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Objective: To evaluate the effect of ventricular opening (VO) on recurrence patterns in patients with newly diagnosed glioblastoma (GBM) treated with bis-chloroethyl-nitrosourea (BCNU) wafer implantation. Methods: This single-center retrospective study included 40 patients with newly diagnosed GBM who received BCNU wafer implantation after tumor resection between March 2013 and February 2022. The patients were categorized into two groups based on whether VO occurred during the GBM resection. While 18 patients had VO, 22 did not have VO. In cases with VO, the ventricular wall defect is closed with gelatin or oxidized regenerated cellulose and fibrin glue before BCNU wafer implantation. Recurrence patterns-classified as local, diffuse, distant, or multifocal-and time to recurrence were compared between patients with and without VO. Results: The median follow-up period for the entire cohort was 32.2 months (interquartile range, 16.7-38 months). Median survival time was comparable between patients with VO and patients without VO (38 vs. 26 months, p=0.53). Recurrence occurred in 31/40 patients (77.5%) in entire cohort. The incidence of recurrence was comparable between patients with VO and patients without VO (14 [77.8%] vs. 17 [77.3%], p=1.0). No significant differences were seen between the two groups in time to recurrence (p=0.59) or recurrence patterns (p=0.35). Conclusion: Ventricular opening during surgery with BCNU wafer implantation does not seem to influence the recurrence patterns. Ventricular opening does not induce distant recurrence if appropriate ventricular closure is performed.

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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.

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OBJECTIVE: To evaluate the safety profile of bis-chloroethyl-nitrosourea (BCNU) wafer implantation after malignant glioma resection with or without ventricular opening (VO). METHODS: This single-center retrospective study included 66 consecutive patients with BCNU wafer implantation after malignant glioma resection between March 2013 and August 2021. The patients were categorized into 2 groups based on whether VO occurred during the malignant glioma resection. Fifty-eight patients had glioblastoma, and 8 had anaplastic astrocytoma or oligodendroglioma. Forty-eight patients underwent an initial treatment, and 18 underwent recurrent surgeries. Infection, hydrocephalus, subcutaneous fluid collection, chronic subdural hematoma, early seizure after surgery within 1 month, symptomatic edema surrounding the resected cavity, cyst formation, and postoperative hemorrhage were defined as adverse events (AEs). RESULTS: Thirty-three patients underwent resection with VO, and 33 without. The median survival time was 28 months in the initial treatment group and 11.5 months in the recurrent treatment group. The with and without VO groups had similar median survival times. Postoperative AEs occurred in 7/33 patients (21.2%) with VO and 10/33 (30.3%) without VO, with no difference between them (P = 0.574). CONCLUSIONS: This study showed that VO during surgery with BCNU wafer implantation might not influence the occurrence of postoperative AEs. If VO happens, BCNU wafer implantation can be performed safely with accurate closing of the ventricle.

Asunto(s)

Neoplasias Encefálicas , Glioma , Humanos , Carmustina/efectos adversos , Neoplasias Encefálicas/cirugía , Estudios Retrospectivos , Antineoplásicos Alquilantes/uso terapéutico , Glioma/cirugía , Terapia Combinada

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BACKGROUND: Adjuvant treatment with Gliadel wafers may prolong overall survival (OS) for malignant glioma patients without increasing toxicity. In Japan, the long-term OS of these patients treated with Gliadel 7.7 mg implants has not been studied. We evaluated OS and prognostic factors that might affect OS in Japanese patients with malignant glioma who received the Gliadel 7.7 mg implant. METHODS: This observational, long-term, postmarketing surveillance was an extension of a previous surveillance. Data were collected through case report forms at 2 and 3 years after Gliadel implant. Up to 8 Gliadel wafers (61.6 mg of carmustine) were placed over the tumor resection site. Primary endpoints were OS and prognostic factors that may influence OS. RESULTS: Among the 506 patients analyzed, 62.6% had newly diagnosed disease, and 37.4% had recurrent disease; 79.1% had glioblastoma histological type and 79.6% had World Health Organization Grade IV disease. Patients received a median of 8 wafers. The median OS was 18.0 months; OS rates were 39.8% and 31.5% at 2 and 3 years, respectively. Age ≥65 years (hazard ratio [HR]: 1.456; P = .002), lower resection rate (HR: 1.206; P < .001), recurrence (HR: 2.418; P < .001), and concomitant radiotherapy (HR: 0.588; P < .001) were identified as significant prognostic factors. CONCLUSIONS: This study confirmed the 2- and 3-year OS of Japanese malignant glioma patients with varied backgrounds after Gliadel implant. With a careful interpretation of indirect comparisons with previously reported data, the results suggest that prognosis could be improved with Gliadel implants. CLINICAL TRIAL REGISTRATION: NCT02300506.

