Clinical Course after Carmustine Wafer Implantation for Newly Diagnosed Adult-type Diffuse Gliomas; A controlled propensity matched analysis of a single center cohort.

PURPOSE: It remains unclear whether combining carmustine wafer (CW) implantation with the standard treatment for adult-type diffuse gliomas is safe and has a prognostic impact. This study aimed to investigate the prognostic value and safety of CW implantation. METHODS: Adult patients with IDH-wild-type and -mutant gliomas, grades 3-4 treated with surgical resection, radiotherapy, and temozolomide chemotherapy between 2013 and 2023 were surveyed. CWs were implanted except in cases of intraoperative wide ventricle opening or marked preoperative brain swelling. For survival analyses, a case-matched dataset based on propensity score matching (PSM), including multiple factors (patient background, diagnosis, and extent of resection) was generated. Progression-free survival (PFS), overall survival (OS), and frequency of complications of CW implantation (brain edema, infection, and cerebrospinal fluid leakage) were compared between the CW and non-use groups. RESULTS: In total, 127 patients (75 in the CW use group and 52 in the non-use group) were enrolled. Regardless of stratification, no significant differences in PFS and OS were observed between the CW use and non-use groups. The frequency of postoperative brain edema was significantly higher in the CW use group than in the non-use group. An adjusted dataset containing 41 patients in the CW use and nonuse groups was generated. Even after PSM, CW implantation had no prognostic effect. CONCLUSIONS: CW implantation with standard treatment demonstrated little beneficial effect for the present strategy of CW use.

Machine learning to improve interpretability of clinical, radiological and panel-based genomic data of glioma grade 4 patients undergoing surgical resection.

BACKGROUND: Glioma grade 4 (GG4) tumors, including astrocytoma IDH-mutant grade 4 and the astrocytoma IDH wt are the most common and aggressive primary tumors of the central nervous system. Surgery followed by Stupp protocol still remains the first-line treatment in GG4 tumors. Although Stupp combination can prolong survival, prognosis of treated adult patients with GG4 still remains unfavorable. The introduction of innovative multi-parametric prognostic models may allow refinement of prognosis of these patients. Here, Machine Learning (ML) was applied to investigate the contribution in predicting overall survival (OS) of different available data (e.g. clinical data, radiological data, or panel-based sequencing data such as presence of somatic mutations and amplification) in a mono-institutional GG4 cohort. METHODS: By next-generation sequencing, using a panel of 523 genes, we performed analysis of copy number variations and of types and distribution of nonsynonymous mutations in 102 cases including 39 carmustine wafer (CW) treated cases. We also calculated tumor mutational burden (TMB). ML was applied using eXtreme Gradient Boosting for survival (XGBoost-Surv) to integrate clinical and radiological information with genomic data. RESULTS: By ML modeling (concordance (c)- index = 0.682 for the best model), the role of predicting OS of radiological parameters including extent of resection, preoperative volume and residual volume was confirmed. An association between CW application and longer OS was also showed. Regarding gene mutations, a role in predicting OS was defined for mutations of BRAF and of other genes involved in the PI3K-AKT-mTOR signaling pathway. Moreover, an association between high TMB and shorter OS was suggested. Consistently, when a cutoff of 1.7 mutations/megabase was applied, cases with higher TMB showed significantly shorter OS than cases with lower TMB. CONCLUSIONS: The contribution of tumor volumetric data, somatic gene mutations and TBM in predicting OS of GG4 patients was defined by ML modeling.

Recurrent high grade glioma surgery with carmustine wafers implantation: a long-term nationwide retrospective study.

