Intracerebral Cyst Research Articles

SCIDOT-30. GLITIPNI: A PHASE 1B CLINICAL TRIAL COMBINING SURGICAL RESECTION WITH DIRECT INTRACEREBRAL INJECTION OF IMMUNE CHECKPOINT INHIBITORS IN PATIENTS WITH RECURRENT GLIOBLASTOMA

Abstract INTRODUCTION Intravenous (iv) administration of PD-1 blocking mAb is largely ineffective for the treatment of recurrent glioblastoma (rGB). Combination of iv-ipilimumab (IPI) plus nivolumab (NIVO) is associated with a high incidence of irAE. Intracerebral (ic) administration of immune-checkpoint inhibiting mAb following the resection of rGB could be a more effective and safer alternative to iv-dosing. METHODS Patients underwent maximal safe resection of their rGB followed by ic-injection of 10mg IPI (cohort-1) or 5mg IPI plus 10mg NIVO (cohort-2) in the wall of the resection cavity. In both cohorts 10mg nivolumab was administered iv for a max of 6 doses, starting 1 day pre-operatively. RESULTS 21 pts were included (3 in C-1, 18 in C-2; 8F/13M; median age 56y [range 38–72]; 17 de novo GB, 4 secGB). All patients underwent maximal safe surgical resection followed by ic-injection of IPI and NIVO as planned. Median number of iv-administrations of NIVO was 5 (range 1–8). Treatment was generally well tolerated. Postoperatively, 2 patients experienced a G3 symptomatic increase in perilesional cerebral edema with neurological deterioration, reversible upon steroid treatment. One patient had worsening neurological symptoms related to an inflammatory intracerebral cyst at the resection site, requiring surgical decompression 4 months post-study treatment. Most frequent AEs were fatigue (2pts G3, 8pts G2), postoperative fever (11pts G1) and headache (3pts G2); 1pt developed G3 pneumonitis. No other immune-related AEs or treatment-related deaths occurred. After median follow-up of 60 weeks, median PFS is 14.4 weeks (95% CI 11.2–17.6); 11/21 patients are alive, and 1- and 2y-OS% are respectively 46% (95% CI 19- 73%), and15% (95% CI 0–42%). CONCLUSION This is the first study demonstrating the safety and activity of combined surgical resection of rGB with local intracerebral administration of immune checkpoint-inhibiting mAb. Survival compares favorably to historical controls justifying further investigation of this experimental therapy.

ATIM-38. GLITIPNI: A PHASE 1B CLINICAL TRIAL COMBINING SURGICAL RESECTION WITH DIRECT INTRACEREBRAL INJECTION OF IMMUNE CHECKPOINT INHIBITORS IN PATIENTS WITH RECURRENT GLIOBLASTOMA

Abstract INTRODUCTION Intravenous (iv) administration of PD-1 blocking mAb is largely ineffective for the treatment of recurrent glioblastoma (rGB). Combination of iv-ipilimumab (IPI) plus nivolumab (NIVO) is associated with a high incidence of irAE. Intracerebral (ic) administration of immune-checkpoint inhibiting mAb following the resection of rGB could be a more effective and safer alternative to iv-dosing. METHODS Patients underwent maximal safe resection of their rGB followed by ic-injection of 10mg IPI (cohort-1) or 5mg IPI plus 10mg NIVO (cohort-2) in the wall of the resection cavity. In both cohorts 10mg nivolumab was administered iv for a max of 6 doses, starting 1 day pre-operatively. RESULTS 21 pts were included (3 in C-1, 18 in C-2; 8F/13M; median age 56y [range 38–72]; 17 de novo GB, 4 secGB). All patients underwent maximal safe surgical resection followed by ic-injection of IPI and NIVO as planned. Median number of iv-administrations of NIVO was 5 (range 1–8). Treatment was generally well tolerated. Postoperatively, 2 patients experienced a G3 symptomatic increase in perilesional cerebral edema with neurological deterioration, reversible upon steroid treatment. One patient had worsening neurological symptoms related to an inflammatory intracerebral cyst at the resection site, requiring surgical decompression 4 months post-study treatment. Most frequent AEs were fatigue (2pts G3, 8pts G2), postoperative fever (11pts G1) and headache (3pts G2); 1pt developed G3 pneumonitis. No other immune-related AEs or treatment-related deaths occurred. After median follow-up of 60 weeks, median PFS is 14.4 weeks (95% CI 11.2–17.6); 11/21 patients are alive, and 1- and 2y-OS% are respectively 46% (95% CI 19- 73%), and15% (95% CI 0–42%). CONCLUSION This is the first study demonstrating the safety and activity of combined surgical resection of rGB with local intracerebral administration of immune checkpoint-inhibiting mAb. Survival compares favorably to historical controls justifying further investigation of this experimental therapy.

