Photodynamic therapy using talaporfin sodium for non-totally resectable malignant glioma.

BACKGROUND: For malignant glioma, intraoperative photodynamic therapy (PDT) using talaporfin sodium is a powerful tool for local tumor control, when gross total removal is performed. However, the efficacy of PDT for non-totally resectable malignant glioma has not been clearly confirmed. Therefore, the purpose of this study was to clarify the usefulness of PDT using talaporfin sodium for non-totally resectable malignant glioma. METHODS: Eighteen patients with malignant glioma (16 new onset, 2 recurrent) in whom gross total removal was judged to be difficult from the images obtained before surgery were evaluated. Fifteen patients had glioblastoma (14 newly diagnosed, 1 recurrent), and 3 patients had anaplastic oligodendroglioma (2 newly diagnosed, 1 recurrent). The whole resection cavity was subjected to PDT during the surgery. For newly diagnosed glioblastoma, postoperative therapy involved the combined use of radiation and temozolomide. Bevacizumab treatment was also started at an early stage after surgery. RESULTS: In some patients, reduction of the residual tumor was observed at an early stage of chemoradiotherapy after the surgery, suggesting the positive effect of PDT. Recurrence occurred in 15 of the 18 patients during the course of treatment. Distant recurrence occurred in 8 of these 15 patients, despite good local tumor control. In the 14 patients with newly diagnosed glioblastoma, the median progression-free survival was almost 10.5 months, and the median overall survival was almost 16.9 months. CONCLUSIONS: PDT for malignant glioma is expected to slightly improve local tumor control for non-totally resectable lesions.

Efficacy of interstitial photodynamic therapy using talaporfin sodium and a semiconductor laser for a mouse allograft glioma model.

To investigate the therapeutic potential of photodynamic therapy (PDT) for malignant gliomas arising in unresectable sites, we investigated the effect of tumor tissue damage by interstitial PDT (i-PDT) using talaporfin sodium (TPS) in a mouse glioma model in which C6 glioma cells were implanted subcutaneously. A kinetic study of TPS demonstrated that a dose of 10 mg/kg and 90 min after administration was appropriate dose and timing for i-PDT. Performing i-PDT using a small-diameter plastic optical fiber demonstrated that an irradiation energy density of 100 J/cm2 or higher was required to achieve therapeutic effects over the entire tumor tissue. The tissue damage induced apoptosis in the area close to the light source, whereas vascular effects, such as fibrin thrombus formation occurred in the area slightly distant from the light source. Furthermore, when irradiating at the same energy density, irradiation at a lower power density for a longer period of time was more effective than irradiation at a higher power density for a shorter time. When performing i-PDT, it is important to consider the rate of delivery of the irradiation light into the tumor tissue and to set irradiation conditions that achieve an optimal balance between cytotoxic and vascular effects.

Pathology for severe inflammatory PML with PD1/PD-L1 expression of favorable prognosis: What's a prognostic factor for PML-IRIS?

A 72-year-old woman with dermatomyositis (DM) developed neurological manifestation, and magnetic resonance imaging (MRI) revealed multiple T2/fluid-attenuated inversion recovery (FLAIR)-hyperintense lesions predominantly in the deep white matter of the cerebral hemisphere. Punctate or linear contrast enhancement was observed surrounding the T1-hypointense area. Multiple T2/FLAIR-hyperintense lesions were aligned along with the corona radiata. Malignant lymphoma was first suspected, and a brain biopsy was performed. Pathological investigation suggested the provisional diagnosis of "suspicious of malignant lymphoma." Owing to emergent clinical conditions, high-dose methotrexate (MTX) therapy was conducted, and then T2/FLAIR-hyperintense lesions were dramatically reduced. However, the diagnosis of malignant lymphoma was concerning since multiplex PCR demonstrated clonal restriction of the Ig H gene for B cells and TCR beta genes for T cells. Histopathology revealed the infiltration of both CD4+ and CD8+ T cells, and the CD4+ /CD8+ ratio was 4.0. Moreover, prominent plasma cells were observed, in addition to CD20+ B cells. Atypical cells with enlarged nuclei were present, and they were not hematopoietic but found as glial cells. JC virus (JCV) infection was verified with both immunohistochemistry and in situ hybridization; the final diagnosis was progressive multifocal leukoencephalopathy (PML). The patient was treated with mefloquine and discharged. This case is informative in understanding the host anti-viral response. Variable inflammatory cells were observed, including CD4+ and CD8+ T cells, plasma cells, and a small amount of perivascular CD20+ B cells. PD-1 and PD-L1 expression was observed in lymphoid cells and macrophages, respectively. PML with inflammatory reactions was thought fatal, and autopsy cases of PML with immune reconstitution inflammatory syndrome (IRIS) demonstrated excessive infiltration of only CD8+ T cells. However, this case revealed infiltration of variable inflammatory cells, and a favorable prognosis would be expected under PD-1/PD-L1 immune-checkpoint regulation.

