Clinical and genomic features in patients with second primary glioblastoma following first primary renal cell carcinoma.

PURPOSE: To explore the potential pathogenesis and clinical features of second primary glioblastoma (spGBM) following first primary renal cell carcinoma (fpRCC). METHODS: Patients with spGBM after fpRCC were enrolled from our institution and the SEER dataset. Sanger sequencing, whole genome sequencing, and immunehistochemistry were used to detect molecular biomarkers. RESULTS: Four and 122 cases from our institution and the SEER dataset, respectively, were collected with an overall median age of 69 years at spGBM diagnosis following fpRCC. The median interval time between fpRCC and spGBM was 50.7 months and 4 years, for the four and 122 cases respectively. The median overall survival time was 11.2 and 6.0 months for the two datasets. In addition, spGBM patients of younger age (< 75 years) or shorter interval time (< 1 year) had favorable prognosis (p = 0.081 and 0.05, respectively). Moreover, the spGBM cases were molecularly classified as TERT only paired with TP53 mutation, PIK3CA mutation, EGFR alteration, low tumor mutation burden, and stable microsatellite status. CONCLUSIONS: This is the first study to investigate the pathogenesis and clinical features of spGBM following spRCC. We found that spGBMs are old-age related, highly malignant, and have short survival time. Moreover, they might be misdiagnosed and treated as brain metastases from RCC. Thus, the incidence of spGBMs after fpRCC is underestimated. Further studies are needed to investigate the underlying molecular mechanisms and clinical biomarkers for the development of spGBM following fpRCC.

Systemic immune-inflammation landscape in brain metastasis needing neurosurgical resection: Analysis of 230 consecutive cases in a single center.

BACKGROUND: Systemic immune-inflammation states across the heterogeneous population of brain metastases are very important in the context of brain-immune bidirectional communication, especially among the patients needing neurosurgical resection. Four blood cell ratios based on complete blood count (CBC) test serving as prognostic biomarkers have been highlighted by previous studies, including systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR). However, the presurgical systemic immune-inflammation landscape in brain metastasis needing neurosurgical resection is limited. METHODS: Patients with brain metastases admitted to the Department of Neurosurgery at the National Cancer Center, Cancer Hospital of Chinese Academy of Medical Sciences between January 2016 and December 2019 were included. Based on peripheral blood cell counts in CBC test before neurosurgical resection, four systemic immune-inflammation biomarkers (SII, NLR, PLR, and LMR) were calculated. We characterized the changes of SII, NLR, PLR, and LMR in patients with brain metastasis before neurosurgical resection and the associations of these types of immune-inflammation states with patient demographics. In parallel, the corresponding data from the relative healthy populations without systemic diseases were enrolled as the control in the present study. RESULTS: Brain metastases induced systemic immune-inflammation perturbation, which was characterized by a significant increase in SII (p < .01) and NLR levels (p < .01) and a significant decrease in the LMR level (p < .01) in comparison with the healthy control group. Moreover, patients with male gender, less Karnofsky Performance Status (KPS) scores (<70), specific pathological subtypes, extracranial transfer, and history of both systemic and radiation therapy may have significant differences in one or more of these biomarkers, which indicated poorer systemic immune-inflammation states. CONCLUSIONS: This study provides evidence that brain metastasis is associated with perturbations in presurgical systemic immune-inflammation states. We should pay attention to the systemic immune-inflammation perturbations following brain metastasis in clinic, especially in the subpopulations with high risks.

Identifying Differential Expression Genes and Prognostic Signature Based on Subventricular Zone Involved Glioblastoma.