Letter to the Editor Regarding “Cyst-Peritoneal Shunt for the Treatment of a Progressive Intracerebral Cyst Associated with ASNS Mutation: Case Report and Literature Review”

Letter to the Editor Regarding “Cyst-Peritoneal Shunt for the Treatment of a Progressive Intracerebral Cyst Associated with ASNS Mutation: Case Report and Literature Review”

Intracerebral hydatid cyst: A rare cause of neurosurgical emergency

Intracerebral hydatid cyst: A rare cause of neurosurgical emergency

Kystes intracérébraux révélés par des symptômes extrapyramidaux

We report 3 cases of intracerebral cyst revealed by an unusual evolution of extrapyramidal symptoms. Diagnosis was based on MRI and the patients were treated by a cystoperitoneal or a cysto-atrial shunt. The surgical procedure was successful in the 3 cases, resulting in the rapid disappearance of symptoms.

Neuroendoscopic options in the treatment of mesencephalic expanding cysts: Report of four cases and review of the literature

ObjectiveMesencephalic expanding cysts, also called lacunae, are rare intraparenchymal, multilobulated cavities of variable diameter mostly localized in the thalamo-mesencephalic region. In symptomatic cases, usually presenting with hydrocephalus or midbrain syndrome, surgical treatment is required and, considering their position, a minimally invasive approach should be preferred. MethodsFour cases of expanding mesencephalic cysts endoscopically treated in three different Italian centers are described. Other possible causes of intracerebral cyst were excluded in all cases by complete neuroimaging and laboratory screening. All patients presented with signs and symptoms of midbrain compression and a slight to moderate ventricular dilation was present in three cases. ResultsAll patients underwent endoscopic cyst fenestration into the ventricle, associated with endoscopic third-ventriculostomy (ETV) in two cases and with cyst wall biopsy in one case. One patient suffered from transient worsening of her hemiparesis due to intraoperative bleeding. All patients showed clinical improvement and a reduction in cyst size on follow-up magnetic resonance images (MRI). ConclusionNeuroendoscopy appears to be an effective, probably definitive surgical option in the treatment of symptomatic mesencephalic expanding cysts. Associating ETV with cyst fenestration seems to offer more complete treatment. Deep intracystic navigation and cyst wall biopsy should be avoided.

53. Cryosurgery of brain tumors with ultrasound neuronavigation control

Goal of study: To estimate the results of brain tumor surgery with cryodestruction usage. Materials and methods: The cryodestruction of neuroepithelial tumors was performed in 18 patients. We used a new cryosurgical apparatus. This method of working is based on the passive liquid nitrogen supply and the active evacuation of nascent gaseous one. Tumor stereobiopsy was performed before the cryoprobe introduction. Cryosurgery was performed by introducing the cryoprobe into the tumor with ultrasound neuronavigation control. MRI of the brain was performed before the operation and 1, 3 and 7 days after it on all patients. The efficiency of the cryodestruction and the diagnostic value of ultrasound navigation to control ice-ball generation and postoperative changes in cryodestruction and surrounding zones were estimated. Results: The ultrasound neuronavigation enabled clear visualization of the tumor, the immersion of cryoprobe and ice-ball formation. With ultrasonography a cryoprobe looked like a hyperechoic structure with an acoustic shadow as in all cases with metal equipment. An iceball looked like a hypoechoic tissue near the cryoprobe with hyperechoic contour with 2–3 mm thickness. Pre- and postoperative MRI permitted a comparison of the zones of tumor and cryodestruction. The postoperative MRI showed that there was intracerebral cyst formation in the zone of cryodestruction of the tumor. This cyst had plain clear borders. There was no residual tumor tissue. Haemorrhage of cryodestruction and surrounding zones was not detected. According to MRI the clearest visualization of cryodestruction zone was up to 3 days. There was no extension of perifocal edema within first 3 days, however, an insignificant one was found by the 7th postoperative day. The contrast accumulation at the border of destruction zone was marked by the 5th day, it was the effect of delimiting gliosis formation. Conclusion: Cryodestruction enables the destruction of brain tumors efficiently in a given volume. Ultrasound neuronavigation is an effective method of monitoring ice-ball formation in the brain during freezing and thawing in real time. This method allows destruction of the tumors which are located in functionally significant brain areas and attempts at removal is associated with a high risk of disability and death.

