed a glioma-specific NGS panel, termed "GliomaSCAN," that is capable of capturing single nucleotide variations and insertion/deletion, copy number variation, and selected promoter mutations and structural variations that cover a subset of intron regions in 232 essential glioma-associated genes. We confirmed clinical concordance rate using pairwise comparison of the identified variants from whole exome sequencing (WES), immunohistochemical analysis, and fluorescence in situ hybridization. Results Our panel demonstrated high sensitivity in detecting potential genomic variants that were present in the standard materials. To ensure the accuracy of our targeted sequencing panel, we compared our targeted panel to WES. The comparison results demonstrated a high correlation. Furthermore, we evaluated clinical utility of our panel in 46 glioma patients to assess the detection capacity of potential actionable mutations. Thirty-two patients harbored at least one recurrent somatic mutation in clinically actionable gene. Conclusion We have established a glioma-specific cancer panel. GliomaSCAN highly excelled in capturing somatic variations in terms of both sensitivity and specificity and provided potential clinical implication in facilitating genome-based clinical trials. Our results could provide conceptual advance towards improving the response of genomically guided molecularly targeted therapy in glioma patients.

Most glioblastomas frequently recur at sites of radiotherapy, but it is unclear if changes in the tumor microenvironment due to radiotherapy influence glioblastoma recurrence. Here, we demonstrate that radiation-induced senescent glioblastoma cells exhibit a senescence-associated secretory phenotype that functions through NFκB signaling to influence changes in the tumor microenvironment, such as recruitment of Ly6G+ inflammatory cells and vessel formation. In particular, Ly6G+ cells promote conversion of glioblastoma cells to glioblastoma stem cells (GSCs) through the NOS2-NO-ID4 regulatory axis. Specific inhibition of NFκB signaling in irradiated glioma cells using the IκBα super repressor prevents changes in the tumor microenvironment and dedifferentiation of glioblastoma cells. Treatment with Ly6G-neutralizing antibodies also reduces the number of GSCs and prolongs survival in tumor-bearing mice after radiotherapy. Clinically, a positive correlation exists between Ly6G+ cells and the NOS2-NO-ID4 regulatory axis in patients diagnosed with recurrent glioblastoma. Together, our results illustrate important roles for Ly6G+ inflammatory cells recruited by radiation-induced SASP in cancer cell dedifferentiation and tumor recurrence.

To find genetic markers associated with response to radiotherapy (RT) in glioblastoma (GB) patients.From Jan 2009 to Dec 2016, 161 patients with newly diagnosed IDH-wild type GB were treated with surgery and adjuvant concurrent chemoradiotherapy with the Stupp's regimen, and then genomic research proceeded with their surgical specimens. Among the 161 patients, 49 with clinically measurable disease on postoperative MRI were analyzed. The response evaluation to RT was based on Response Assessment in Neuro-Oncology (RANO) criteria. For genomic analyses to compare between patients with progression and non-progression, Fisher test for DNA mutations and copy number alterations and the Gene Set Enrichment Analysis (GSEA) were performed.RT responses were non-progressive and progressive disease (PD) in 22 (44.9%) and 27 patients (55.1%), respectively. After three months, seven of PD exhibited pseudoprogression. For true response adjusting pseudoprogression from PD, 1-year progression-free survival for true Non-Responders (tNR-group) and true Responders (tR-group) were 0% and 45.4% (p 0.001), and overall survival were 52.5% and 81.1% (p = 0.046), respectively. In genomic analyses, the tNR-group had more CDKN2A deletions (94.4% vs. 55.6%, p = 0.013), EGFR mutations (33.3% vs. 3.7%, p = 0.012) and less TP53 mutations (22.2% vs. 40.7%, p = 0.333) than the tR-group. In GSEA, immune-related gene sets were enriched in the tNR-group, and in contrast, some gene sets related with cell cycle were enriched in tR-groups.The RANO criteria were feasible for the short-term response evaluation from RT despite of pseudoprogression. Genomic differences such as CDKN2A deletion, EGFR mutation, and immune- or inflammation-related related gene sets enrichment were found to be potentially predictive markers of RT.

