scholarly journals Vasculogenic Mimicry Formation Predicts Tumor Progression in Oligodendroglioma

2021 ◽  
Vol 27 ◽  
Author(s):  
Jing Xie ◽  
Xue Kong ◽  
Wei Wang ◽  
Yuan Li ◽  
Mengyu Lin ◽  
...  

Vasculogenic mimicry (VM) has been identified as an important vasculogenic mechanism in malignant tumors, but little is known about its clinical meanings and mechanisms in oligodendroglioma. In this study, VM-positive cases were detected in 28 (20.6%) out of 136 oligodendroglioma samples, significantly associated with higher WHO grade, lower Karnofsky performance status (KPS) scores, and recurrent tumor (p < 0.001, p = 0.040, and p = 0.020 respectively). Patients with VM-positive oligodendroglioma had a shorter progress-free survival (PFS) compared with those with VM-negative tumor (p < 0.001), whereas no significant difference was detected in overall survival (OS) between these patients. High levels of phosphorylate serine/threonine kinases Ataxia-telangiectasia mutated (pATM) and phosphorylate Ataxia-telangiectasia and Rad3-Related (pATR) were detected in 31 (22.8%) and 34 (25.0%), respectively out of 136 oligodendroglioma samples. Higher expressions of pATM and pATR were both associated with a shorter PFS (p < 0.001 and p < 0.001). VM-positive oligodendroglioma specimens tended to exhibit higher pATM and pATR staining than VM-negative specimens (rs = 0.435, p < 0.001 and rs = 0.317, p < 0.001). Besides, Hypoxia-inducible factor-1α (HIF1α) expression was detected in 14(10.3%) samples, correlated with higher WHO grade and non-frontal lobe (p = 0.010 and p = 0.029). However, no obvious connection was detected between HIF1α expression and VM formation (p = 0.537). Finally, either univariate or multivariate analysis suggested that VM was an independent unfavorable predictor for oligodendroglioma patients (p < 0.001, HR = 7.928, 95%CI: 3.382–18.584, and p = 0.007, HR = 4.534, 95%CI: 1.504–13.675, respectively). VM is a potential prognosticator for tumor progression in oligodendroglioma patients. Phosphorylation of ATM and ATR linked to treatment-resistance may be associated with VM formation. The role of VM in tumor progression and the implication of pATM/pATR in VM formation may provide potential therapeutic targets for oligodendroglioma treatment.

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi15-vi15
Author(s):  
Yanwei Liu ◽  
Xia Shan ◽  
Xiaoguang Qiu

Abstract Our previous data showed that WHO grade II/III gliomas with isocitrate dehydrogenase wide-type (IDH-wt) and telomerase reverse transcriptase promoter mutation (TERTp-mut) have dismal prognosis as glioblastoma. This study compared concurrent chemoradiotherapy(CRT) with radiotherapy(RT) alone on the outcome of these patients. Between September 2016 and November 2018, 30 eligible grade II/III glioma patients with IDH-wt and TERTp-mut were randomly assigned to receive either RT (60 Gy in 30 daily fractions for 6 weeks) alone (n=15) or concurrent CRT with daily temozolomide and adjuvant temozolomide (n=15). The median follow-up duration was 15.5 months. The median age was 51 years (range, 24–66 years). The median Karnofsky performance status (KPS) score at randomization was 80 (range, 60–80). Surgery was the primary treatment. The characteristics of the two treatment groups were well balanced at baseline. The 1-year OS rate was significant difference between CRT group (92.3%; 95% CI: 77.8–100) and RT alone group(71.1%; 95% CI: 47.0–95.2) (p = 0.019). Local, distant, and combined tumor recurrence patterns were observed in 4 (26.7%), 1 (6.7%), and 3 patients (20%) in the CRT group and 4 (26.7%), 3 (20%), and 3 patients (20%) in the RT alone group. Those treated with RT alone had shorter median PFS (9 vs 18 months, HR: 0.517; 95% CI: 0.193 to 1.386; p = 0.19). CRT with temozolomide and extent of resection were statistically significant predictors for survival on univariate analysis. Multivariate analysis showed that CRT was associated with a significantly better OS compared with RT alone (OR=0.195; 95% CI, 0.044 to 0.867; p=0.032). Consequently, concurrent CRT with daily temozolomide and adjuvant temozolomide for newly diagnosed IDHwt/TERTp-mut grade II/III gliomas had significantly better OS compared with RT alone. A large multi-center prospective randomized trial is warranted. The trial has been registered at ClinicalTrials.gov (NCT02766270).


Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1451
Author(s):  
Michele Da Broi ◽  
Paola Borrelli ◽  
Torstein R. Meling

Background: Although gross total resection (GTR) is the goal in meningioma surgery, this can sometimes be difficult to achieve in skull base meningiomas. We analyzed clinical outcomes and predictors of survival for subtotally resected benign meningiomas. Methods: A total of 212 consecutive patients who underwent subtotal resection (STR) for benign skull base meningioma between 1990–2010 were investigated. Results: Median age was 57.7 [IQR 18.8] years, median preoperative Karnofsky performance status (KPS) was 80.0 [IQR 20.0], 75 patients (35.4%) had posterior fossa meningioma. After a median follow-up of 6.2 [IQR 7.9] years, retreatment (either radiotherapy or repeated surgery) rate was 16% at 1-year, 27% at 3-years, 34% at 5-years, and 38% at 10-years. Ten patients (4.7%) died perioperatively, 9 (3.5%) had postoperative hematomas, and 2 (0.8%) had postoperative infections. Neurological outcome at final visit was improved/stable in 122 patients (70%). Multivariable analysis identified advanced age and preoperative KPS < 70 as negative predictors for overall survival (OS). Patients who underwent retreatment had no significant reduction of OS. Conclusions: Advanced age and preoperative KPS were independent predictors of OS. Retreatments did not prolong nor shorten the OS. Clinical outcomes in STR skull base meningiomas were generally worse compared to cohorts with high rates of GTR.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wen Yin ◽  
Hecheng Zhu ◽  
Jun Tan ◽  
Zhaoqi Xin ◽  
Quanwei Zhou ◽  
...  

Abstract Background Gliomas account for the majority of fatal primary brain tumors, and there is much room for research in the underlying pathogenesis, the multistep progression of glioma, and how to improve survival. In our study, we aimed to identify potential biomarkers or therapeutic targets of glioma and study the mechanism underlying the tumor progression. Methods We downloaded the microarray datasets (GSE43378 and GSE7696) from the Gene Expression Omnibus (GEO) database. Then, we used weighted gene co-expression network analysis (WGCNA) to screen potential biomarkers or therapeutic targets related to the tumor progression. ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumors using Expression data) algorithm and TIMER (Tumor Immune Estimation Resource) database were used to analyze the correlation between the selected genes and the tumor microenvironment. Real-time reverse transcription polymerase chain reaction was used to measure the selected gene. Transwell and wound healing assays were used to measure the cell migration and invasion capacity. Western blotting was used to test the expression of epithelial-mesenchymal transition (EMT) related markers. Results We identified specific module genes that were positively correlated with the WHO grade but negatively correlated with OS of glioma. Importantly, we identified that 6 collagen genes (COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, and COL5A2) could regulate the immunosuppressive microenvironment of glioma. Moreover, we found that these collagen genes were significantly involved in the EMT process of glioma. Finally, taking COL3A1 as a further research object, the results showed that knockdown of COL3A1 significantly inhibited the migration, invasion, and EMT process of SHG44 and A172 cells. Conclusions In summary, our study demonstrated that collagen genes play an important role in regulating the immunosuppressive microenvironment and EMT process of glioma and could serve as potential therapeutic targets for glioma management.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi85-vi85
Author(s):  
Christopher Douglas ◽  
Daniela Bota ◽  
Kaijun Di ◽  
Bhaskar Das ◽  
Javier Lepe

