Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance.

AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

Time-of-Flight MR Angiography for Detection of Cerebral Hyperperfusion Syndrome after Superficial Temporal Artery-Middle Cerebral Artery Anastomosis in Moyamoya Disease.

BACKGROUND AND PURPOSE: Cerebral hyperperfusion syndrome is a potential complication of superficial temporal artery-MCA anastomosis for Moyamoya disease. In this study, we evaluated whether TOF-MRA could assess cerebral hyperperfusion syndrome after superficial temporal artery-MCA anastomosis for this disease. MATERIALS AND METHODS: This retrospective study included patients with Moyamoya disease who underwent superficial temporal artery-MCA single anastomosis. TOF-MRA and SPECT were performed before and 1-6 days after anastomosis. Bilateral ROIs on the source image of TOF-MRA were manually placed directly on the parietal branch of the superficial temporal artery just after branching the frontal branch of the superficial temporal artery and on the contralateral superficial temporal artery on the same axial image, respectively. The change ratio of the maximum signal intensity of the superficial temporal artery on TOF-MRA was calculated by using the following formula: (Postoperative Ipsilateral/Postoperative Contralateral)/(Preoperative Ipsilateral/Preoperative Contralateral). RESULTS: Of 23 patients (26 sides) who underwent the operation, 5 sides showed cerebral hyperperfusion syndrome postoperatively. There was a significant difference in the change ratio of signal intensity on TOF-MRA observed between the cerebral hyperperfusion syndrome and non-cerebral hyperperfusion syndrome groups (cerebral hyperperfusion syndrome group: 1.88 ± 0.32; non-cerebral hyperperfusion syndrome group: 1.03 ± 0.20; P = .0009). The minimum ratio value for the cerebral hyperperfusion syndrome group was 1.63, and the maximum ratio value for the non-cerebral hyperperfusion syndrome group was 1.30. Thus, no overlap was observed between the 2 groups for the change ratio of signal intensity on TOF-MRA. CONCLUSIONS: Diagnosis of cerebral hyperperfusion syndrome is indicated by an increase in the change ratio of signal intensity on TOF-MRA by more than approximately 1.5 times the preoperative levels.

Role of surgery, radiotherapy and chemotherapy in papillary tumors of the pineal region: a multicenter study.

Papillary tumor of the pineal region (PTPR), recently described as a distinct clinicopathological entity, can show aggressive biological behavior. The optimal therapeutic approach of PTPR has not been well defined. The role of surgery, radiotherapy, and chemotherapy in the treatment of PTPR was analyzed in a large multicenter series. In order to determine factors that influence prognosis, outcome data of a series of 44 patients with histopathologically proven PTPR were retrospectively analyzed. Of the 44 patients, 32 were still alive after a median follow-up of 63.1 months. Twelve patients experienced progressive disease, with seven undergoing two relapses and five more than two. Median overall survival (OS) was not achieved. Median progression-free survival (PFS) was 58.1 months. Only gross total resection and younger age were associated with a longer OS, radiotherapy and chemotherapy having no significant impact. PFS was not influenced by gross total resection. Radiotherapy and chemotherapy had no significant effect. This retrospective series confirms the high risk of recurrence in PTPR and emphasizes the importance of gross total resection. However, our data provide no evidence for a role of adjuvant radiotherapy or chemotherapy in the treatment of PTPR.

Preoperative evaluation of the deep cerebral veins using 3-tesla magnetic resonance imaging.