Hypermutagenesis refers to marked increase in the number of mutations due to continuous mutagenic process. Hypermutated tumors, have being found in several tumor types, are associated with inherited or acquired alterations in the DNA repair pathways. Hypermutation has been observed in a subset of adult glioma patients as a direct result of temozolomide(TMZ)‐induced mutagenesis. In our study, we have identified a rare subset of treatment‐naïve adult gliomas with de novo hypermutator phenotype and explored the evolution of spontaneous and treatment‐induced hypermutagenesis. We conducted Whole‐Exome Sequencing (WES), Whole‐Transcriptome Sequencing (WTS), and Single‐Cell Sequencing (SCS) of TMZ‐naïve and post‐TMZ‐treated hypermutated tumors to identify distinct clinical or genomic manifestations that contribute to the development of hypermutation in untreated adult gliomas. TMZ‐naïve hypermutated tumors were marked by absence of IDH1 somatic mutation and MGMT promoter (pMGMT) methylation, two genomic traits that were significantly associated with the TMZ‐induced hypermutagenic event in glioblastoma, and harbored inherited alterations in the mismatch repair (MMR) machinery. The immediate family members of the TMZ‐naive hypermutated glioma patients were also previous diagnosed with cancer development history, suggesting that germline dysfunction of the MMR pathway could potentially pose hereditary risk to genetic predisposition of carcinogenesis in gliomas. Lastly, both TMZ‐naïve and post‐TMZ‐treated hypermutated tumors exhibited a significant accumulation of neoantigen loads, suggesting immunotherapeutic alternatives. Our results present new and unique understanding of hypermutagenic process in adult gliomas and an important step towards clinical implication of immunotherapy in glioma treatment., What's new? Hypermutation has been observed in a subset of adult glioma patients as a direct result of temozolomide (TMZ)‐induced mutagenesis, leading to therapeutic resistance. Here, the authors identified a rare subset of pre‐treatment adult glioma patients with de novo hypermutator phenotype. TMZ‐naïve hypermutated tumors lacked somatic mutation of IDH1 and MGMT promoter methylation, and harbored both germline and somatic dysregulation of mismatch repair machinery encoding genes. Patients with TMZ‐naïve hypermutagenesis demonstrated high incidence of cancer‐development history in their immediate family members. Both TMZ‐naïve and post‐TMZ treated hypermutated tumors exhibited a significant accumulatin of neoantigen loads, pointing towards potential implementation of immunotherapy.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

A late-onset treatment-related changes (TRCs), which represent radiographic radiation necrosis (RN), frequently occur after stereotactic radiosurgery (SRS) for brain metastases and often need surgical treatment. This study aimed to validate the true pathology and investigate clinical implication of surgically resected TRCs on advanced magnetic resonance imaging (MRI).Retrospective analyses of 86 patients who underwent surgical resection after radiosurgery of brain metastases were performed. Fifty-four patients displayed TRCs on preoperative MRI, comprising pure RN in 19 patients (TRC-RN group) and mixed viable tumor cells in 35 patients (TRC-PD group). Thirty-two patients revealed the consistent diagnosis of progressive disease in both MRI and histopathology (PD-PD group). The TRC-PD group showed larger prescription isodose volume (9.4 cm3) than the TRC-RN (4.06 cm3, p=0.014) group and a shorter time interval from SRS to preoperative MRI diagnosis (median 4.07 months) than the PD-PD group (median 8.77 months, p=0.004). Progression-free survival was significantly different among the three groups (p

An organoid array chip was developed by adopting a micropillar and microwell structure to test safety and efficacy of drugs using high dose drug heat map. In the chip, we encapsulated patient-derived cells in alginate and grow them to maturity for more than 7 days to form cancer organoids. When screening drug compounds in a high-density organoid array due to lack of number of patient-derived cells, changing media without damage of organoids is a very tedious and difficult process. Organoids grown in conventional well plates needed too many cells and were also easily damaged due to multiple pipetting during maintenance culture or during experimental procedures. To solve those problem, we applied a micropillar and microwell structure to the organoid array. We used patient-derived cells from patients with Glioblastoma multiforme (GBM), the most common and lethal form of central nervous system cancer, to validate the array chip performance. After forming more than 100µm-diameter organoids in 12 [[EQUATION]] 36 pillar array chip (25mm [[EQUATION]] 75mm), we tested 70 drug compounds (6 replicates) with high high-dose to find out high safety and efficacy drug candidates. Comparing the drug response of organoids derived from normal cells and cancer cells, we identified four compounds (Dacomitinib, Cediranib, Ly2835219, BGJ398) as drug candidates without toxicity to GBM cells.

