Inhibition of autophagy at a late stage enhances imatinib-induced cytotoxicity in human malignant glioma cells.

Malignant gliomas are common primary tumors of the central nervous system. The prognosis of patients with malignant glioma is poor in spite of current intensive therapy and thus novel therapeutic modalities are necessary. Imatinib mesylate, a tyrosine kinase inhibitor, is effective in the therapy of tumors including leukemias but not as a monotherapy for malignant glioma. Recently, it is thought that the adequate modulation of autophagy can enhance efficacy of anticancer therapy. The outcome of autophagy manipulation, however, seems to depend on the autophagy initiator, the combined stimuli, the extent of cellular damage and the type of cells, and it is not yet fully understood how we should modulate autophagy to augment efficacy of each anticancer therapy. In this study, we examined the effect of imatinib with or without different types of autophagy inhibitors on human malignant glioma cells. Imatinib inhibited the viability of U87-MG and U373-MG cells in a dose dependent manner and caused nonapoptotic autophagic cell death. Suppression of imatinib-induced autophagy by 3-methyladenine or small interfering RNA against Atg5, which inhibit autophagy at an early stage, attenuated the imatinib-induced cytotoxicity. In contrast, inhibition of autophagy at a late stage by bafilomycin A1 or RTA 203 enhanced imatinib-induced cytotoxicity through the induction of apoptosis following mitochondrial disruption. Our findings suggest that therapeutic efficiency of imatinib for malignant glioma may be augmented by inhibition of autophagy at a late stage, and that appropriate modulation of autophagy may sensitize tumor cells to anticancer therapy.

Quantitative analysis of delayed neuronal death in the hippocampal subfields of SHRSP and SHR.

Transient forebrain ischemia and reperfusion induces delayed neuronal death (DND) in the hippocampal Cornu Ammonis 1 (CA1) subfield of stroke-prone spontaneously hypertensive rat (SHRSP). The vulnerability to DND is potentially related to the genetic susceptibility to stroke in this strain. To elucidate the mechanism of DND in SHRSP, however, it is essential to establish a method for quantitative evaluation of DND, which is not available yet. Male SHRSPs and spontaneously hypertensive rats (SHRs) at 12 weeks of age were used in the experiment. The bilateral common carotid arteries were surgically occluded with aneurysmal clips for 10 min. The brain was taken out 7 days after the experiment of the transient ischemia, and was sliced into serial coronal sections. Quantitative estimation of the number of viable pyramidal cells in the CA1 and CA2/3 subfields was performed based on the stereology with a random and systematic sampling. The transient ischemia and reperfusion (TIR) significantly reduced the number of viable pyramidal cells in CA1 of SHRSP (61000 +/- 20100 in TIR vs. 128500 +/- 21900 in the sham-operation, P < 0.000001 by Student's t-test), while no significant difference was observed in SHR (140300 +/- 30800 in TIR vs. 128200 +/- 16700 in the sham-operation, P = 0.35). Further analysis revealed a dorsal-ventral gradient in the distribution of DND in CA1 of SHRSP with the most severe change in the dorsal area. The quantitative measurement using a stereological method is useful in the precise evaluation of DND in SHRSP. This method can be applied in the studies of effects of medical treatments on the 'ischemia/reperfusion' insult.

Indoleamine 2,3-dioxygenase as a new target for malignant glioma therapy. Laboratory investigation.

OBJECT: Indoleamine 2,3-dioxygenase (IDO), a kynurenine pathway (KP) enzyme catalyzing oxidation of the essential amino acid tryptophan (Trp), is thought to be involved in the immune resistance of malignant tumors through T-cell inactivation caused by Trp depletion and metabolite accumulation. Human malignant gliomas may use this strategy to escape immune attack. The object of this study was to investigate the possibility of IDO-dependent Trp depletion by malignant gliomas and the practicability of using an IDO inhibitor together with anticancer drugs to reserve Trp without decreasing the cytotoxicity of the drugs. METHODS: The authors studied expression of IDO and other KP enzymes and the effects of an IDO inhibitor, 1-methyl L-tryptophan (1MT), on Trp metabolism and cytotoxicity of anticancer drugs, together with direct measurement of KP metabolites, in cultured human malignant glioma cells. RESULTS: Upon interferon-gamma (IFN-gamma) stimulation, the glioma cells greatly increased their IDO mRNA expression concomitant with depletion of Trp. The IDO inhibitor 1MT successfully prevented Trp consumption by the stimulated glioma cells. Combining 1MT with anticancer drugs (temozolomide, bischloroethylnitrosourea [BCNU], etoposide and cisplatin) did not interfere with the drugs' suppression of growth of LN229 glioma cells but rather increased their inhibitory effects on IDO activity. CONCLUSIONS: These findings suggest that the robust IDO expression with rapid consumption of Trp in human glioma cells induced by IFN-gamma could lead to immune resistance in glioma cells. Indoleamine 2,3-dioxygenase inhibitors that prevent Trp depletion could be used with anticancer drugs to improve therapeutic effects.