Cerebral MRI and EEG studies in the initial management of pediatric headaches

High resolution imaging modalities and electroencephalographic studies (EEG) are used in the assessment of children with headaches. We evaluated the role of cerebral MRI (cMRI) and EEG in the initial assessment of children with headache as the chief complaint of initial presentation. A retrospective chart analysis was performed at a tertiary University Hospital. 209 patients were included in this study [mean age 11.3 years; male 91 (43.5%); female 118 (56.5%)]. The following types of headaches were seen: Unclassified headache: 23.4%; probable migraine 17.2%, migraine without aura 13.4%, complicated migraine 12.4%, migraine with aura 1.0%; tension-type 15.3%, and cluster headaches 0.5%, and secondary headaches 16.7%. In 93 children (44.5%) abnormal physical/neurological findings were noted (multiple entries possible). On cMRI studies the following findings were seen: Infection of sinuses (7.2%), pineal cysts (2.4%), arachnoidial cyst and Chiari malformation (1.9%), unspecified signal enhancement (1.0%), and pituitary enlargement, inflammatory lesion, angioma, cerebral ischaemia, and intra-cerebral cyst (each 0.5%). Electroencephalographic findings included both focal and generalised abnormal slowing (5.3%) and Spike-wave complexes (3.3%). Despite abnormal findings on neurological/physical examination in a substantial number of children with headaches, the yield of pathological cMRIs was low. The use of EEG recordings was not contributory to the diagnostic and therapeutic approach. More research is needed to better define those patients who are likely to have an intracranial pathology.

Partially calcified giant intracerebral hydatid cyst in a pediatric child

Partially calcified giant intracerebral hydatid cyst in a pediatric child

The timing of sulfadiazine therapy impacts the reactivation of latent Toxoplasma infection in IRF-8−/− mice

The process of reactivation of latent infection with Toxoplasma gondii in immunosuppressed hosts is yet not fully understood. In the past, a number of murine models of reactivation in immunocompromised mice have been described using sulfadiazine to establish latent infection before withdrawal and subsequent reactivation. We studied the process of reactivation in brains of mice with a targeted mutation in the interferon-regulatory factor (IRF)-8 gene after withdrawal of sulfadiazine therapy. IRF-8(-/-) mice were orally infected with five cysts of the ME 49 strain of T. gondii. To allow establishment of latent infection with cyst formation, mice were treated with sulfadiazine starting either 3, 5, 6, or 7 days postinfection. Sulfadiazine was withdrawn after 14-21 days to allow reactivation. We observed that timing of sulfadiazine therapy had a marked impact on the course of infection and reactivation. Mice treated late after infection (days 5-7) showed increased mortality and decreased time to death compared to mice treated early after infection (group A). In the blood of mice with late (days 5-7) but not early (day 3) initiation of treatment, T. gondii-specific deoxyribonucleic acid was detected by polymerase chain reaction. Using double staining with stage-specific antibodies, tachyzoites were detectable in brains of mice with late initiation of sulfadiazine treatment but rarely within cysts thus indicating continued invasion of parasites across the blood-brain barrier. Intracerebral cyst rupture or bradyzoite-tachyzoite conversion was not detectable in IRF-8(-/-) mice when sulfadiazine therapy was initiated late after infection. These results indicate that continued invasion of tachyzoites rather than reactivation of latent cerebral infection impacts the course of infection in this model of reactivated toxoplasmosis. In conclusion, the timing of sulfadiazine therapy is of utmost importance for the course of infection in immunocompromised mice.

Presence of filamin in the astrocytic inclusions of Aicardi syndrome

Aicardi syndrome affects only females and has been hypothesized to be an X-linked dominant male-lethal disorder. Because no familial cases can be studied for genetic linkage analysis, the mutated gene has remained elusive. With the goal of selecting genes for mutation analysis by a functional candidate approach, a detailed pathologic analysis of two brains from deceased Aicardi syndrome patients was performed. The presence of micrencephaly, absent or hypoplastic corpus callosum, polymicrogyria, heterotopia, ventriculomegaly, intracerebral cyst, and intracytoplasmic eosinophilic inclusions was confirmed in glial fibrillary acidic protein–positive astrocytes in the cortex and heterotopias, but not in white matter. The inclusions demonstrated strong immunolabeling with antibodies to filamin and vimentin but weak labeling with antibodies to proteins S100 and microtubule-associated protein 1. These findings suggested that an underlying defect in the cytoskeleton, which involves filamin, may cause this condition. Because the filamin A gene in Xq28 is mutated in another disorder with heterotopia, familial bilateral periventricular heterotopia, mutation analysis of filamin A in Aicardi syndrome patients was pursued. No mutations were found, and the full-length protein was expressed in both brain samples. Future studies will focus on investigation of X-linked genes that may affect function of filamin or other cytoskeletal proteins.