RESUMEN

PURPOSE OF REVIEW: Glioblastoma is the commonest primary brain cancer in adults whose outcomes are amongst the worst of any cancer. The current treatment pathway comprises surgery and postoperative chemoradiotherapy though unresectable diffusely infiltrative tumour cells remain untreated for several weeks post-diagnosis. Intratumoural heterogeneity combined with increased hypoxia in the postoperative tumour microenvironment potentially decreases the efficacy of adjuvant interventions and fails to prevent early postoperative regrowth, called rapid early progression (REP). In this review, we discuss the clinical implications and biological foundations of post-surgery REP. Subsequently, clinical interventions potentially targeting this phenomenon are reviewed systematically. RECENT FINDINGS: Early interventions include early systemic chemotherapy, neoadjuvant immunotherapy, local therapies delivered during surgery (including Gliadel wafers, nanoparticles and stem cell therapy) and several radiotherapy techniques. We critically appraise and compare these strategies in terms of their efficacy, toxicity, challenges and potential to prolong survival. Finally, we discuss the most promising strategies that could benefit future glioblastoma patients. There is biological rationale to suggest that early interventions could improve the outcome of glioblastoma patients and they should be investigated in future trials.

Asunto(s)

Neoplasias Encefálicas , Glioblastoma , Adulto , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/terapia , Carmustina/uso terapéutico , Quimioradioterapia , Glioblastoma/tratamiento farmacológico , Glioblastoma/terapia , Humanos , Microambiente Tumoral

RESUMEN

To cure the illness in the brain glioblastoma, the Gliadel wafer, as the first FDA-approved chemotherapy, was available on the market since 1997. Due to the complex studies in vivo, more and more researchers have paid their attention to investigate the dynamic process in the brain by numerical methods. This study aimed to simulate the drug concentration in the cavity after drug releases from Gliadel wafers into the brain tumor by a two-dimensional simulation. The government equations, the parameters, and corresponding initial and boundary conditions are specified. Then the models are discretized and solved by finite element method (FEM) and finite difference method (FDM) based on C++ library Adaptive Finite Element Package (AFEPack) and MATLAB, respectively. First of all, the numerical convergence of the method is studied by numerical results represented in several successively refined meshes, which shows the reliability of our method. In the results from FEM, a steady state of the pressure in the normal tissue can be simulated. As for FDM, the changes of drug concentration are displayed at six different times. The numerical method in this paper is an effective tool for the numerical study on drug release from polymers. Additionally, convection is a critical factor in drug transportation. Moreover, the simulation approach can be used as the guild for remedy optimization and dynamic analysis of other drugs (paclitaxel) for tumor treatment in the clinic. This mathematical model has wide applications about drug release in multiple dosage forms, such as long sustained release microspheres, oral extended release hydrophilic matrix tablets, hydrogel, and sustained release topical rings.

Asunto(s)

Neoplasias Encefálicas , Glioblastoma , Encéfalo/patología , Neoplasias Encefálicas/tratamiento farmacológico , Carmustina/uso terapéutico , Preparaciones de Acción Retardada/uso terapéutico , Glioblastoma/tratamiento farmacológico , Humanos , Reproducibilidad de los Resultados

