Pathophysiology of Postoperative Hearing Disorders after Vestibular Schwannoma Resection: Insights from Auditory Brainstem Response and Otoacoustic Emissions.

Background: In order to better understand the pathophysiology of surgically induced hearing loss after vestibular schwannoma (VS) surgery, we postoperatively analyzed the hearing status in a series of patients where hearing was at least partially preserved. Methods: Hearing was assessed through tonal audiometry, speech discrimination score, maximum word recognition score (dissyllabic word lists-MaxIS), otoacoustic emissions (OAEs), and auditory brainstem response (ABR). The magnetic resonance imaging (MRI) tumor characterization was also noted. Results: In a series of 24 patients operated on for VS over 5 years, depending on the results of this triple hearing exploration, we could identify, after surgery, patients with either a myelin alteration or partial damage to the acoustic fibers, others with a likely partial cochlear ischemia, and some with partial cochlear nerve ischemia. One case with persisting OAEs and no preoperative ABR recovered hearing and ABR after surgery. Long follow-up (73 ± 57 months) revealed a mean hearing loss of 30 ± 20 dB with a drastic drop of MaxIS. MRI revealed only 25% of fundus invasion. Conclusion: a precise analysis of hearing function, not only with classic audiometry but also with ABR and OEAs, allows for a better understanding of hearing damage in VS surgery.

The Recent Management of Vestibular Schwannoma Radiotherapy: A Narrative Review of the Literature.

BACKGROUND: Radiotherapy (RT) plays an important role in the therapeutic management of vestibular schwannoma (VS). Fractionated stereotactic radiotherapy (FSRT) or radiosurgery (SRS) are the two modalities available. The purpose of this article is to review the results of VS RT studies carried out over the last ten years. MATERIALS AND METHODS: A literature search was performed with PubMed and Medline by using the words vestibular schwannoma, acoustic neuroma, radiotherapy, and radiosurgery. RESULTS: In small (<3 cm) VS, SRS offers a local control rate of >90%, which seems similar to microsurgery, with a favorable tolerance profile. Hypofractionated FSRT (three to five fractions) is a relatively recent modality and has shown similar outcomes to normofractionated FSRT. Hearing preservation may highly differ between studies, but it is around 65% at 5 years. CONCLUSIONS: SRS and FRST are non-invasive treatment options for VS. SRS is often preferred for small lesions less than 3 cm, and FSRT for larger lesions. However, no randomized study has compared these modalities.

Challenging foreign body surgery: residual needlefish jaws.

We report a case of a needlefish jaws retained near the C5-C6 joint that was associated with chronic pain and inflammation and seen confirmed by FDG-PET scan. Two unsuccessful surgeries using an anterior approach were complicated by vascular and nerve injuries. We used image-guided surgery with a posterior approach.

Prevention of cerebrospinal fluid leak after vestibular schwannoma surgery: a case-series focus on mastoid air cells' partition.

BACKGROUND: Petrous bone pneumatization may be related to cerebrospinal fluid (CSF) leak secondary to vestibular schwannoma surgery. OBJECTIVE: To assess the association between petrous bone pneumatization and CSF leak in vestibular schwannoma surgery. METHODS: A retrospective study included 222 consecutive vestibular schwannoma patients treated via a retrosigmoid or translabyrinthine approach in a 17-year period in one University Hospital. Association of CSF leak and petrous bone pneumatization, as seen on CT scans, was assessed on ANOVA and Student's t or Chi-squared test in case of non-parametric distribution. RESULTS: One hundred and 75 resections were performed on a retrosigmoid approach and 47 on a translabyrinthine approach. Mean age was 53.6 ± 12.9 years. Mean follow-up was 5 years 6 months. Twenty-six patients (11.7%) showed CSF leak and 8 (3.6%) meningitis. Approach (p = 0.800), gender (p = 0.904), age (p = 0.234), body-mass index (p = 0.462), tumor stage (p = 0.681) and history of schwannoma surgery (p = 0.192) did not increase the risk of CSF leak. This risk was unrelated to mastoid pneumatization (p = 0.266). There was a highly significant correlation between internal acousticus meatus (IAM) posterior wall pneumatization and CSF leak after retrosigmoid surgery (p = 0.008). Eustachian tube packing in the translabyrinthine approach did not decrease risk of CSF leak (p = 0.571). CONCLUSION: Degree of petrous bone pneumatization was not significantly related to risk of CSF leak, but pneumatization of the posterior IAM wall increased this risk in retrosigmoid surgery. Eustachian tube packing in the translabyrinthine approach is not sufficient to prevent postoperative CSF leak. Both approaches had similar rates of CSF leaks, around 12%.

