Prognostic value of the modified systemic inflammation score in non-small-cell lung cancer with brain metastasis.

BACKGROUND: Brain metastases (BM) from non-small-cell lung cancer (NSCLC) is the most common brain malignancy. Systemic inflammation biomarkers have recently been evaluated as prognosis indicators in several tumors. The combination of these markers has not been evaluated in NSCLC with BM yet. Here, we explored the predictive value of pretreatment inflammatory biomarkers and established a novel, clinically applicable prognostic index for NSCLC patients with BM. METHODS: A retrospective investigation of 951 NSCLC patients newly diagnosed with BM at Sun Yat-sen University Cancer Center was conducted. We randomly divided patients into a training cohort (n = 674) or validation cohort (n = 277). Receiver operating characteristic (ROC) curve analysis was carried out to obtain the optimal cut-off values of pretreatment systemic inflammatory indexes. The associations between serum biomarkers and overall survival (OS) were analyzed by Kaplan-Meier curves and Cox proportional models. The resulting prediction model has been externally verified through the validation cohort. RESULTS: The optimal cut-off value of the neutrophil-lymphocyte ratio (NLR) in predicting OS was 4.71, while the clinical standard of 40 mg/L was chosen as the optimal cut-off value of albumin. Univariate and multivariate analyses revealed that patients receiving local treatment, chemotherapy, a NLR < 4.71 and albumin ≥ 40 mg/l independently predicted improved survival. We combined the two inflammatory indexes (NLR and albumin level) to establish the modified systemic inflammation score (mSIS) which divides patients into low risk, medium risk or high-risk groups. The 1-year OS rates of three groups were 59.7%, 40.5% and 29.4%, respectively in the training cohort. The same result was verified in the validation cohort with the 1-year OS rates 69.7%, 47.0% and 7.7%, respectively. The mSIS exhibited better discrimination power than the American Joint Committee on Cancer's (AJCC) 7th T + N staging system in the training cohort (Harrell's concordance index (C-index): 0.744 vs 0.502, P < 0.05), and the discrimination was also superior to that of AJCC's 7th T + N staging system in the validation cohort (C-index: 0.724 vs 0.527, P < 0.05). The 1-year and 2-year OS rates of the AUC also exhibited superior survival predictive ability to that of the AJCC's 7th T + N staging system in NSCLC patients with BM. CONCLUSION: The pretreatment mSIS may be an independent prognostic factor for OS in NSCLC patients with BM and warrants further research.

The application of fluorescein sodium for the resection of medulloblastoma.

INTRODUCTION: Surgical resection of medulloblastoma (MB) remains a challenge. At present, a variety of tracers have been used for intraoperative tumor visualization. However, there are few reports on the intraoperative visualization of MB. Hence, we reported our experience of applying fluorescein sodium (FS) in MB surgery. METHODS: We retrospectively analyzed the clinical information of patients with MB confirmed by surgery and pathology from January 2016 to December 2020 from Sun Yat-sen University Cancer Center. A total of 62 patients were enrolled, of which 27 received intraoperative FS and 35 did not. The intraoperative dose of FS was 3 mg/kg. RESULTS: Among the 62 patients, 42 were males, and twenty were females. The age of onset in the FS group was 9.588 ± 7.322, which in the non-fluorescein sodium group was 13.469 ± 10.968, p = 0.198. We did not find significant differences in tumor location, tumor size, tumor resection, tumor histology, and preoperative symptoms (hydrocephalus, headache, vomit, balance disorder) between the groups. There was no significant difference in the postoperative symptoms (hydrocephalus, headache, vomiting, balance disorder, and cerebellar mutism). However, patients in the FS group had a relatively low incidence of balance disorder and cerebellar mutism. There was definite fluorescence of tumor in all cases of the FS group, and even the tiny metastatic lesion was visible. No case had side effects related to the use of FS. CONCLUSIONS: FS is safe and effective in MB surgery. Whether the application of FS for surgery can reduce complications remains to be studied in the future.

Multi-parametric Z-spectral MRI may have a good performance for glioma stratification in clinical patients.