Background: Studies have suggested that glioblastoma (GBM) cells originate from the subventricular zone (SVZ) and that GBM contact with the SVZ correlated with worse prognosis and higher recurrence. However, research on differentially expressed genes (DEGs) between GBM and the SVZ is lacking. Methods: We performed deep RNA sequencing on seven SVZ-involved GBMs and paired tumor-free SVZ tissues. DEGs and enrichment were assessed. We obtained GBM patient expression profiles and clinical data from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases. The least absolute shrinkage and selection operator Cox regression model was utilized to construct a multigene signature in the CGGA cohort. GBM patient data from TCGA cohort were used for validation. Results: We identified 137 (97 up- and 40 down-regulated) DEGs between GBM and healthy SVZ samples. Enrichment analysis revealed that DEGs were mainly enriched in immune-related terms, including humoral immune response regulation, T cell differentiation, and response to tumor necrosis factor, and the MAPK, cAMP, PPAR, PI3K-Akt, and NF-κb signaling pathways. An eight-gene (BCAT1, HPX, NNMT, TBX5, RAB42, TNFRSF19, C16orf86, and TRPC5) signature was constructed. GBM patients were stratified into two risk groups. High-risk patients showed significantly reduced overall survival compared with low-risk patients. Univariate and multivariate regression analyses indicated that the risk score level represented an independent prognostic factor. High risk score of GBM patients negatively correlated with 1p19q codeletion and IDH1 mutation. Immune infiltration analysis further showed that the high risk score was negatively correlated with activated NK cell and monocyte counts, but positively correlated with macrophage and activated dendritic cell counts and higher PD-L1 mRNA expression. Conclusion: Here, a novel gene signature based on DEGs between GBM and healthy SVZ was developed for determining GBM patient prognosis. Targeting these genes may be a therapeutic strategy for GBM.

Preoperative blood testing for glioblastoma, brain metastases, and primary central nervous system lymphoma differentiation.

Background: Differentiating glioblastoma (GBM), brain metastases, and primary central nervous system lymphoma (PCNSL) in clinical practice is difficult. This study aimed to evaluate the diagnostic value of routine blood biomarkers in patients with GBM, brain metastases, and PCNSL and find a preoperative differential diagnostic tool for these tumors. Methods: The perioperative medical records of 70 GBM, 41 PCNSL, and 81 brain metastases patients and their preoperative blood test results were compared and analyzed, and a diagnostic model to differentiate among them established. Results: Patient age, plateletcrit, international normalized ratio (INR), and thrombin time (TT) were independently associated with differential diagnosis by multinomial logistic regression. Compared with GBM patients, brain metastases patients were significantly older (OR =1.055, 95% CI: 1.016-1.094, P=0.005) and had lower plateletcrit levels (OR =0.008, 95% CI: 0.004-0.017, P=0.027). In addition, patients with GBM had lower INR and higher TT than patients with the other two tumor types. A diagnostic model including these parameters, had an accuracy of 88.2% and 76.1% for brain metastases and GBM, respectively. Conclusions: Preoperative plateletcrit, INR, and TT may be used as inexpensive blood diagnostic biomarkers for differentiating brain metastases from other intracranial malignant tumors.

Free Flap Transfer, a Safe and Efficient Method for Reconstruction of Composite Skull Base Defects After Salvage Resection of Advanced Intracranial and Extracranial Communicating Tumors.

OBJECTIVE: Surgical treatment of advanced intracranial and extracranial communicating skull base tumors is challenging, especially for the reconstruction of the large composite defect left by tumor resection. The aim of the study is to evaluate the utility of the free flap reconstruction of the defects resulting from radical resection of these tumors in a single institution. METHODS: The clinical data of 17 consecutive patients who underwent free flap reconstruction for defect left by salvage resection of advanced intracranial and extracranial communicating tumors from 2013 to 2019 were retrospectively collected and analyzed. RESULTS: There were 5 squamous cell carcinomas, 4 adenoid cystic carcinomas, 2 basal cell carcinomas, 2 meningiomas, 1 anaplastic hemangiopericytoma, 1 pleomorphic adenoma, 1 osteosarcoma, and 1 chondrosarcoma. All patients had recurrent neoplasms, 2 of whom had pulmonary metastasis. A modified radical cervical dissection was performed in 6 patients. The anterolateral thigh myocutaneous flap and rectus abdominis myocutaneous flap were used in 15 patients (88.2%) and 2 patients (11.8%), respectively. Complications were seen in 3 of 17 patients (17.6%) with 1 total flap loss. The median progression-free survival duration was 31 months. The 3- and 5-year progression-free survival rates were 0.47 and 0.24, respectively. The mean overall survival duration was 66 months. The 3- and 5-year overall survival rates were 0.85 and 0.68, respectively. CONCLUSIONS: Free flap transfer is a safe and effective method with acceptable complications, useful for reconstruction of large composite skull base defects after salvage resection of advanced intracranial and extracranial communicating tumors. The functional and cosmetic results are satisfying.