PURPOSE: Widespread use of carmustine wafers (CW) to treat high-grade gliomas (HGG) has been limited by uncertainties about its efficacy. To assess the outcome of patients after recurrent HGG surgery with CW implantation and, search for associated factors. METHODS: We processed the French medico-administrative national database between 2008 and 2019 to retrieve ad hoc cases. Survival methods were implemented. RESULTS: 559 patients who had CW implantation after recurrent HGG resection at 41 different institutions between 2008 and 2019 were identified. 35.6% were female and, median age at HGG resection with CW implantation was 58.1 years, IQR [50-65.4]. 520 patients (93%) had died at data collection with a median age at death of 59.7 years, IQR [51.6-67.1]. Median overall survival (OS) was 1.1 years, 95%CI[0.97-1.2], id est 13.2 months. Median age at death was 59.7 years, IQR [51.6-67.1]. OS at 1, 2 and 5 years was 52.1%, 95%CI[48.1-56.4], 24.6%, 95%CI[21.3-28.5] & 8%, 95%CI[5.9-10.7] respectively. In the adjusted regression, bevacizumab given before CW implantation, (HR = 1.98, 95%CI[1.49-2.63], p < 0.001), a longer delay between the first and the second HGG surgery (HR = 1, 95%CI[1-1], p < 0.001), RT given before and after CW implantation (HR = 0.59, 95%CI[0.39-0.87], p = 0.009) and TMZ given before and after CW implantation (HR = 0.81, 95%CI[0.66-0.98], p = 0.034) remained significantly associated with a longer survival. CONCLUSION: OS of patients with recurrent HGG that underwent surgery with CW implantation is better in case of prolonged delay between the two resections and, for the patients who had RT and TMZ before and after CW implantation.

Carmustine wafer implantation for supratentorial glioblastomas, IDH-wildtype in "extreme" neurosurgical conditions.

We assessed the feasibility of Carmustine wafer implantation in "extreme" conditions (i.e. patients > 80 years and Karnofsky Performance Status score < 50) and of implantation ≥ 12 Carmustine wafers in adult patients harbouring a newly diagnosed supratentorial glioblastoma, IDH-wildtype. We performed an observational, retrospective single-centre cohort study at a tertiary surgical neuro-oncological centre between January 2006 and December 2021. Four hundred eighty patients who benefited from a surgical resection at first-line treatment were included. We showed that Carmustine wafer implantation in patients > 80 years, in patients with a Karnofsky performance status score < 50, and that implantation ≥ 12 Carmustine wafers (1) did not increase overall postoperative complication rates, (2) did not affect the completion of standard radiochemotherapy protocol, (3) did not worsen the postoperative Karnofsky Performance Status scores, and (4) did not significantly affect the time to oncological treatment. We showed that the implantation of ≥ 12 Carmustine wafers improved progression-free survival (31.0 versus 10.0 months, p = 0.025) and overall survival (39.0 versus 16.5 months, p = 0.041) without increasing postoperative complication rates. Carmustine wafer implantation during the surgical resection of a newly diagnosed supratentorial glioblastoma, IDH-wildtype is safe and efficient in patients > 80 years and in patients with preoperative Karnofsky Performance Status score < 50. The number of Carmustine wafers should be adapted (up to 16 in our experience) to the resection cavity to improve survival without increasing postoperative overall complication rates.

Ventricular opening and cerebrospinal fluid circulation accelerate the biodegradation process of carmustine wafers suggesting their immunomodulation potential in the human brain.

PURPOSE: Opening the ventricular system during glioblastoma surgery is often necessary, but the consequent effect on the tumor microenvironment of glioblastoma remains unknown. Implantation of carmustine wafer enables direct drug delivery to the tumor site; however, the exact mechanism of the wafer's biodegradation process is unclear, and the available data is limited to in vivo non-human mammalian studies. We hypothesized that the ventricular opening affects the degradation process of the wafer and the glioblastoma tumor microenvironment. METHODS: This study included 30 glioblastoma patients. 21 patients underwent carmustine wafer implantation during initial surgery. All patients underwent repeated surgical resection upon recurrence, allowing for pathological comparison of changes associated with wafer implantation. Immunohistochemical analyses were performed using CD68, TMEM119, CD163, IBA1, BIN1, and CD31 antibodies to highlight microglia, macrophages, and tumor vascularity, and the quantitative scoring results were correlated with clinical, molecular, and surgical variables, including the effect of the ventricular opening. RESULTS: The carmustine wafer implanted group presented significantly less TMEM119-positive microglia within the tumor (P = 0.0002). Simple and multiple regression analyses revealed that the decrease in TMEM119-positive microglia was correlated with longer intervals between surgeries and opened ventricular systems. No correlation was observed between age, methylated O6-methylguanine DNA methyltransferase promoter expression, and the extent of surgical resection. CONCLUSIONS: Our study findings strongly suggest that biomaterials may possess immunomodulation capacity, which is significantly impacted by the ventricular opening procedure. Furthermore, our data highlights the pathophysiological effects of the ventricular opening within the surrounding human brain, especially after the wafer implantation.