Diagnosis of congenital hydrocephalus and delivery of its patients in Japan.

The study population included 193 patients with prenatally diagnosed (fetal) hydrocephalus and 181 with postnatally (12 or less than 12 months after birth) diagnosed (infantile) hydrocephalus identified by a nationwide questionnaire survey of congenital hydrocephalus performed in 2000. Of 180 patients with fetal, 101 (56.1%) were diagnosed before week 32 of gestation and 18 (10%) were diagnosed week 37 and later of gestation. In patients with fetal hydrocephalus, US was used in more than 80% of the cases, whereas in patients with infantile hydrocephalus, CT was used in more than half of the cases. For diagnosis of fetal hydrocephalus, either US or MRI had become dominantly utilized and CT had gone out of use in 1996-2000. The adoption ratio of cesarean delivery to transvaginal delivery was around 7 to 3 in patients with fetal hydrocephalus, and 2 to 7 in patients with infantile hydrocephalus, respectively, with significant difference between fetal hydrocephalus and infantile hydrocephalus groups (p < 0.001). Clinical outcomes in patients with fetal hydrocephalus was better in those delivered transvaginally than in those by cesarean delivery, although without no statistical significance (p = 0.124) and those in patients with infantile hydrocephalus showed almost no difference between transvaginal and cesarean delivery groups. There was a tendency for the Apgar score at 5 min to be lower in smaller birth weight infants with a body weight of less than 2000g. This score could be useful as an index for predicting immediate postnatal death in patients with fetal hydrocephalus.

Fungal meningitic hydrocephalus with repeated shunt malfunction.

A 33-year-old female presented with a rare case of fungal meningitis caused by Aspergillus detected for the first time at 15 years after onset. The meningitis repeatedly occurred over a period of 15 years. On admission, cerebrospinal fluid examination found cell count 1340/high-power field, protein 158 mg/dl, and sugar 8 mg/dl, indicating meningitis, although no bacterial or fungal species were detected. Cerebral computed tomography demonstrated hydrocephalus and cervical computed tomography demonstrated a mass lesion on the ventral side of the spinal cord from C4 to C6. Fungal meningitis was suspected and treated with amphotericin B. Her symptoms improved and she was eventually discharged. She was readmitted for recurrence of meningitis and hydrocephalus 2 months later. Amphotericin B was administered and a ventriculoperitoneal (VP) shunt was placed. Shunt malfunction recurred seven times. Aspergillus was detected for the first time from the atrium side of the ventriculoatrial shunt tube at 15 years after onset. Fluconazole was administered. She had narrowing of the cisterna magna, and underwent foramen magnum decompression. The VP shunt was finally reconstructed. Fluconazole administration was continued. Combination of foramen magnum decompression and long-term administration of fluconazole was effective in this case.

[Quantitative assessment of the usefulness of MR-fusion Tl-SPECT image in the diagnosis of brain tumor].

