Surgical management and long-term outcomes of primary intracranial leiomyosarcoma: a case series and review of literature.

Primary intracranial leiomyosarcomas (PILMSs) are extremely rare neoplasms, and their management remains unclear. The authors aimed to enunciate the radiological features and design a treatment protocol based on previously published cases combined with our series. Clinical data from all 12 cases of PILMS treated at their institute between 2008 and 2018 were reviewed. Meanwhile, they searched the Ovid MEDLINE, Embase, PubMed, Web of Science and Cochrane databases using the keywords "leiomyosarcoma" and "intracranial," "central nervous system," "cerebral," or "brain" Previously published data were processed and used according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The authors' cohort included 4 males (33.3%) and 8 females (66.7%) ranging in age from 13 to 67 years with a mean of 44.1 ± 5.0 years. Gross total resection (GTR), subtotal resection, and partial resection were achieved in 8 (66.7%), 3 (25%), and 1 (8.3%) patient, respectively, and only four patients (33.3%) received adjuvant therapy after surgery. After a mean follow-up of 30.5 ± 7.6 months, 6 patients (50%) experienced recurrences, and all of them died at the final. Twenty-seven patients (15 were male and 12 were female), in the literature cases, were identified between January 1980 and November 2019, presenting with PILMS. GTR and non-GTR were achieved in 21 (77.8%) and 6 (22.2%) patients, respectively. Postoperative radiotherapy was administrated in 17 patients (63.0%), and postoperative chemotherapy was administrated in 9 patients (33.3%), After a mean follow-up of 22.2 ± 4.1 months, recurrence and death occurred in 8 (36.4%) and 4 (14.8%) cases, respectively. In the pooled cases, the univariate analysis model revealed that only GTR was a significantly favorable factor for increased progression-free survival (hazard ratio 0.270, 95% confidence interval = 0.093-0.787, p = 0.016) and overall survival (hazard ratio 0.255, 95% confidence interval = 0.073-0.890, p = 0.032). GTR was recommended as an optimal treatment; meanwhile, postoperative radiation was also a choice to help increase the survival of patients of PILMS.

MicroRNA-221/222 Inhibits the Radiation-Induced Invasiveness and Promotes the Radiosensitivity of Malignant Meningioma Cells.

The controversy of adjuvant radiotherapy of meningiomas is at least partially due to the insufficient understanding on meningioma cells' response to irradiation and the shortage of radiosensitivity-promotion methods. MicroRNA-221 and microRNA-222 were identified as critical regulators of radiosensitivity in several other tumors. However, their effect in meningiomas has yet to be confirmed. Therefore, the malignant meningioma IOMM-Lee cells were adopted, transfected with microRNA-221/222 mimics or inhibitors, and irradiated with different dosages. The effects of radiation and microRNA-221/222 were then assessed in vitro and in vivo. Radiation dose increases and microRNA-221/222 downregulation synergistically inhibited cell proliferation and colony formation, prevented xenograft tumor progression, and promoted apoptosis, but antagonistically regulated cell invasiveness. Pairwise comparisons revealed that only high-dose radiations (6 and 8 Gy) can significantly promote cell invasiveness in comparison with unirradiated counterparts. Further comparisons exhibited that downregulating the microRNA-221/222 expression can reverse this radiation-induced cell invasiveness to a level of untransfected and unirradiated cells only if cells were irradiated with no more than 6 Gy. In addition, this approach can promote IOMM-Lee's radiosensitivity. Meanwhile, we also detected that the dose rate of irradiation affects cell cycle distribution and cell apoptosis of IOMM-Lee. A high dose rate irradiation induces G0/G1 cell cycle arrest and apoptosis-promoting effect. Therefore, for malignant meningiomas, high-dose irradiation can facilitate cell invasiveness significantly. Downregulating the microRNA-221/222 level can reverse the radiation-induced cell invasiveness while enhancing the apoptosis-promoting and proliferation-inhibiting effects of radiation and promoting cell radiosensitivity.

Adverse Factors of Treatment Response and Overall Survival in Pediatric and Adult Patients with Pineoblastoma.