Preoperative stereotactic radiosurgery for brain metastases: the STEP study protocol for a multicentre, prospective, phase-II trial.

BACKGROUND: Surgery is an important therapeutic option for brain metastases. Currently, postoperative stereotactic radiosurgery (SRT) leads to 6-month and 1-year local control estimated at 70 and 62% respectively. However, there is an increased risk of radio-necrosis and leptomeningeal relapse. Preoperative SRT might be an alternative, providing local control remains at least equivalent. It is an innovative concept that could enable the stereotactic benefits to be retained with advantages over post-operative SRT. METHODS: STEP has been designed as a national, multicentre, open-label, prospective, non-randomized, phase-II trial. Seventeen patients are expected to be recruited in the study from 7 sites and they will be followed for 12 months. Patients with more than 4 distinct brain metastases, including one with a surgical indication, and an indication for SRT and surgery, are eligible for enrolment. The primary objective of the trial is to assess 6-month local control after preoperative SRT. The secondary objectives include the assessment of local control, radio-necrosis, overall survival, toxicities, leptomeningeal relapse, distant control, cognitive function, and quality of life. The experimental design is based on a Flemming plan. DISCUSSION: There is very little data available in the literature on preoperative SRT: there have only been 3 American single or two-centre retrospective studies. STEP is the first prospective trial on preoperative SRT in Europe. Compared to postoperative stereotactic radiotherapy, preoperative stereotactic radiotherapy will enable reduction in the irradiated volume, leptomeningeal relapse and the total duration of the combined treatment (from 4 to 6 weeks to a few days). TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT04503772 , registered on August 07, 2020. Identifier with the French National Agency for the Safety of Medicines and Health Products (ANSM): N°ID RCB 2020-A00403-36, registered in February 2020. PROTOCOL: version 4, 07 December 2020.

Significant correlation between gross tumor volume (GTV) D98% and local control in multifraction stereotactic radiotherapy (MF-SRT) for unresected brain metastases.

BACKGROUND: Stereotactic radiotherapy (SRT) should be applied with a biologically effective dose with an α/ß of 12 (BED12) ≥ 40 Gy to reach a 1-year local control (LC) ≥ 70%. The aims of this retrospective study were to report a series of 81 unresected large brain metastases treated with Linac-based multifraction SRT according to the ICRU 91 and to identify predictive factors associated with LC. METHODS: Included in this study were the first 81 brain metastases (BM) consecutively treated with Linac-based volumetric modulated arc therapy (VMAT) multifraction SRT from 2017 to 2019. The prescribed dose was 33 Gy for the GTV and 23.1 Gy (70% isodose line) for the PTV in 3 fractions (3f). Mean BM largest diameter and GTV were 25.1 mm and 7.2 cc respectively. Mean follow-up was 10.2 months. RESULTS: LC was 79.7% and 69.7% at 1 and 2 years respectively. Significant predictive factors of LC were GTV D98% (HR = 0.84, CI 95% = 0.75-0.95, p = 0.004) and adenocarcinoma as the histological type (HR = 0.29, CI 95% = 0.09-0.96, p = 0.042) in univariate and multivariate analysis. A threshold of 29 Gy for GTV D98% was significantly correlated to LC (1-year LC = 91.9% for GTV D98% ≥ 29 Gy vs 69.6% for GTV D98% < 29 Gy (p = 0.030)), corresponding to a BED12 = 52.4 Gy. No tumor progression was observed for a BED12 ≥ 53.4 Gy, corresponding to a GTV D98% ≥ 20 Gy /1f and GTV D98% ≥ 29.4 Gy 3f. Median OS was 15 months. Symptomatic radionecrosis occurred in 4.9% of cases. CONCLUSION: The GTV D98% is a strong reproducible significant predictive factor of LC for brain SRT. Dose prescription should lead to a GTV BED12 98% ≥ 52.4-53.4 Gy to significantly improve LC, corresponding to respectively a GTV D98% ≥ 19.7-20 Gy/1f and 29-29.4 Gy/3f.