Expression of green fluorescent fusion proteins in pancreatic acinar cells

A 27-year-old male had experienced an episode of severe headache and nausea, sometimes accompanied by an inability to name objects. Magnetic resonance imaging showed a huge cyst within the left temporal lobe and a high degree of brain shift by it. A small round mass, which appeared to be a mural nodule, was located in the tip of left middle fossa. It was highly enhancing together with its attached dura mater, but the cyst wall was not enhanced. Sphenoid ridge meningioma with an associated intracerebral cyst or cystic glioma invading the dura mater was suspected. During surgery the small tumor was found to be arising from the sphenoid ridge and evaginating into the tip of the temporal lobe. The intracerebral cyst had a smooth surface and the tumor was visible outside the cyst through its wall. The tumor was totally removed, but the cyst wall was left without excision. Postoperatively he had no symptoms. Histological examination showed a microcystic meningioma. It is stressed that differentiations of cystic meningiomas from other cystic tumors and, of intratumoral from extratumoral cystic meningiomas using radiological, operative or histological findings are important.

Classic and unusual appearances of hydatid disease in children.

In endemic regions, hydatid disease is commoner in children than in adults. The hydatid cysts may have classic appearances, but unusual sites and appearances may cause diagnostic difficulties. To assess the classic and unusual appearances of hydatid disease in children. A 3-year retrospective review of available imaging of proven hydatid disease at a tertiary paediatric institution. RESULTS. Review of imaging of 21 children (9 boys, 12 girls), with a mean age of 8 years and 1 month, demonstrated cysts in the liver ( n=9), lung ( n=8), brain ( n=7), spleen ( n=2), heart ( n=1), orbit ( n=1) and soft tissues ( n=1). Multi-organ involvement occurred in eight cases with two cases that did not involve the liver. Complicated cysts were found in 13 cases and usually involved the liver ( n=8) and lung ( n=5). An unusual case of spontaneous cerebrospinal fluid (CSF) spread was also documented. Hydatid disease in children classically involves the liver, lung and brain but can involve almost any organ and numerous organs simultaneously. Whether hydatid disease is discovered incidentally or by intentional imaging, extended imaging is recommended to identify multifocal disease which may also display complicated cysts that may assist in the diagnostic process. All patients with one known site should undergo a minimum of an abdominal US and CT scan of the chest and brain. CT may be used instead of US of the abdomen, and MRI may be used to replace CT of the brain. Over 50% of cases in our study showed complicated cysts. Unique findings of this study include multi-organ involvement without liver cysts. Multiplicity and complications of cysts can assist diagnosis. Intraventricular and intrathecal CSF spread of a spontaneously ruptured intracerebral cyst has not, to our knowledge, been previously reported.

Intracerebral cyst associated with meningioma

A 27-year-old male had experienced an episode of severe headache and nausea, sometimes accompanied by an inability to name objects. Magnetic resonance imaging showed a huge cyst within the left temporal lobe and a high degree of brain shift by it. A small round mass, which appeared to be a mural nodule, was located in the tip of left middle fossa. It was highly enhancing together with its attached dura mater, but the cyst wall was not enhanced. Sphenoid ridge meningioma with an associated intracerebral cyst or cystic glioma invading the dura mater was suspected. During surgery the small tumor was found to be arising from the sphenoid ridge and evaginating into the tip of the temporal lobe. The intracerebral cyst had a smooth surface and the tumor was visible outside the cyst through its wall. The tumor was totally removed, but the cyst wall was left without excision. Postoperatively he had no symptoms. Histological examination showed a microcystic meningioma. It is stressed that differentiations of cystic meningiomas from other cystic tumors and, of intratumoral from extratumoral cystic meningiomas using radiological, operative or histological findings are important.

Neuronavigator-guided cerebral biopsy.