RESUMEN

Clinical trial data of Carmustine implant (Gliadel Wafer) in Japanese patients with malignant glioma are limited; thus, we conducted a postmarketing surveillance study to evaluate the safety of Gliadel in real-world clinical practice in Japan. In this postmarketing surveillance study, all patients who received Gliadel placement for malignant glioma surgeries from its market launch (January 9, 2013) to July 10, 2013 were enrolled from 229 institutions using a central registration system. Up to eight wafers of Gliadel (containing 61.6 mg of carmustine) were used to cover the site of brain tumor resection intraoperatively according to the size and shape of the tumor resection cavity. The observation period lasted 3 months after Gliadel placement. Patients were followed up for 1 year postoperatively. Safety was assessed by the incidence of adverse events (AEs) and adverse drug reactions (ADRs). In total, 558 patients were included. Most patients (66.7%) received eight Gliadel wafers. The percentage of patients with ADRs was 35.7% (365 ADR episodes in 199 patients). Of the AEs of special interest, the most common were cerebral edema (22.2%, 124/558 patients), convulsion (9.9%, 55/558 patients), impaired healing (4.8%, 27/558 patients), and infection (3.4%, 19/558 patients). This first all-case postmarketing surveillance report of the safety of Gliadel in real-world clinical practice in Japan suggests that the risk of toxicity with Gliadel placement is relatively tolerable. The survival benefits of Gliadel placement should be evaluated and considered carefully by the clinician taking into account possible toxicities.

Asunto(s)

Neoplasias Encefálicas , Glioma , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/cirugía , Carmustina/efectos adversos , Ácidos Decanoicos , Glioma/tratamiento farmacológico , Glioma/cirugía , Humanos , Japón , Poliésteres , Resultado del Tratamiento

RESUMEN

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU, or Carmustine) wafers are intraoperatively implantable wafers used to achieve local tumor control. There is scarce data about the behavior of wafers in the long-term follow-up of implanted cases. We reviewed the data of 64 patients with newly diagnosed glioblastoma treated by surgery, BCNU wafers, radiation therapy, and temozolomide administration. This cohort included 55 patients who presented first recurrence, and 49 of them showed tumor progression to death. The MR imaging of each patient at the terminal stage and an autopsy case were used to elucidate the tumor progression pattern after the wafer implantation. We subdivided the first recurrence pattern into local, distant, and multifocal based on MR imaging or into infield, outfield, and marginal based on the radiation field. The first recurrence pattern was 33 patients (60%) with local, 13 (24%) with distant, and nine (16%) with multifocal recurrence, or 38 patients (69%) with infield, 13 (24%) with outfield, and four (7%) with marginal. The median and mean time intervals between MR imaging at the terminal stage and death were 2.0 and 2.3 months, respectively. Of note, 13 patients with first distant recurrence had no obvious radiological local tumor progression even at the terminal stage. Long-term follow-up after BCNU wafer implantation revealed that patients with first distant recurrence had long-lasting local tumor control until the terminal stage.

Asunto(s)

Antineoplásicos Alquilantes/administración & dosificación , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Carmustina/administración & dosificación , Glioblastoma/diagnóstico por imagen , Glioblastoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/cirugía , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Glioblastoma/cirugía , Humanos , Imagen por Resonancia Magnética/tendencias , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/cirugía , Estudios Retrospectivos , Adulto Joven

RESUMEN

Glioblastoma is one of the most aggressive brain tumors and is associated with a very low overall median survival despite the current treatment. The standard of care used in clinic is the Stupp's protocol which consists of a maximal resection of the tumor when possible, followed by radio and chemotherapy using temozolomide. However, in most cases, glioblastoma cells infiltrate healthy tissues and lead to fatal recurrences. There are a lot of hurdles to overcome in the development of new therapeutic strategies such as tumor heterogeneity, cell infiltration, alkylating agent resistance, physiological barriers, etc., and few treatments are on the market today. One of them is particularly appealing because it is a local therapy, which does not bring additional invasiveness since tumor resection is included in the gold standard treatment. They are implants: the Gliadel® wafers, which are deposited post-surgery. Nevertheless, in addition to presenting important undesirable effects, it does not bring any major benefit in the therapy despite the strategy being particularly attractive. The purpose of this review is to provide an overview of recent advances in the development of innovative therapeutic strategies for glioblastoma using an implant-type approach. The combination of this local strategy with effective targeting of the tumor microenvironment as a whole, also developed in this review, may be of interest to alleviate some of the obstacles encountered in the treatment of glioblastoma.

