Multiregional Sequencing of IDH-WT Glioblastoma Reveals High Genetic Heterogeneity and a Dynamic Evolutionary History.

Glioblastoma is one of the most common and lethal primary neoplasms of the brain. Patient survival has not improved significantly over the past three decades and the patient median survival is just over one year. Tumor heterogeneity is thought to be a major determinant of therapeutic failure and a major reason for poor overall survival. This work aims to comprehensively define intra- and inter-tumor heterogeneity by mapping the genomic and mutational landscape of multiple areas of three primary IDH wild-type (IDH-WT) glioblastomas. Using whole exome sequencing, we explored how copy number variation, chromosomal and single loci amplifications/deletions, and mutational burden are spatially distributed across nine different tumor regions. The results show that all tumors exhibit a different signature despite the same diagnosis. Above all, a high inter-tumor heterogeneity emerges. The evolutionary dynamics of all identified mutations within each region underline the questionable value of a single biopsy and thus the therapeutic approach for the patient. Multiregional collection and subsequent sequencing are essential to try to address the clinical challenge of precision medicine. Especially in glioblastoma, this approach could provide powerful support to pathologists and oncologists in evaluating the diagnosis and defining the best treatment option.

Arterial aneurysms associated with intracranial dural arteriovenous fistulas: epidemiology, natural history, and management. A systematic review.

Arterial aneurysms are uncommon among patients with dural arteriovenous fistulae (DAVFs), and there is limited information available to guide treatment decisions in such cases. We performed a systematic review of the literature, including a case of a DAVF associated with a flow-related intraorbital ophthalmic artery (OA) aneurysm that we have recently managed. The purpose of our study was to clarify epidemiology, natural history, and management of these lesions. A total of 43 published cases of DAVF associated aneurysms were found in 26 studies on the topic. Anterior cranial fossa was the most common location (40%), and ethmoidal branches were the most common arterial feeders (55%). In about 63% of cases, the aneurysm was located on artery unrelated to DAVF supply. Approximately 10% of intracranial DAVFs were associated with aneurysms located in the intraorbital OA. Overall, 70% of lesions were Borden type III, and 50% of patients presented with hemorrhage. In approximately 17% of cases, the source of bleeding was a feeding artery aneurysm. All of the reported intraorbital OA aneurysms associated with DAVFs remained stable during follow-up. DAVF associated aneurysms are fairly rare. Anterior cranial fossa location and direct cortical venous drainage are common among these lesions. The aneurysms are less likely to be located on feeding arteries, and hemorrhagic presentation related to flow-related aneurysm rupture is uncommon.

Cancer astrocytes have a more conserved molecular status in long recurrence free survival (RFS) IDH1 wild-type glioblastoma patients: new emerging cancer players.

Glioblastoma is a devastating disease that despite all the information gathered so far, its optimal management remains elusive due to the absence of validated targets from clinical studies. A better clarification of the molecular mechanisms is needed. In this study, having access to IDH1 wild-type glioblastoma of patients with exceptionally long recurrence free survival (RFS), we decided to compare their mutational and gene expression profile to groups of IDH1 wild-type glioblastoma of patients with shorter RFS, by using NGS technology. The exome analysis revealed that Long-RFS tumors have a lower mutational rate compared to the other groups. A total of 158 genes were found differentially expressed among the groups, 112 of which distinguished the two RFS extreme groups. Overall, the exome data suggests that shorter RFS tumors could be, chronologically, in a more advanced state in the muli-step tumor process of sequential accumulation of mutations. New players in this kind of cancer emerge from the analysis, confirmed at the RNA/DNA level, identifying, therefore, possible oncodrivers or tumor suppressor genes.

Survival outcomes following repeat surgery for recurrent glioblastoma: a single-center retrospective analysis.

The aim of the present study is to evaluate the impact of extent of resection at initial and repeat craniotomy on overall survival of patients with recurrent glioblastoma. The authors retrospectively reviewed the records of all adults patients who underwent repeat resection of recurrent glioblastoma following radiation and chemotherapy at an academic tertiary-care institution between 2011 and 2015. We evaluated the survival outcomes with regard to extent of resection considering both the initial and repeat resections. The role of possible prognostic factors that may affect survival after repeat resection, including age, preoperative performance status, tumor location and adjuvant treatment, was evaluated using Cox regression analyses. Forty-eight patients were included in this study. The overall median survival of 14 patients who had subtotal resection at recurrence after initial subtotal resection did not statistically differ from seven patients who had gross-total resection at recurrence after initial subtotal resection (18 months vs. 22 months, p = 0.583). The overall median survival of 13 patients who had gross-total resection at recurrence after initial gross-total resection was significantly increased compared with survival of 13 patients who had subtotal resection at recurrence after initial gross-total resection (47 months vs. 14 months, p = 0.009). A Cox proportional hazards model was created demonstrating that preoperative performance status at recurrence (HR 0.418, p = 0.035) and the extent of repeat resection (HR 0.513, p = 0.043) were independent predictors of survival. Gross-total resection at repeat craniotomy is associated with longer overall survival and should be performed whenever possible in patients with recurrent glioblastoma and in good performance status.