Patient with Diffuse Midline Glioma, H3 K27-altered, Carrying an FGFR1 Mutation Who Experienced Thalamic Hemorrhage: A Case Report and Literature Review.

Diffuse midline glioma (DMG), H3 K27M-altered, is a tumor with a poor prognosis mainly found in children. An adolescent patient presented with thalamic hemorrhage, which initially could not be diagnosed as DMG by pathological analysis. A neoplasm in the lateral ventricle close to the previous thalamic hemorrhagic lesion was detected 12 months after the hemorrhage. Thus, endoscopic resection was performed, and a diagnosis was made. Gene expression profiling demonstrated mutation in genes, such as H3F3A and FGFR1. FGFR1 mutation was associated with intratumoral hemorrhage in low-grade gliomas and contributed to longer survival than wild-type FGFR1 in DMG H3K27M. Our findings suggest that patients with DMG, H3 K27-altered, with FGFR1 mutation may be predisposed to intratumoral hemorrhaging and/or have a longer survival time than patients without FGFR1 mutation.

First Clinical Report of the Intraoperative Macro- and Micro-Photodiagnosis and Photodynamic Therapy Using Talaporfin Sodium for a Patient with Disseminated Lumbar Medulloblastoma.

Photodiagnosis (PD) and photodynamic therapy (PDT) using the second-generation photosensitizer talaporfin sodium together with an exciting laser for primary intracranial malignant tumors is well recognized in Japan, and many medical institutions are introducing this new therapeutic option. In particular, intraoperative PDT using talaporfin sodium for infiltrating tumor cells in the cavity walls after the resection of malignant glioma is now covered by health insurance after receiving governmental approvement, and this method has been recommended in therapeutic guidelines for primary malignant brain tumors in Japan. On the other hand, experimental and clinical studies on the development of novel therapeutic strategies for malignant spinal cord tumors have not been reported to date, although their histological features are almost identical to those of intracranial malignant tumors. Therefore, the clinical outcomes of malignant spinal cord tumors have been less favorable than those of malignant brain tumors. In this report, we performed the PD and PDT using talaporfin sodium on a patient with a metastatic lumbar lesion that was detected on magnetic resonance image (MRI) 50 months after the resection of cerebellar medulloblastoma who presented with lumbago and sciatica. We were able to detect the target lesion in the conus medullaris using a surgical microscope, and detected the disseminated medulloblastoma cells floating in the cerebrospinal fluid using a compact fluorescence microscope. Furthermore, we performed PDT to the resected lumbar lesion with the adjuvant platinum-based chemotherapy, and the patient survived a meaningful life for more than 2 years after the lumbar surgery. This report describes the first case of a human patient in whom the efficacy of PD and PDT was demonstrated for a malignant spinal cord tumor.

A Case of Primary Central Nervous System Lymphoma That Developed in a Patient Receiving Fingolimod Therapy for Multiple Sclerosis.