OBJECTIVE: Intracranial pineoblastomas are rare neoplasms with poor prognosis. The aim of this study was to describe the independent prognostic factors and treatment strategies for overall survival in pediatric and adult patients. METHODS: Sixty-four patients were surgically treated between January 2012 and December 2018. RESULTS: The series included 37 (57.8%) males and 27 (42.2%) females. Gross total resection was achieved in 41 (64.1%) cases, and the 1-, 3-, and 5-year rates of overall survival were 86.3, 52.3, and 36.6%, respectively. In the pediatric group (n=42), 28 patients (66.7%) were male, with the median, and the mean age was 4 and 6.2±4.7 years, respectively. After a median follow-up of 25.0 months, twenty-six patients (61.9%) died, and the 1-, 3-, and 5-year rates of overall survival were 84.9, 46.4, and 26.7%, respectively. Postoperative radiotherapy (p=0.058) and postoperative chemotherapy (p=0.183) had a positive influence on the increased overall survival. Meanwhile, postoperative radiotherapy combined with chemotherapy following surgery had a positive impact on overall survival (p=0.174, Log rank). In the adult group, the mean overall survival was 67.3±9.3 months (range, 0.8-95.3 months), and the 1-, 3-, and 5-year rates of overall survival were 89.5, 64.4, and 64.4%, respectively. In this group, no statistical association was observed between clinical factors and outcomes. However, patients who received postoperative radiotherapy (60.7 vs 57.6 month, mean survival; p=0.510, Log rank) or chemotherapy (63.0 vs 59.9 month, mean survival; p=0.404, Log rank) had better survival rates compared with those who declined. CONCLUSION: In the pediatric group, surgery with postoperative radiotherapy and chemotherapy was a favorable factor for overall survival. In the adult group, a positive trend in overall survival was found when patients received radiation and/or chemotherapy following surgery.

Prognostic and predictive value of an immune infiltration signature in diffuse lower-grade gliomas.

BACKGROUNDLower-grade gliomas (LGGs) vary widely in terms of the patient's overall survival (OS). There is no current, valid method that could exactly predict the survival. The effects of intratumoral immune infiltration on clinical outcome have been widely reported. Thus, we aim to develop an immune infiltration signature to predict the survival of LGG patients.METHODSWe analyzed 1216 LGGs from 5 public data sets, including 2 RNA sequencing data sets and 3 microarray data sets. Least absolute shrinkage and selection operator (LASSO) Cox regression was used to select an immune infiltration signature and build a risk score. The performance of the risk score was assessed in the training set (329 patients), internal validation set (140 patients), and 4 external validation sets (405, 118, 88, and 136 patients).RESULTSAn immune infiltration signature consisting of 20 immune metagenes was used to generate a risk score. The performance of the risk score was thoroughly verified in the training and validation sets. Additionally, we found that the risk score was positively correlated with the expression levels of TGF-ß and PD-L1, which were important targets of combination immunotherapy. Furthermore, a nomogram incorporating the risk score, patient's age, and tumor grade was developed to predict the OS, and it performed well in all the training and validation sets (C-index: 0.873, 0.881, 0.781, 0.765, 0.721, and 0.753).CONCLUSIONThe risk score based on the immune infiltration signature has reliable prognostic and predictive value for patients with LGGs and is a potential biomarker for the cotargeting immunotherapy.FUNDINGThis work was supported by The National Natural Science Foundation of China (grant nos. 81472370 and 81672506), the Natural Science Foundation of Beijing (grant no. J180005), the National High Technology Research and Development Program of China (863 Program, grant no. 2014AA020610), and the National Basic Research Program of China (973 Program, grant no. 2014CB542006).

Natural history of brainstem cavernous malformations: prospective hemorrhage rate and adverse factors in a consecutive prospective cohort.