Second surgery for recurrent glioblastoma: A concise overview of the current literature.

Optimal treatment for recurrent glioblastoma continues to evolve. Currently, however, there is no consensus in the literature on the role of reoperation in the management of these patients, as several studies provide evidence for a longer overall survival in selected patients with recurrent glioblastoma who underwent second surgery and other studies report a limited impact of second surgery in the clinical course. In this paper, a review of the current literature was performed to analyze the role of reoperation in patients with recurrent glioblastoma and to report the overall survival from diagnosis, progression-free survival and quality of life. Using PubMed and Ovid Medline databases, we performed a review of the literature of the last seven years, finding a total of 28 studies and 2279 patients who underwent second surgery, that were included in the final analysis. The median overall survival from diagnosis and the median survival from second surgery were 18.5 months and 9.7 months, respectively. Extent of resection at reoperation improves overall survival, even in patients with subtotal resection at initial operation. Preoperative performance status and age are important predictors of a longer survival, reason why younger patients with a good preoperative performance status could benefit from reoperation.

Disseminated bone metastases from occult thyroid cancer effectively treated with debulking surgery and a single dosimetry-guided administration of radioiodine.

In this paper we report on a successful management of multiple bone metastases from differentiated thyroid cancer. In 2007, a 75-year-old female patient, previously referred for thyroidectomy for multinodular goiter, underwent surgical removal of a lumbar mass with histological findings of metastasis from well differentiated thyroid cancer. After surgery, serum thyroglobulin (sTg) was 204.4 ng/mL. A diagnostic/dosimetric (123)I WBS was performed, following stimulation by rTSH. Serial WBSs were acquired, along with SPECT/CT and bone scan for localization of lesions. sTg raised to 3.810 ng/mL, and (123)I WBS showed thyroid remnants and numerous areas with high iodine-uptake corresponding to skeletal sites, the two largest loading on the skull, with osteolytic pattern. Calculated radiation absorbed dose for skull lesions, determined by mean of MIRD methodology, was 63.5 mGy/MBq. The patient underwent surgical removal of the two major skull lesions. Successively, 100 mCi (131)I was administered after stimulation by rTSH, with stimulated sTg 297 ng/mL. After 8 months, diagnostic WBS was negative both for remnants and metastases and rTSH-stimulated Tg was 0.6 ng/mL. To date, the patient has maintained sTg values <1 ng/mL during L-T4 suppressive therapy and after rTSH stimulations. In this unusual case of extensive bone cancerous involvement with high iodine avidity, a multidisciplinary approach based on surgery and dosimetry-guided radiometabolic therapy allowed to accurately assess the patient, execute a small number of treatments and achieve a complete remission of the disease in a very short time, with no additive morbidity.

Investigating molecular alterations to profile short- and long-term recurrence-free survival in patients with primary glioblastoma.

Glioblastoma (GB) is the most aggressive type of primary brain tumor. Despite the progress in recent years regarding the diagnosis and treatment of GB, the recurrence rate remains high, due to the infiltrative and dispersive nature of the tumor, which typically results in poor patient prognosis. In the present study, 19 formalin-fixed, paraffin-embedded GB samples were selected from patients with GB tumors. The samples were classified into a short or long recurrence-free survival (RFS) group, based on the time of first recurrence of the disease in the patients. The 19 samples were molecularly characterized for mutations in the isocitrate dehydrogenase 1 (IDH1) gene, amplification of the epidermal growth factor receptor (EGFR) gene, presence of the EGFR variant III, and methylation of the promoter region of the O6-methylguanine-DNA methyltransferase (MGMT) gene. Then, the expression of 84 genes involved in cell-cell and cell-matrix interactions, and that of 84 microRNAs (miRNAs) associated with brain cancer, was profiled. In addition, a copy number variation analysis of 23 genes reported to undergo frequent genomic alterations in human glioma was also performed. Differences in the expression levels of a number of genes were detected across the short and long RFS groups. Among these genes, 5 in particular were selected, and a 5-genes combination approach was developed, which was able to differentiate between patients with short and long RFS outcome. The high levels of sensitivity and precision displayed by this 5-genes combination approach, which were confirmed with a cross-validation method, provide a strong foundation for further validation of the involvement of the aforementioned genes in GB in a larger patient population. In conclusion, the present study has demonstrated how the expression pattern of miRNAs and mRNAs in patients with GB defines a particular molecular hallmark that may increase or reduce the aggressive behavior of GB tumors, thus influencing the survival rates of patients with GB, their response to therapy and their tendency to suffer a relapse.