Discriminating surgical bed cysts from bacterial brain abscesses after Carmustine wafer implantation in newly diagnosed IDH-wildtype glioblastomas.

Carmustine wafers can be implanted in the surgical bed of high-grade gliomas, which can induce surgical bed cyst formation, leading to clinically relevant mass effect. An observational retrospective monocentric study was conducted including 122 consecutive adult patients with a newly diagnosed supratentorial glioblastoma who underwent a surgical resection with Carmustine wafer implantation as first line treatment (2005-2018). Twenty-two patients (18.0%) developed a postoperative contrast-enhancing cyst within the surgical bed: 16 surgical bed cysts and six bacterial abscesses. All patients with a surgical bed cyst were managed conservatively, all resolved on imaging follow-up, and no patient stopped the radiochemotherapy. Independent risk factors of formation of a postoperative surgical bed cyst were age ≥ 60 years (p = 0.019), number of Carmustine wafers implanted ≥ 8 (p = 0.040), and partial resection (p = 0.025). Compared to surgical bed cysts, the occurrence of a postoperative bacterial abscess requiring surgical management was associated more frequently with a shorter time to diagnosis from surgery (p = 0.009), new neurological deficit (p < 0.001), fever (p < 0.001), residual air in the cyst (p = 0.018), a cyst diameter greater than that of the initial tumor (p = 0.027), and increased mass effect and brain edema compared to early postoperative MRI (p = 0.024). Contrast enhancement (p = 0.473) and diffusion signal abnormalities (p = 0.471) did not differ between postoperative bacterial abscesses and surgical bed cysts. Clinical and imaging findings help discriminate between surgical bed cysts and bacterial abscesses following Carmustine wafer implantation. Surgical bed cysts can be managed conservatively. Individual risk factors will help tailor their steroid therapy and imaging follow-up.

Implantation of Carmustine wafers after resection of malignant glioma with and without opening of the ventricular system.

OBJECTIVE: Implantation of biodegradable Carmustine wafers in patients with malignant glioma is not generally recommended when the ventricular system is opened during tumor resection. Thrombin/fibrinogenn-covered collagen fleeces showed promising results in sufficiently closing ventricular defects. The aim of this study was to evaluate the postoperative morbidity in patients with implanted Carmustine wafers either with opened or intact ventricular system. METHODS: A consecutive series of patients who underwent resection of malignant glioma with implantation of Carmustine wafers was analyzed. In case of opening of the ventricular system, the defect in the ventricle wall was sealed using a collagen sponge coated with fibrinogen and thrombin prior to the implantation of the wafers. Postoperative adverse events (AE) and Karnofsky performance status scale (KPS) at follow up were compared between both groups. RESULTS: Fifty-four patients were included. The ventricular system was opened in 33 patients and remained intact in 21 patients. Both groups were comparable in terms of age, rate of primary and recurrent glioma, preoperative KPS, rate of gross total resection and number of implanted wafers. Postoperative AEs occurred in 9/33 patients (27.3%) with opened and in 5/21 patients (23.8%) with intact ventricular system (p = 0.13). At follow-up assessments, KPS was not significantly different between both groups (p = 0.18). Opened ventricular system was not associated with a higher incidence of postoperative AEs (p = 0.98). CONCLUSION: Appropriate closure of opened ventricular system during resection of malignant glioma allows for a safe implantation of Carmustine wafers and is not associated with a higher incidence of postoperative AEs.

Implantation of carmustine wafers (Gliadel®) for high-grade glioma treatment. A 9-year nationwide retrospective study.