201Tl-SPECT (single photon emission computed tomography) had a disadvantage of low spatial resolution with a limited ROI (region of interest) setting. Recently, the diagnosis of brain tumors has been improved by fusion-imaging employing MRI (magnetic resonance imaging) with Tl-SPECT. In order to assess the usefulness of MR-fusion Tl-SPECT quantitatively, we have compared non-fusion (NF) and MR-fusion (MR-F) imaging with Tl-SEPCT in patients with brain tumors. A total of 38 patients (M/F=14/24) hospitalized at our institution during a 5-year period, each with a histologically confirmed brain tumor, were studied. The index of Tl was used for the early ratio (ER), delayed ratio (DR), and retention index (RI), There was no significant difference between NF and MR-F, which were examined using the test-retest method by 2 observers (N&H), but the Pearson's correlation coefficient was higher for MR-F than for NF. The RI value for MR-F was significantly correlated with the WHO histological grading (r=0.605, n=38, p<0.00l). The DR value for MR-F was significantly correlated with MIB-1 index (r=0.464, n=24, p=0.022). We estimated the RI cut-off value for both NF and MR-F in malignancy by ROC analysis. A cut-off value of RI=0.63 and RI=0.70 was good for NF and MR-F, respectively. The likelihood ratio (LR) of RI was higher for MR-F (LR=6.897) than for NF (LR=2.978), suggesting that RI=0.7 for MR-F was suitable for diagnosis of malignant brain tumor. We conclude that MR-fusion Tl-SPECT is better for quantitative analysis of brain tumors than non-fusion Tl-SPECT.

Otogenic tension pneumocephalus complicated by eustachian tube insufflation in a patient with a ventriculoperitoneal shunt. Case report.

Spontaneous tension pneumocephalus (TPC) related to shunt surgery has sometimes been reported with reference to the Valsalva maneuver and osseous defects of the tegmen tympani. Here, the authors report on a case of TPC complicated by eustachian tube (ET) insufflation and a ventriculoperitoneal (VP) shunt. This 78-year-old man had undergone VP shunt insertion 3 weeks before readmission to the hospital with a diagnosis of TPC, a left temporal porencephalic cyst, and air accumulation and late leakage of cerebrospinal fluid (CSF) into the left tympanic cavity. The TPC was controlled successfully by ligation of the shunt tube. The authors discuss the pathophysiology of this complicated TPC case, which illustrates the risk of ET insufflation in patients undergoing CSF shunt surgery.

Subarachnoid hemorrhage in the presence of both intracranial dissecting and saccular aneurysms--two case reports.

Two patients presented with subarachnoid hemorrhage (SAH) associated with both intracranial dissecting and saccular aneurysms. Case 1, a 48-year-old woman, had a saccular aneurysm of the right internal carotid artery and dissecting aneurysms of the bilateral vertebral arteries. Case 2, a 52-year-old man, had three saccular aneurysms in the anterior circulation and a dissecting aneurysm of the unilateral vertebral artery. A saccular aneurysm was responsible for the SAH in both patients. Ruptured saccular aneurysms were treated with surgical clipping and unruptured dissecting aneurysms remained untreated. SAH recurred due to bleeding from an untreated dissecting aneurysm 4 days after the initial SAH in Case 1. Triple-H therapy, which causes increased hemodynamic stress, was not administered for symptomatic cerebral vasospasm after SAH in Case 2, because of the risk of bleeding from the untreated dissecting aneurysm, and the patient suffered cerebral infarction. The risk factors for this rare association are unclear, but both patients were smokers and had hypocholesterolemia including low apolipoprotein E levels. The clinical management of patients with SAH and both dissection and saccular aneurysms is complicated. Asymptomatic dissecting aneurysm has a benign clinical course in general, but hemodynamic stress related to stroke may induce abrupt development of dissecting aneurysms. Prophylactic obliteration during the acute stage of SAH may provide better outcomes if the unruptured dissecting lesion appears as obvious aneurysmal dilatation or pearl-and-string sign and is safely treatable with endovascular trapping.

Nationwide survey of the etiology and associated conditions of prenatally and postnatally diagnosed congenital hydrocephalus in Japan.

A nationwide survey in 2000 investigated the causative and associated central nervous system (CNS) lesions of congenital hydrocephalus in Japan. The etiology and associated diseases in 393 patients with congenital hydrocephalus were analyzed and compared between 193 patients with prenatally diagnosed (fetal) hydrocephalus and 181 with postnatally diagnosed (infantile) hydrocephalus. Of 393 patients of congenital hydrocephalus, 355 (90.3%) had primary hydrocephalus and 28 (7.1%) had secondary hydrocephalus. Of 355 patients with primary hydrocephalus, 85 (23.9%) had simple hydrocephalus associated with no other CNS anomaly and 270 (76.1%) had complicated hydrocephalus associated with other CNS anomalies. Destructive cystic lesions, holoprosencephaly, and agenesis of the corpus callosum were significantly predominant in fetal hydrocephalus. Arachnoid cyst was somewhat predominant in infantile hydrocephalus. The majority of cases of congenital hydrocephalus were primary hydrocephalus and two thirds were complicated hydrocephalus. Several complications showed marked predominance in fetal hydrocephalus.