Hydrocephalus following bilateral dumbbell-shaped c2 spinal neurofibromas resection and postoperative cervical pseudomeningocele in a patient with neurofibromatosis type 1: a case report.

Study Design Case report. Objective To present a rare case of hydrocephalus following bilateral dumbbell-shaped C2 spinal neurofibromas resection and postoperative cervical pseudomeningocele in a patient with neurofibromatosis type 1 (NF1). Methods The patient's clinical course is retrospectively reviewed. A 37-year-old man affected by NF1 referred to our department for progressive weakness of both lower extremities and gait disturbance. Radiological imaging showed bilateral dumbbell-shaped C2 spinal neurofibromas. After its resection, at the 1-month follow-up evaluation, the patient reported headache and nausea. A CT brain scan showed a postoperative cervical pseudomeningocele and an increase in the ventricular sizes, resulting in hydrocephalus. Results A ventriculoperitoneal shunting was performed using a programmable valve opening pressure set to 120 mmH20. After surgery, the patient's neurological status markedly improved. Conclusion Hydrocephalus must be considered a possible complication of cervical spine tumor resection.

Accessibilome of human glioblastoma: collagen-VI-alpha-1 is a new target and a marker of poor outcome.

Functional targeted therapy has unfortunately failed to improve the outcome of glioblastoma patients. Success stories evidenced by the use of antibody-drug conjugates in other tumor types are encouraging, but targets specific to glioblastoma and accessible through the bloodstream remain scarce. In the current work, we have identified and characterized novel and accessible proteins using an innovative proteomic approach on six human glioblastomas; the corresponding data have been deposited in the PRIDE database identifier PXD001398. Among several clusters of uniquely expressed proteins, we highlight collagen-VI-alpha-1 (COL6A1) as a highly expressed tumor biomarker with low levels in most normal tissues. Immunohistochemical analysis of glioma samples from 61 patients demonstrated that COL6A1 is a significant and consistent feature of high-grade glioma. Deposits of COL6A1 were evidenced in the perivascular regions of the tumor-associated vasculature and in glioma cells found in pseudopalisade structures. Retrospective analysis of public gene-expression data sets from over 300 glioma patients demonstrated a significant correlation of poor patient outcome and high COL6A1 expression. In a proof-of-concept study, we use chicken chorioallantoic membrane in vivo model to show that COL6A1 is a reachable target for IV-injected antibodies. The present data warrant further development of human COL6A1 antibodies for assessing the quantitative biodistribution in the preclinical tumor models.

The bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1) provides long-term survival in a murine glioma model.

BACKGROUND: Glioblastomas are largely unresponsive to all available treatments and there is therefore an urgent need for novel therapeutics. Here we have probed the antineoplastic effects of a bacterial protein toxin, the cytotoxic necrotizing factor 1 (CNF1), in the syngenic GL261 glioma cell model. CNF1 produces a long-lasting activation of Rho GTPases, with consequent blockade of cytodieresis in proliferating cells and promotion of neuron health and plasticity. METHODS: We have tested the antiproliferative effects of CNF1 on GL261 cells and human glioma cells obtained from surgical specimens. For the in vivo experiments, we injected GL261 cells into the adult mouse visual cortex, and five days later we administered either a single intracerebral dose of CNF1 or vehicle. To compare CNF1 with a canonical antitumoral drug, we infused temozolomide (TMZ) via minipumps for 1 week in an additional animal group. RESULTS: In culture, CNF1 was very effective in blocking proliferation of GL261 cells, leading them to multinucleation, senescence and death within 15 days. CNF1 had a similar cytotoxic effect in primary human glioma cells. CNF1 also inhibited motility of GL261 cells in a scratch-wound migration assay. Low dose (2 nM) CNF1 and continuous TMZ infusion significantly prolonged animal survival (median survival 35 days vs. 28 days in vehicle controls). Remarkably, increasing CNF1 concentration to 80 nM resulted in a dramatic enhancement of survival with no obvious toxicity. Indeed, 57% of the CNF1-treated animals survived up to 60 days following GL261 glioma cell transplant. CONCLUSIONS: The activation of Rho GTPases by CNF1 represents a novel potential therapeutic strategy for the treatment of central nervous system tumors.