OBJECTIVES: To comprehensively and noninvasively risk-stratify glioma grade, isocitrate dehydrogenase (IDH) genotype, and 1p/19q codeletion status using multi-contrast Z-spectral magnetic resonance imaging (MRI). METHODS: One hundred and thirteen patients with glioma were retrospectively included. Multiple contrasts contributing to Z-spectra, including direct saturation of water (DSW), semi-solid magnetization transfer contrast (MTC), amide proton transfer (APT) effect, aliphatic nuclear Overhauser effect, and the 2-ppm chemical exchange saturation transfer peak (CEST@2ppm), were fitted with five individual Lorentzian functions. Z-spectral contrasts were compared according to the three most important risk stratifications: tumor grade, IDH genotype, and 1p/19q codeletion status. We further investigated the differentiation of 1p/19q codeletion status within IDH mutant gliomas. The stratification performance of individual Z-spectral contrasts and their combination was quantified using receiver operating characteristic (ROC) analyses. RESULTS: DSW was significantly different within grade, IDH genotypes, and 1p/19q codeletion status. APT was significantly different with grade and IDH mutation, but not with 1p/19q subtypes. CEST@2ppm was only significantly different with 1p/19q codeletion subtypes. DSW and CEST@2ppm were the two Z-spectral contrasts able to differentiate 1p/19q codeletion subtypes within IDH mutant gliomas. For differentiating glioma grades using ROC analyses, DSW achieved the largest AUC. For differentiating IDH genotypes, DSW and APT achieved comparable AUCs. DSW was the best metric for differentiating 1p/19q codeletion status within all patients and within the IDH mutant patients. Combining all Z-spectral contrasts improved sensitivity and specificity for all risk stratifications. CONCLUSIONS: Multi-parametric Z-spectral MRI serves as a useful, comprehensive, and noninvasive imaging technique for glioma stratification in clinical patients. KEY POINTS: • Multiple contrasts contributing to Z-spectra were separately fitted with Lorentzian functions. • Z-spectral contrasts were compared within the three most important and common tumor risk stratifications for gliomas: tumor grade, IDH genotype, and 1p/19q codeletion status. • The stratification performance of individual Z-spectral contrasts and their combination was quantified using receiver operating characteristic analyses, which found Z-spectral MRI to be a useful and comprehensive imaging biomarker for glioma stratification.

Assessment of ctDNA in CSF may be a more rapid means of assessing surgical outcomes than plasma ctDNA in glioblastoma.

We aimed to develop a high-throughput deep DNA sequencing assay of cerebrospinal fluid (CSF) to identify clinically relevant oncogenic mutations that contribute to the development of glioblastoma (GBM) and serve as biomarkers to predict patients' responses to surgery. For this purpose, we recruited five patients diagnosed with highly suspicious GBM according to preoperative magnet resonance imaging. Subsequently, patients were histologically diagnosed with GBM. CSF was obtained through routine lumbar puncture, and plasma from peripheral blood was collected before surgery and 7 days after. Fresh tumor samples were collected using routine surgical procedures. Targeted deep sequencing was used to characterize the genomic landscape and identify mutational profile that differed between pre-surgical and post-surgical samples. Sequence analysis was designed to detect protein-coding exons, exon-intron boundaries, and the untranslated regions of 50 genes associated with cancers of the central nervous system. Circulating tumor DNAs (ctDNAs) were prepared from the CSF and plasma from peripheral blood. For comparison, DNA was isolated from fresh tumor tissues. Non-silent coding variants were detected in CSF and plasma ctDNAs, and the overall minor allele frequency (MAF) of the former corresponded to an earlier disease stage compared with that of plasma when the tumor burden was released (surgical removal). Gene mutation loads of GBMs significantly correlated with overall survival (OS, days) (Pearson correlation = -0.95, P = 0.01). We conclude that CSF ctDNAs better reflected the sequential mutational changes of driver genes compared with those of plasma ctDNAs. Deep sequencing of the CSF of patients with GBM may therefore serve as an alternative clinical assay to improve patients' outcomes.

Application of fluorescein sodium in the resection of vermis pilocytic astrocytomas.

BACKGROUND: Pilocytic astrocytomas (PAs) are slow growing neoplasms and usually located at the cerebellum. There has been certainty regarding the truthful benefit of surgical resection for patients with PA. Gross total resection (GTR) of PAs, especially those being situated in deep regions, remains a surgical challenge. Generally, they are considered as benign and usually develop in young patients. PAs, belonging to WHO I can be cured by radical resection. The patients with PA have excellent prognosis if complete resection can be conducted. The use of fluorescein in vermis PA surgery has not been yet reported. Our data presents fluorescein facilitates surgical resection of vermis PA. METHODS: Five milligrams per kilogram of fluorescein sodium was intravenously injected directly before general anesthesia for the three patients with PA. The yellow 560 filter was employed for microsurgical tumor resection. Surgical outcomes were assessed concerning the extent of resection. RESULTS: Most portion of PA in the three cases was found to be highly fluorescent after intravenous fluorescein sodium injection, which markedly enhanced tumor visibility. Gross total resection in all of the patients was achieved without further neurological deficits. No adverse effects and complications resulting from fluorescein sodium were observed over the postoperative course. CONCLUSIONS: Intraoperative guidance by fluorescein sodium as a new, simple, safe, and practical procedure can enhance the fidelity of tumor tissue and increase the possibility of completely resecting PAs.