Neuronavigators are new dynamic interactive instruments that use on-line computers to orient imaging data to the surgical field and guide the neurosurgeon to his target. We have been working since 1987 on a neuronavigator that serves not only as a precise pointer, but also as a dynamic arm that can be used to hold instruments, such as biopsy guides. The neuronavigator arm consists of six joints with optical encoders and is attached to the Mayfield headholder. The arm is connected to a workstation running customized 3D image graphics software. Special instruments and surgical technique have been developed. Here, we report on early clinical experience with ten biopsy procedures: 4 low-grade and 3 high-grade astrocytomas, one craniopharyngioma and one chronic intracerebral haematoma and intracerebral cyst, both of the latter with surrounding tumour suspect tissue. In all glioma cases serial biopsies were taken from optimal sites under ultrasound imaging control. Eight cases showed representative tumour tissue, while in two cases neoplasia was ruled out. The neuronavigator proved to be versatile, allowing comprehensive imaging data to be adapted to the surgical field.

A purified parasite antigen (p30) mediates CD8+ T cell immunity against fatal Toxoplasma gondii infection in mice.

Induction of protective immunity against acute and chronic toxoplasmosis can be achieved using p30, the major membrane and excreted/secreted protein of Toxoplasma gondii. This protein, when administered to outbred mice in the presence of the saponin Quil A, is able to induce almost 100% protection against acute infection without evidence of intracerebral cyst development. Adoptive transfer of immune splenocytes from immunized inbred A/J mice conferred a significant level (p less than 0.001) of protection against subsequent challenge. Phenotypic analysis in outbred as well as two different strains of inbred mice (A/J and C57BL/6) demonstrated that CD8+ T cells are selectively stimulated by this immunization protocol. T cell depletion studies using specific mAb directed at either CD3+ or CD8+ T cell phenotype, followed by adoptive transfer, failed to confer protective immunity, whereas CD4+ depletion had no effect. These cytotoxic CD8+ T cells produced high titers of both IFN-gamma and IL-2. Moreover, these CD8+ T cells were directly parasiticidal against radiolabeled extracellular T. gondii, further supporting the critical immune function of these p30 Ag-specific CD8+ T cells in host immunity against T. gondii infection.

Intracerebral Epithelial Cyst: Immunohistological diagnosis and endoneurosurgical treatment

This report details an additional case of the very rare instance of a respiratory epithelium-lined intracerebral cyst without communication with the ventricular system. Immunohistologic analysis supports an epithelial rather than neuroectodermal origin. Management using endoneurosurgical techniques is described.

A convexity intracerebral arachnoid cyst: A CT entity to be differentiated from a cystic glioma

A 65-year-old female with an intracerebral cyst was examined in our clinic. It was suspected to be a cystic glioma by the preoperative neuroradiological studies, even with the use of sophisticated CT techniques. By operative and histopathological examination, it was confirmed as an arachnoid cyst mainly embedded in the parenchyma.

The penetration of misonidazole and desmethylmisonidazole into brain tumours and other central nervous system tissues in man.

The concentration of drug after oral administration of 1 g misonidazole to patients undergoing neurosurgery has been studied in samples taken from intracerebral tumours, normal brain, cerebrospinal fluid and brain tumour cyst fluid. A total of 31 patients yielded samples at various times 2-8 h after drug administration. Results show a considerable range of tumour/plasma percentages but from about 2-5 h after drug administration this averaged between 65-80%. Normal brain and CSF showed similar good penetration but drug entry into cyst fluid was lower (30-50%). A further study with desmethylmisonidazole given to 11 additional patients showed a similar range of tumour penetration but lower concentrations in CSF and cyst fluid (10-20%). Low values were also seen in some but not all of the normal brain tissue samples. Necrotic tumour also had much lower concentrations than macroscopically viable tissue. These results are discussed in terms of their clinical relevance to sensitiser studies on patients with brain tumours with drugs of different lipophilicities.

Congenital Intracerebral Epithelial Cysts

The problem of intracerebral congenital epithelial cysts is discussed with reference to five clinical cases. On the basis of their morphological structure the author differentiates the intracerebral cyst with a ciliated, columnar epithelium from the ependymal cyst proper (more frequently located in the lateral recess of the medulla oblongata) and the posterior cerebellar cyst of meningeal arachnoid origin. The cyst with a ciliated columnar epithelium appears to be an ectopic intracerebral tissue, whose neuroepithelial or endodermic origin still remains to be demonstrated. This cyst has been commonly described as a colloid (epithelial) cyst of the 3rd ventricle but may also be localized at other points in the central nervous system. One of the cases studied was an epithelial cyst in the frontal lobe, without any connexion with the ventricle, and evolving as a cerebral tumour.