Fingolimod is an oral medication for the prevention of multiple sclerosis relapse, and its efficacy has been demonstrated in several clinical trials. Fingolimod has various side effects, such as arrhythmia and hepatic dysfunction. In addition, there have been rare reports of the development of lymphoproliferative disorders in patients undergoing fingolimod therapy, including primary central nervous system lymphoma (PCNSL). We diagnosed and treated a multiple sclerosis patient who developed PCNSL while undergoing fingolimod therapy. Fourteen months after starting fingolimod therapy, the patient developed aphasia, and underwent biopsy analysis for a lesion displaying a homogeneous gadolinium-enhanced lesion in the left frontal lobe. The lesion was diagnosed as diffuse large B-cell lymphoma by pathological examination. After the diagnosis, the patient received chemotherapy together with methotrexate combination therapy, and the lesion became smaller and the patient's symptoms improved. Although several autopsy cases of PCNSL in patients who received fingolimod therapy have been reported, there have been few reports to date of patients diagnosed by biopsy analysis.

Preliminary Report: Rapid Intraoperative Detection of Residual Glioma Cell in Resection Cavity Walls Using a Compact Fluorescence Microscope.

OBJECTIVE: The surgical eradication of malignant glioma cells is theoretically impossible. Therefore, reducing the number of remaining tumor cells around the brain-tumor interface (BTI) is crucial for achieving satisfactory clinical results. The usefulness of fluorescence-guided resection for the treatment of malignant glioma was recently reported, but the detection of infiltrating tumor cells in the BTI using a surgical microscope is not realistic. Therefore, we have developed an intraoperative rapid fluorescence cytology system, and exploratorily evaluated its clinical feasibility for the management of malignant glioma. MATERIALS AND METHODS: A total of 25 selected patients with malignant glioma (newly diagnosed: 17; recurrent: 8) underwent surgical resection under photodiagnosis using photosensitizer Talaporfin sodium and a semiconductor laser. Intraoperatively, a crush smear preparation was made from a tiny amount of tumor tissue, and the fluorescence emitted upon 620/660 nm excitation was evaluated rapidly using a compact fluorescence microscope in the operating theater. RESULTS: Fluorescence intensities of tumor tissues measured using a surgical microscope correlated with the tumor cell densities of tissues evaluated by measuring the red fluorescence emitted from the cytoplasm of tumor cells using a fluorescence microscope. A "weak fluorescence" indicated a reduction in the tumor cell density, whereas "no fluorescence" did not indicate the complete eradication of the tumor cells, but indicated that few tumor cells were emitting fluorescence. CONCLUSION: The rapid intraoperative detection of fluorescence from glioma cells using a compact fluorescence microscope was probably useful to evaluate the presence of tumor cells in the resection cavity walls, and could provide surgical implications for the more complete resection of malignant gliomas.

Clinical application of the mirror irradiation technique in photodynamic therapy for malignant glioma.

BACKGROUND: Intraoperative photodynamic therapy (PDT) using talaporfin sodium for malignant glioma is effective both in the experimental and in the clinical setting. Because the irradiation unit is fixed to the objective lens of the operating microscope, blind spots for irradiation exist. To overcome this problem, we developed a mirror reflecting system using a modified dental mirror. METHODS: The developed mirror is made of stainless steel, has a mirror-polished surface, and is rhodium coated on 1 side, which is the reflecting surface. The reflection rate was measured using He-Ne laser irradiation. The reflection intensity was measured using a laser power meter when the incident angle to the mirror was changed to 60°, 45°, and 30°, and the reflectance was calculated by the direct received light intensity from the laser. After confirming the safety of the fundamental experiment, PDT was performed with this developed mirror on 9 patients with malignant glioma (4 with recurrence and 5 newly diagnosed). RESULTS: The energy efficiency of the mirror was approximately 70 %, and apparent irregular reflection was not observed. Even during clinical use, apparent complications, such as irregular reflection, did not occur upon using the mirror in any of the patients. In all patients, recurrence did not occur in the site where mirror irradiation was performed, but in a deep site or a distant site to which sufficient laser irradiation did not reach. CONCLUSION: PDT using our newly developed mirror involves few instrumental changes compared with the conventional irradiation method, and is effective, safe, and inexpensive.