BACKGROUND: Carmustine wafers (CW) are approved to treat newly or recurrent high-grade gliomas (HGG). Widespread use has been limited regarding some doubtful uncertainties about their efficacy, related increased risk of infection and expensive cost. OBJECTIVE: To describe the epidemiology of CW implantation, search for related complications, long-term survival and associated prognostic factors. METHODS: We processed the French medico-administrative national database to retrieve appropriate cases operated between 2010 and 2018. A survival analysis was conducted. RESULTS: We identified 1659 patients treated in 39 institutions. Median age at CW implantation was 61 years and there was an over-representation of male (63.5%). 491 patients (29.6%) had previous diagnosis of glioma. Time between the first surgery and CW implantation was 0.9 years, IQR[0.6, 1.6]. The frontal lobe was the most frequently involved 29%. 131 patients (7.9%) had to be re operated on for a complication of which 121 for surgical site infection. At one year, 514 patients (31%) had died. Median overall survival (OS) was 1.4 years, 95% CI [1.3, 1.5]. OS at 1 and 2 year was 66%, 95%CI [63.7, 68.5], 32.3%, 95%CI [29.9, 35]. In the adjusted Cox regression, male gender & age at CW implantation were established as independent factors of OS in all three groups. Patients with recurrent HGG have a significant worse prognosis (HR = 0.71, 95% CI [0.62, 0.80] p < 0.001). A post-operative diagnosis of infection or intracranial bleeding eventually leading to a redo surgery was not associated with a decrease OS. CONCLUSION: Over the past 9 years, there is a significant decrease utilisation of CW in France. OS after CW implantation is significantly variable as influenced by many factors such as age, gender or recurrent disease but not by post-operative complications. Compare to previous results, CW may increase the OS and this effect seems more pronounced when adjuvant RT/TMZ is given.

miRNA-26a expression influences the therapy response to carmustine wafer implantation in patients with glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme is the most frequent malignant brain tumor in adults being marked with a very poor prognosis. Therapy concept implies concomitant radio-chemotherapy and facultative implantation of carmustine-eluted wafer. Current literature suggests microRNA 26a expression in glioblastoma to interact with alkylating chemotherapy. Subsequently, the aim of this study was to investigate the correlation of miRNA-26a expression and carmustine wafer implantation and its potential usefulness as a predictive marker for therapy response. METHODS: In total, 229 patients with glioblastoma multiforme were included into the final analysis. Of them, 80 cases were recruited from the Saarland University Medical Center for a retrospective matched-pair analysis stratified after therapy regime: One group (carmustine wafer group; n=40) received concomitant radio-chemotherapy with carmustine wafer implantation. The other group (control group; n=40) only received concomitant radio-chemotherapy. The results were confirmed by comparing them with an independent dataset of 149 patients from the TCGA database. All tumor specimens were evaluated for miRNA-26a expression, MGMT promoter methylation, and IDH1 R132H mutation status, and the results were correlated with the clinical data. RESULTS: Twenty-three patients in the carmustine wafer group showed low expression of miRNA-26a, while 17 patients showed a high expression. In the control group, 28 patients showed low expression, while 12 patients showed a high expression. The patients with high miRNA-26a expression in the carmustine wafer group were characterized by a significantly longer overall (hazard ratio [HR] 2.750 [95% CI 1.352-5.593]; p=0.004) and progression-free survival (HR 3.091 [95% CI 1.436-6.657]; p=0.003) than patients with low miRNA-26a expression. The 17 patients in the carmustine wafer group with high miRNA-26a expression showed a significantly longer progression-free survival (p=0.013) and overall survival (p=0.007) compared with the control group. There were no such correlations identified within the control group. TCGA datasets supported these findings. CONCLUSIONS: MiRNA-26a expression turned out to be a promising predictor of therapy response and clinical outcome in glioblastoma patients treated with carmustine wafer implantation. For evaluation of the role of miRNA-26a in a combined therapy setting, further studies are needed in order to translate general findings to the patient's individual situation.

Extent of resection and Carmustine wafer implantation safely improve survival in patients with a newly diagnosed glioblastoma: a single center experience of the current practice.