Stereotactic Radiosurgery for Vestibular Schwannomas: Reducing Toxicity With 11 Gy as the Marginal Prescribed Dose.

BACKGROUND: Stereotactic radiosurgery (SRS) is a common treatment option for vestibular schwannomas. Historically, a dose de-escalation of the marginal prescribed dose from 16 Gy to 12-13 Gy has been done to limit toxicity without reducing local control (LC). We aimed to retrospectively report outcomes of Linac-based SRS for vestibular schwannomas treated with different doses. METHODS: Included in the study were 97 stage 1 (1%), 2 (56%), 3 (21.5%), and 4 (21.5%) vestibular schwannomas treated with Linac-based (Novalis®) SRS from 1995 to 2019. No margin was added to the GTV to create the PTV. The median marginal prescribed dose was 14 Gy (range: 12-16 Gy) before 2006 and then 11 Gy for all patients (61 pts). Mean tumor volume was 1.96 cm3, i.e., about 1.6 cm in diameter. Mean follow-up was 8.2 years. RESULTS: Following SRS, LC at 3, 5, and 10 years was 100%, 98.4%, and 95.6%, respectively [100% for those with ≤ 13 Gy as the marginal prescribed dose (NS)]. Toxicity to the trigeminal nerve was reported in 7.2% of cases (3.3% and 0% for transient and permanent toxicity for 11 Gy). The marginal prescribed dose was the only significant predictive factor in univariate and multivariate analysis (HR = 1.77, 95% CI = 1.07-3.10, p = 0.028). Toxicity to the facial nerve was reported in 6.2% of cases. The marginal prescribed dose was again the only significant predictive factor in univariate and multivariate analysis (HR = 1.31, 95% CI = 0.77-2.23, p = 0.049). CONCLUSION: Linac-based SRS for stages 1-3 vestibular schwannomas provides excellent outcomes: a 10-year LC rate of over 95%, with a permanent facial or trigeminal toxicity rate of under 5%. A marginal prescribed dose of 11 Gy seems to decrease nerve toxicity and facial toxicity in particular, without reducing LC. Prospective studies with longer follow-up are needed.

Patterns of Failure After Linear Accelerator Radiosurgery for Cerebral Arteriovenous Malformations.

BACKGROUND: Numerous studies have assessed the predictive factors for the arteriovenous malformation (AVM) response to stereotactic radiosurgery (SRS). However, only a few have discussed the causes of failure. The aim of the present study was to evaluate the patterns of failure in patients with AVM who had undergone linear accelerator SRS. METHODS: We performed a retrospective analysis of 288 patients who had undergone linear accelerator SRS in our institution from 1995 to 2011. Failure was defined from the findings of the follow-up angiogram at 5 years, with failure identified in 44 patients. The distribution of causes was estimated using a descriptive analysis of literature-based causes, including a minimal margin dose of <18 Gy, a residual nidus outside the initial targeted volume, previous embolization, recanalization, and the size of the target volume. We also analyzed the associations among the causes. RESULTS: Incomplete nidus identification (41%) and previous embolization (77%) were the most frequently observed conditions in patients with failure. Patients who had undergone previous embolization, for whom the cause of failure had always been identified (P = 0.001), were younger (P = 0.004) and had had a larger nidus volume (P = 0.025). Recanalization was rare (5 of 34 patients) and had occurred exclusively in women (P = 0.048). Larger nidus volumes were less frequent (mean, 2.18 ± 2.2 cm3; range, 0.13-10.8 cm3) and had been observed mainly in women when >2 cm3 (P = 0.012). An insufficient dose was observed in 9 patients and had occurred in the case of a larger volume (P = 0.031), which had resulted in dosimetry constraints in 3 patients and treatment in the vicinity of eloquent zones in 6 patients. No known cause was found in 5 patients, 4 of whom had had a low Spetzler-Martin grade (I and II; P = 0.003), suggestive of radioresistance. CONCLUSION: The results of our detailed analysis have highlighted the distribution of the causes of failure and the potential role of radioresistance in treatment failure.

Transcriptional alterations in glioma result primarily from DNA methylation-independent mechanisms.

