Japan promotes research related to intractable diseases and financially supports patients with these diseases. Intractable diseases are designated as those that fulfill the following criteria: (1) rarity (affecting less than 0.1% of the population in Japan), (2) unknown etiology, (3) lack of effective treatment, (4) necessity of long-term treatment, and (5) existence of objective diagnostic criteria and not necessarily equal to rare diseases in other countries. The construction of a national database is required to promote research to clarify the pathogenesis of these diseases and to develop pharmaceutical products and medical devices. The Ministry of Health, Labor, and Welfare launched an online registration system in 2001, but many problems associated with gathering and utilizing information on patients with intractable diseases remain. In this paper, we describe the present status of the national registry of designated intractable diseases in Japan and discuss future prospects.
Convection-enhanced delivery (CED) circumvents the blood–brain barrier by delivering agents directly into the tumor and surrounding parenchyma. CED can achieve large volumes of distribution by continuous positive-pressure infusion. Although promising as an effective drug delivery method in concept, the administration of therapeutic agents via CED is not without challenges. Limitations of distribution remain a problem in large brains, such as those of humans. Accurate and consistent delivery of an agent is another challenge associated with CED. Similar to the difficulties caused by immunosuppressive environments associated with gliomas, there are several mechanisms that make effective local drug distribution difficult in malignant gliomas. In this review, methods for local drug application targeting gliomas are discussed with special emphasis on CED. Although early clinical trials have failed to demonstrate the efficacy of CED against gliomas, CED potentially can be a platform for translating the molecular understanding of glioblastomas achieved in the laboratory into effective clinical treatments. Several clinical studies using CED of chemotherapeutic agents are ongoing. Successful delivery of effective agents should prove the efficacy of CED in the near future.
The objective of this phase I/II study was to examine the efficacy and toxicity profile of temozolomide (TMZ) plus nimustine (ACNU). Patients who had received a standard radiotherapy with one or two previous chemo-regimens were enrolled. In phase I, the maximum-tolerated dose (MTD) by TMZ (150 mg/m2/day) (Day 1-5) plus various doses of ACNU (30, 35, 40, 45 mg/m2/day) (Day 15) per 4 weeks was defined on a standard 3 + 3 design. In phase II, these therapeutic activity and safety of this regimen were evaluated. Forty-nine eligible patients were enrolled. The median age was 50 years-old. Eighty percent had a KPS of 70–100. Histologies were glioblastoma (73%), anaplastic astrocytoma (22%), anaplastic oligodendroglioma (4%). In phase I, 15 patients were treated at four cohorts by TMZ plus ACNU. MTD was TMZ (150 mg/m2) plus ACNU (40 mg/m2). In phase II, 40 patients were treated at the dose of cohort 3 (MTD). Thirty-five percent of patients experienced grade 3 or 4 toxicities, mainly hematologic. The overall response rate was 11% (4/37). Sixty-eight percent (25/37) had stable disease. Twenty-two percent (8/37) showed progression. Progression-free survival (PFS) rates at 6 and 12 months were 24% (95% CI, 12–35%) and 8% (95% CI, 4–15%). Median PFS was 13 months (95% CI, 9.2–17.2 months). Overall survival (OS) at 6 and 12 were 78% (95% CI, 67–89%) and 49% (95% CI, 33–57%). Median OS was 11.8 months (95% CI, 8.2–14.5 months). This phase I/II study showed a moderate toxicity in hematology and may has a promising efficacy in OS, without inferiority in PFS.
This study examined the accuracy of functional magnetic resonance imaging (fMRI) in identifying the language-dominant hemisphere and the situations in which the Wada test can be skipped among patients with gliomas located near speech areas. We examined 74 patients [48 men (64.9%); mean ± standard deviation age of 42.7 ± 13.6 years (range: 13 to 70 years); 71 right-handed, 2 left-handed, and 1 ambidextrous] with gliomas located near speech areas. All patients underwent the Wada test and fMRI, and 34 patients underwent awake surgery. The “last-and-first” task was administered during fMRI. The Wada test was successful in determining the language-dominant hemisphere in 73 patients (98.6%): left hemisphere in 68 patients (91.9%), right hemisphere in 4 patients (5.4%), and bilateral in 1 patient (1.4%). The dominant hemisphere for right-handed patients (n = 71) was the left hemisphere in 67 patients (94.3%), right hemisphere in 3 patients (4.2%), and undetectable in 1 patient (1.4%). The fMRI was successful in determining the language-dominant hemisphere in 53 patients (71.6%). The results of the Wada test and fMRI were inconsistent in 5 patients (8.6%), of which 3 (5.2%) exhibited dominance in opposite hemispheres. Furthermore, 2 of these 3 cases (2.7%) were contralateral false positive cases, whereby fMRI identified the right-hemisphere as language dominant for right-handed individuals with tumors in the left hemisphere. Based on these findings, we concluded that the Wada test can be skipped if language dominancy can be detected by fMRI.