For newly diagnosed glioblastomas treated with resection in association with the standard combined chemoradiotherapy, the impact of Carmustine wafer implantation remains debated regarding postoperative infections, quality of life, and feasibility of adjuvant oncological treatments. To assess together safety, tolerance and efficacy of Carmustine wafer implantation and of extent of resection for glioblastoma patients in real-life experience. Observational retrospective monocentric study including 340 consecutive adult patients with a newly diagnosed supratentorial glioblastoma who underwent surgical resection with (n = 123) or without (n = 217) Carmustine wafer implantation as first-line oncological treatment. Carmustine wafer implantation and extent of resection did not significantly increase postoperative complications, including postoperative infections (p = 0.269, and p = 0.446, respectively). Carmustine wafer implantation and extent of resection did not significantly increase adverse events during adjuvant oncological therapies (p = 0.968, and p = 0.571, respectively). Carmustine wafer implantation did not significantly alter the early postoperative Karnofsky performance status (p = 0.402) or the Karnofsky performance status after oncological treatment (p = 0.636) but a subtotal or total surgical resection significantly improved those scores (p < 0.001, and p < 0.001, respectively). Carmustine wafer implantation, subtotal and total resection, and standard combined chemoradiotherapy were independently associated with longer event-free survival (adjusted Hazard Ratio (aHR), 0.74 [95% CI 0.55-0.99], p = 0.043; aHR, 0.70 [95% CI 0.54-0.91], p = 0.009; aHR, 0.40 [95% CI 0.29-0.55], p < 0.001, respectively) and with longer overall survival (aHR, 0.69 [95% CI 0.49-0.96], p = 0.029; aHR, 0.52 [95% CI 0.38-0.70], p < 0.001; aHR, 0.58 [95% CI 0.42-0.81], p = 0.002, respectively). Carmustine wafer implantation in combination with maximal resection, followed by standard combined chemoradiotherapy is safe, efficient, and well-tolerated in newly diagnosed supratentorial glioblastomas in adults.

Evaluation of serial changes on computed tomography and magnetic resonance imaging after implantation of carmustine wafers in patients with malignant gliomas for differential diagnosis of tumor recurrence.

Carmustine wafers are approved for localized treatment of malignant glioma. In this study, overall changes in computed tomography (CT) and magnetic resonance (MR) images of malignant glioma patients treated with carmustine wafer implantation were evaluated. The subjects were 25 patients undergoing craniotomy for malignant glioma resection and carmustine wafer implantation. Changes in the appearance of wafers, the resection cavity, and the adjacent parenchyma on CT and MR imaging were evaluated retrospectively. On CT, the wafers changed from an initially high-dense to an iso-dense appearance. All MR studies showed a low-intense wafer within 2 days. The wafers changed to a high- or iso-intense appearance on fluid attenuated inversion recovery and T1-weighted imaging, whereas they changed to an iso- to low-intense appearance on T2-weighted imaging. Gas in the cavity increased gradually after surgery, achieved a peak at 1 week postoperatively, and then disappeared in 1-3 months. Increased volume of the resection cavity was observed in 48% of patients. Regarding changes in the adjacent parenchyma, obvious contrast enhancement at the wall of the resection cavity was seen in 91% of cases at 1 month, but this disappeared gradually. Edema around the resection cavity was increased in 7 patients (28%), of whom only two experienced symptoms due to edema. We conclude that these radiological changes after carmustine wafer implantation should be carefully followed up, because these changes can easily be mistaken for infectious disease or recurrent tumors.

Unmanageable Cerebrospinal Fluid Leakage With Eosinophilic Meningitis in a Gliadel Wafer Implant Patient.

Gliadel wafer implants (Eisai Inc., Woodcliff Lake, NJ, USA) have shown their efficacy in prolonging survival in patients with malignant gliomas. The safety of Gliadel wafers has also been reported; however, there is a certain risk of adverse events. We present a rare case of refractory cerebrospinal fluid (CSF) leakage with eosinophilic meningitis in a patient with glioblastoma who underwent tumor resection with Gliadel wafer implants. A 60-year-old man presented with a glioblastoma in the right temporal lobe. The patient underwent tumor resection with Gliadel wafer implants. During the postoperative course, the patient presented with intractable CSF leakage and the development of a pseudomeningocele. A delayed rise in blood and CSF eosinophil count (a few weeks after the primary operation) and positive drug-induced lymphocyte stimulation test (DLST) results against the Gliadel wafer led to the diagnosis of an allergic reaction to these implants. Removal of the Gliadel wafers resolved the eosinophilic reaction; however, the patient subsequently required a shunt procedure for persistent hydrocephalus. This case highlights the importance of investigating rare causes of refractory CSF leakage and hydrocephalus due to allergic reactions to Gliadel wafers. Delayed elevations of eosinophils in blood and CSF tests may lead to a diagnosis of eosinophilic meningitis. DLST against Gliadel wafers is also useful for diagnosis when it is available. To control the hydrocephalus, not only the shunt procedure but also wafer removal must be considered; however, patients with limited life expectancy are generally hesitant to undergo such additional procedures.