In cancer cells, aberrant DNA methylation is commonly associated with transcriptional alterations, including silencing of tumor suppressor genes. However, multiple epigenetic mechanisms, including polycomb repressive marks, contribute to gene deregulation in cancer. To dissect the relative contribution of DNA methylation-dependent and -independent mechanisms to transcriptional alterations at CpG island/promoter-associated genes in cancer, we studied 70 samples of adult glioma, a widespread type of brain tumor, classified according to their isocitrate dehydrogenase (IDH1) mutation status. We found that most transcriptional alterations in tumor samples were DNA methylation-independent. Instead, altered histone H3 trimethylation at lysine 27 (H3K27me3) was the predominant molecular defect at deregulated genes. Our results also suggest that the presence of a bivalent chromatin signature at CpG island promoters in stem cells predisposes not only to hypermethylation, as widely documented, but more generally to all types of transcriptional alterations in transformed cells. In addition, the gene expression strength in healthy brain cells influences the choice between DNA methylation- and H3K27me3-associated silencing in glioma. Highly expressed genes were more likely to be repressed by H3K27me3 than by DNA methylation. Our findings support a model in which altered H3K27me3 dynamics, more specifically defects in the interplay between polycomb protein complexes and the brain-specific transcriptional machinery, is the main cause of transcriptional alteration in glioma cells. Our study provides the first comprehensive description of epigenetic changes in glioma and their relative contribution to transcriptional changes. It may be useful for the design of drugs targeting cancer-related epigenetic defects.

Second course of stereotactic radiosurgery for locally recurrent brain metastases: Safety and efficacy.

In the present study, we have evaluated the efficacy and toxicity of repeated brain metastases (BM) stereotactic radiosurgery (SRS2) following local failure of a prior radiosurgical procedure (SRS1). Between December 1996 and August 2015, 30 patients with 36 BM underwent SRS2 with a median dose of 18Gy. All BM were located outside critical structures. Following SRS2, local control at 6 months and one year were respectively 82.9% (IC 95%: 67.6-91.9) and 67.8% (IC 95%: 51-81). On multivariate analysis, planning target volume (PTV) < 3cc (HR: 0.19 (0.1-0.52)) and whole brain radiotherapy (WBRT) prior to SRS2 (HR: 0.25 (0.1-0.64)) were significantly associated with a better local control. One- and two-year overall survival rates after SRS2 were respectively 65.5% (IC 95%: 47.3-80%) and 27.6% (IC 95%: 14.7-45.7). Median overall survival following SRS2 was 14.2 months (range 1-106). Nineteen (63%) patients died from progressive systemic disease. Three (10%) patients died from out-field progressive brain disease and 8 (27%) in-field. Concerning toxicities, edema, radionecrosis, and hemorrhages were identified in 5 (12.8%), 4 (10.2%), and 5 (12.8%) patients respectively. No toxicity resulted in a neurological deficit. On univariate analysis, toxicities were significantly associated with PTV > 7cc (p = 0.02) and all patients had a WBRT before SRS2. A second course of SRS for locally recurrent brain metastases showed encouraging rates of local control. This treatment led to acceptable toxicities, especially for brain metastases smaller than 7cc, in our selected cohort of patients with BM located outside critical structures. Further studies are needed.

Non-invasive intraoperative monitoring of cochlear function by cochlear microphonics during cerebellopontine-angle surgery.

In vestibular-schwannoma (VS) surgery, hearing-preservation rate remains low. Besides damage to the cochlear nerve, intraoperative cochlear ischemia is a potential cause of hearing loss. Here, we used non-invasive cochlear microphonic (CM) recordings to detect the cochlear vascular events of VS surgery. Continuous intraoperative CM monitoring, in response to 80-95 dB SPL, 1-kHz tone-bursts, was performed in two samples of patients undergoing retrosigmoid cerebellopontine-angle surgery: one for VS (n = 31) and one for vestibular neurectomy or vasculo-neural conflict causing intractable trigeminal neuralgia, harmless to hearing (n = 19, control group). Preoperative and postoperative hearings were compared as a function of intraoperative CM changes and their chronology. Monitoring was possible throughout except for a few tens of seconds when drilling or suction noises occurred. Four patterns of CM time course were identified, eventless, fluctuating, abrupt or progressive decrease. Only the VS group displayed the last two patterns, mainly during internal-auditory-canal drilling and the ensuing tumor dissection, always with postoperative loss of hearing as an end result. Conversely, eventless and fluctuating CM patterns could be associated with postoperative hearing loss when the cochlear nerve had been reportedly damaged, an event that CM is not meant to detect. Cochlear ischemia is a frequent event in VS surgery that leads to deafness. The findings that CM decrease raised no false alarm, and that CM fluctuations, insignificant in control cases, were easily spotted, suggest that CM intraoperative monitoring is a sensitive tool that could profitably guide VS surgery.