PSMA PET/MR is a New Imaging Option for Identifying Glioma Recurrence and Predicting Prognosis.

BACKGROUND: Glioma is characterized by a high recurrence rate, while the results of the traditional imaging methods (including magnetic resonance imaging, MRI) to distinguish recurrence from treatment-related changes (TRCs) are poor. Prostate-specific membrane antigen (PSMA) (US10815200B2, Deutsches Krebsforschungszentrum, German Cancer Research Center) is a type II transmembrane glycoprotein overexpressed in glioma vascular endothelium, and it is a promising target for imaging and therapy. OBJECTIVE: The study aimed to assess the performance of PSMA positron emission tomography/ magnetic resonance (PET/MR) for diagnosing recurrence and predicting prognosis in glioma patients. MATERIALS AND METHODS: Patients suspected of glioma recurrence who underwent 18F-PSMA-1007 PET/MR were prospectively enrolled. Eight metabolic parameters and fifteen texture features of the lesion were extracted from PSMA PET/MR. The ability of PSMA PET/MR to diagnose glioma recurrence was investigated and compared with conventional MRI. The diagnostic agreement was assessed using Cohen κ scores and the predictive parameters of PSMA PET/MR were obtained. Kaplan-Meier method and Cox proportional hazard model were used to analyze recurrence- free survival (RFS) and overall survival (OS). Finally, the expression of PSMA was analyzed by immunohistochemistry (IHC). RESULTS: Nineteen patients with a mean age of 48.11±15.72 were assessed. The maximum tumorto- parotid ratio (TPRmax) and texture features extracted from PET and T1-weighted contrast enhancement (T1-CE) MR showed differences between recurrence and TRCs (all p <0.05). PSMA PET/MR and conventional MRI exhibited comparable power in diagnosing recurrence with specificity and PPV of 100%. The interobserver concordance was fair between the two modalities (κ = 0.542, p = 0.072). The optimal cutoffs of metabolic parameters, including standardized uptake value (SUV, SUVmax, SUVmean, and SUVpeak) and TPRmax for predicting recurrence were 3.35, 1.73, 1.99, and 0.17 respectively, with the area under the curve (AUC) ranging from 0.767 to 0.817 (all p <0.05). In grade 4 glioblastoma (GBM) patients, SUVmax, SUVmean, SUVpeak, TBRmax, TBRmean, and TPRmax showed improved performance of AUC (0.833-0.867, p <0.05). Patients with SUVmax, SUVmean, or SUVpeak more than the cutoff value had significantly shorter RFS (all p <0.05). In addition, patients with SUVmean, SUVpeak, or TPRmax more than the cutoff value had significantly shorter OS (all p <0.05). PSMA expression of glioma vascular endothelium was observed in ten (10/11, 90.9%) patients with moderate-to-high levels in all GBM cases (n = 6/6, 100%). CONCLUSION: This primitive study shows multiparameter PSMA PET/MR to be useful in identifying glioma (especially GBM) recurrence by providing excellent tumor background comparison, tumor heterogeneity, recurrence prediction and prognosis information, although it did not improve the diagnostic performance compared to conventional MRI. Further and larger studies are required to define its potential clinical application in this setting.

The Association Between Socioeconomic Factors at Diagnosis and Survival in Medulloblastoma: A Propensity Score-Matched Analysis and Population-Based Study.