To test the safety and efficacy of drugs via a high does drug heat map, a multi-spheroids array chip was developed by adopting a micropillar and microwell structure. In the chip, patient-derived cells were encapsulated in alginate and grown to maturity for more than 7 days to form cancer multi-spheroids. Multi-spheroids grown in conventional well plates require many cells and are easily damaged as a result of multiple pipetting during maintenance culture or experimental procedures. To address these issues, we applied a micropillar and microwell structure to the multi-spheroids array. Patient-derived cells from patients with Glioblastoma (GBM), the most common and lethal form of central nervous system cancer, were used to validate the array chip performance. After forming multi-spheroids with a diameter greater than 100μm in a 12×36 pillar array chip (25mm × 75mm), we tested 70 drug compounds (6 replicates) using a high-dose to determine safety and efficacy for drug candidates. Comparing the drug response of multi-spheroids derived from normal cells and cancer cells, we found that four compounds (Dacomitinib, Cediranib, LY2835219, BGJ398) did not show toxicity to astrocyte cell and were efficacious to patient-derived GBM cells.

PTEN is one of the most frequently altered tumor suppressor genes in malignant tumors. The dominant-negative effect of PTEN alteration suggests that the aberrant function of PTEN mutation might be more disastrous than deletion, the most frequent genomic event in glioblastoma (GBM). This study aimed to understand the functional properties of various PTEN missense mutations and to investigate their clinical relevance. The genomic landscape of PTEN alteration was analyzed using the Samsung Medical Center GBM cohort and validated via The Cancer Genome Atlas dataset. Several hotspot mutations were identified, and their subcellular distributions and phenotypes were evaluated. We established a library of cancer cell lines that overexpress these mutant proteins using the U87MG and patient-derived cell models lacking functional PTEN. PTEN mutations were categorized into two major subsets: missense mutations in the phosphatase domain and truncal mutations in the C2 domain. We determined the subcellular compartmentalization of four mutant proteins (H93Y, C124S, R130Q, and R173C) from the former group and found that they had distinct localizations; those associated with invasive phenotypes (‘edge mutations’) localized to the cell periphery, while the R173C mutant localized to the nucleus. Invasive phenotypes derived from edge substitutions were unaffected by an anti-PI3K/Akt agent but were disrupted by microtubule inhibitors. PTEN mutations exhibit distinct functional properties regarding their subcellular localization. Further, some missense mutations (‘edge mutations’) in the phosphatase domain caused enhanced invasiveness associated with dysfunctional cytoskeletal assembly, thus suggesting it to be a potent therapeutic target.

// Dong Geon Kim 1, 2 , Kang Ho Kim 2 , Yun Jee Seo 2 , Heekyoung Yang 2, 3 , Eric G. Marcusson 6 , Eunju Son 2, 4 , Kyoungmin Lee 1, 2 , Jason K. Sa 1, 2 , Hye Won Lee 1, 2, 5 , Do-Hyun Nam 1, 2, 3 1 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea 2 Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea 3 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea 5 Department of Urology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea 6 Providence Therapeutics, Calgary, Canada Correspondence to: Do-Hyun Nam, email: nsnam@skku.edu Keywords: anti-miR, glioblastoma, intratumoral injection, intraventricular injection, delivery efficiency Received: December 03, 2015 Accepted: March 28, 2016 Published: April 19, 2016 ABSTRACT Small non-coding RNAs called miRNAs are key regulators in various biological processes, including tumor initiation, propagation, and metastasis in glioblastoma as well as other cancers. Recent studies have shown the potential for oncogenic miRNAs as therapeutic targets in glioblastoma. However, the application of antisense oligomers, or anti-miRs, to the brain is limited due to the blood-brain barrier (BBB), when administered in the traditional systemic manner. To induce a therapeutic effect in glioblastoma, anti-miR therapy requires a robust and effective delivery system to overcome this obstacle. To bypass the BBB, different delivery administration methods for anti-miRs were evaluated. Stereotaxic surgery was performed to administer anti-Let-7 through intratumoral (ITu), intrathecal (ITh), and intraventricular (ICV) routes, and each method’s efficacy was determined by changes in the expression of anti-Let-7 target genes as well as by immunohistochemical analysis. ITu administration of anti-miRs led to a high rate of anti-miR delivery to tumors in the brain by both bolus and continuous administration. In addition, ICV administration, compared with ITu administration, showed a greater distribution of the miR across entire brain tissues. This study suggests that local administration methods are a promising strategy for anti-miR treatment and may overcome current limitations in the treatment of glioblastoma in preclinical animal models.