Analysis of a nationwide survey on treatment and outcomes of congenital hydrocephalus in Japan.

A nationwide questionnaire survey of congenital hydrocephalus in 2000 investigated the treatment and clinical outcomes for congenital hydrocephalus in Japan to evaluate the factors influencing clinical outcome. Surgical treatment was performed in 341 of 380 patients who survived the early neonatal period. Of 321 patients who had shunt operations, 295 (91.9%) underwent ventriculoperitoneal shunting and nine (2.8%) ventriculoatrial shunting. Programmable valves were used in 83 (33.6%) of the 247 patients at the first shunting and in 97 (39.3%) at the last shunting. The incidence of complications after the first shunting was 55.4% (46 of 83 patients) in the programmable and 61.6% (101 of 164) in the non-programmable valve groups. The types of shunt complication differed significantly between these groups (p < 0.001), as the incidence of shunt infection and malfunction was lower in the programmable valve group. Clinical outcome was generally better with later delivery stage during gestation (p < 0.02). The clinical outcome was statistically significantly better in term patients who underwent early shunt placement than in those who underwent late shunt placement (p < 0.05).

Symptomatic hemorrhage associated with recurrent pilocytic astrocytoma with granulation tissue--case report.

A 51-year-old woman had been followed up for 10 years for recurrence of pilocytic astrocytoma 5 years after the initial treatment consisting of subtotal resection, chemotherapy, and radiation therapy. The patient presented with sudden onset of headache and vomiting. Computed tomography and T(2)*-weighted magnetic resonance imaging revealed hemorrhage in the tumor located in the right basal ganglia, thalamus, and hypothalamus. She underwent gross total resection of the lesion. Histological examination confirmed recurrent pilocytic astrocytoma with organizing hematoma and granulation tissue. Although neither symptomatic hemorrhage nor late benign recurrence is common, careful long-term follow up is necessary for patients with pilocytic astrocytoma.

Heavy water inhibiting the expression of transforming growth factor-beta1 and the development of kaolin-induced hydrocephalus in mice.

OBJECT: The authors investigated the effects of heavy water (D2O) on intrameningeal fibrosis and on the expression of cytokine production in mice with kaolin-induced hydrocephalus. METHODS: Mice in which kaolin was injected into the cisterna magna were divided into two groups: 1) Group H, which had free access to H2O as tap water; and 2) Group D, which had free access to 30% D2O as tap water before and after kaolin injection. A distilled water-injected group, which had free access to H2O as tap water was designated the sham-operated group. The authors examined the effects of D2O within 28 days after injection on the development of hydrocephalus and intrameningeal fibrosis, as well as on the expression levels of several inflammatory and fibrogenic cytokines: transforming growth factor-beta1 (TGFbeta1), fibroblast growth factor-2 (FGF2), platelet-derived growth factor (PDGF)-BB, and interleukin (IL)-6. The cerebral ventricles were less expanded, and intrameningeal fibrosis was milder in Group D than in Group H. The proliferation of fibroblasts was assessed by applying the bromodeoxyuridine labeling index, which was lower in Group D than in Group H. Expression of TGFbeta1 in the macrophages, choroid plexus, and meninges was inhibited in Group D but not in Group H. The serum level of total TGFbeta1 was significantly lower in Group D than in Group H on Day 14, whereas the levels of FGF2, PDGF-BB, and IL-6 did not differ significantly among the groups. CONCLUSIONS: Administration of D2O prevented the development of kaolin-induced hydrocephalus in mice and inhibited intrameningeal fibrosis and upregulation of TGFbeta1.

The role of cerebral cyst formation in the intractability of epilepsy.