BACKGROUND: Medulloblastoma (MB) is the most common malignant brain tumor of childhood. The associations between socioeconomic statuses (SES) and survival outcomes of medulloblastoma remain unclear. The aim of this study was to develop a nomogram to predict medulloblastoma specific death (MBSD) and overall survival (OS) in patients with medulloblastoma, taking into account socioeconomic factors in patients with medulloblastoma. METHODS: We included patients diagnosed with MB between 1975 and 2016 from the Surveillance, Epidemiology, and End Results database. Propensity Score Matching (PSM) was performed to reduce selection bias. Multivariate cox proportional hazards model was used to assess SES impact and clinically relevant variables of medulloblastoma specific death and overall survival. Independent prognostic factors determined by multivariate analysis were used to construct nomograms. RESULTS: A total of 2660 patients were enrolled after matching. Study showed unemployed rate (MBSD, high level vs. low level, P = 0.020) (OS, high level vs. low level, P = 0.017), and marital status (OS, married vs unmarried/unknown, P = 0.029) were important factors affecting prognosis of medulloblastoma in male. Meanwhile, median household income (MBSD, quartile 1 vs. quartile 3, P = 0.047) (OS, quartile 1 vs. quartile 2, P = 0.017) (OS, quartile 1 vs. quartile 3, P = 0.014), residence (MBSD, urban vs. rural, P = 0.041), and insurance status (MBSD, insured vs. uninsured/unknown, P = 0.002)(OS, insured vs. uninsured/unknown, P = 0.001) were significant factors affecting prognosis of medulloblastoma in female. Through the calibration plot and C-index test, our nomogram was also of predictive significance. CONCLUSIONS: The unique features of MB have provided a scenario for analysis of the impact of racial, ethnic, gender, and socioeconomic factors. The current findings have important public health implications for achieving the goal of a healthy population. Given the known morbidity rates, long-term psychological, financial and medical burdens that these children and their families must bear, it is critical to identify and address these gaps.

Adjuvant Temozolomide Chemotherapy With or Without Interferon Alfa Among Patients With Newly Diagnosed High-grade Gliomas: A Randomized Clinical Trial.

Importance: High-grade gliomas (HGGs) constitute the most common and aggressive primary brain tumor, with 5-year survival rates of 30.9% for grade 3 gliomas and 6.6% for grade 4 gliomas. The add-on efficacy of interferon alfa is unclear for the treatment of HGG. Objectives: To compare the therapeutic efficacy and toxic effects of the combination of temozolomide and interferon alfa and temozolomide alone in patients with newly diagnosed HGG. Design, Setting, and Participants: This multicenter, randomized, phase 3 clinical trial enrolled 199 patients with newly diagnosed HGG from May 1, 2012, to March 30, 2016, at 15 Chinese medical centers. Follow-up was completed July 31, 2021, and data were analyzed from September 13 to November 24, 2021. Eligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed HGG and had received no prior chemotherapy, radiotherapy, or immunotherapy for their HGG. Interventions: All patients received standard radiotherapy concurrent with temozolomide. After a 4-week break, patients in the temozolomide with interferon alfa group received standard temozolomide combined with interferon alfa every 28 days. Patients in the temozolomide group received standard temozolomide. Main Outcomes and Measures: The primary end point was 2-year overall survival (OS). Secondary end points were 2-year progression-free survival (PFS) and treatment tolerability. Results: A total of 199 patients with HGG were enrolled, with a median follow-up time of 66.0 (95% CI, 59.1-72.9) months. Seventy-nine patients (39.7%) were women and 120 (60.3%) were men, with ages ranging from 18 to 75 years and a median age of 46.9 (95% CI, 45.3-48.7) years. The median OS of patients in the temozolomide plus interferon alfa group (26.7 [95% CI, 21.6-31.7] months) was significantly longer than that in the standard group (18.8 [95% CI, 16.9-20.7] months; hazard ratio [HR], 0.64 [95% CI, 0.47-0.88]; P = .005). Temozolomide plus interferon alfa also significantly improved median OS in patients with O6-methylguanine-DNA methyltransferase (MGMT) unmethylation (24.7 [95% CI, 20.5-28.8] months) compared with temozolomide (17.4 [95% CI, 14.1-20.7] months; HR, 0.57 [95% CI, 0.37-0.87]; P = .008). Seizure and influenzalike symptoms were more common in the temozolomide plus interferon alfa group, with 2 of 100 (2.0%) and 5 of 100 (5.0%) patients with grades 1 and 2 toxic effects, respectively (P = .02). Finally, results suggested that methylation level at the IFNAR1/2 promoter was a marker of sensitivity to temozolomide plus interferon alfa. Conclusions and Relevance: Compared with the standard regimen, temozolomide plus interferon alfa treatment could prolong the survival time of patients with HGG, especially the MGMT promoter unmethylation variant, and the toxic effects remained tolerable. Trial Registration: ClinicalTrials.gov Identifier: NCT01765088.

Complications following titanium cranioplasty compared with nontitanium implants cranioplasty: A systematic review and meta-analysis.