Identifying Predictive Gene Expression and Signature Related to Temozolomide Sensitivity of Glioblastomas.

Temozolomide (TMZ) is considered a standard chemotherapeutic agent for glioblastoma (GBM). Characterizing the biological molecules and signaling pathways involved in TMZ sensitivity would be helpful for selecting therapeutic schemes and evaluating prognosis for GBM. Thus, in the present study, we selected 34 glioma cell lines paired with specific IC50 values of TMZ obtained from CancerRxGene and RNA-seq data downloaded from the Cancer Cell Line Encyclopedia to identify genes related to TMZ sensitivity. The results showed that 1,373 genes were related to the response of GBM cells to TMZ. Biological function analysis indicated that epithelial-mesenchymal transition, Wnt signaling, and immune response were the most significantly activated functions in TMZ-resistant cell lines. Additionally, negative regulation of telomere maintenance via telomerase was enriched in TMZ-sensitive glioma cell lines. We also preliminarily observed a synergistic effect of combination treatment comprising TMZ and a telomerase inhibitor in vitro. We identified six genes (MROH8, BET1, PTPRN2, STC1, NKX3-1, and ARMC10) using the random survival forests variable hunting algorithm based on the minimum error rate of the gene combination and constructed a gene expression signature. The signature was strongly related to GBM clinical characteristics and exhibited good prognosis accuracy for both The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets. Patients in the high score group had a shorter survival time than those in the low score group (11.2 vs. 22.2 months, hazard ratio = 7.31, p = 4.59e-11) of the TCGA dataset. The CGGA dataset was selected as a validation group with 40 patients in the high score set and 43 patients in the low score set (12.5 vs. 28.8 months, hazard ratio = 3.42, p = 8.61e-5). Moreover, the signature showed a better prognostic value than MGMT promoter methylation in both datasets. We also developed a nomogram for clinical use that integrated the TMZ response signature and four other risk factors to individually predict patient survival after TMZ chemotherapy. Overall, our study provides promising therapeutic targets and potential guidance for adjuvant therapy of GBM.

A proposed scheme for the classification and surgical planning of falcine meningioma treatment.

Falcine meningiomas (FM) represent a surgical challenge even in the microsurgical era. An individualised surgical approach to different FM is indispensable, but there have been few reports in this regard. Thus, based on our series of 20 patients with FM who underwent surgery between October 2001 and June 2010, we propose a classification scheme for FM removal and demonstrate its effectiveness. FM in our series were classified into four types, according to tumour growth patterns on coronal MRI: Type I, hemispheroid-shaped tumours invaginating deeply into one hemisphere without shifting the falx (10 patients); Type II, olive-shaped tumours shifting the falx substantially to the contralateral side (six patients); Type IIIA, globular- or dumbbell-shaped tumours extending into both hemispheres, but to different extents (one patient); and Type IIIB, globular- or dumbbell-shaped tumours extending into both hemispheres to approximately equal extent (three patients). An ipsilateral interhemispheric approach was performed for Type I tumours, and a contralateral transfalcine approach for Type II. Type IIIA tumour was approached from the side where the smaller tumour was located. Type IIIB tumours were approached from the non-dominant hemisphere. Simpson grade I resection was achieved in all 20 patients. The follow-up ranged from 12 months to 114 months. There was no postoperative mortality, serious neurological deficits, or tumour recurrence. The preliminary results suggest that the proposed scheme can facilitate surgical planning and accomplish complete tumour resection with minimal invasion.

Triple dumbbell-shaped jugular foramen schwannomas.

PURPOSE: Triple dumbbell-shaped jugular foremen schwannomas (DSJFSs) have high cervical extension according to Bulsara's classification. One-stage, single-discipline, total removal of triple DSJFSs is not always possible due to their both intracranial and cervical extensions. We evaluated our experience in one-stage resection of triple DSJFSs by using a combined neurosurgical and head and neck approach. METHODS: Between October 2004 and May 2009, eight patients with triple DSJFSs were treated surgically at our institute. The clinical and radiological features, operative procedures and outcomes are retrospectively reviewed. RESULTS: Total tumour removal was achieved in seven patients and near total in one. New cranial nerve (CN) paresis occurred after surgery in one patient and worsening of preoperative CN deficits was noted in three. Two patients experienced cerebrospinal fluid leakage and one of them had a repeated operation with closure of the dural deficit. Follow-up period ranged from 23 to 60 months (mean 38 months). All CN dysfunction had improved considerably at the last follow-up examination. There have been no clinical or radiological signs of tumour recurrence. CONCLUSIONS: One-stage total resection of triple DSJFSs can be achieved by a multidisciplinary cranial base team composed of neurosurgeons and head and neck surgeons via a craniocervical approach.