Salvage carbon ion radiotherapy for recurrent solitary fibrous tumor: A case report and literature review.

BACKGROUND: Malignant solitary fibrous tumor (MSFT) arising from the spinal cord is extremely rare and poorly understood mesenchymal neoplasms: only a few MSFT in the spinal canal has been described. We describe the clinical course of the patient with MSFT arising from the thoracic spinal cord. CASE REPORT: We describe the clinical course of the patient and the radiological and pathological findings of the tumor. The tumor had been resected by microscopic posterior approach and video-assisted thoracic surgery, but local recurrence was observed by MRI at 1-year follow-up period. No metastatic lesion was confirmed. Then, carbon ion radiotherapy (CIRT) was administered to the recurrent lesion. Local suppression has been observed for 40 months after irradiation. CONCLUSION: Dumbbell-shaped MSFT arising from thoracic spinal cord is a highly unusual presentation. CIRT might be effective for treatment of recurrent tumors.

Diffused light attenuation at 664 nm for PDT in salted cadaver brain.

BACKGROUND: We investigated light attenuation at 664 nm, which is the excitation wavelength of photodynamic therapy (PDT) using talaporfin sodium, in a salted cadaver brain. Estimation of therapeutic lesions is important to ensure the effectiveness and safety of brain tumor PDT. Previously reported optical properties of the human brain vary widely. In this study, we measured the light attenuation in brain tissue using a practical method. We employed a salted cadaver brain, in which the mechanical and optical properties can be maintained as close as possible to those under operative conditions. METHODS: A neuroendoscope was inserted into the brain until the cerebral ventricle was reached. A thin cylindrical diffuser probe was advanced 10 mm from the endoscope tip. By another path from the brain surface, an optical fiber for measurement was inserted into a puncture needle, and a pair of needles was used to puncture the tissue and reach the same cerebral ventricle in which the endoscope tip was positioned. The attenuation of light intensities in the frontal lobe and cerebellum was measured by varying the bundle tip position. The starting positions of the bundle were confirmed by the endoscopic view. The measured light intensity attenuations were fitted with an exponential curve. RESULTS: The following attenuation coefficients were obtained: 0.20 ± 0.05 mm-1 in the cerebrum and 0.27 ± 0.05 mm-1 in the cerebellum. CONCLUSION: As conventional spectroscopic measurement may overestimate attenuation in the whole tissue, in situ measurement using the withdrawal technique might be appropriate for measurement of inhomogeneous biological tissues.

[Undetectable anti-platelet factor 4/heparin antibodies with IgG-specific chemiluminescent immunoassays in a heparin-induced thrombocytopenia patient].

A 51-year-old man with a 9-month history of narrowing of visual fields and papilledema was admitted to the Department of Neurosurgery. Upon admission, glycerol was intravenously administered and heparin flushes were initiated to maintain intravenous access. Brain MRI revealed right transverse and sigmoid sinus thrombosis on hospital day 2, and the patient was treated with unfractionated heparin. On hospital day 9, the patient had a seizure and impaired mental status. Moreover, on hospital day 10, the platelet count decreased to less than half compared with that documented upon admission. The patient was then switched from heparin to argatroban because thrombosis exacerbation due to heparin-induced thrombocytopenia (HIT) was suspected. Despite negative IgG-specific chemiluminescent immunoassay for anti-platelet factor 4 (PF4) /heparin antibodies, positive functional assay led to the diagnosis of HIT. Warfarin was initiated and the platelet count was restored. Because maintaining the patient's PT-INR within the therapeutic range was difficult probably due to concomitant antimicrobial administration for complicating pneumonia, anticoagulation was switched to rivaroxaban. No bleeding or thrombotic complications developed. Thus, the presentation and clinical course should be considered for an accurate diagnosis of HIT. This is particularly important when the immunological assay is negative for anti-PF4/heparin antibodies. Furthermore, anticoagulation with rivaroxaban can be useful in the management of the subacute phase of HIT.

First autopsy analysis of the efficacy of intra-operative additional photodynamic therapy for patients with glioblastoma.