Abstract Glioblastoma (GBM), a WHO grade IV brain cancer, exhibits strong treatment resistance and a high rate of reoccurrence, which gives it a dismal prognosis, a 5% survival rate in the first 5 years. LonP1, a mitochondrial master regulator, can drive metabolic transformation, cytokine production, EMT, and treatment resistance in various cancer types, but its role in GBM remains unexplored. Our research group has previously shown that LonP1 is overexpressed in human malignant gliomas, particularly glioblastoma, and that this is associated with disease prognosis. Here, we present findings that demonstrate that LonP1 seems to drive enhanced tumor progression, invasiveness, angiogenesis in different high grade glioblastomas based on TCGA-subtype. Furthermore, in collaboration with Professor Bhaskar Das, we have validated a lead compound, BT317, with on-target inhibition of LonP1 protease activity. BT317 has enhanced activity against glioma stem cell lines (GSC) and has demonstrated low toxicity and efficacy in an intracranial xenograft model. This preliminary data highlights the potential of using combinatorial, pharmacological LonP1 and proteasome inhibition as a novel strategy for targeting specific subtypes of GBM.


2013 ◽  
Vol 119 (4) ◽  
pp. 871-877 ◽  
Author(s):  
Dale Ding ◽  
Zhiyuan Xu ◽  
Ian T. McNeill ◽  
Chun-Po Yen ◽  
Jason P. Sheehan

Object Parasagittal and parafalcine (PSPF) meningiomas represent the second most common location for intracranial meningiomas. Involvement of the superior sagittal sinus or deep draining veins may prevent gross-total resection of these tumors without significant morbidity. The authors review their results for treatment of PSPF meningiomas with radiosurgery. Methods The authors retrospectively reviewed the institutional review board–approved University of Virginia Gamma Knife database and identified 65 patients with 90 WHO Grade I parasagittal (59%) and parafalcine (41%) meningiomas who had a mean MRI follow-up of 56.6 months. The patients' mean age was 57 years, the median preradiosurgery Karnofsky Performance Status score was 80, and the median initial tumor and treatment volumes were 3 and 3.7 cm3, respectively. The median prescription dose was 15 Gy, isodose line was 40%, and the number of isocenters was 5. Kaplan-Meier analysis was used to determine progression-free survival (PFS). Univariate and multivariate Cox regression analyses were used to identify factors associated with PFS. Results The median overall PFS was 75.6 months. The actuarial tumor control rate was 85% at 3 years and 70% at 5 years. Parasagittal location, no prior resection, and younger age were found to be independent predictors of tumor PFS. For the 49 patients with clinical follow-up (mean 70.8 months), the median postradiosurgery Karnofsky Performance Status score was 90. Symptomatic postradiosurgery peritumoral edema was observed in 4 patients (8.2%); this group comprised 3 patients (6.1%) with temporary and 1 patient (2%) with permanent clinical sequelae. Two patients (4.1%) died of tumor progression. Conclusions Radiosurgery offers a minimally invasive treatment option for PSPF meningiomas, with a good tumor control rate and an acceptable complication rate comparable to most surgical series.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi46-vi46
Author(s):  
Fumi Higuchi ◽  
Takeo Uzuka ◽  
Keisuke Ueki

Abstract Oligodendrogliomas with 1p/19q-codeletion are relatively slow progressive tumors that show good response to chemo-radiation therapy after resection. The median survival is about 15 years regardless of WHO grade, although recurrences are mostly inevitable and there is no standard treatment for recurrence. We experienced 5 oligodendroglioma cases who underwent re-radiation for recurrent tumors after chemo-radiation treatment. We retrospectively investigated those for response to re-radiation, the duration from first radiation to second radiation, and Karnofsky Performance Status (KPS) before and after the re-radiation. Patients were all male; the median radiation dose for primary tumor was 60Gy (54-60Gy), the median age at first radiation was 46 years (35-59), the median duration from the first radiation to re-radiation was 65 months (range 18-116 months), and the median follow-up period after re-radiation was 15 months (1-39 months). In all 5 cases, tumors showed good response to re-radiation. In 3 of the 5 cases, tumor recurred in corpus callosum and/or lateral side of cerebral hemisphere or basal ganglia contiguous with primary tumor sites and were radiated by IMRT (50Gy/25fr) . In 2 cases, tumors recurred around the fourth ventricle and posterior fossa and underwent conventional radiation (54Gy/30fr and 30Gy/10fr). In 2 of the 5 cases, the tumors re-recurred 24 months later after re-radiation, but the KPS were maintained until re-recurrence. For oligodendrogliomas, re-radiation therapy appears to be very effective to recurrent tumors after first chemo-radiation. Although evaluation for longer-term side effects is to be examined, re-radiation appears to be a good option for recurrent oligodendrogliomas after first chemo-radiation therapy.


