Temozolomide radiochemotherapy for high-grade glioma patients with hemodialysis: a case series of 7 patients.

BACKGROUND: The pharmacokinetics of temozolomide (TMZ) in patients with severe renal impairments (creatinine clearance, <36 mL/min/m2) or in hemodialysis (HD) patients has not been investigated. TMZ and its metabolic products are mainly excreted in urine, as retention of these in the body may result in increased adverse events in HD patients. METHODS: Seven HD patients with high-grade gliomas from 6 institutions were included in the study. Patient characteristics, treatment schedule, clinical course, pathological/molecular findings, and adverse events were evaluated. RESULTS: The histopathological diagnoses were isocitrate dehydrogenase (IDH) wild-type glioblastoma in 4 cases, not other specified (NOS) glioblastoma in 2 cases, and IDH-mutant anaplastic astrocytoma in 1 case. Five of the 7 patients completed radiotherapy (48-60 Gy) with concomitant TMZ (75 mg/m2) followed by adjuvant 5-day TMZ (150 mg/m2) every 28 days. During the entire course of treatment with TMZ, severe (Common Terminology Criteria for Adverse Events [CTCAE] ≥ Grade 3) lymphocytopenia occurred in 57%, neutropenia in 0%, and thrombocytopenia in 14% of the patients. Generally, the frequency and degree of myelosuppression do not increase in HD patients with high-grade gliomas. Two of the 7 (28.5%) patients died of infectious disease despite having no direct correlation to myelosuppression; that is similar to the death rate of 21.9% resulting from infection in HD patients in Japan. CONCLUSIONS: Decreasing the dose of TMZ might not be required in HD patients with high-grade gliomas during concomitant radiochemotherapy and maintenance therapy. However, careful clinical and hematological observation is required to avoid critical hematotoxicity and infection.

[Clinicopathological Study of Pilomyxoid-Spectrum Astrocytomas:An Analysis of the BRAF Gene. Report of Two Cases].

In contrast to pilocytic astrocytomas(PAs), pilomyxoid astrocytomas(PMAs)demonstrate monophasic piloid cells with angiocentric distribution and a more aggressive clinical course. Recently, several reports have described combined histological features of both subtypes;accordingly, these were termed intermediate pilomyxoid tumors(IPTs). The KIAA1549-BRAF fusion gene has been found in approximately 70% of PAs, but is reportedly rare in PMAs. We describe a clinicopathological study of two patients with pilomyxoid-spectrum astrocytoma(PMSA). Case 1 was of a 29-year-old man who presented with a generalized seizure. Gadolinium-magnetic resonance imaging(Gd-MRI)demonstrated a less enhanced tumor in the left temporal lobe. Case 2 was of a 9-year-old boy who presented with headache. Gd-MRI revealed an irregularly enhanced tumor in the left cerebellum. In Case 1, the tumor showed monomorphous bipolar cells in a myxoid background and angiocentric arrangement;therefore, the diagnosis was PMA. In Case 2, part of the tumor had a myxoid, angiocentric pattern characteristic of PMA;the other part had a biphasic pattern characteristic of PA. PMA and PA were mixed in a 7:3 ratio;therefore, IPT was diagnosed. No BRAF V600E mutations were found by immunohistochemistry and sequencing in either case. Three major KIAA1549-BRAF fusion subtypes were analyzed by quantitative reverse transcription polymerase chain reaction(RT-PCR)and sequencing. No fusions were found in Case 1. However, K16-B9 fusion was identified in Case 2, and this fusion was more prevalent in the PA component than in the PMA component. In summary, no BRAF V600E mutations were found in PMSAs, but KIAA1549-BRAF fusion was identified in IPT, particularly in the PA component.

Clinicopathologic study of pineal parenchymal tumors of intermediate differentiation.