Meningiomas are the most common primary intracranial tumors. Since the adhesions in the plane of dissection are of interest in surgical planning, we suggest that digital image subtraction of FLAIR data from the T2 sequence of MRI may represent better the CSF spaces in the brain–tumor interface and may be a predictor of the intraoperative cleavage plane. From 2006 to 2016, 83 convexity meningiomas were resected in the Department of Neurosurgery of the University Hospital Complex of Vigo, an analysis of preoperative MRI was performed to assess peritumoral edema (PTE), tumor volume, among others; a digital subtraction of T2-FLAIR sequences was performed and analyzed in relationship to the cleavage plane described in the intraoperative report and postoperative neurological deficits. Simpson grade 1 resection was achieved in 85.54%, the overall 5-year PFS was 93.75%. Our rate of permanent new neurological deficit was 4.82% and the overall complication rate of 14.46%. The grade of PTE was proportional to tumor volume, 20 ± 2.8, 30 ± 5.3, and 34 ± 4.3 cm3 for grades 1, 2, and 3, respectively, positive cleft sign on image subtraction was predictive of good intraoperative cleavage plane and low grade cleavage plane (P = 0.04), and was a protective factor for postoperative neurological deficit (P = 0.02). Positive cleft sign in T2-FLAIR digital subtraction image is an independent predictor of good intraoperative cleavage plane, PTE is an independent predictor of the bad cleavage plane. Negative cleft sign in the image subtraction and a bad intraoperative cleavage plane are predictors of postoperative neurological deficit.
We describe the efficacy and technical aspects of infiltrated preoperative embolization of meningioma by penetration of very dilute glue. In this method, a 13% n-butyl-cyanoacrylate (NBCA)-lipiodol mixture is injected extremely slowly from the middle meningeal artery (MMA) in a similar manner to plug and push injection of ethylene vinyl alcohol copolymer mixed with tantalum and dimethyl sulfoxide (Onyx®) after the tortuous side feeders are proximally embolized. The glue is infiltrated into small tumor arteries and extends to inaccessible feeders from deep meningeal arteries. Since 2011, we have used this technique in the embolization of 32 cases preoperatively diagnosed with meningioma. Intratumoral embolization was possible in 30 cases (94%), and a greater than 50% reduction in contrast area of contrast-enhanced T1-weighted MR imaging (T1-WI) was achieved in 18 cases (56%). Two cases achieved complete devascularization, showing a remarkable shrinkage in tumor size after embolization. If excessive reflux of embolization and the resulting migration of glue into normal arteries is achieved, this method provides extremely effective devascularization on surgical extirpation. It might also be applicable to surgically untreatable meningiomas as a semi-radical treatment option.
Immature teratoma (IMT) is normally treated by resection and adjuvant therapy. The present unusual case of recurrent germinoma occurred 21 years after total resection of pineal IMT. A 3-year-old boy presented with headache, disturbance of consciousness, and Parinaud’s syndrome. Magnetic resonance (MR) imaging revealed a pineal mass lesion, and total resection of the tumor was achieved. The histological diagnosis was mature teratoma. He did not receive further treatment, and did well without recurrence for 20 years. However, he suffered headache 21 years after resection, and MR imaging revealed a homogeneously enhanced pineal mass with low minimum apparent diffusion coefficient value and proton MR spectroscopy showed a huge lipid peak. The levels of tumor markers were not elevated. Cerebrospinal fluid (CSF) cytology found atypical cells with large nuclei and irregularly shaped nucleoli. To elucidate the relationship between the primary and recurrent tumors, we reviewed the histological specimens and CSF cytology at the initial treatment and found a subset of incompletely differentiated components resembling fetal tissues in the histological specimen and atypical large cells in the CSF. Based on these radiological and histological findings, we presume that the recurrent disease was disseminated germinoma after the resection of disseminated IMT. He received chemotherapy and craniospinal radiation therapy, and the enhanced lesion and atypical cells in the CSF disappeared. This case demonstrates that disseminated IMT can be controlled for the long term without adjuvant therapy, but may recur as germinoma. Tumor dormancy may account for this unusual course.