OBJECTIVE: Given the paucity of data on the natural history of brainstem cavernous malformations (CMs), the authors aimed to evaluate the annual hemorrhage rate and hemorrhagic risk of brainstem CMs. METHODS: Nine hundred seventy-nine patients diagnosed with brainstem CMs were referred to Beijing Tiantan Hospital from 2006 to 2015; 224 patients were excluded according to exclusion criteria, and 47 patients were lost to follow-up. Thus, this prospective observational cohort included 708 cases (324 females). All patients were registered, clinical data were recorded, and follow-up was completed. RESULTS: Six hundred ninety (97.5%) of the 708 patients had a prior hemorrhage, 514 (72.6%) had hemorrhagic presentation, and developmental venous anomaly (DVA) was observed in 241 cases (34.0%). Two hundred thirty-seven prospective hemorrhages occurred in 175 patients (24.7%) during 3400.2 total patient-years, yielding a prospective annual hemorrhage rate of 7.0% (95% CI 6.2%-7.9%), which decreased to 4.7% after the 1st year. Multivariate Cox regression analysis after adjusting for sex and age identified hemorrhagic presentation (HR 1.574, p = 0.022), DVA (HR 1.678, p = 0.001), mRS score ≥ 2 on admission (HR 1.379, p = 0.044), lesion size > 1.5 cm (HR 1.458, p = 0.026), crossing the axial midpoint (HR 1.446, p = 0.029), and superficially seated location (HR 1.307, p = 0.025) as independent adverse factors for prospective hemorrhage, but history of prior hemorrhage was not significant. The annual hemorrhage rates were 8.3% and 4.3% in patients with and without hemorrhagic presentation, respectively; the rate was 9.9%, 6.0%, and 1.0% in patients with ≥ 2, only 1, and 0 prior hemorrhages, respectively; and the rate was 9.2% in patients with both hemorrhagic presentation and focal neurological deficit on admission. CONCLUSIONS: The study reported an annual hemorrhage rate of 7.0% exclusively for brainstem CMs, which significantly increased if patients presented with both hemorrhagic presentation and focal neurological deficit (9.2%), or any other risk factor. Patients with a risk factor for hemorrhage needed close follow-up regardless of the number of prior hemorrhages. It should be noted that the referral bias in this study could have overestimated the annual hemorrhage rate. This study improved the understanding of the natural history of brainstem CMs, and the results are important for helping patients and physicians choose a suitable treatment option based on the risk factors and stratified annual rates.Clinical trial registration no.: ChiCTR-POC-17011575 (http://www.chictr.org.cn/).

Natural Growth Dynamics of Untreated Skull Base Chordomas In Vivo.

OBJECTIVE: To study the natural growth dynamics of skull base chordomas. METHODS: A retrospective study of skull base chordomas was performed. Patients with ≥2 preoperative magnetic resonance (MR) images and with pathologically confirmed chordomas were enrolled. All clinical data and MR images were studied. RESULTS: Twenty-one patients with pathologically confirmed skull base chordomas were enrolled. The mean volume of the tumors at diagnosis was 19.9 ± 17.0 cm3, with a mean interval examination period of 22.4 ± 26.1 (range, 3-113) months. The mean tumor volume change was approximately 15.4 ± 16.3 cm3. The mean specific growth rate was 8% ± 9% per month, and the mean specific growth volume was 0.8 ± 0.7 cm3 per month. The tumor MR signal index grade, female gender, no dura mater breakthrough, endophytic type, small tumors, and soft tumor texture were related to a higher tumor growth rate (P < 0.05), and small tumors showed the greatest growth rate compared with the middle-sized and large tumors. Curve estimation was performed using a power function (R2 = 0.545). CONCLUSIONS: The skull base chordoma is a slow-growing tumor. The cases involving characteristics of female gender, endophytic type, small tumor size, and MR grade 3 showed a higher growth rate.

Identification and validation of a 21-mRNA prognostic signature in diffuse lower-grade gliomas.