OBJECTIVE: Pineal parenchymal tumors of intermediate differentiation (PPTID) are extremely rare tumor entities, and only limited data are available regarding their pathologic features and biologic behaviors. Because grading criteria of pineal parenchymal tumors (PPTs) have yet to be established, the treatment strategy and prognosis of PPTIDs remain controversial. We describe the clinicopathologic study of six patients with PPTID and compare responses for the treatment and prognosis with cases of pineocytoma (PC) and pineoblastoma (PB). From this analysis, we attempt to clarify the treatment strategy for PPTIDs. METHODS: This study included 15 patients with PPTs, consisting of 6 PCs, 6 PPTIDs, and 3 PBs. We focused on the 6 patients with PPTIDs. All PPTID cases were treated surgically, and radiotherapy and chemotherapy were administered as adjuvant therapies in some cases. We have earlier reported the histopathologic study (Neuropathology 32:647-653, 2012). Briefly, we examined mitotic figures and necrosis by hematoxylin-eosin staining and immunohistochemical markers such as neuronal markers (synaptophysin, neurofilament (NF), and neuronal nuclear antigen), and an MIB-1 labeling index was determined. RESULTS: In the PPTID cases, the extent of resection was variable and the recurrence rates among patients varied according to stage and treatment. All PC patients underwent total resection with no recurrence. All PB patients underwent resection and adjuvant therapy with radiotherapy and chemotherapy. There were no recurrences in patients with PC or PB. The results of histopathologic findings have been already reported as mentioned above. Briefly, the results indicated no mitotic figure or necrosis in any of the six cases of PPTID, but those features were observed in PB cases. All cases even including PC and PB were immunopositive for neuronal markers. The MIB-1 labeling index of PPTID was 3.5%, whereas it was 0% in PC and 10.5% in PB. CONCLUSIONS: Good radiosensitivity of PPTIDs was observed in our series. Because there are cases with discrepancies between images and pathologic findings, it is very difficult to determine the proper treatment strategy for PPTIDs. Proliferative potential was correlated with World Health Organization grade, although the immunoreactivity of neuronal markers did not correlate with the histologic grade.

[Gamma knife radiosurgery for trigeminal neuralgia: analysis of a multi institutional study].

A multi-institutional study was conducted to evaluate the results of gamma knife radiosurgery (GKRS) for the treatment of trigeminal neuralgia. Eleven hundred and thirty-five patients at 39 centers were analyzed. Three hundred and sixty-nine patients had undergone percutaneous nerve block and 173 patients had undergone microvascular decompression (MVD) prior to GKRS. GKRS was performed for 69.4% of patients targeted at the nerve root entry zone (REZ) and for 20.4% of patients targeted at the retrogasserian region (RGR). The target dose of the GKRS used in the current study varied from 70 to 90 Gy (mean: 77.8Gy). The median follow-up period after GKRS was 21.1 months (range 1 to 125 months). Six hundred and eighty-nine patients (66%) responded with excellent or good control (pain free), 157 (15%) obtained fair control (more than 50% relief), and 192 (19%) experienced treatment failure. After 3 years, 64% of cases were pain free and 80% had more than 50% pain relief. After 4 years, 37 patients underwent additional GKRS, 36 MVD and 36 percutaneous nerve block. Tolerable hypoesthesia or paresthesia occurred in 129 patients (11%), whereas bothersome symptoms developed in 8 patients (1%). But no patient developed deafferentation pain. Nine patients (1%) complained of dry eye, but no other abnormalities of the cornea and conjunctiva were found on ophthalmological examination. Higher maximum radiosurgical dose was associated with a significantly greater factor of complete pain relief (p=0.0101). GKRS is a safe and effective alternative treatment for trigeminal neuralgia, and is a minimally invasive treatment. In addition it provided benefit to a patient population unwilling or unable to undergo more invasive surgical approaches.

Expression of O6-methylguanine DNA methyltransferase (MGMT) and immunohistochemical analysis of 12 pineal parenchymal tumors.

Pineal parenchymal tumors (PPTs) are rare neoplasms which occupy less than 1% of primary CNS tumors. Because of their rare incidence, previous reports on PPTs are limited in number and the useful molecular markers for deciding histological grading and even selecting chemotherapy are undetermined. In this study, we conducted immunohistochemical analysis of 12 PPT specimens, especially for expression of O6-methylguanine DNA methyltransferase (MGMT) to assess whether temozolomide (TMZ) could serve as a possible alternative therapy for PPTs. We analyzed 12 PPTs, consisting of three pineocytomas, six PPTs of intermediate differentiation (PPTIDs), and three pineoblastomas. Immunohistochemical analysis was performed using antibodies against MGMT, synaptophysin, neurofilament protein (NF), p53, and neuronal nuclear antigen (NeuN). Immunohistochemically, 11 out of 12 cases were positive for MGMT. The mean MIB-1 labeling index was less than 1% in pineocytoma, 3.5% in PPTID, and 10.5% in pineoblastoma. All 12 cases were positive for synaptophysin and 11 cases, except one PPTID case, showed positive for NF. Nuclear staining of NeuN was negative in all cases although cytoplasmic staining of NeuN was observed in five cases. No case was positive for p53. Eleven out of 12 cases of PPTs demonstrated MGMT expression, suggesting chemoresistancy to TMZ treatment. This is the first report showing MGMT expression in PPTs. In addition, MIB-1 labeling index correlated with WHO grade, although the immunoreactivity of synaptophysin, NF, NeuN and p53 did not correlate with the histological grade.