Asunto(s)

Neoplasias Encefálicas , Glioblastoma , Humanos , Poliésteres , Temozolomida

RESUMEN

High grade gliomas are associated with poor prognosis and high mortality. Conventional treatments and management of high grade gliomas have shown little improvement in 5-year overall survival. This phase I trial evaluated the safety, immunogenicity, and potential synergy of surgical resection with Gliadel Wafer implantation, followed by autologous tumor lysate-pulsed dendritic cell (DC) vaccine in patients with malignant glioma. Primary end points of this study were safety and surrogate markers of immunogenicity, overall survival, and progression free survival. Following surgical resection, Gliadel Wafers were placed along the resection cavity. Patients subsequently received intradermal injections of autologous tumor lysate-pulsed DC vaccines 3 times at 2 week intervals. Treatment response was evaluated clinically and through MRI at regular intervals. Twenty-eight patients received Gliadel Wafers and DC vaccination: 11 newly diagnosed (8 glioblastoma [GBM], 2 anaplastic astrocytoma [AA], and 1 anaplastic oligodendroglioma [AO]) and 17 recurrent (15 GBMs, 1 AA, and 1 AO) high grade gliomas. Immunogenicity data was collected for 20 of the 28 patients. Five of 20 patients showed elevated IFN-γ responses following vaccination. Median progression-free survival and overall survival for all GBM patients in the trial from the start of vaccination were 3.6 months and 16.9 months respectively. Comparisons between vaccine responders and non-vaccine responders were not statistically significant. Adjuvant autologous dendritic cells pulsed with tumor-lysate following resection and Gliadel Wafer placement is safe, elicits modest immunogenicity and shows similar clinical outcomes in patients who had DC vaccination in previous studies.

Asunto(s)

Neoplasias Encefálicas/terapia , Vacunas contra el Cáncer/uso terapéutico , Carmustina/uso terapéutico , Ácidos Decanoicos/uso terapéutico , Células Dendríticas/trasplante , Glioma/terapia , Poliésteres/uso terapéutico , Adulto , Anciano , Antígenos de Neoplasias/inmunología , Antineoplásicos/uso terapéutico , Terapia Combinada/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vacunación/métodos

RESUMEN

Glioblastoma multiforme (GBM) has few clinically approved therapeutic regimens. One of these therapeutic options includes placing biodegradable wafers releasing BCNU (Gliadel®) into the tumor bed at the time of surgical removal of the tumor. Due to the significant benefit this polymer technology has had clinically, we have prepared wafers releasing Temozolomide (TMZ), an anticancer drug used systemically for treating GBM. TMZ delivered via polymer wafer could be used as a complementary treatment with or as an alternative to Gliadel®. TMZ is an alkylating agent which is water soluble. To remain comparable with the preclinical studies that led to Gliadel® the same size of wafers were formulated with TMZ. Wafers were loaded with 50% w/w TMZ in poly(lactic acid-glycolic acid) (PLGA) and showed reliable release of high dose TMZ for a period of 4 weeks. To achieve this 30-day release of the highly water soluble drug, we developed an encapsulation method, where the drug powder was first coated with the polymer to form core-shell particles in which the coating shell served as a rate controlling membrane for the drug particles. Wafers were also made with a co-loading of TMZ and BCNU. All wafers were tested in vivo by treating an intracranial 9 L gliosarcoma model in F344 rats. Rats that were either untreated or treated with blank wafer died within 11 days while the median survival for rats treated with systemic TMZ was 18 days. The group that received the BCNU alone wafer had a median survival of 15 days, the group that received the TMZ wafer alone had a median survival of 19 days, and the group treated with the BCNU-TMZ wafer had a median survival of 28 days with 25% of the animals living long term (p < .0038 vs. Control; p < .001 vs. Blank Polymer). These findings demonstrate the potential of this newly designed wafer for treating GBM. Moreover, this concept, can pave the way for other drug combinations that may improve the clinical application of numerous agents to treat solid tumors.