The study aim to demonstrate the therapeutic tissue depth of photodynamic therapy (PDT) using the photosensitizer talaporfin sodium and semiconductor laser for malignant glioma from an autopsy finding. Three patients diagnosed with glioblastoma by pre-operative imaging (1 newly diagnosed patient and 2 patients with recurrence) were treated with intra-operative additional PDT and adjuvant therapy such as post-operative radiotherapy or chemotherapy. All three patients died of brain stem dysfunction owing to cerebrospinal fluid dissemination or direct invasion of the tumor cells from 13, 18, or 20 months after PDT. Antemortem magnetic resonance images demonstrated no tumor recurrence in the site of PDT, and autopsy was performed for the pathological analysis. Macroscopic observation demonstrated no tumor recurrence in two patients, but one patient demonstrated tumor recurrence in the therapeutic depth of PDT. Microscopic analysis demonstrated histopathological changes reaching depths of 9, 11, and 18 mm (mean: 12.7 mm) from the surface of the cavity of tumor resection, suggesting the therapeutic tissue depth of PDT to be in this range. This region demonstrated glial scarring with infiltration of T lymphocytes and macrophages, with slight degeneration of small vessel walls. However, viable tumor tissues were observed beyond or around the therapeutic tissue depth of PDT in two patients. PDT for glioblastoma prevented early local recurrence, which suggests the possibility that activation of the immune mechanisms was involved. The therapeutic tissue depth was suggested to be 9-18 mm from the surface of the cavity of tumor resection; however, the viable tumor tissues were demonstrated beyond this therapeutic range.

A Case of Rapidly-Progressing Cervical Spine Subependymoma with Atypical Features.

This was a study of the case of a 60-year-old woman who presented with a six-month history of headache and numbness radiating to the right arm. MRI revealed a fusiform intramedullary spinal tumor spanning C2 to C5 at the hospital where she first presented. As her right upper limb weakness had presented gradually, she visited our hospital after one and a half years. Neurological examination revealed muscle weakness in the right deltoid, but no sensory disturbance. The patient underwent a C2-C6 total laminectomy and posterior midline myelotomy from the posterior median fissure of the spinal cord. The intraoperative histological diagnosis was glioma. Pathological findings in low magnification demonstrated clusters of small uniform nuclei embedded in a dense and fibrillary matrix in hematoxylin-eosin staining (H.E.). On immunohistochemical staining, the tumor cells were weakly positive for glial fibrillary acidic protein (GFAP), but negative for the epithelial membrane antigen (EMA). The histopathological findings were consistent with the diagnosis of a subependymoma. However, the MIB-1 labeling index was of moderately high level up to approximately 8%. In this case, we performed total resection because the tumor had rapidly increased in size and was of atypical form in histological findings. It should be minded that some of subependymomas have a possibility of rapidly increasing in size with progressing neurological deficits.

Intraoperative Photodiagnosis for Malignant Glioma Using Photosensitizer Talaporfin Sodium.

Objective: The aim of this study was to demonstrate the clinical feasibility of intraoperative photodiagnosis (PD) of malignant brain tumor using talaporfin sodium (TPS), which is an agent used in photodynamic therapy (PDT) for cancers. Methods: Forty-seven patients diagnosed with malignant gliomas by preoperative imaging (42 patients with gliomas and 5 patients with other brain tumors) received an intravenous injection of TPS at 40 mg/m2 24 h before resection. During surgery, these patients were irradiated with diode laser light at 664 nm, and tumor fluorescence was observed. The fluorescence intensity was visually rated on a 3-point rating scale [strong fluorescence, weak fluorescence and no fluorescence]. TPS concentrations in 124 samples from 47 cases were measured by HPLC (High performance liquid chromatography). Results: The fluorescence intensity was confirmed to be weak in all patients with Grade II gliomas and strong in almost all patients with Grade III or IV gliomas, reflecting the histological grade of malignancy. In patients with non-glioma brain tumors except for 1 patient with a metastatic brain tumor, the fluorescence intensity was strong. The mean TPS concentration in tissues was 1.62 µg/g for strong fluorescence areas, 0.67 µg/g for weak fluorescence areas and 0.19 µg/g for no fluorescence areas. Conclusions: Establishment of an appropriate fluorescence observation system enabled fluorescence-guided resection of malignant brain tumors using TPS, and the fluorescence intensity of tumors correlated with the TPS concentrations in tissues. These results suggest that TPS is a useful photosensitizer for both intraoperative fluorescence diagnosis and photodynamic therapy.