Decompressive craniectomy is widely used to treat medically refractory intracranial hypertension. There were still few studies focusing on the complications between titanium cranioplasty with non-titanium materials cranioplasty. Our systematic review and meta-analysis aimed to assess the complications following titanium cranioplasty and to make a comparison with nontitanium materials. A systematic review was used to review titanium cranioplasty characters in recent articles. A systematic literature review and meta-analysis were performed by using PubMed/MEDLINE, Scopus, the Cochrane databases and Embase for studies reporting on cranioplasty procedures that compared complication outcomes between titanium with non-titanium materials. The final 15 studies met inclusion criteria and represented 2258 cranioplasty procedures (896 titanium, 1362 nontitanium materials). Overall complications included surgical site infection, hematoma, implant exposure, seizure, cerebrospinal fluid leak, imprecise fitting. Titanium cranioplasty was associated with a significant decrease in overall complications rate (OR, 0.72; P = 0.007), hematoma rate (OR, 0.31; P = 0.0003) and imprecise fitting rate (OR, 0.35; P = 0.04). However, it also suggested that titanium cranioplasty can be greatly increased implant exposure rate (OR, 4.11; P < 0.00001). Our results confirmed the advantages of titanium cranioplasty in reducing complications including hematoma, imprecise fitting, and also suggested that clinicians should pay more attention to postoperative implant exposure. With new synthetic materials emerging, it would also be interesting to study the cost-effect and functional outcomes associated with cranioplasty materials.

Computational study on novel natural inhibitors targeting BCL2.

Ideal lead compounds and candidate drugs with inhibitory effect on BCL2 were screened from ZINC database, which laid a foundation for drug development and compound improvement of drug treatment for diffuse large B-cell lymphoma (DLCBL). Identification of potential BCL2 inhibitors by computer-aided virtual screening. Libdock was applied to 17,931 compounds and the top 20 were selected for further analysis. Selected compounds were performed absorption, distribution, metabolism, and excretion (ADME) and toxicity prediction. The binding affinity between the selected ligands and BCL2 was confirmed by Molecular docking. The new natural compounds, ZINC00000255131 and ZINC00013298233, were found to bind closely with BCL2. Furthermore, they all scored lower in ames-induced mutagenicity, rodent carcinogenicity, non-developmental toxicity potential, and cytochrome P4502D6 tolerance. Molecular dynamics simulation shows that the combinations of ZINC00000255131 and ZINC00013298233 with BCL2 in the natural environment are more stable. Two new compounds, ZINC00000255131 and ZINC00013298233, were found to be potential inhibitors of BCL2. These compounds have been proved to be safe, which is of great significance for the development and improvement of DLCBL drugs.

Prognostic Value of the Systemic Immune-Inflammation Index and Prognostic Nutritional Index in Patients With Medulloblastoma Undergoing Surgical Resection.

Background: The progression and metastasis of cancers are associated with systematic immune inflammation and nutritional dysfunction. The systemic immune-inflammation index and prognostic nutritional index (PNI) have shown a prognostic impact in several malignancies. Therefore, our study aimed to evaluate immune inflammation and nutritional index prognostic significance in patients with medulloblastoma (MB). Methods: We retrospectively analyzed 111 patients with MB between 2001 and 2021 at our institution. The optimal cutoff values for systemic immune-inflammation index (SII), neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte counts ration (MLR), and PNI were evaluated with receiver operating characteristic (ROC) curve analysis. Clinical characteristics and SII, NLR, MLR, and PNI were tested with the Pearson's chi-squared test. The Kaplan-Meier survival curves and the Cox proportional hazards model were used to evaluate the effects of immune inflammation and nutritional index on overall survival (OS). Results: Receiver operating characteristic curve analysis determined the optimal SII, NLR, MLR, and PNI cutoff values of 2,278, 14.83, 0.219, and 56.5 that significantly interacts with OS and divided the patients into two groups. Comparative survival analysis exhibited that the high-SII cohort had significantly shorter OS (p = 0.0048) than the low-SII cohort. For the univariate analysis, the results revealed that preoperative hydrocephalus (p = 0.01), SII (p = 0.006), albumin-bilirubin score (ALBI) (p = 0.04), and coSII-PNI were predictors of OS. In the multivariate analysis, preoperative hydrocephalus (p < 0.001), ALBI (p = 0.010), SII (p < 0.001), and coSII-PNI as independent prognostic factors were significantly correlated with OS. Conclusion: The preoperative SII, ALBI, and coSII-PNI serve as robust prognostic biomarkers for patients with MB undergoing surgical resection.

Effective natural inhibitors targeting poly ADP-ribose polymerase by computational study.