Asunto(s)

Antineoplásicos Alquilantes/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Carmustina/administración & dosificación , Ácidos Decanoicos/administración & dosificación , Preparaciones de Acción Retardada/química , Glioblastoma/tratamiento farmacológico , Poliésteres/administración & dosificación , Temozolomida/administración & dosificación , Animales , Antineoplásicos Alquilantes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carmustina/uso terapéutico , Ácidos Decanoicos/uso terapéutico , Implantes de Medicamentos/química , Femenino , Poliésteres/uso terapéutico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Ratas Endogámicas F344 , Temozolomida/uso terapéutico

RESUMEN

Randomized, controlled trials have shown significant improvement of survival after implantation of 1,3-bis(2-Chloroethyl)-1-nitrosourea (BCNU) wafers for patients suffering from high-grade glioma. A combination of local chemotherapy with BCNU and concomitant radiochemotherapy with temozolomide (TMZ) appears to be attractive to enhance the overall survival, even though these treatments may potentially cumulate their toxicity. We report a clinical case of a patient submitted to this combined treatment protocol. Severe brain edema and a cystic formation in the surgical cavity rapidly developed. Data supporting the use of Gliadel® combined with TMZ comes from small retrospective studies, and some series have shown a very high rate of adverse events (AEs) when this multimodality treatment is applied. Combined protocols of local and systemic chemotherapy might provide survival benefits, although AEs seem currently underestimated.

RESUMEN

Biomaterials to treat cancers hold therapeutic potential; however, their translation to bedside treatment requires further study. The carmustine (1,3-bis (2-chloroethyl)-1-nitrosourea; BCNU) wafer, a biodegradable polymer, currently is the only drug that is able to be placed at the surgical site to treat malignant tumors. However, how this wafer affects the surrounding tumor microenvironment is not well understood to date. We retrospectively reviewed all patients with glioblastoma treated with and without BCNU wafers who underwent repeat resection at tumor recurrence. We investigated radiological imaging; the interval between the two surgeries; and immunohistochemistry of CD3, CD4, CD8, CD20, CD68, FOXP3, and PD1. We implanted BCNU wafers in 41 newly diagnosed glioblastoma patients after approval of the wafer in Japan. Of them, 14 underwent surgery at recurrence and tissue was obtained from around the wafers. The interval between the first and second surgeries ranged from 63 to 421 days. The wafer could be observed on magnetic resonance imaging at up to 226 days, whereas intraoperatively the biodegraded material of the wafer could be found at up to 421 days after the initial surgery. Immunohistochemical analysis demonstrated that CD8+ and CD68+ cells were significantly increased, but FOXP3+ cells did not increase, after wafer implantation compared to tissue from cases without wafer implantation. MRI data and immune cells, as well as interval between surgeries and immune cells, demonstrated positive correlation. These results helped us to understand the bioactivity of bioengineered materials and to establish a new approach for immunotherapy.

Asunto(s)

Antineoplásicos Alquilantes/administración & dosificación , Carmustina/administración & dosificación , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Implantes Absorbibles , Adulto , Anciano , Biomarcadores de Tumor/inmunología , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/patología , Encéfalo/cirugía , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/cirugía , Niño , Femenino , Glioblastoma/diagnóstico por imagen , Glioblastoma/tratamiento farmacológico , Glioblastoma/inmunología , Glioblastoma/cirugía , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/cirugía , Estudios Retrospectivos

RESUMEN

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.

Asunto(s)

Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Carmustina/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/diagnóstico por imagen , Femenino , Glioblastoma/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tomografía Computarizada por Rayos X

RESUMEN

BACKGROUND: Although a subdural fluid collection frequently is observed, diagnostic methods that differentiate between the subdural collection caused by external hydrocephalus and that caused by subdural hygroma have not been established. Here, we report a case of external hydrocephalus caused by Gliadel-induced eosinophilic meningitis that has been previously reported in only 1 case and can be diagnosed by time-spatial labeling inversion pulse magnetic resonance imaging (time-SLIP MRI). CASE DESCRIPTION: A tumor located in the left temporal was detected incidentally in an 81-year-old man by examination of a head injury. The tumor was surgically resected and diagnosed as a high-grade glioma during the surgery; Gliadel wafers subsequently were implanted. Three weeks after the resection, the patient showed disturbed consciousness, and computed tomography revealed a subdural fluid collection. The out-flow of cerebrospinal through the resection cavity was detected by time-SLIP MRI. Cerebrospinal tests indicated high white blood cell counts and high protein levels, with more than 90% of the white blood cell count comprising eosinophils. Therefore, we suspected that the subdural fluid collection was caused by external hydrocephalus because of Gliadel-induced eosinophilic meningitis. We surgically removed the Gliadel wafers and subsequently performed a surgery to insert a ventriculoperitoneal shunt. Histologic examination indicated eosinophilic accumulation around the Gliadel wafers. The patient's symptoms improved after the insertion of a ventriculoperitoneal shunt. CONCLUSIONS: In the present case, time-SLIP MRI was a useful and noninvasive method for diagnosing external hydrocephalus which was caused by eosinophilic meningitis because of Gliadel-induced eosinophilic meningitis.