PURPOSE: Diffuse low-grade and intermediate-grade gliomas, also known as lower-grade gliomas (LGGs), are a class of central nervous system tumors. Overall survival varies greatly between patients, highlighting the importance of evaluating exact outcomes to facilitate individualized clinical management. We aimed to identify an mRNA-based prognostic signature to predict the survival of patients with LGGs. METHODS: A total of 874 LGGs from two public datasets were included. Least absolute shrinkage and selection operator (LASSO) Cox regression was used to select the most prognostic mRNAs and build a risk score. A nomogram incorporating the risk score and clinical factors was established for individualized survival prediction. The performance of the nomogram was assessed in the training set (329 patients), internal validation set (140 patients), and external validation set (405 patients). RESULTS: 21 most prognostic mRNAs remained following the LASSO Cox regression. The 21-mRNA signature successfully stratified patients into high- and low-risk groups (P < 0.001 for all datasets in Kaplan-Meier analysis). Subsequent gene set enrichment analysis identified 19 essential biological processes in high-risk LGGs. Furthermore, a nomogram incorporating the risk score, age, grade, and 1p/19q status was developed with favorable calibration and high predictive accuracy in the training set and validation sets (C-index: 0.877, 0.878, and 0.812, respectively). CONCLUSION: The 21-mRNA signature has reliable prognostic value for LGGs and might facilitate the effective stratification and individualized management of patients.

Treatment strategy and long-term outcomes of primary intracranial rhabdomyosarcoma: a single-institution experience and systematic review.

OBJECTIVE: Primary intracranial rhabdomyosarcoma (PIRMS) is rare, and the effects of the treatment strategy on overall survival (OS) are unclear. This study aimed to evaluate risk factors pertinent to OS and to propose an optimal treatment strategy. METHODS: Clinical data of patients with PIRMS treated at Beijing Tiantan Hospital and from the English-language literature between 1946 and 2018 were reviewed. A literature review was performed via Ovid, MEDLINE, Embase, PubMed, Web of Science, and Cochrane databases using the terms "rhabdomyosarcoma," "intracranial," "cerebral," and "brain." Previously published data were processed and used according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: There were 8 males (66.7%) and 4 females with PIRMS at our institution, with a mean age of 24.3 years. Gross-total resection was achieved in 4 patients (33.3%), and adjuvant radiation and chemotherapy were administered in 5 (45.5%) and 3 (27.3%) patients, respectively. After a mean follow-up period of 13.7 months, all patients developed local-regional recurrence and died of the disease. Twenty-nine cases (14 female and 15 male) were reported in the literature with a median age of 9.0 years. After a mean follow-up duration of 18.6 months, 13 patients (44.8%) developed recurrences, 7 patients (24.1%) had extracranial metastasis, and 14 patients (48.3%) died. In the pooled cases, adjuvant radiation (hazard ratio [HR] 0.089, 95% confidence interval [CI] 0.027-0.288, p < 0.001) and age < 10 years (HR 0.227, 95% CI 0.077-0.666, p = 0.007) were independent predictors of good local-regional progression-free survival (LR-PFS). Adjuvant radiation therapy (HR 0.301, 95% CI 0.110-0.828, p = 0.020) and age < 10 years (HR 0.359, 95% CI 0.131-0.983, p = 0.046) were significant predictors for favorable OS in the multivariate model. CONCLUSIONS: Due to the rarity of the disease, a poor outcome of PIRMS was demonstrated based on the pooled cohort. Use of radiation was associated with improved outcomes and should be considered to improve OS/LR-PFS. Further study is required to identify the optimal treatment regimen.Systematic review no.: CRD42019121249 (crd.york.ac.uk/PROSPERO/).

Determination of parthenolide in rat plasma by UPLC-MS/MS and its application to a pharmacokinetic study.

A rapid, sensitive and selective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination and pharmacokinetic investigation of parthenolide in rat plasma. Sample preparation was accomplished through a simple one-step deproteinization procedure with 0.2mL of acetonitrile containing 30ng/mL of pirfenidone (IS), and to a 0.1mL plasma sample. Plasma samples were separated by UPLC on an Acquity UPLC BEH C18 column using a mobile phase consisting of acetonitrile-0.1% formic acid in water with gradient elution. The total run time was 3.0min and the elution of parthenolide was at 1.33min. The detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction-monitoring (MRM) mode using the respective transitions m/z 249.2→231.1 for parthenolide and m/z 186.2→92.1 for pirfenidone (IS), respectively. The calibration curve was linear over the range of 2.0-500ng/mL with a lower limit of quantitation (LLOQ) of 2.0ng/mL. Mean recovery of parthenolide in plasma was in the range of 78.2-86.6%. Intra-day and inter-day precision were both <8.3%. This method was successfully applied in pharmacokinetic study after oral and intravenous administration of parthenolide in rats.