The tumoral A genotype of the MGMT rs34180180 single-nucleotide polymorphism in aggressive gliomas is associated with shorter patients' survival.

Malignant gliomas are the most common primary brain tumors. Grade III and IV gliomas harboring wild-type IDH1/2 are the most aggressive. In addition to surgery and radiotherapy, concomitant and adjuvant chemotherapy with temozolomide (TMZ) significantly improves overall survival (OS). The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter is predictive of TMZ response and a prognostic marker of cancer outcome. However, the promoter regions the methylation of which correlates best with survival in aggressive glioma and whether the promoter methylation status predictive value could be refined or improved by other MGMT-associated molecular markers are not precisely known. In a cohort of 87 malignant gliomas treated with radiotherapy and TMZ-based chemotherapy, we retrospectively determined the MGMT promoter methylation status, genotyped single nucleotide polymorphisms (SNPs) in the promoter region and quantified MGMT mRNA expression level. Each of these variables was correlated with each other and with the patients' OS. We found that methylation of the CpG sites within MGMT exon 1 best correlated with OS and MGMT expression levels, and confirmed MGMT methylation as a stronger independent prognostic factor compared to MGMT transcription levels. Our main finding is that the presence of only the A allele at the rs34180180 SNP in the tumor was significantly associated with shorter OS, independently of the MGMT methylation status. In conclusion, in the clinic, rs34180180 SNP genotyping could improve the prognostic value of the MGMT promoter methylation assay in patients with aggressive glioma treated with TMZ.

Validation of a noninvasive test routinely used in otology for the diagnosis of cerebrospinal fluid shunt malfunction in patients with normal pressure hydrocephalus.

OBJECTIVE: Ventriculoperitoneal shunting is the first-line treatment for normal pressure hydrocephalus. Noninvasive auditory tests based on recorded otoacoustic emissions were assessed, as currently used for universal neonatal hearing screenings, for the diagnosis of cerebrospinal fluid shunt malfunction. The test was designed based on previous works, which demonstrated that an intracranial pressure change induces a proportional, characteristic, otoacoustic-emission phase shift. METHODS: Forty-four patients with normal pressure hydrocephalus (23 idiopathic and 21 secondary cases) were included in this prospective observational study. The male:female sex ratio was 1.44, the age range was 21-87 years (mean age 64.3 years), and the range of the follow-up period was 1-3 years (mean 20 months). Patients were implanted with a Sophy SU8 adjustable-pressure valve as the ventriculoperitoneal shunt. The phase shifts of otoacoustic emissions in response to body tilt were measured preoperatively, immediately postoperatively, and at 3-6 months, 7-15 months, 16-24 months, and more than 24 months postoperatively. Three groups were enrolled: Group 1, 19 patients who required no valve opening-pressure adjustment; Group 2, 18 patients who required valve opening-pressure adjustments; and Group 3, 7 patients who required valve replacement. RESULTS: In Group 1, phase shift, which was positive before surgery, became steadily negative after surgery and during the follow-up. In Group 2, phase shift, which was positive before surgery, became negative immediately after surgery and increasingly negative after a decrease in the valve-opening pressure. In Group 3, phase shift was positive in 6 cases and slightly negative in 1 case before revision, but after revision phase shift became significantly negative in all cases. CONCLUSIONS: Otoacoustic emissions noninvasively reflect cerebrospinal fluid shunt function and are impacted by valve-opening pressure adjustments. Otoacoustic emissions consistently diagnosed shunt malfunction and predicted the need for surgical revision. The authors' diagnostic test, which can be repeated without risk or discomfort by an unskilled operator, may address the crucial need of detecting valve dysfunction in patients with poor clinical outcome after shunt surgery.

STAT3 Serine 727 Phosphorylation: A Relevant Target to Radiosensitize Human Glioblastoma.