BACKGROUND: Surgical treatment of deep-seated tumors such as supratentorial intraventricular and thalamic-pineal-tectal region tumors carries a risk of postoperative deficits due to possible damage to deep cerebral veins including the internal cerebral vein. It is often difficult to identify whether the vessel encountered during surgery needs to be preserved or not through the small operative field. Therefore, preoperative evaluation of deep venous structures is important. We evaluated the usefulness of 3-Tesla magnetic resonance imaging (3 T MRI) for this purpose. METHODS: First, the ability to detect deep venous structures was compared with both 3-dimensional computed tomographical angiography (3D-CTA) and 3 T MRI in patients without any damage to deep venous structures. Images of 7 consecutive patients suffering from insulo-opercular gliomas who underwent both imaging modes for the identification of lateral striate arteries were reconstructed for evaluation of the deep cerebral veins. Subsequently, surgery for tumors at the supratentorial intraventricular and thalamic-pineal-tectal regions was prospectively performed with preoperative evaluation of deep venous system only using 3 T MRI. RESULTS: Information on the deep venous systems acquired by 3 T MRI was as useful as that acquired by 3D-CTA. Until today, we have treated 8 cases of supratentorial intraventricular and thalamic-pineal-tectal region tumors with preoperative evaluation of the deep venous system using 3 T MRI without any morbidity. CONCLUSION: Information on the deep venous system obtained with 3 T MRI aids the surgery of supratentorial intraventricular and thalamic-pineal-tectal region tumors. As the required sequences of 3 T MRI are same as those necessary for the neuronavigation system, and 3 T MRI can be achieved without the use of iodine-based contrast agents, 3 T MRI can be an alternative for preoperative evaluation of the deep venous systems.

Chlorination by-products of fenitrothion.

The mutagens produced through chemical reaction between chlorine and the insecticide fenitrothion were studied by using a quadrupole GC-MS. The mutagenicity and the mutagen formation potential (MFP) of the identified by-products were evaluated by the Ames assay (preincubation method) using Salmonella typhimurium TA100 without exogenous activation by S9 mix (TA100-S9). Before conducting GC/MS analyses, six compounds were presumed to be produced in chlorinated fenitrothion. These compounds were confirmed to be produced by the GC/MS analyses, but none of them were mutagenic. One of the chlorination by-products, 3-methyl-4-nitrophenol, has 19 times greater MFP than that of fenitrothion. This result suggests that a major mutagen in chlorinated fenitrothion will be produced via a chemical reaction between chlorine and 3-methyl-4-nitrophenol.

Virtually peeling off the skull and scalp: a simple way of mapping the superficial cerebral veins on the brain surface.

PURPOSE: A simple MRI postprocessing technique was developed to display superficial cerebral veins (SCVs) along with brain surface structures. MATERIALS AND METHODS: Thirty-one consecutive patients with brain tumors were studied. All patients underwent brain MR examination, from which three-dimensional (3D) images were reconstructed. Simulation images of craniotomy were created by cutting away the signal from the skull and scalp at the region corresponding to the window planned for surgery. Detectability of the SCVs was evaluated by comparing the simulation images with intraoperative photographs. Reasons for those undetectable SCVs on simulation images of craniotomy were discussed. RESULTS: Detectability of the SCVs >2 mm was 100%; those from 1 to 2 mm was 88.5%, and those from 0.5 to 1 mm 56.9%. Effacement of cortical sulci/subarachnoid space around the supposed craniotomy site, dural/meningeal contrast enhancement and insufficient spatial resolution of the source images were regarded as the main reasons for undetectable SCVs. CONCLUSION: Virtually peeling off the skull and scalp well demonstrates the SCVs along with brain surface structures. This simple technique can provide useful information about the SCVs and their relationships with cortical structures and tumors for preoperative surgical planning.

Primary CNS lymphoma treated with combined intra-arterial ACNU and radiotherapy.

OBJECT: To assess whether nimustine (ACNU), a drug that can cross the blood brain barrier, combined with radiotherapy, improved the survival of patients with primary central nervous system lymphoma (PCNSL). CLINICAL MATERIALS AND METHODS: Between 1995 and 2005, we treated 63 immunocompetent PCNSL patients with combination therapy consisting of intra-arterial ACNU (100 mg/m(2)) and whole brain radiotherapy (36-50 Gy). Their median age was 60 years (range 28-81). The median follow-up was 24 months. FINDINGS: With this regimen we achieved a complete response rate of 75% (43 of 57 patients). Kaplan-Meier estimates for median progression-free survival and median overall survival were 26 and 39 months, respectively. The 3- and 5-year survival rates were 51% (95% confidence interval [CI], 36-65%) and 32% (95% CI, 17-47%), respectively. By multivariate analysis, age (<60 vs. > or =60 years) was the only statistically significant prognostic factor; the WBRT dose, sex, and number of tumors were not significant prognostic factors in this study. Myelosuppression was the most frequent side effect, 60% of patients experienced grade 3-4 leukopenia. Late neurotoxicity as a result of treatment was observed in 14 of 43 patients (34%) and higher age (>60) was associated with a high risk of neurotoxicity. CONCLUSION: The intra-arterial administration of ACNU combined with radiation therapy yielded a high response rate at acceptable toxicity levels in younger patients with PCNSL. However, late neurotoxicity was a serious complication in patients above 60 years of age.