[Lateral cervical approach for resection of cervical dumbbell-shape neurogenic tumors].

OBJECTIVE: To study the indication and character of the lateral-cervical approach for treating dumble-shape neurogenic tumors in cervical spine. METHODS: Retrospectively review the clinical data of 14 dumble-shape neurogenic tumors in cervical spine, from October 2005 to October 2011. Among them 8 were males and 6 were females, range from 11 to 60 years old. The maximum tumor diameter range from 3.0 to 8.0 cm, with an average of 4.8 cm; the intraspinal tumor diameter range from 1.3 to 3.8 cm, with an average of 2.1 cm. According to Asazuma classification, 9 cases were type IIc, 2 cases were type IIIb, 2 cases were type IV, 1 case was type VI. Involving the neck segment C(1)-C(2) in 1 case, C(2)-C(3) in 1 case, C(3)-C(4) in 2 cases, C(4)-C(5) in 2 cases, C(5)-C(6) in 3 cases, C(6)-C(7) in 4 cases and C(2)-C(4) in 1 case. All cases performed surgery with general anethesia. The head and neck surgeon performed surgery with lateral cervical approach, in the space between the anterior and the medius scalenus, exposed the transverse process and the intervertebral foramen as the anatomy marker, resected the extraspinal tumor part. The neurosurgery expanded the intervertebral foramen, and resected the intraspinal tumor with microscope, and repaired the dura. Then head and neck surgeon closed the wounds. RESULTS: Pathology proved 3 neurolimmoas and 11 Schwannomas, 12 cases received gross total resection, 2 cases received subtotal resection, the average blood loss during operation was 292 ml, the average operation time was 129 minutes, the average stay in hospital days was 7.1 days. The vertebral artery were exposed in 2 cases, and no vertebral artery injury occurred, there were 3 cases dissect the cervical nerve roots. No cerebrospinal fluid leakage, hematoma, newly branchial plexus injury, sympathic nerve injury or tracheal edema occurred. In 3 to 24 months, with an average of 13.5 months follow-up period, 2 cases with subtotal resection had no tumor progression, and 12 cases with gross total resection had no tumor recurrence. CONCLUSIONS: Lateral-cervical approach is minimal invasive, easily to perform and recovery fine. It can be adopt for Asazuma type IIc, IIIb and IV tumors which not grow over the midline in spine and expand to deep layer of the deep cervical fascia out spine.

[Microneurosurgical treatment of massive tuberculum sellae meningiomas].

OBJECTIVE: To summarize the characteristics of the pathological anatomy and blood supply model of massive tuberculum sellae meningiomas (MTSM) and explore its corresponding microneurosurgical strategies. METHODS: The clinical data of 16 MTSM patients were reviewed retrospectively. From January 1998 to January 2010, according to their unique pathological anatomy and blood supply model, all patients underwent microneurosurgical removal with induced hypotension through tumor corridor by the bi-subfrontal anterior longitudinal fission (n = 14), right frontolateral approach (n = 1) and pterional approach (n = 1). There were 5 males and 11 females with a mean age of 48.5 years old (range: 26 - 65). But the mean follow-up period was 74.9 months (range: 4 - 132) in 2/4 cases. RESULTS: Among all cases, the mean tumor diameter was 58.9 mm (range: 51.1 - 76.2 mm). Simpson grade I, II, III, IV removal of MTSMs were accomplished in 3, 9, 3 and 1 case respectively. One case died within 4 postoperative days. Visual acuity improved in 10 patients, remained unchanged in 2 and deteriorated in 2. Transient postoperative diabetes insipidus occurred in 9 cases. CONCLUSION: It is critical to understand the unique characteristics of pathological anatomy and blood supply model of MTSM so as to adopt proper microneurosurgical strategies to remove it in situ.