Radiotherapy is an essential component of glioma standard treatment. Glioblastomas (GBM), however, display an important radioresistance leading to tumor recurrence. To improve patient prognosis, there is a need to radiosensitize GBM cells and to circumvent the mechanisms of resistance caused by interactions between tumor cells and their microenvironment. STAT3 has been identified as a therapeutic target in glioma because of its involvement in mechanisms sustaining tumor escape to both standard treatment and immune control. Here, we studied the role of STAT3 activation on tyrosine 705 (Y705) and serine 727 (S727) in glioma radioresistance. This study explored STAT3 phosphorylation on Y705 (pSTAT3-Y705) and S727 (pSTAT3-S727) in glioma cell lines and in clinical samples. Radiosensitizing effect of STAT3 activation down-modulation by Gö6976 was explored. In a panel of 15 human glioma cell lines, we found that the level of pSTAT3-S727 was correlated to intrinsic radioresistance. Moreover, treating GBM cells with Gö6976 resulted in a highly significant radiosensitization associated to a concomitant pSTAT3-S727 down-modulation only in GBM cell lines that exhibited no or weak pSTAT3-Y705. We report the constitutive activation of STAT3-S727 in all GBM clinical samples. Targeting pSTAT3-S727 mainly in pSTAT3-Y705-negative GBM could be a relevant approach to improve radiation therapy.

[Elderly patients with glioblastoma: state of the art]. / Glioblastome du sujet âgé : état de l'art.

The incidence of glioblastoma increases with age, with a median age, at diagnosis, of 65 years. Indeed, the optimization of standard of care of elderly glioblastoma patients in an aging population in Western countries becomes crucial. The age remains the main prognostic factor of glioblastoma. Survival among elderly patients is significantly less than among younger patients. The median survival of elderly glioblastoma patients is generally inferior to 6 months. More aggressive tumor behavior, less aggressive treatments, increased toxicity of therapies and more unfavorable clinical factors and comorbidities could explain a higher severity of the disease in the elderly. The balance between treatment efficacy and quality of life is a major focus because of the shorter life expectancy of patients. The standard of care of glioblastoma in elderly patients remains controversial. Large optimal resection, when achievable, should be preferred to biopsy. Survival is longer after adjuvant radiotherapy, either normofractionated over 6-weeks course or hypofractionated over 3-weeks course, for patients with good clinical status. Hypofractionation is often preferred because of shorter procedure. Chemotherapy alone with temozolomide can be proposed to patients with methylated MGMT promoter. A phase III randomized study, testing short-course adjuvant radiotherapy with or without temozolomide in elderly patients with good clinical status, is ongoing.

Vasospasm of labyrinthine artery in cerebellopontine angle surgery: evidence brought by distortion-product otoacoustic emissions.

In cerebellopontine angle (CPA) surgery, postoperative deafness can be due to alteration of cochlear blood flow that is supplied by the labyrinthine artery (LA). In particular, vasospasm is likely to occur and, if so, can be reversed. This work attempted to track down vascular events occurring during CPA surgery. Twenty consecutive patients with vestibular schwannoma were tested with useful preoperative hearing and presence of otoacoustic emissions (OAEs). Distortion-product otoacoustic emissions (DPOAEs), well-known to react within seconds to cochlear ischemia, were used intraoperatively to indirectly monitor cochlear blood flow. Continuous intraoperative monitoring of DPOAEs revealed three different time patterns associated with distinct auditory outcomes. Pattern P1-acute (n = 4) happened when the LA was severed: DPOAEs immediately and irreversibly foundered and led to postoperative deafness. Pattern P2-protracted (n = 7) revealed a progressive deterioration of DPOAEs from the beginning of tumor debulking, likely due to a steady decrease of cochlear blood flow, with postoperative deafness. Pattern P3-unstable (n = 5) corresponded to large DPOAE oscillations between their normal level and noise floor. It was due to acute LA vasospasm that could be reversed in three cases by topical nimodipin. Last, four patients had uneventful cochlear monitoring. In conclusion, cochlear ischemia can occur in vestibular schwannoma surgery, giving three different patterns among which vasospasm can be reversed if detected early.

MRI tumor response and clinical outcomes after LINAC radiosurgery on 50 patients with recurrent malignant gliomas.