Delayed post-traumatic fronto-ethmoidal sinus mucocele evaluated with short and long TE MR spectroscopy.

Mucoceles are slow-growing, benign, expansile, mucoid-filled masses developing after obstruction of the sinus ostium. Late post-traumatic mucoceles are relatively rare entities and the literature is limited to single case reports. We describe an unusual case of post-traumatic fronto-ethmoidal mucocele, evaluated with computed tomography (CT), magnetic resonance imaging (MRI) and proton MR-spectroscopy ((1)H-MRS). As a contribution to the diagnostic work-up of the mucocele, (1)H-MRS demonstrates a dominant peak at 2.0 ppm at long echo time (TE) and an additional component at 3.8 ppm at short TE due to mucus glycoprotein compounds of the mucocele.

Management and outcome of high-grade multicentric gliomas: a contemporary single-institution series and review of the literature.

BACKGROUND: Multicentric malignant gliomas are well-separated tumours in different lobes or hemispheres, without anatomical continuity between lesions. The purpose of this study was to explore the clinical features, the pathology and the outcome according to the management strategies in a consecutive series of patients treated at a single institution. In addition, an analysis of the existing literature is presented. METHODS: For the institutional analysis, a retrospective review of all patients who underwent treatment for multicentric gliomas in the last 7 years was performed. For the analysis of the literature, a MEDLINE search with no date limitations was accomplished for surgical treatment of multicentric malignant gliomas. RESULTS: Two hundred and thirty-nine patients with glioma were treated in our department. Eighteen patients (7.5 %) with a mean age of 64 years (age range, 37-78 years) presented multicentric malignant gliomas. Thirteen patients (72 %) underwent surgical resection of at least one lesion that was followed by adjuvant treatment in all but one case. Five patients (28 %) underwent stereotactic biopsy and thereafter received chemotherapy. A survival advantage was associated with resection of at least one lesion followed by adjuvant treatment (median overall survival 12 months) compared with 4 months for stereotactic biopsy followed by chemotherapy. Similar results were obtained from the review of the literature. CONCLUSIONS: Resection of at least one lesion seems to play a significant role in the management of selected patients with multicentric malignant gliomas. Multi-institutional studies on larger series are warranted to define how aggressively the patients with malignant multicentric gliomas should be treated.

Epidural spinal cord compression in Langerhans cell histiocytosis: a case report.

Langerhans cell histiocytosis, also known as histiocytosis X, is a rare proliferative disorder of histiocytes. Spinal involvement in the course of Langerhans cell histiocytosis in adult is rare, and epidural location is exceptional. We present a rare case of epidural involvement by Langerhans cell histiocytosis in a 71-year-old man to highlight the importance of considering Langerhans cell histiocytosis in the differential diagnosis of epidural spinal cord compression.

Use of near-infrared indocyanine videoangiography and Flow 800 in the resectioning of a spinal cord haemangioblastoma.

Haemangioblastomas are hypervascularized tumours. Their surgical management requires a complete resectioning and a prompt handling of the vascular inlets and outlets. The use of intraoperative indocyanine green video angiography (ICG-VAG) depicts the precise vascular pattern for the surgeon. Its use is safe and easy, and the procedure can be repeated during the operation. Here we present a case of spinal haemangioblastoma treated with the aid of intraoperative ICG-VAG and the Flow 800 software. The use of the Flow 800 allowed the surgeon to detect, at a glance, minimal changes in the vascular supply during the dissection. The colour-coded images generated by the Flow 800 increase the ICG-CAG sensitivity, improving the capability to detect changes in vascular patterns.

Three-dimensional microsurgical anatomy of cerebellar peduncles.