Local therapy in glioma: An evolving paradigm from history to horizons (Review).

Despite the implementation of multimodal treatments after surgery, glioblastoma (GBM) remains an incurable disease, posing a significant challenge in neuro-oncology. In this clinical setting, local therapy (LT), a developing paradigm, has received significant interest over time due to its potential to overcome the drawbacks of conventional therapy options for GBM. The present review aimed to trace the historical development, highlight contemporary advances and provide insights into the future horizons of LT in GBM management. In compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols criteria, a systematic review of the literature on the role of LT in GBM management was conducted. A total of 2,467 potentially relevant articles were found and, after removal of duplicates, 2,007 studies were screened by title and abstract (Cohen's κ coefficient=0.92). Overall, it emerged that 15, 10 and 6 clinical studies explored the clinical efficiency of intraoperative local treatment modalities, local radiotherapy and local immunotherapy, respectively. GBM recurrences occur within 2 cm of the radiation field in 80% of cases, emphasizing the significant influence of local factors on recurrence. This highlights the urgent requirement for LT strategies. In total, three primary reasons have thus led to the development of numerous LT solutions in recent decades: i) Intratumoral implants allow the blood-brain barrier to be bypassed, resulting in limited systemic toxicity; ii) LT facilitates bridging therapy between surgery and standard treatments; and iii) given the complexity of GBM, targeting multiple components of the tumor microenvironment through ligands specific to various elements could have a synergistic effect in treatments. Considering the spatial and temporal heterogeneity of GBM, the disease prognosis could be significantly improved by a combination of therapeutic strategies in the era of precision medicine.

Is Carmustine Wafer Implantation in Progressive High-Grade Gliomas a Relevant Therapeutic Option? Complication Rate, Predictors of Complications and Onco-Functional Outcomes in a Series of 53 Cases.

Background/Objectives: The aim was to determine the complication rate and the predictors of complications and survival in high-grade glioma surgically managed at progression with implantation of Carmustine wafers. Methods: A retrospective series of 53 consecutive patients operated on between 2017 and 2022 was built. Results: The median age was 55 ± 10.9 years. The rates of global and infectious complications were 35.8% and 18.9%, respectively. In multivariate analysis, patients with a preoperative neurological deficit were more prone to develop a postoperative complication (HR = 5.35 95% CI 1.49-19.26, p = 0.01). No predictor of infectious complication was identified. In the grade 4 glioma subgroup (n = 44), progression-free and overall survival (calculated starting from the reresection) reached 3.95 months, 95% CI 2.92-5.21 and 11.51 months, 95% CI 9.11-17.18, respectively. Preoperative KPS > 80% (HR = 0.97 95% CI 0.93-0.99, p = 0.04), Gross Total Resection (HR = 0.38 95% CI 0.18-0.80, p = 0.01), and 3-month postoperative KPS > 80% (HR = 0.35 95% CI 0.17-0.72, p = 0.004) were predictors of prolonged overall survival. Conclusions: Surgical resection is a relevant option in high-grade gliomas at progression, especially in patients with a preoperative KPS > 80%, without preoperative neurological deficit, and amenable to complete resection. In patients elected for surgery, Carmustine wafer implantation is associated with a high rate of complications. It is consequently critical to closely monitor the patients for whom this option is chosen.

Newly Diagnosed High-Grade Glioma Surgery with Carmustine Wafers Implantation. A Long-Term Nationwide Retrospective Study.