Modified surgical technique for the treatment of idiopathic spinal cord herniation.

OBJECTIVE AND IMPORTANCE: Spinal cord herniation is not a common disease and only 80 cases have been reported to the best of our knowledge. The treatment of this lesion is thought to be difficult and a better surgical technique has not been established. CLINICAL PRESENTATION: A 57-year-old man presented with gradually worsening spastic gait and hypoesthesia in the bilateral lower extremities suspected to be due to Brown-Séquard syndrome. Magnetic resonance imaging showed a thoracic spinal cord herniation into the anterior hiatus at T2 - 3. INTERVENTION: A modified technique of closure of the hiatus in front of the herniation was performed. A surgical artificial dural membrane was introduced between the herniated portion of the thoracic cord and the dural hiatus and was placed to cover the whole dural defect in order to minimize the operative procedure at the ventral side of the spinal cord. On subsequent magnetic resonance imaging, the herniation was remarkably improved and patient's symptoms were abolished. CONCLUSION: The direct widening of the dural defect has been reported to be the only treatment providing a good outcome. We suggest that our modified technique for its closure can be as safe and effective as the direct widening method.

Malignant transformation of pleomorphic xanthoastrocytoma.

A 31-year-old woman presented with a pleomorphic xantho-astrocytoma (PXA) manifesting as epilepsy. The tumour was partially resected. Histological examination revealed cellular pleomorphism and cytoplasmic vacuolation consistent with PXA, but no mitoses, necrosis, or endothelial proliferation. Follow-up neuro-imaging showed the residual tumour had grown rapidly with dissemination in the spinal cord. The recurrent lesion was totally resected and was shown to be glioblastoma. The patient has survived without signs of recurrence for 36 months after adjuvant radiochemotherapy. The biological behaviour of PXA cannot be predicted based on the histological features and careful follow up is essential.

Stereotactic radiosurgery followed by whole ventricular irradiation for primary intracranial germinoma of the pineal region.

Intracranial germinomas can be cured by radiotherapy and/or chemotherapy. Three patients with pineal germinoma were treated with stereotactic radiosurgery using the gamma knife (10 - 12 Gy) to the tumors followed by whole ventricular irradiation (24 Gy). All patients had solitary pineal tumor measuring less than 3 cm, clinically compatible with germinoma, normal cerebrospinal fluid (CSF) and serum levels of alpha-fetoprotein and beta-human chorionic gonadotropin, no disseminated disease on spinal magnetic resonance (MR) imaging, and no abnormal CSF cytology. All patients showed complete response to the combined radiotherapy, and MR imaging has shown no recurrence of the tumor. Combined radiotherapy using gamma knife radiosurgery is effective for pineal germinoma, and reduced the cost of treatment with less need for hospitalization.

Intraoperative localisation of the lip sensory area by somatosensory evoked potentials.

Accurate localisation of the central sulcus enables maximum tumour resection with minimum morbidity in peri-Rolandic surgery. We investigated intraoperative somatosensory evoked potentials (SSEPs) with combined recording of lower lip and median nerve stimuli during craniotomy in nine patients with peri-Rolandic glioma. Using a custom clip electrode, the lip mucous membrane was stimulated with biphasic pulses with 0.2 ms duration, 10-14 mA intensity and a frequency of 0.7 Hz. Polarity inversion of the SSEP was detected across the central sulcus using median nerve and/or lower lip stimulation in eight of the nine patients in whom the tumour did not infiltrate the lip or hand sensory area. Recording of SSEPs with lower lip stimulation is useful if the resection margin is planned lateral to the hand representation area, if the hand representation area is not exposed by the craniotomy, or if the SSEPs for median nerve stimulation are not clear due to tumour infiltration.

Atypical teratoid/rhabdoid tumour with leptomeningeal dissemination in an adult.