OBJECT: This study was designed to screen ideal lead compounds and drug candidates with an inhibitory effect on PARP from the drug library (ZINC database). RESULTS: Two effective natural compounds ZINC000003938684 and ZINC000014811844 were found to bind to PARP in the ZINC database, showing a higher binding affinity. Also, they were predicted to have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6. Molecular dynamics simulation showed that ZINC000003938684 and ZINC000014811844 had a more favorable potential energies with PARP, which could exist stably in natural circumstances. CONCLUSION: This study suggested that ZINC000003938684 and ZINC000014811844 were ideal potential inhibitors of PARP targeting. These compounds were safe drug candidates and had important implications for the design and improvement of CMET target drugs. METHODS: A battery of computer-aided virtual techniques were used to identify potential inhibitors of PARP. LibDock is used for structure-based screening followed by ADME (absorption distribution, metabolic excretion) and toxicity prediction. Molecular docking was performed to demonstrate the binding affinity mechanism between the ligand and PARP. Molecular dynamics simulations were used to evaluate the stability of ligand-receptor complexes.

Unique genomic features and prognostic value of COSMIC mutational signature 4 in lung adenocarcinoma and lung squamous cell carcinoma.

BACKGROUND: Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, and prognosis. Among the signatures cataloged at COSMIC, mutational signature 4 has been linked to smoking. However, the distribution of signature 4 in Chinese lung cancer patients has not been evaluated, and its clinical value has not been evaluated. Here we survey mutational signatures in Chinese lung cancer patients and explore the relationship between signature 4 and other genomic features in the patients. METHODS: We extracted mutational signatures from whole-exome sequencing data of Chinese non-small cell lung cancer patients. The data included 401 lung adenocarcinoma (LUAD) and 92 squamous cell carcinoma (LUSC). We then performed statistical analysis to search for genomic and clinical features that can be linked to mutation signatures. RESULTS: We found signature 4 is the most frequent mutational signature in LUSC and the second most frequent in LUAD. Fifty-six LUAD and thirty-five LUSC patients were named with high signature 4 similarities (cosine similarity >0.7). These patients have shorter survival and higher tumor mutational burden comparing to those with low signature 4 similarities. Dozens of genes with single nucleotide variation, index mutations, and copy number variations were differentially enriched in the patients with high signature 4 similarities. Among these genes, CSMD3, LRP1B, TP53, SYNE1, SLIT2, FGF4, and FGF19 are common in both LUADs and LUSCs with high signature 4 similarities, showing that these genes are tightly associated with signature 4. CONCLUSIONS: The present study is the first to report a comparison in Chinese NSCLC patients with or without COSMIC mutational signature 4. These results will help find the Signature 4 related mutational process in NSCLC.

Identification of a Twelve-Gene Signature and Establishment of a Prognostic Nomogram Predicting Overall Survival for Medulloblastoma.

BACKGROUND: Medulloblastoma is the common pediatric malignant tumor with poor prognosis in cerebellum. However, MB is always with clinical heterogeneity. To provide patients with more clinically beneficial treatment strategies, there is a pressing need to develop a new prognostic prediction model as a supplement to the prediction outcomes of clinical judgment. MATERIALS AND METHODS: Four datasets of mRNA expression and clinical data were downloaded from gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) were identified and functionally enriched among GSE50161, GSE74195, GSE86574. Then we used STRING and Cytoscape to constructed and analyze protein-protein interaction network (PPI) and hub genes. Univariate cox regression analysis was performed to identify overall survival-related hub genes in an unique dataset from GSE85217 as train cohort. Lasso Cox regression model was used to construct the prognostic gene signature. Time-dependent receiver operating characteristic (ROC), Kaplan-Meier curve, univariate and multivariate Cox regression analysis were used to assess the prognostic capacity of the twelve-gene signature. A unique dataset from GSE85217 was downloaded to further validate the results. Finally, we established the nomogram by using the gene signature and validated it with ROC curve. Gene set enrichment analysis (GSEA) was carried out to further investigate its potential molecular mechanism. Besides, the twelve genes expression at the mRNA and protein levels was validated using external database such as Oncomine, cBioportal and HPA, respectively. RESULTS: A twelve-gene signature comprising FOXM1, NEK2, CCT2, ACTL6A, EIF4A3, CCND2, ABL1, SYNCRIP, ITGB1, NRXN2, ENAH, and UMPS was established to predict overall survival of medulloblastoma. The ROC curve showed good performance in survival prediction in both the train cohort and the validation cohort. The twelve-gene signature could stratify patients into a high risk and low risk group which had significantly different survival. Univariate and multivariate Cox regression revealed that the twelve-gene signature was an independent prognostic factor in medulloblastoma. Nomogram, which included twelve-gene signatures, was established and showed some clinical benefit. CONCLUSION: Our study identified a twelve-gene signature and established a prognostic nomogram that reliably predicts overall survival in medulloblastoma. The above results will help us to better analyze the pathogenesis and treatment of medulloblastoma in the future.