OBJECTIVES: The aims of the present study were: (1) to examine single focal, intractable epilepsy associated with gliotic changes and (2) to discuss the mechanisms underlying seizure intractability. PATIENTS AND METHODS: Records of 34 patients with surgically treated intractable epilepsy were analysed retrospectively. Thirteen out of 34 patients had single epileptic focus histologically identified as a gliotic change. Seizure types, neuroradiological findings including the location and size of the foci, the hemosiderin deposition and calcification, intra-operative findings, and pathological findings of 13 patients were analysed in this study. Whether cyst formation was presented was also recorded. Tailored resections of epileptogenic lesions were performed using electrocorticography and ultrasonography. RESULTS: Cyst formations were observed in 10 out of 13 patients. In eight of the patients with cyst formation, seizures initially were well controlled, but the subsequent seizures increased in both severity and frequency in a stepwise manner. All patients with cyst formation became seizure free after the removal of the cyst wall and surrounding gliotic tissue. CONCLUSIONS: Analyses of the clinical courses, pathological and hydrodynamic findings suggest that the gliotic changes secondarily induced by cystic changes in brain parenchyma appear to play an important role in seizure intractability. We adapted the 'Starling resistor model' of hydrodynamics as a hypothetical model for the intracranial cyst and fluid passage to explain the mechanisms of the formation of epileptogenic gliotic changes.

The key to improving prognosis for aneurysmal subarachnoid hemorrhage remains in the pre-hospitalization period.

BACKGROUND: Despite advances in neurosurgical management, aneurismal subarachnoid hemorrhage (aSAH) still has high mortality and morbidity. This study aimed to clarify how delaying hospital admission after aSAH contributes to worse prognosis even today and to find the possibility for an improvement of its prognosis by early admission. METHODS: Four hundred twenty-one consecutive patients are the basis for this study. Cause of delay was classified into 5 categories: patient delay (PD), doctor delay (DD), transportation delay (TD), no delay (ND) (within 2 hours of onset), and others. Condition of each patient was assessed at time of onset and admission using H&K. The relationships between cause of delay and worsening of Hunt and Kosnik grading (H&K) were examined. RESULTS: The median delay time was 1.7 days. Only 41% of patients visited our institution without delay. Admission delay, especially PD and DD, exhibited a significant correlation to worsening of H&K. In addition to nondirect admission, misdiagnosis or delayed diagnosis contributed significantly to worsening of H&K. Incidence of DD has declined in recent years, whereas that of PD has increased. Consequently, no change in total number of delays was found. CONCLUSIONS: There remains much room for an improvement of prognosis for aSAH by early admission. We need to fully realize this reality and to directly face this problem.

[Clinical efficacy and cost benefit of oral antimicrobial prophylaxis with levofloxacin on neurological surgery].

OBJECTIVE: The clinical efficacy and cost benefit of oral antimicrobial prophylaxis with levofloxacin (LVFX) on neurosurgical operation were evaluated. PATIENTS AND METHODS: Fifty patients undergone burr hole drainage for chronic subdural hematoma were enrolled into this study. These patients had preoperative intravenous drip infusion of 1.0 g of cefazolin (CEZ), and were given oral 200 mg of LVFX twice a day for postoperative 6 days on their operations. Clinical effect on prophylaxis of postsurgical infection and surgical site infection as well as safeness of the drug were assessed. Their clinical course were retrospectively compared with another fifty patients as control group who had intravenous administration of CEZ for consecutive 7 days on same operation. RESULTS: There were no patients who had postsurgical infection and surgical site infection as well as drug related adverse effect, whereas three patients in control group suffered urinary infections or respiratory tract infection during their postsurgical course. CONCLUSIONS: Less invasive oral antimicrobial prophylaxis with LVFX is effective to prevent postoperative infections and surgical site infections, and attractive from the medical economic point of view.

Synergistic augmentation of antimicrotubule agent-induced cytotoxicity by a phosphoinositide 3-kinase inhibitor in human malignant glioma cells.