A 22-year-old man presented with a rare case of atypical teratoid/rhabdoid tumour (AT/RT). Magnetic resonance imaging showed a left cerebellar mass with leptomeningeal dissemination. Partial resection was performed. Histological examination revealed AT/RT. Postoperatively, whole neuraxis and local irradiation were performed. Three-drug chemotherapy with ifosfamide, cisplatin, and etoposide, and adjuvant intrathecal administration of methotrexate were repeated. Near complete response was achieved, and no tumour recurrence/progression has been noticed during the follow up of 24 months. Intensive radiochemotherapy can successfully control AT/RT, even with leptomeningeal dissemination.

Combined three-dimensional anisotropy contrast imaging and magnetoencephalography guidance to preserve visual function in a patient with an occipital lobe tumor.

OBJECTIVE: Three-dimensional anisotropy contrast (3-DAC) magnetic resonance imaging and magnetoencephalography (MEG) of visually evoked magnetic fields (VEFs) were used to accurately localize the optic radiation and primary visual cortex before surgery for an occipital tumor. PATIENT AND METHODS: A 26-year-old male presented with an occipital lobe tumor located intrinsically underneath the right calcarine fissure. 3-DAC imaging showed that the right optic radiation was located along the superior and lateral surfaces of the lesion. Mapping of the VEFs demonstrated that the primary visual cortex was located superior and lateral to the lesion. The lesion was totally resected via an infero-medial cortical incision using a frameless stereotactic system. Histopathology indicated a pilocytic astrocytoma. No visual deficit was found before or after surgery. CONCLUSION: Combined 3-DAC imaging and MEG can provide essential information about the optic radiation and primary visual cortex for planning the surgical treatment of occipital lobe tumors.

Routine clinical adoption of magnetic resonance imaging was associated with better outcome after surgery in elderly patients with a malignant astrocytic tumour: a retrospective review.

BACKGROUND: There is controversy about extensive surgical treatment for a malignant astrocytic tumour in more elderly patients who may have poorer outcomes and higher complication rates. This retrospective study investigated outcome in elderly patients with malignant astrocytic tumour before and after the adoption of routine clinical use of magnetic resonance (MR) imaging. METHODS: During 1982 through 1999, 88 patients with malignant astrocytic tumour aged 60 years or over were treated in our institute. Thirty-seven patients had an anaplastic astrocytoma and 51 had a glioblastoma. Thirty-seven patients treated from 1982 to 1988 did not have pre-operative evaluation by MR imaging (Group A), 26 patients treated from 1989 to 1995 had preoperative MR imaging evaluation (Group B), and 25 patients treated after 1996 underwent preoperative MR imaging with functional brain mapping and intra-operative navigation system monitoring (Group C). FINDINGS: The median survival time was 8.8 months in Group A, 12.7 months in Group B, and 17.6 months in Group C. Patients with glioblastoma in Group B (11.7 months, n = 15) and Group C (16.0 months, n = 19) had significantly longer median survival time than in Group A (6 months, n = 17) (P = 0.0054 between Groups A and B, P = 0.0024 between Groups A and C). Better preoperative performance status, more thorough surgical resection, and better performance status after the initial treatment was obtained after the introduction of MR imaging, and patients with the optimal indicators showed significantly longer survival time compared with the patients without these factors. INTERPRETATION: Pre-operative MR imaging may contribute to longer survival time by providing an earlier diagnosis in patients with better performance status, by allowing more thorough surgical resection, and resulting in better performance status after the treatment.

Stereotactic radiosurgery for nodular dissemination of anaplastic ependymoma.

Dissemination of primary intracranial ependymoma occurs in 10% of all cases and is difficult to treat, so this may be one of the major reasons for the poor prognosis. Two patients with nodular dissemination of anaplastic ependymoma were treated with repeated stereotactic radiosurgery using the gamma knife (GK), resulting in tumour control over 21 months. GK radiosurgery is a safe and effective treatment option for providing good local control in patients with nodular dissemination of ependymoma.

Neurohypophyseal germinoma histologically misidentified as granulomatous hypophysitis.