Assessment of circulating tumor DNA in cerebrospinal fluid by whole exome sequencing to detect genomic alterations of glioblastoma.

BACKGROUND: Cerebrospinal fluid (CSF) has been demonstrated as a better source of circulating tumor DNA (ctDNA) than plasma for brain tumors. However, it is unclear whether whole exome sequencing (WES) is qualified for detection of ctDNA in CSF. The aim of this study was to determine if assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma. METHODS: CSFs of ten glioblastoma patients were collected pre-operatively at the Department of Neurosurgery, Sun Yat-sen University Cancer Center. ctDNA in CSF and genome DNA in the resected tumor were extracted and subjected to WES. The identified glioblastoma-associated mutations from ctDNA in CSF and genome DNA in the resected tumor were compared. RESULTS: Due to the ctDNA in CSF was unqualified for exome sequencing for one patient, nine patients were included into the final analysis. More glioblastoma-associated mutations tended to be detected in CSF compared with the corresponding tumor tissue samples (3.56 ±â€Š0.75 vs. 2.22 ±â€Š0.32, P = 0.097), while the statistical significance was limited by the small sample size. The average mutation frequencies were similar in CSF and tumor tissue samples (74.1% ±â€Š6.0% vs. 73.8% ±â€Š6.0%, P = 0.924). The R132H mutation of isocitrate dehydrogenase 1 and the G34V mutation of H3 histone, family 3A (H3F3A) which had been reported in the pathological diagnoses were also detected from ctDNA in CSF by WES. Patients who received temozolomide chemotherapy previously or those whose tumor involved subventricular zone tended to harbor more mutations in their CSF. CONCLUSION: Assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma, which may provide useful information for the decision of treatment strategy.

The utility of 3-dimensional-printed models for skull base meningioma surgery.

BACKGROUND: Skull base meningioma surgery is often difficult and complicated to perform. Therefore, this study aims to investigate the effectiveness of 3-dimensional (3D)-printed models of skull base meningioma in the representation of anatomical structures, the simulation of surgical plans, and patient education on surgical outcomes. METHODS: A retrospective study of 35 patients (3D group: 19 patients and non-3D group: 16 patients) with skull base meningioma was conducted. Mimics software was used to create 3D reconstructions (with the skull, blood vessels, nerves, and tumors set to different colors), and 3D solid models were printed to determine the surgical protocols and communication pathways with the patient. RESULTS: The 3D-printed model can visually display the relationship of different structures, including the skull, blood vessels, cranial nerves, and tumors. The surgeon should select the proper surgical approaches before surgery through the model and pay attention to protecting the important structures during the operation. According to the models, the surgeon should cut off the blood supply to the tumor to reduce intraoperative bleeding. For patients with skull base bone destruction, the skull base repair should be prepared in advance. Patients and their families should have a thorough understanding of the disease through the model, and there should be effective communication between doctors and patients. CONCLUSIONS: The 3D-printed model of a skull base meningioma can present the structures in a detailed manner and facilitate in helping the surgeon to develop a surgical plan. At the same time, it helps patients and their families to understand the condition and the surgical plan, which is conducive to better patient education.

Pretreatment neutrophil-to-lymphocyte ratio plus albumin-to-gamma-glutamyl transferase ratio predict the diagnosis of grade III glioma.

BACKGROUND: The present study explored the predictive value of systemic inflammatory indexes in diagnosing grade III gliomas of oligodendroglial origin. METHODS: A retrospective study of 154 patients with grade III gliomas was conducted. Systemic inflammatory indexes, including neutrophil-to-lymphocyte ratio (NLR), albumin-to-gamma-glutamyl transferase ratio (AGR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, prognostic nutritional index, and fibrinogen-to-albumin ratio, were reviewed. The resulting predictive model was externally validated using a demographic-matched cohort of 49 grade III glioma patients. RESULTS: In the training set, gliomas of oligodendroglial origin tended to have a lower NLR (P=0.018) and a higher AGR (P=0.036) than those with tumors of astrocytic origin. Moreover, both NLR and AGR had predictive value for oligodendroglial tumors, when compared with astrocytic tumors. The best diagnostic value was obtained using NLR + AGR (AUC =64.9%, 95% CI: 55.5-74.3%, P=0.005). In the validation set, NLR + AGR satisfactorily predicted the presence of oligodendroglial tumors (AUC =66.5%, 95% CI: 50.6-82.4%, P<0.05) and co-deletion of 1p/19q (AUC =73.7%, 95% CI: 59.2-88.1%, P=0.005). Multivariate analysis further demonstrated NLR + AGR as an independent predictor for overall survival. CONCLUSIONS: Pretreatment NLR and AGR aid in prognosis and diagnosing grade III oligodendroglial gliomas.