BACKGROUND: The place of radiosurgery (RS) as an option in the treatment of recurrent malignant glioma is still debated on in the absence of prospective randomized trials. OBJECTIVE: To assess the clinical outcome and MRI response after radiosurgery of recurrent malignant glioma. METHODS: We evaluated 50 consecutive patients treated in a single institution. Between 2001 and 2008, 34 glioblastoma (GBM) and 16 anaplastic oligodendroglioma (AO) patients were treated with linear accelerator (Linac) RS for recurrence. RESULTS: The median marginal dose was 15 Gy and the median gross tumor volume (GTV) was 6.64 ml. No patient had acute (< 3 months) neurological morbidity after RS. Ten patients (20%) were reoperated on after RS, histopathological findings included necrosis alone in 3 cases (6%). The median overall survival was 21.5 months for GBM and 57.9 months for AO. The median survival after RS was 9.5 months for GBM and 32.9 months for AO. The median progression-free survival after RS was 6.7 months for GBM and 18 months for AO. MRI volume modifications after RS showed a transitory reduction or stabilization of disease linked to significantly improved survival in 58.8% of patients with GBM, 81.1% of patients with AO. Pathological subtype (AO versus GBM), MRI response, KPS >70, marginal dose > 13 Gy, largest diameter of GTV < 25 mm and GTV < 7 ml were the main prognostic factors, associated with improved survival or PFS from RS. CONCLUSION: The magnitude of the survival increase compared to historical RPA classes may not be due to selection bias alone. Linac RS in selected patients with recurrent malignant glioma was well tolerated, effective and can be considered as one of several re-treatment options.

Increased expression of the oncogenic KLF6-SV1 transcript in human glioblastoma.

BACKGROUND: Gliomas constitute the vast majority of primary central nervous system tumors in adults. Glioblastoma multiforme (GBM) is the most aggressive form of these primary brain tumors. There is a need to define diagnostic and prognostic markers that may help to distinguish GBM from non-GBM tumors. The Krüppel-like factor 6 (KLF6) gene has recently emerged as a promising candidate. The goal of our study was to determine if there is a link between KLF6 splice variants expression and different grades of gliomas. METHODS: Fifty-three primary gliomas tumor samples were analyzed using quantitative real-time PCR for the total KLF6, wild-type and alternatively spliced (SV1) KLF6 mRNA. RESULTS: Compared to the non-GBM group, the GBM group had a 2.2-fold increase in the mean level of total KLF6 mRNA expression. GBM showed a 2.1-fold increase in the KLF6 splicing ratio. In addition, KLF6-SV1 mRNA expression levels were also 2.2-fold higher in the GBM group, suggesting that the increase in the KLF6 splicing ratio was due to increased expression of the KLF6-SV1 oncogenic splice variant. CONCLUSIONS: Our study demonstrates that quantification of total and spliced forms of KLF6 may provide a new and useful supplementary molecular tool for grading glioma.

Prolonged survival for patients with newly diagnosed, inoperable glioblastoma with 3-times daily ultrafractionated radiation therapy.

Ultrafractionation of radiation therapy is a novel regimen consisting of irradiating tumors several times daily, delivering low doses (<0.75 Gy) at which hyperradiosensitivity occurs. We recently demonstrated the high efficiency of ultrafractionated radiotherapy (RT) on glioma xenografts and report here on a phase II clinical trial to determine the safety, tolerability, and efficacy of an ultrafractionation regimen in patients with newly and inoperable glioblastoma (GBM). Thirty-one patients with histologically proven, newly diagnosed, and unresectable supratentorial GBM (WHO grade IV) were enrolled. Three daily doses of 0.75 Gy were delivered at least 4 hours apart, 5 days per week over 6-7 consecutive weeks (90 fractions for a total of 67.5 Gy). Conformal irradiation included the tumor bulk with a margin of 2.5 cm. The primary end points were safety, toxicity, and tolerability, and the secondary end points were overall survival (OS) and progression-free survival (PFS). Multivariate analysis was used to compare the OS and PFS with the EORTC-NCIC trial 26981-22981/CE.3 of RT alone vs radiation therapy and temozolomide (TMZ). The ultrafractionation radiation regimen was safe and well tolerated. No acute Grade III and/or IV CNS toxicity was observed. Median PFS and OS from initial diagnosis were 5.1 and 9.5 months, respectively. When comparing with the EORTC/NCIC trial, in both PFS and OS multivariate analysis, ultrafractionation showed superiority over RT alone, but not over RT and TMZ. The ultrafractionation regimen is safe and may prolong the survival of patients with GBM. Further investigation is warranted and a trial associating ultra-fractionation and TMZ is ongoing.