Asunto(s)

Hidrocefalia/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Meningitis/diagnóstico por imagen , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Neoplasias Encefálicas/tratamiento farmacológico , Carmustina/efectos adversos , Ácidos Decanoicos/efectos adversos , Glioma/tratamiento farmacológico , Humanos , Hidrocefalia/etiología , Hidrocefalia/cirugía , Masculino , Meningitis/complicaciones , Meningitis/cirugía , Poliésteres/efectos adversos , Lóbulo Temporal/cirugía , Derivación Ventriculoperitoneal

RESUMEN

Although carmustine (Gliadel) wafers improve local tumor control and extend the overall survival in patients with malignant glioma, adverse effects have been documented. The authors report the first case of eosinophilic meningitis triggered by the placement of Gliadel wafers. A 61-year-old man with a history of alimentary allergy and glioblastoma in the right frontal lobe underwent resection followed by the implantation of Gliadel wafers. Three weeks later he suffered the sudden onset of headache, vomiting, and progressive consciousness disturbance. Computed tomography revealed enlargement of the ventricular system and subdural space on the side of the tumor. His CSF leukocyte count increased up to 3990 cells/mm3; 95% of the cells were eosinophilic granulocytes (EGs), suggesting eosinophilic meningitis. Laboratory examination showed the patient to have various elevated allergy indicators. The administration of corticosteroids failed to improve his condition. Despite the insertion of a lumbar drain his symptoms failed to improve. He underwent a second surgical intervention to remove the Gliadel wafers. Histologically, EGs had assembled around the wafers. Eosinophilic infiltrate was present in the brain parenchyma around small vessels. After ventriculoperitoneal shunting his course was favorable. A drug lymphocyte stimulation test against the Gliadel wafers failed to demonstrate a positive reaction; polifeprosan, the wafer matrix without 1,3-bis(2-chloroethyl)-1-nitrosourea, yielded a positive reaction. These findings strongly suggest that although extremely rare, polifeprosan (the wafer matrix) can elicit an allergic reaction. When eosinophilic meningitis is suspected after the implantation of Gliadel wafers, their immediate removal should be considered.

Asunto(s)

Antineoplásicos/efectos adversos , Neoplasias Encefálicas/tratamiento farmacológico , Encéfalo/diagnóstico por imagen , Carmustina/efectos adversos , Ácidos Decanoicos/efectos adversos , Eosinofilia/etiología , Glioma/tratamiento farmacológico , Meningitis/etiología , Poliésteres/efectos adversos , Antineoplásicos/administración & dosificación , Carmustina/administración & dosificación , Ácidos Decanoicos/administración & dosificación , Sistemas de Liberación de Medicamentos/efectos adversos , Implantes de Medicamentos , Eosinofilia/diagnóstico por imagen , Humanos , Masculino , Meningitis/diagnóstico por imagen , Persona de Mediana Edad , Poliésteres/administración & dosificación , Resultado del Tratamiento

RESUMEN

Polifeprosan 20 with carmustine (GLIADEL®) polymer implant wafer is a biodegradable compound containing 3.85% carmustine (BCNU, bischloroethylnitrosourea) implanted in the brain at the time of planned tumor surgery, which then slowly degrades to release the BCNU chemotherapy directly into the brain thereby bypassing the blood-brain barrier. Carmustine implant wafers were demonstrated to improve survival in randomized placebo-controlled trials in patients undergoing a near total resection of newly diagnosed or recurrent malignant glioma. Based on these trials and other supporting data, carmustine wafer therapy was approved for use for newly diagnosed and recurrent malignant glioma in the United States and the European Union. Adverse events are uncommon, and as this therapy is placed at the time of surgery, it does not add to patient treatment burden. Nevertheless, this therapy appears to be underutilized. This article reviews the evidence for a favorable therapeutic ratio for the patient and the potential barriers. Consideration of these issues is important for optimal use of this therapeutic approach and may be important as this technology and other local therapies are further developed in the future.