1989 ◽  
Vol 7 (9) ◽  
pp. 1288-1294 ◽  
Author(s):  
S I Bearman ◽  
F R Appelbaum ◽  
A Back ◽  
F B Petersen ◽  
C D Buckner ◽  
...  

Ninety-five patients transplanted for malignant lymphoma were retrospectively evaluated for regimen-related toxicity (RRT) and early posttransplant survival. Nineteen patients developed life-threatening (grade 3) or fatal (grade 4) RRT in one or more organs. Grade 3 or 4 RRT was more common in patients with advanced disease versus those transplanted earlier in their course (P = .008), and was more common in patients with advanced disease conditioned with cytarabine (Ara-C)/total body irradiation (TBI) versus those prepared with cyclophosphamide (CY)/TBI (P = .033). There was no significant difference in the incidence of grade 3 or 4 toxicity in autologous, histocompatibility locus antigen (HLA)-identical, or HLA-mismatched marrow recipients. Grade 3 or 4 RRT tended to be more common and 100-day survival worse in patients with a Karnofsky performance status of less than 90 (P = .063 and .0002, respectively). Patients receiving 20 Gy or more of mediastinal irradiation before coming to transplant had more idiopathic or cytomegalovirus (CMV) interstitial pneumonitis than those who received less than 20 Gy (30% v 9%, P = .027). The probability of survival decreased with the number of organs in which toxicity was observed (P = .0001). Severe or fatal toxicities directly related to the preparative regimen are a significant problem in the treatment of patients with advanced malignant lymphoma and can be reduced by carrying out transplantation earlier in the course of the disease.


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e20631-e20631
Author(s):  
J. T. D'Olimpio ◽  
M. R. Chasen ◽  
R. Sharma ◽  
M. Diego ◽  
V. Gullo ◽  
...  

e20631 Background: AVR118 represents a new class of cytoprotective drugs in managing symptoms associated with anorexia\/ cachexia. In a previous study in patients with advanced HIV-AIDS, an improvement in appetite, strength and alertness was noted. The precise mechanism of action is not understood, but activity may be related to AVR118's adenosine based components. Other active components include guanosine and branched chain amino acids leucine and valine. Objective: To determine the effect of AVR118 on appetite, early satiety and nutritional intake in patients with advanced cancer. Secondary endpoints include changes in performance status, lean muscle mass and quality of Life (QOL). Methods: Eligible adult patients received 4.0 ml of AVR118 subcutaneous daily injections. Patients underwent bi-monthly evaluations during the 28 day initial treatment (phase A) Evaluations included Karnofsky performance status, Edmonton Symptoms Assessment Scale (ESAS), Patient Generated Subjective Global Assessment (PG-SGA), Simmonds Functional Assessment, Dyspepsia Symptom Severity Index, Weight, Lean Body Mass, skin fold thickness and grip strength. Patients who benefited from phase A could elect to continue with therapy (phase B). Results: Currently, of 16 enrolled patients 7 have completed phase A. All 7 patients chose to continue with AVR118 treatment (phase B). Improvements in anorexia and PG-SGA scores were seen in 7/7 and 6/7 patients respectively. Weight stabilization or gain was observed in 5/7 patients. All other parameters showed no significant difference. There was AVR118 has been well tolerated and no serious side effects have been reported. Conclusions: Based on these positive results, the primary endpoints have been achieved and the study will be expanded from 14 to 30 patients. [Table: see text]


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9017-9017 ◽  
Author(s):  
Yuanjue Sun ◽  
Baorui Liu ◽  
Ping Liu ◽  
Changping Wu ◽  
Rongsheng Zheng ◽  
...  