A high dose of dexmedetomidine using the BIS monitor™ for diagnostic and interventional cardiac catheterization in a toddler with congenital heart disease.

Dexmedetomidine (DEX) for sedation in diagnostic and interventional cardiac catheterization (DICC) has been reported to require other drugs or rescue drugs because of its insufficient sedative effect when used alone. We administered DEX and adjusted its dose according to the bispectral index (BIS) monitor™ for DICC in a toddler; consequently, a high dose of DEX had to be administered. The patient was a 1-year and 4-month-old boy who was scheduled to undergo DICC after intracardiac repair. We used DEX alone as the sedative because this was expected to avoid oxygen supply and mechanical ventilation and to produce a safe situation for procedures around the neck. DEX was administered at the dose of 1-15 µg/kg/h according to BIS monitor™; administration of cardiovascular drugs or oxygen supply or assist ventilation, except chin lift, were not needed. The maximum predicted plasma concentration (pCp) of DEX and mean pCp were calculated as 6.1 and 4.1 ng/mL, respectively. A high dose of DEX may be required for DICC sedation, as for MRI sedation, in many cases. Although further studies should be conducted to reveal the merits and demerits of DEX in cardiac catheterization, a high dose of DEX may be useful in some cases.

Radiation-induced osteosarcomas after treatment for frontal gliomas: a report of two cases.

Most radiation-induced osteosarcomas of the skull are reported to arise in the facial bone or paranasal sinus after radiotherapy for retinoblastoma and/or pituitary adenoma. Here we report two cases of radiation-induced osteosarcoma in the paranasal sinus after treatment for frontal glioma. Case 1 was a 56-year-old woman who underwent surgical resection of a left frontal tumor in October 1990. The histological diagnosis was a low-grade glioma, and radiotherapy of 54 Gy was administered. Sixteen years later, in September 2006, the patient noted an enlarging subcutaneous mass in the right frontal region. CT showed an osteolytic mass in the right frontal sinus. An open biopsy established the histopathological diagnosis of osteosarcoma, and the patient subsequently died of rapid tumor regrowth. Case 2 was a 58-year-old man who underwent partial removal of a bifrontal tumor in May 1996. The histological diagnosis was anaplastic oligoastrocytoma, and radiotherapy of 56 Gy was administered. Twelve years later, in March 2008, the patient was readmitted to our hospital for reasons of marked deterioration in general physical condition. Tumor recurrence was suspected in the left frontal lobe, and CT demonstrated an osteolytic mass in the left frontal and ethmoid sinus. A secondary operation was performed, and the pathological specimens were diagnosed as osteosarcoma. Radiotherapy was readministered, but the subject died of rapid tumor regrowth. From these clinicopathological findings, both cases were diagnosed as radiation-induced osteosarcoma. Radiation-induced osteosarcomas appeared 16 and 12 years after radiotherapy in cases 1 and 2, respectively. As the prognosis of radiation-induced osteosarcoma is poorer than that of primary osteo-sarcoma, careful attention is required for consideration of the long-term survival of patients with glioma.

Long-term prognostic assessment of 185 newly diagnosed gliomas: Grade III glioma showed prognosis comparable to that of Grade II glioma.

OBJECTIVE: We evaluated the prognoses of newly diagnosed gliomas through WHO Grades II, III and IV to assess the overall tendency of treatment results for glioma in our institute. Furthermore, statistical analysis was performed to determine factors influencing the prognosis. METHODS: A total of 185 newly diagnosed glioma patients were operated on from 2000 to 2006. The primary endpoint was the overall survival from the date of surgery. The factors assessed as to whether they influenced the prognosis were the WHO grades of sex, age, location of the lesion, pre-operative Karnofsky Performance Status (KPS), extent of resection and whether or not radiation therapy was performed. RESULTS: The WHO grades influenced the survival significantly (P < 0.0001). The Grades II and III showed no statistically significant difference in survival (P = 0.174), whereas Grades III and IV showed a significant difference (P < 0.0001). The factor influencing survival as well as the grades was the KPS (P < 0.0001). The comparison of survival over WHO grades in the same KPS group was performed for 2 KPS groups (KPS = 100, KPS 80-90), and these also showed significant differences (P = 0.0009 and 0.0143, respectively). CONCLUSIONS: Despite the different distributions of the KPS, the Grade III glioma patients showed survival comparable to that of the Grade II. On the other hand, the Grade IV glioma patients showed significantly poorer survival compared with Grade II or III.