We report a case of neurohypophyseal germinoma appearing as predominantly granulomatous reaction in the first histological examination. A 12-year-old boy presented with diabetes insipidus, panhypopituitarism, and bitemporal hemianopsia. Transsphenoidal exploration for the intrasellar mass lesion extending to the suprasellar region was performed in May 1999. Histological examination revealed granulomatous hypophysitis and corticosteroid therapy was initiated. Six months later, the lesion relapsed despite corticosteroid therapy. Subtotal removal of the lesion was performed via an anterior interhemispheric approach in December 1999. Histological examination revealed typical germinoma. Subsequently, the patient underwent irradiation of 20 Gy to the tumour site and 24 Gy to the whole brain. Magnetic resonance imaging confirmed tumour remission. We must consider the possibility of neurohypophyseal germinoma in patients with granulomatous hypophysitis which does not respond to corticosteroid therapy, and perform re-exploration for more specimens to achieve the correct diagnosis.

Recurrent intracranial germinoma outside the initial radiation field with progressive malignant transformation.

A 19-year-old man with a pure germinoma in the pineal region was successfully treated with chemotherapy followed by 24 Gy local irradiation. Eight months later, magnetic resonance (MR) imaging detected ventricular wall dissemination outside the radiation field. Near complete response was achieved again after 28.8 Gy whole brain and 24 Gy whole spine irradiation. Two months later, MR imaging demonstrated recurrence of a mass at the corpus callosum. Gamma knife radiosurgery did not control this mass, so tumour resection was performed. Histological examination revealed immature teratoma. Enlargement of the recurrent mass at the trigone of the left lateral ventricle was found in spite of additional chemotherapy. Tumour extirpation was performed and histological examination revealed embryonal carcinoma. The patient died of tumour progression 34 months after the initial treatment. By a combination of chemotherapy regiments in use today, the initial radiation field to treat intracranial germinomas should not be confined to the tumour bed.

Surgical treatment of a mixed pineocytoma/pineoblastoma in a 72-year-old patient.

BACKGROUND: Although pineal parenchymal tumours are very rare in elderly patients, we recently successfully treated a 72-year-old male patient. Interestingly, the histology of his pineal parenchymal tumour was mixed pineocytoma/pineoblastoma, which is reported to be extremely rare in aged patients. We present his clinical manifestations, follow-up MRI, surgical treatment, pathological findings, and review the literature. CLINICAL MATERIAL: This 72-year-old man had a mass in the pineal region detected 3 years previously on MRI in February 1996 following symptoms of headache and vertigo. Two years later, he experienced gait disturbance and disorientation. CT scans disclosed obstructive hydrocephalus, and ventriculo-peritoneal shunt placement was then performed. The tumour mass began to enlarge in July 1999 (at age 72). On October 13, 1999, total removal of the pineal region tumour was performed through an occipital transtentorial approach. The postoperative course was uneventful. The pathological diagnosis of the tumour was mixed pineocytoma/pineoblastoma. CONCLUSION: Pineal parenchymal tumours are uncommon in elderly patients, and mixed pineocytoma/pineoblastomas are particularly rare. We followed this patient closely for more than 3.5 years and finally performed total surgical removal of the tumour, with excellent outcome. The present case suggests that a mixed pineocytoma/pineoblastoma tumour is controllable even in elderly patients through careful evaluation and management.

(201)Tl-SPECT, (1)H-MRS, and MIB-1 labeling index of central neurocytomas: three case reports.

BACKGROUND: The proliferative activity and metabolic features of three central neurocytomas were investigated using the findings of thallium-201 single photon emission computed tomography ((201)Tl-SPECT) and proton magnetic resonance spectroscopy ((1)H-MRS), and the MIB-1 labeling index (MIB-1 LI). METHOD: The early and delayed (201)Tl indices were calculated as the ratio of tumour to normal brain tissue uptake by (201)Tl-SPECT. In vivo single-voxel (1)H-MRS was performed with echo time of 272 msec to evaluate the metabolites including choline (Cho), N-acetyl aspartate (NAA) and creatine/phosphocreatine (Cre). An external standard reference was used to semiquantitate each metabolite. MIB-1 LI was determined in the surgical specimens. FINDINGS: The MIB-1 LI was 0.5%, 1.2%, and 7.5% in an atypical central neurocytoma without intraventricular extension. Significant (201)Tl uptake was observed on delayed images in all three central neurocytomas. (1)H-MRS showed the high Cho peaks relative to the NAA and Cre peak. The signal at 3.55 ppm, which may be due to inositol or glycine, was observed in one central neurocytoma. INTERPRETATION: Both (201)Tl-SPECT and (1)H-MRS did not reflect the proliferative potential of central neurocytomas.