Microvascular Decompression for Oculomotor Nerve Palsy Due to Compression by Infundibular Dilatation of Posterior Communicating Artery.

BACKGROUND: Oculomotor nerve palsy is occasionally a key indicator of an internal carotid posterior communicating (ICPC) artery bifurcation aneurysm. The interval between the onset of palsy and the time of surgery is considered to be the most important factor affecting recovery from oculomotor nerve palsy. We encountered a rare case of oculomotor nerve palsy due to compression by the infundibular dilatation of the posterior communicating artery (PcomA) rather than by an ICPC aneurysm. CASE DESCRIPTION: We report the case of a 70-year-old woman who presented with pain in the left forehead and left oculomotor nerve palsy with a prominence at the bifurcation of the left internal carotid artery and PcomA on neuroradiologic imaging, indicating a small aneurysm. However, the positional relationship between the bulging lesion and PcomA was not apparent. The intraoperative microscopic view showed that the lesion was an infundibular dilatation of the PcomA rather than an aneurysm, compressing the oculomotor nerve. Microvascular decompression of the lesion resulted in the disappearance of her symptoms after 3 months. CONCLUSIONS: For the treatment of a symptomatic ICPC unruptured aneurysm, direct observation by open surgery is important when the relationship between the PcomA and aneurysm is not clear by neuroradiologic imaging.

Pathologic Findings and Clinical Course of Midline Paraventricular Gliomas Diagnosed Using a Neuroendoscope.

INTRODUCTION: Removal of midline paraventricular gliomas is difficult because of their deep localization and invasive character, requiring biopsy for pathologic diagnosis. This study aimed to assess the pathologic findings and clinical course of midline paraventricular gliomas diagnosed using a neuroendoscope. METHODS: This study was performed as a retrospective investigation using a neuroendoscope of 26 patients whose tumors were diagnosed as midline paraventricular gliomas. The main loci of the lesions were the thalamus (11 patients), tectum (6 patients), and other areas (9 patients). Of these 26 patients, 21 (81%) had accompanying obstructive hydrocephalus. Surgery was performed via the lateral ventricle using a flexible scope. For patients with obstructive hydrocephalus, we added endoscopic third ventriculostomy, septostomy, and/or plasty of the foramen of Monro. Pathologic diagnosis was determined according to hematoxylin-eosin staining and immunohistochemistry using anti-GFAP, anti-Ki-67, anti-H3-K27M, and anti-IDH1-R132H antibodies. RESULTS: The pathologic diagnoses were grade I (5 patients), grade II (3 patients), grade III (6 patients), and grade IV (4 patients) gliomas. Six patients were diagnosed as having high-grade glioma, which was difficult to distinguish between grade III and grade IV. Two patients were undiagnosable. H3-K27M was strongly positive in 8 of 15 patients with high-grade glioma. All patients with high-grade gliomas died or received best supportive care within 2 years after surgery. CONCLUSIONS: Neuroendoscopic surgery is useful for midline paraventricular gliomas in terms of the treatment of obstructive hydrocephalus, as well as pathologic diagnosis and genetic analysis, which are required under the World Health Organization 2016 classification.

A case of unruptured aneurysm of the internal carotid artery presenting as olfactory hallucinations.