Because the aberrantly activated phosphoinositide 3-kinase (PI3K)/Akt pathway renders tumor cells resistant to cytotoxic insults, including those related to anticancer drugs, inhibition of the pathway may possibly restore or augment the effectiveness of chemotherapy. Using the human malignant glioma cell lines U87, A172, LN18, and LN229, we examined effects of the PI3K inhibitor LY294002 on both apoptosis and cytotoxicity induced by chemotherapeutic agents, including antimicrotubule agents vincristine and paclitaxel, an alkylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea, a topoisomerase II inhibitor etoposide, and a DNA cross-linking agent cisplatin (cis-diamminedichloroplatinum), and we compared the LY294002-induced enhancement of effects of those agents. Ten to 20 micro M LY294002 augmented both apoptosis and caspase 3-like activity caused by antimicrotubule agents to a larger extent than induced by 1,3-bis(2-chloroethyl)-1-nitrosourea, etoposide, and cisplatin in all four malignant glioma cell lines examined. The same doses of LY294002 enhanced cytotoxicity more efficiently with antimicrotubule agents than with other chemotherapeutic agents. Quantitative analyses using a modified isobologram and median effect plot method revealed that enhancement by LY294002 of vincristine- or paclitaxel-induced cytotoxicity was synergistic, whereas enhancement by the PI3K inhibitor of the other chemotherapeutic agent-induced cytotoxicity was additive. Our study indicates that the synergistic augmentation of the cytotoxicity by LY294002 occurs specifically with antimicrotubule agents, at least partially through an increase in caspase 3-dependent apoptosis, and we suggest that inhibitors of the PI3K/Akt pathway in combination with antimicrotubule agents may induce cell death effectively and be a potent modality to treat patients with malignant gliomas.

Epilepsy and variation in the frontal lobe artery.

A patient with a rare variation of fronto-orbital artery (FOA) that developed generalized tonic and clonic seizures is reported. The epilepsy focus was in her left frontal region, where blood was supplied by the contralateral fronto-orbital artery. The region was vulnerable to ischemic changes due to a decrease in blood CO2 gas caused by an increase in endogenous progesterone in the luteal period. The anomaly illustrates an important mechanism of ischemia in epilepsy.

Inhibitory effect of deuterium oxide on cerebral vasospasm after experimental subarachnoid hemorrhage in a rabbit model.

OBJECT: We wished to determine the inhibitory effect of deuterium oxide (D(2)O) on cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH). METHODS AND RESULTS: An established rabbit single-hemorrhage was used. Thirty-five rabbits were randomly divided into four groups: non-treatment, sham control, lower-D(2)O, and higher-D(2)O treatment groups. Angiography was performed before (day 0) and after (day 2) SAH and the CVS ratio was calculated by comparing the diameter of the basilar artery (BA) on day 2 with that on day 0. After death, blood clot volume was assessed and the BA was dissected from the brain for histological examination. The CVS ratio in D(2)O-treatment groups was significantly higher in comparison with that in non-treatment and sham control groups (p < 0.0001). Furthermore, the volume of blood clot around the BA was reduced significantly in D(2)O-treatment groups, compared with those in both the non-treatment and the sham control groups (p < 0.05). Histological examination showed that the BA represented less folding of the internal elastic lumina in D(2)O-treatment groups, while a corrugation of the intima with the thickened vessel wall was seen in both the non-treatment and sham control groups. CONCLUSION: Therapeutic administration of D(2)O into the cisterna magna exhibited an inhibitory effect on CVS after SAH in rabbits.

Unusual variant of the anterior cerebral artery.

A rare abnormality of the A1 segment of the anterior cerebral artery (ACA) is reported. The right ACA bifurcated into two parts at the middle point of the A1 segment, and these segments did not rejoin. The superior right A1 segment connected with the left A1 and formed a single pericallosal artery. The inferior right A1, from which the right ophthalmic artery originated, had no connection with the left A1.

Supratentorial primitive neuroectodermal tumor in an aged patient--case report--.

An 88-year-old woman presented with a supratentorial primitive neuroectodermal tumor (PNET) manifesting as disturbance of consciousness and left hemiplegia. Magnetic resonance imaging showed a large mass lesion in the right frontotemporal region. She underwent biopsy of the lesion that confirmed the diagnosis of PNET. Her poor condition only allowed chemotherapy with methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU), vincristine, and prednisolone to be performed. The patient died approximately 6 months after diagnosis due to enlargement of the tumor. Supratentorial PNET is a rare tumor, especially in adults. Multimodal therapy consisting of gross total or subtotal resection, radiation therapy, and chemotherapy is generally considered necessary for patients with supratentorial PNET. However, the condition of each patient should be considered in determining the therapeutic plan, especially in the case of extremely aged patients, since supratentorial PNET is malignant and long-term survival is rare despite aggressive treatment.