BACKGROUND: Widespread use of carmustine wafers (CWs) to treat high-grade gliomas (HGG) has been limited by uncertainties about their efficacy. We sought to assess the outcome of patients after newly diagnosed HGG surgery with CW implantation and search for associated factors. METHODS: We processed the French medico-administrative national database between 2008 and 2019 to retrieve ad hoc cases. Survival methods were implemented. RESULTS: In total, 1608 patients who had CW implantation after HGG resection at 42 different institutions between 2008 and 2019 were identified; 36.7% were female and, median age at HGG resection with CW implantation was 61.5 years, interquartile range (IQR) [52.9-69.1]. A total of 1460 patients (90.8%) had died at data collection at a median age at death of 63.5 years, IQR [55.3-71.2]. Median overall survival (OS) was 1.42 years, 95% confidence interval [CI] 1.35-1.49, i.e., 16.8 months. Median age at death was 63.5 years, IQR [55.3-71.2]. OS at 1, 2, and, 5 years was 67.4%, 95% CI 65.1-69.7; 33.1%, 95% CI 30.9-35.5; and 10.7%, 95% CI 9.2-12.4, respectively. In the adjusted regression, sex (hazard ratio [HR] 0.82, 95% CI 0.74-0.92, P < 0.001), age at HGG surgery with CW implantation (HR 1.02, 95% CI 1.02-1.03, P < 0.001), adjuvant radiotherapy (HR 0.78, 95% CI 0.7-0.86, P < 0.001), chemotherapy by temozolomide (HR 0.7, 95% CI 0.63-0.79, P < 0.001), and redo surgery for HGG recurrence (HR 0.81, 95% CI 0.69-0.94, P = 0.005) remained significantly associated with the outcome. CONCLUSIONS: OS of patients with newly diagnosed HGG who underwent surgery with CW implantation is better in young patients, those of the female sex, and for those who complete concomitant chemoradiotherapy. Redo surgery for HGG recurrence also was associated with prolonged survival.

Symptomatic cerebral vasospasm in the setting of carmustine wafer placement for glioblastoma: A case presentation and review of literature.

BACKGROUND: Gliadel placement in glioblastoma resection, particularly with concurrent chemoradiation, has demonstrated an improvement in survival. There have been several reported adverse effects, some of which lend to significantly increased morbidity and mortality. With only two other cases described in literature, cerebral vasospasm secondary to carmustine-impregnated wafers is an extremely rare side effect. CASE DESCRIPTION: We report the case of a 51-year-old female who presented with the left lower limb paresis 8 days after high-grade glioma resection provoked by carmustine wafer placement. CONCLUSION: We urge surgeons to reconsider placement of carmustine wafers in nations where the surgical resection cavity includes exposed large cerebral vasculature. We also propose the early identification of this devastating complication in the postoperative period by maintaining a high clinical suspicion and prompt utilization of computed tomography and digital subtraction angiography in the management and treatment of these patients accordingly.

MiRNA-181d Expression Significantly Affects Treatment Responses to Carmustine Wafer Implantation.

BACKGROUND: Standard therapeutic protocols for glioblastoma, the most aggressive type of brain cancer, include surgery followed by chemoradiotherapy. Additionally, carmustine-eluting wafers can be implanted locally into the resection cavity. OBJECTIVE: To evaluate microRNA (miRNA)-181d as a prognostic marker of responses to carmustine wafer implantation. METHODS: A total of 80 glioblastoma patients (40/group) were included in a matched pair analysis. One group (carmustine wafer group) received concomitant chemoradiotherapy with carmustine wafer implantation (Stupp protocol). The second group (control group) received only concomitant chemoradiotherapy. All tumor specimens were subjected to evaluations of miRNA-181d expression, results were correlated with further individual clinical data. The Cancer Genome Atlas (TCGA) dataset of 149 patients was used as an independent cohort to validate the results. RESULTS: Patients in the carmustine wafer group with low miRNA-181d expression had significantly longer overall (hazard ratio [HR], 35.03, [95% confidence interval (CI): 3.50-350.23], P = .002) and progression-free survival (HR, 20.23, [95% CI: 2.19-186.86], P = .008) than patients of the same group with a high miRNA-181d expression. These correlations were not observed in the control group. The nonsignificance in the control group was confirmed in the independent TCGA dataset. The carmustine wafer group patients with low miRNA-181d expression also had a significantly longer progression-free (P = .049) and overall survival (OS) (P = .034), compared with control group patients. Gross total resection correlated significantly with longer OS (P = .023). CONCLUSION: MiRNA-181d expression significantly affects treatment responses to carmustine wafer implantation.

In vitro Study of Serial Changes to Carmustine Wafers (Gliadel) with MR Imaging and Computed Tomography.