INTRODUCTION The true pathology and clinical implication of treatment-related image changes (TRICs) after stereotactic radiosurgery (SRS) for brain metastases (BM) have not been established. This study compared the surgical pathology and outcomes of intracranial metastatic lesions featured as TRICs or progressive disease (PD) in advanced magnetic resonance imaging (MRI).METHODS A total of 86 patients who underwent surgical resection of brain metastases previously treated with gamma knife radiosurgery (GKS) from 2009 to 2019 were retrospectively reviewed and classified by MRI findings and histopathology.RESULTS Among 54 patients with TRICs in preoperative MRI, the histopathology of pure radiation necrosis (RN) was confirmed in 19 patients (TRIC-RN) and mixed or predominant viable tumor cells in 35 patients (TRIC-PD). Thirty-two patients diagnosed with PD exhibited the metastatic histology well correlated with imaging (PD-PD). The TRIC-PD group showed larger prescription isodose volume (9.4 cm3) than the TRIC-RN (4.06 cm3, p=0.014) group and shorter time interval from GKS to preoperative MRI diagnosis related to neurological deficits (median 4.07 months) than the PD-PD group (median 8.77 months, p=0.004). Significant differences in progression-free survival were confirmed among the three groups (pCONCLUSIONS The brain metastatic lesions diagnosed as TRICs after GKS frequently contained viable tumor cells, while they exhibited the benign prognosis as RN after surgical resection. These findings suggest that TRICs on advanced MRI can serve as a prognostic factor, regardless of the histologic heterogeneity.

Background: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer-related mortality worldwide. The genetic and physiological complexity of HCC is a major barrier to the study of tumorigenesis and identification of therapeutic targets. The three-dimensional (3D) culture of cancer cells within an extracellular matrix (ECM) provides an in vitro tumor model that best recapitulates in vivo tumor pathophysiology.Methods: In the current study, we cultured cells and made spheroids by aggregating cells or diffusing cells in Matrigel attached on the tip of the 96-pillar plate. According to the initial cell position in Matrigel, two 3D-HCC cancer in-vitro models (diffused spheroid model and aggregated spheroid model) were established. These two models were applied to drug sensitivity assays to identify drug sensitivity changes. The protein expression and cytokine activation related to the drug resistance and maintenance of the physiological properties of HCC cells were analyzed in both models. This 3D culture method not only maintained the phenotype of the tumor but allowed easy high-throughput screening (HTS) due to its 96-array plate configuration.Results: The Aggregated Spheroid Model (ASM) showed higher expression of cancer markers associated with proliferation, tight junctions formation and epithelial cell identity in HCC cells, as well as cytokine factors associated with immune cell recruitment/activation, ECM regulation, cancer interaction, and angiogenesis regulation.Conclusions: Overall, the proposed ASM better recapitulates the tumor microenvironment, demonstrating the involvement of the ECM/tight junctions in the cell-to-cell signaling processes. This provides more instructive data for in vitro screening of tumor cells.

Objective The retroinfundibular and upper clival regions are challenging to access using the endoscopic endonasal approach because these regions are obstructed by the dorsum sellae and posterior clinoid processes. We evaluated the safety and clinical efficacy of endoscopic dorsum sellar resection (DSR) and identified the optimal indications for endoscopic DSR in patients with craniopharyngioma. Methods A retrospective study was conducted of patients who had undergone treatment with an endoscopic endonasal approach from January 2014 to January 2019. We identified a total of 50 patients who had undergone DSR. The indications for DSR included the following: 1) a tumor involving the upper clivus; 2) a tumor located behind the dorsum sellae; and 3) a tumor involving the interpeduncular or prepontine cistern. We evaluated the clinical outcomes, postoperative endocrinological status, and surgical morbidities. Results Of the 50 patients, 16 had been treated for craniopharyngioma, 30 for chordoma, 2 for pituitary adenoma, 1 for schwannoma, and 1 for chondrosarcoma. An extradural approach for DSR with posterior clinoidectomy was performed in 33 patients (66.0%) and an interdural transcavernous approach in 17 patients (34.0%). The overall gross total tumor resection rate was 92.0% (46 of 50 patients). Postoperatively, 28 of 33 patients (84.8%) with normal pituitary function preoperatively showed preservation of hormonal function postoperatively. Conclusions DSR with or without posterior clinoidectomy is a challenging procedure that requires considerable effort and advanced surgical techniques. However, it can be safely performed with accumulating experience and a thorough knowledge of the surrounding anatomical structures.