An Unusual Combination of Mirror-Image Dextrocardia with Familial Medulloblastoma: Is There a Histogenetic Relationship?

BACKGROUND: The occurrence of medulloblastoma in the absence of hereditary syndromes is rare. Dextrocardia with situs inversus is also called mirror-image dextrocardia. A combination of mirror-image dextrocardia with medulloblastoma has not been reported previously. To the best of our knowledge, this is the first report of this rare combination in a family with medulloblastoma. METHODS: The clinical manifestation, radiographic characteristics, treatment, and outcomes of 3 medulloblastoma cases in 2 cousins and their maternal uncle was described. Tumor samples of the 2 cousins were first examined for histologic subtypes. Total RNA of their tumors was extracted from formalin-fixed and paraffin-embedded samples. Then, expression of 22 subgroup-specific genes and 3 housekeeping genes was analyzed by the NanoString nCounter Analysis System. The posttest data were normalized by NanoStringNorm package for molecular subgroup prediction. RESULTS: The proband remains tumor free and alive up to the latest follow-up. His cousin, who had combined mirror-image dextrocardia with situs inversus, died of anoxia after surgery and his uncle died of tumor 2.5 years after surgery. Medulloblastoma of the 2 cousins was classified as classic and molecular group 4 subtype. CONCLUSIONS: The same classic and molecular group 4 subtype of the 2 cousins may suggest a similar genetic predisposition. Involvement of the Otx2 gene dysfunction in both group 4 subtype medulloblastoma and mirror-image dextrocardia with situs inversus points to a possible mechanism that dysfunction of a shared signaling pathway such as Otx2 might be the underlying cause of these 2 conditions in this family.

Langerhans cell histiocytosis of skull: a retrospective study of 18 cases.

BACKGROUND: The present study presents 18 cases of Chinese patients harboring a Langerhans cell histiocytosis (LCH) of the skull. METHODS: Eighteen consecutive patients were diagnosed as LCH of the skull and confirmed pathologically between March 2002 and February 2014. In the present study, the patients of LCH without skull involvement were excluded. According to disease extent at diagnosis, the 18 LCH patients with skull involvement were divided into three groups: (I) unifocal-monosystem group, including ten cases with solitary skull lesion; (II) multifocal-monosystem group, including two cases with multiple bone lesions and no extra-skeletal involvement; (III) multisystem group, including six cases with LCH lesions involving both skeletal and extra-skeletal system. In unifocal-monosystem group, excision of the skull lesion was performed in eight of ten cases, a low dosage of local radiotherapy and a purposeful observation was accept by the remaining two cases of this group after biopsy respectively. In multifocal-monosystem group, both of the two cases were received chemotherapy. In multi-system group, all the six cases were managed with systemic chemotherapy, after their diagnoses of LCH were confirmed. RESULTS: The mean age at the time of diagnosis was 9.4 years. There was a male predominance in this disease male/female ratio was 3.5:1. In our cases, a skull mass with or without tenderness was the most common chief complaint (13 cases, 72.2%), and frontal bone was the most frequent affected locations of skull (6 cases, 33.3%). In unifocal-monosystem group, nine of ten remained free from LCH, the remain one lesion recurred 22 months after his surgical excision. In multifocal-monosystem group, a complete response (CR) was obtained in one of them, and a stable disease (SD) of multiple osseous lesions was obtained in another one. In the multi-system group, a CR in four cases and a partial response (PR) in one case were obtained, and a progressive disease (PD) was observed in the remaining one. CONCLUSIONS: The unifocal-monosystem of LCH of the skull is a clinicopathological entity with a good outcome, and resection, irradiation or purposeful observation are also can be been utilized as the choice of treatment. For the multifocal bone lesions and multisystem lesions of LCH, chemotherapy is an effective treatment as a systemic therapy. There is no enough publication literature to determine guidelines or indications for managing this disease.