PURPOSE: Implantation of carmustine wafers (Gliadel) in vivo is accompanied by characteristic serial changes on MRI and CT, such as transient hyperintensity of the wafers on T1-weighted images (T1WIs) and considerable gas accumulation in surgical resection cavities. The purpose of this study was to evaluate intrinsic imaging changes to carmustine wafers in vitro. METHODS: Three phantoms simulating a surgical resection cavity were constructed. Each contained either a carmustine wafer fixed with oxidized regenerated cellulose and fibrin sealant, an unfixed carmustine wafer, or a fixed polyethylene control disk, immersed in phosphate-buffered saline. Image acquisition of the phantoms was performed on MRI and CT until 182 days after construction. The radiological appearances of the object in each phantom were assessed by visual evaluation and quantification of the region of interest. The volume of gas around the objects at 24 h after constructing the phantoms was also measured. RESULTS: The carmustine wafers showed low signal intensities on T1WIs and T2-weighted images (T2WIs), and high densities on CT images at 24 h. The signal intensities and CT densities gradually approximated those of saline over a period of months. However, the carmustine wafers never showed hyperintensity on T1WIs in vitro. The fixed carmustine wafer showed slower radiological changes, as compared to the unfixed wafer. The gas volume around the fixed carmustine wafer was greater than that around the fixed control disk. CONCLUSION: Changes to the carmustine wafers probably reflected penetration of fluid inside and degradation of the hydrophobic matrix. Reported transient hyperintensity of wafers on T1WIs in vivo is regarded as the result of biological reactions, whereas the initial production of gas is considered as an intrinsic characteristic of wafers.

Importance and accuracy of intraoperative frozen section diagnosis of the resection margin for effective carmustine wafer implantation.

For effective implantation of carmustine (BCNU) wafers, it is important to determine the order of priority with reference to the intraoperative frozen section diagnosis of the resection margin (IOFM). The accuracy of IOFM and patterns of tumor recurrence with implantation of BCNU wafers were studied retrospectively. Forty-six cases of newly diagnosed malignant glioma were evaluated. Tumors were resected after intraoperative frozen section diagnosis (IOFD). IOFM was performed for resection walls and evaluated on a three-level scale (-, no tumor invasion; 1+, minor cell invasion; 2+, evident cell invasion). The results were used for effective BCNU wafer implantation. The IOFM sections were then thawed, frozen-paraffin marginal (FPM) sections were prepared, and IOFM was evaluated with FPM sections. The accuracy of IOFD grading was compared to that of the formalin fixed paraffin-embedded section and was 76.1%. The accuracy of IOFM was compared with the FPM section in 148 specimens from 42 patients. The IOFM accuracy was 80.4%. BCNU wafers were implanted in 25 patients and there was recurrence in 15. Local recurrence was seen in 40% (6 patients). However, there was no recurrence immediately below the BCNU wafers. With properly performed IOFM, BCNU wafers can be efficiently implanted, and local recurrence immediately below the BCNU wafers can be inhibited.

The Survival Advantage of "Supratotal" Resection of Glioblastoma Using Selective Cortical Mapping and the Subpial Technique.

BACKGROUND: A substantial body of evidence suggests that cytoreductive surgery is a prerequisite to prolonging survival in patients with glioblastoma (GBM). OBJECTIVE: To evaluate the safety and impact of "supratotal" resections beyond the zone of enhancement seen on magnetic resonance imaging scans, using a subpial technique. METHODS: We retrospectively evaluated 86 consecutive patients with primary GBM, managed by the senior author, using a subpial resection technique with or without carmustine (BCNU) wafer implantation. Multivariate Cox proportional hazards regression was used to analyze clinical, radiological, and outcome variables. Overall impacts of extent of resection (EOR) and BCNU wafer placement were compared using Kaplan-Meier survival analysis. RESULTS: Mean patient age was 56 years. The median OS for the group was 18.1 months. Median OS for patients undergoing gross total, near-total, and subtotal resection were 54, 16.5, and 13.2 months, respectively. Patients undergoing near-total resection ( P = .05) or gross total resection ( P < .01) experienced statistically significant longer survival time than patients undergoing subtotal resection as well as patients undergoing ≥95% EOR ( P < .01) when compared to <95% EOR. The addition of BCNU wafers had no survival advantage. CONCLUSIONS: The subpial technique extends the resection beyond the contrast enhancement and is associated with an overall survival beyond that seen in similar series where resection of the enhancement portion is performed. The effect of supratotal resection on survival exceeded the effects of age, Karnofsky performance score, and tumor volume. A prospective study would help to quantify the impact of the subpial technique on quality of life and survival as compared to a traditional resection limited to the enhancing tumor.