The microsurgical anatomy of cerebellar peduncles and their relationships with neighbouring fasciculi were investigated by using a fibre dissection technique. As the dissection progressed, photographs of each progressive layer were obtained and stereoscopic images were created using the 3D anaglyphic method. These findings provided the anatomical basis for a conceptual division of cerebellar peduncles into segments. The middle cerebellar peduncle (MCP) was divided into two segments: cisternal and intracerebellar segments. The inferior cerebellar peduncle (ICP) was divided into three segments: cisternal, ventricular and intracerebellar segments. The superior cerebellar peduncle (SCP) was divided into three segments: intracerebellar, intermediate and intrategmental segments. The fibre dissection technique disclosed a constant course of peduncular fibres inside the white core of the cerebellum. The pontocerebellar fibres of the MCP pass over and laterally to the bundles of the ICP and SCP. The centripetal fibres of the ICP wrap around the radiation of the SCP and the dentate nucleus, directed towards the cortex of the vermis. The centrifugal bundle of the SCP ascends towards the mesencephalon where it sinks passing below the fibres the lateral lemniscus. The knowledge gained by studying the intrinsic anatomy of the cerebellum is useful to accomplish appropriate surgical planning and, ultimately, to understand the repercussions of surgical procedures on the white matter tracts in this region.

Incidence and management of late postsurgical seizures in clinical practice.

AIM: Seizures are a frequent complication in patients who undergo neurosurgery, and can complicate the post-operative course and deteriorate patients' quality of life. Evidence on the prophylactic anticonvulsant therapy after craniotomy is still lacking. MATERIAL AND METHODS: We undertook an observational longitudinal study following neurosurgical supratentorial interventions, to evaluate seizures onset or persistence, and differences in effectiveness between conventional and newer AEDs. RESULTS: A total of 100 consecutive subjects were enrolled. Each patient underwent a neurosurgical treatment by craniotomy. Pre-operative seizures occurred in 33% patients, early seizures in 13%. Late seizures occurred in 46 patients. At baseline (1 month after surgery) and during follow up the main therapeutic regimen was monotherapy. At last follow up adjustment of antiepileptic regimen or AED dosage had rendered 27 subjects seizure free. People taking newer AEDs at baseline maintain the same antiepileptic regimen more often than patients taking conventional AEDs; late seizures tended to have a higher incidence in the latter group. Adverse events from baseline AEDs were reported by 17% of patients. CONCLUSION: In this study population late postsurgical seizures had a remarkable occurrence. Newer AEDs were continued more often than conventional AEDs, with a better tolerability but no significant differences in late seizures incidence.

Clip assisted use of gelatin-thrombin matrix sealant as a rescue procedure to treat a hidden arterial tear.

Major intracranial arteries can be injured during tumor removal. Surgeons routinely manage this event by using either microvascular direct repair, by-pass of the wounded segment or the placement of a sutureless device. These procedures, however, are not always possible due to artery brittleness, deep operating field, vascular configuration, or restricted viewing field. In this particular case, we illustrate an example of innovative use of gelatin-thrombin matrix sealant used to repair a hidden tear of pericallosal-callosomarginal bifurcation. A 49-year-old man underwent resection of a recurrent left frontal glioma. During an attempt to remove a firmly attached portion of the tumor, a tear occured in the pericallosal-callosomarginal bifurcation. The wall defect was repaired with a temporary vascular clip placed on the pericallosal artery and gelatin-thrombin matrix sealant sprayed over the tear. An intraoperative indocyanine videoangiography showed patency of both the pericallosal and callosomarginal arteries. Gelatin-thrombin matrix sealant is useful to control bleeding from an artery when the viewing field is restricted. In some cases, however, blood outflow must first be reduced in order to allow clot formation.

Perioperative high-dose-rate brachytherapy in the treatment of recurrent malignant gliomas.

PURPOSE: To assess the feasibility and effectiveness of perioperative high-dose-rate brachytherapy for recurrent malignant gliomas. PATIENTS AND METHODS: Between 2005 and 2008, 21 patients (14 males and seven females) with relapsed malignant glioma underwent a second surgery followed by a brachytherapy implant in the surgical cavity. Median age was 60 years, and median Karnofsky performance status 80. A single fraction of 18 Gy specified at 5 mm depth was administered perioperatively. Then, the applicator was removed nonsurgically. Mean postoperative hospitalization time was 3 days. RESULTS: At the time of analysis, 15 patients (71%) had died and six (29%) were alive. Median follow-up was 32.3 months. Median overall survival from diagnosis amounted to 21.7 months. Median survival after recurrence was 8.0 months, and 6-month progression-free survival 42%. Patients were stratified into classes according to the prognostic recursive partitioning analysis. CONCLUSION: Perioperative brachytherapy has proven to be safe and well tolerated in patients with recurrent malignant glioma. No severe toxicity was reported, and the treatment has proven to be effective in symptomatic recurrences of malignant gliomas.