RESUMEN

Since 2003, only two chemotherapeutic agents, evaluated in phase III trials, have been approved by the US Food and Drug Administration for treatment of newly diagnosed high-grade glioma (HGG): Gliadel wafers (intracranially implanted local chemotherapy) and temozolomide (TMZ) (systemic chemotherapy). Neither agent is curative, but each has been shown to improve median overall survival (OS) compared to radiotherapy (RT) alone. To date, no phase III trial has tested these agents when used in sequential combination; however, a number of smaller trials have reported favorable results. We performed a systematic literature review to evaluate the combination of Gliadel wafers with standard RT (60 Gy) plus concurrent and adjuvant TMZ (RT/TMZ) for newly diagnosed HGG. A literature search was conducted for the period of January 1995 to September 2015. Data were extracted and categorized, and means and ranges were determined. A total of 11 publications met criteria, three prospective trials and eight retrospective studies, representing 411 patients who received Gliadel plus standard RT/TMZ. Patients were similar in age, gender, and performance status. The weighted mean of median OS was 18.2 months (ten trials, n = 379, range 12.7 to 21.3 months), and the weighted mean of median progression-free survival was 9.7 months (seven trials, n = 287, range 7 to 12.9 months). The most commonly reported grade 3 and 4 adverse events were myelosuppression (10.22 %), neurologic deficit (7.8 %), and healing abnormalities (4.3 %). Adverse events reflected the distinct independent safety profiles of Gliadel wafers and RT/TMZ, with little evidence of enhanced toxicity from their use in sequential combination. In the 11 identified trials, an increased benefit from sequentially combining Gliadel wafers with RT/TMZ was strongly suggested. Median OS tended to be improved by 3 to 4 months beyond that observed for Gliadel wafers or TMZ when used alone in the respective phase III trials. Larger prospective trials of Gliadel plus RT/TMZ are warranted.

Asunto(s)

Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Carmustina/uso terapéutico , Dacarbazina/análogos & derivados , Ácidos Decanoicos/uso terapéutico , Glioblastoma/patología , Glioblastoma/terapia , Poliésteres/uso terapéutico , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/mortalidad , Carmustina/administración & dosificación , Carmustina/efectos adversos , Quimioradioterapia , Quimioterapia Adyuvante , Ensayos Clínicos Fase III como Asunto , Terapia Combinada/métodos , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dacarbazina/uso terapéutico , Ácidos Decanoicos/administración & dosificación , Ácidos Decanoicos/efectos adversos , Supervivencia sin Enfermedad , Implantes de Medicamentos , Glioblastoma/mortalidad , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Poliésteres/administración & dosificación , Poliésteres/efectos adversos , Temozolomida , Estados Unidos , United States Food and Drug Administration

RESUMEN

INTRODUCTION: Glioblastoma multiforme (GBM) is the most prevalent primary neoplasm of the brain. Moreover, the prognosis of patients with GBM has been poor, with almost uniform progressive neurological impairment and rapid death. Despite the availability of multimodal treatments through surgery, focal radiation, and chemotherapy, no major progress has been reported until recently. Area covered: The development of interstitial biodegradable carmustine wafers (Gliadel) for treating selected patients with malignant gliomas has resulted in marginal survival benefits in such patients (only approximately 2 months longer than that of those who did not receive the treatment). Therefore, this study summarizes several recent representative studies, presents emerging studies, and highlights the directions for additional developments in this area. An overview of the current knowledge of preclinical developments, efficacy and safety observed in clinical trials and practice following drug approval, and future avenues of research is imperative. Expert opinion: Studies are being conducted to improve the efficacy of interstitial chemotherapy by using nanobiotechnology and polymeric material science in addition to different chemotherapeutic, antiangiogenesic, and gene therapy agents and growth factors. Nanocarrier-based noninvasive techniques may have considerable potential to enhance the efficacy of GBM treatment.

Asunto(s)

Antineoplásicos Alquilantes/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Carmustina/administración & dosificación , Terapia Combinada , Ácidos Decanoicos/administración & dosificación , Glioma/tratamiento farmacológico , Glioma/patología , Humanos , Poliésteres/administración & dosificación , Pronóstico