9017 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of many commonly used chemotherapeutic. This side effect of chemotherapy can be debilitating and effective treatment for CIPN remains elusive. Previous studies demonstrated that Acetyl-L-Carnitine (ALC) is effective in attenuating CIPN, controlled study is needed to substantiate ALC’s effect in treatment of CIPN. Methods: This study was designed to evaluate the efficacy and safety of Acetyl-L-Carnitine (ALC) Hydrochloride Enteric-coated Tablet (oral administration) in the treatment of CIPN. It was a prospective, randomized, double-blinded, placebo-controlled and paralleled clinical study (registration No. 2007L03540). Of 239 subjects enrolled in the study (NCI grade 2 or above), 118 subjects received 3g/day ALC orally for 8 weeks and 121 received placebo. Primary endpoint was set as improvement of peripheral neuropathy at least 1 grade and assessment was made in week 4, 8 and 12 after enrollment. Results: In full analyses set (FAS) and per-proposal set (PPS), the peripheral sensory neuropathy was significantly ameliorated in ALC group with 50.5% and 51.6% patients meeting the primary endpoint at week 8 and 12 respectively while only 24.1% and 23.1% of patients in the placebo group at week 8 and 12 respectively (p<0.001 in both sets). Secondary endpoint such as nerve electrophysiological test and Physical Condition Score (Karnofsky performance status, KPS) were also significantly improved in patients with ALC treatment (in FAS, P=0.0463 and P=0.022; in PPS, P=0.0076and P=0.0064, respectively). Cancer-related fatigue was significantly alleviated after ALC treatment in PPS (P=0.0135). Safety: 236 subjects were included in safety assessment and 41 patients experienced 62 adverse events during the course of study. There was no significant difference in AE/SAE incidence between the two groups (P=0.3903). Conclusions: Oral administration of ALC is effective in attenuating CIPN as well as in reducing cancer-related fatigue and improving physical conditions in cancer patients. The treatment of oral ALC is safe and well tolerated.


2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 487-487
Author(s):  
Stefan Stremitzer ◽  
Anna Sophie Berghoff ◽  
Nico Benjamin Volz ◽  
Wu Zhang ◽  
Dongyun Yang ◽  
...  

487 Background: Brain metastases (BM) in colorectal cancer (CRC) are rare, developing in only 0.3-9% of the patients, and considered a late-stage manifestation of the disease. The aim of this study was to investigate whether genetic variants of genes involved in BM-related pathways, such as integrin, invasion- and adhesion-mediating, angiogenic and tumor suppressing pathways, are associated with outcome. Methods: Genomic DNA was extracted from formalin-fixed paraffin embedded resected BM from 70 patients with histologically proven CRC. Single nucleotide polymorphisms (SNP) in seven genes (CXCR4, MMP9, ST6GALNAC5, ITGAV, ITGB1, ITGB3, KLF4) were analyzed by direct Sanger DNA sequencing and evaluated for association with overall survival (OS) from resection of BM. Only SNPs with an allele frequency of ≥ 10% were analyzed. Results: In univariate analysis, rs17577 (MMP9) and rs4642 (ITGB3) showed a significant difference in OS [(G/G 7.4 months, G/A 5.1 months; HR (95% CI) 1.83 (0.95-3.53), p = 0.0440) and (A/A 9.4 months, A/G 4.8 months, G/G 4.3 months; HR (95% CI) 0.81 (0.44-1.49) and 2.14 (0.98-4.67), p = 0.0354), respectively]. In multivariate analysis adjusted for baseline characteristics [primary tumor site (right colon, left colon, rectal), chemotherapy before BM (yes/no), BM location (supratentorial, infratentorial, both), Karnofsky performance status (<80, 80-100)], rs2236599 (KLF4), and rs10171481 (ITGAV) are significant in OS [(G/G 7.4 months, G/A or A/A 4.8 months; HR (95% CI) 3.19 (1.55-6.53), p = 0.0016) and (A/A 5.7 months, A/G 4.4 months, G/G 15.5 months; HR (95% CI) 0.61 (0.29-1.29) and 0.25 (0.10-0.60), p = 0.0082), respectively]. Conclusions: This study suggests for the first time a prognostic effect of the SNPs involved in the BM pathway. Further analyses are needed to confirm these findings.


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