BACKGROUND: Olfactory hallucination, a symptom of medial temporal lobe epilepsy, is rarely associated with unruptured intracranial aneurysms. CASE DESCRIPTION: We encountered this situation in a 70-year-old woman with an unruptured aneurysm at the bifurcation of the internal carotid and posterior communicating artery. We were able to achieve epileptic control by craniotomy clipping and medial temporal lesionectomy. CONCLUSION: According to our knowledge, previous reports are limited to cases of large middle cerebral artery aneurysms compressing the lateral orbitofrontal cortex, and this is apparently the first report of a case where olfactory hallucinations occurred from direct stimulation of the entorhinal cortex by an internal carotid and posterior communicating artery bifurcation aneurysm. We examined the pathophysiology underlying the development of olfactory hallucinations. We found craniotomy clipping and focal resection to be useful from the standpoint of seizure control. Whether seizure control can also be obtained with intracranial aneurysm coiling should be investigated in the future.

Expression and gene doses changes of the p53-regulator PPM1D in meningiomas: a role in meningioma progression?

The aim of our study was to clarify the expression and gene copy number levels of protein phosphatase 1D magnesium-dependent, delta isoform (PPM1D), which is thought to be a regulator of the p53 protein in meningiomas of all three different WHO grades. Genomic DNA and mRNA were extracted from frozen tissues of meningiomas (WHO grade I, 20 cases; grade II, 17 cases; grade III, 20 cases). For analysis of the mRNA expression and gene dosage level of PPM1D, semiquantitative duplex RT-PCR, real-time RT-PCR, and semiquantitative duplex PCR were performed. We also analyzed several genes which locate near PPM1D in the genomic locus 17q22-24 using semiquantitative duplex RT-PCR. We found that the mean mRNA expression of PPM1D is higher in WHO grade II and III meningiomas than in grade I tumors. This finding is accompanied by moderate gene dosage increases for PPM1D in meningiomas of higher grades. Other genes located in the vicinity of PPM1D also showed mRNA overexpression in single meningioma cases. For these genes, however, no significant expression differences between meningioma grades could be observed. Thus, PPM1D in the chromosomal location 17q22-24 might be the most relevant candidate gene with respect to a potential functional implication in meningioma progression.

Clinicopathological analysis in patients with neuroendocrine tumors that metastasized to the brain.

BACKGROUND: A neuroendocrine tumor (NET) can develop anywhere in the body, but is mainly found in the pancreas, gastrointestinal tract, and lungs. This report is a retrospective study of the clinicopathological features of NET patients with brain metastasis whose tissue diagnosis was made at our hospital. METHODS: Patients with brain metastasis evidenced by clinical records and images were accumulated among 302 patients in whom tissue diagnosis of NETs was made at our hospital between 2008 and 2013. In the patients, the primary lesion, pathological classification, pattern of metastasis, details of treatment, and outcomes were analyzed. RESULTS: Brain metastasis was observed in 31 patients (10.3%). The primary lesion was in the lungs in 26 patients (83.9%), and the mammary glands, esophagus, and uterus in 1 patient each. Primary lesions were unknown in 2 patients, including 1 patient in whom NETs were detected in the lymph nodes alone. Pathological classification of the primary lesion was NET Grade 2 (Ki-67: 3 to 20%) in 3 patients and neuroendocrine carcinoma (NEC, Ki-67: ≥ 21%) in 26 patients. The median period from onset of the primary lesion up to diagnosis of brain metastasis was 12.8 months, and the brain lesion preceded brain metastasis in 6 patients. Ten patients had a single metastasis whereas 21 patients had multiple metastases, but no characteristics were observed in their images. Brain metastasis was extirpated in 10 patients. Stereotactic radiotherapy alone was administered in 6 patients, and brain metastasis was favorably controlled in most of the patients with coadministration of cranial irradiation as appropriate. The median survival period from diagnosis of brain metastasis was 8.1 months, and the major cause of death was aggravation of the primary lesion or metastatic lesions in other organs. CONCLUSION: Most of NET patients with brain metastasis showed the primary lesion of NEC in the lungs, and they had multiple metastases to the liver, lymph nodes, bones, and so forth at the time of diagnosis of brain metastasis. The guidelines for accurate diagnosis and treatment of NETs should be immediately established based on further analyses of NET patients with brain metastasis.