The evolution of cancer chemotherapy has been a major advance in medical science in the late 20th century. However, patients with malignant gliomas have not benefitted much. The blood-brain barrier (BBB), which always hinders the entry of therapeutic agents into the central nervous system (CNS), may at least partly be responsible. Convection-enhanced delivery (CED), a method for distributing large and small molecular weight compounds bypassing the BBB, enables robust distribution of the infused molecules at the site of infusion. CED is promising as an effective treatment not only for malignant gliomas but also for multiple CNS disorders because this method can effectively distribute multiple molecules that are potentially effective against different diseases. Although the method is quite simple, several problems require solution in developing novel CED-based strategies, including what, where, when, and how to infuse. This review discusses basic considerations when developing CED-based strategies for CNS diseases, focusing mainly on brain tumors.
Malignant glioma is the most common primary brain tumor and accounts for the majority of diagnoses. Treatment has involved a combination of surgery, radiation, and chemotherapy, yet these modalities rarely extend the life of the patient to more than one year from diagnosis. Integrins are expressed in tumor cells and tumor endothelial cells, and are important in angiogenesis and invasion in glioma. αvβ3 and αvβ5 integrins regulate cell adhesion, and inhibitors of these integrins suppress tumor growth in certain pre-clinical models. Several integrin-targeted drugs are in clinical trials as potential compounds for the treatment of cancer. Among them, cilengitide is a novel integrin antagonist for the treatment of glioblastoma. The multimodal anti-glioma effects are based on its cytotoxic, anti-angiogenic, anti-invasive, and synergetic effects. Preclinical studies showed a promising synergy between cilengitide and radiochemotherapy in order to normalize tumor vasculature and attenuate tumor invasion. Cilengitide is currently being assessed in phase III trials for patients with glioblastoma multiforme and in phase II trials for other types of cancers, demonstrating promising therapeutic outcomes to date. The results of these and other clinical studies are expected with great hope and interest. A more clear understanding of the benefits and pitfalls of each approach can then lead to the design of strategies to derive maximal benefit from these therapies.
Treatment of recurrent glioblastoma is still challenging. Stereotactic radiosurgery has been accepted as a treatment option for recurrent glioblastoma after standard chemotherapy and irradiation. However, the efficacy of stereotactic radiosurgery at recurrence has been limited, mainly due to the highly infiltrative nature of the tumor which makes the lesion difficult to define as the target. To enhance the efficacy of stereotactic radiosurgery, several methods of targeting based on neuroimaging technology such as positron emission tomography and magnetic resonance imaging have been adopted to irradiate as many of the viable tumor cells as possible and showed some enhanced efficacy. In a trial of intensified treatment by extending the irradiation field, improvement of local control did not result in longer survival. Radiation-induced adverse event is another problem after stereotactic radiosurgery for recurrent glioblastoma because almost all patients underwent irradiation as a part of the initial treatment. To overcome the side effects associated with re-irradiation, use of bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor, has shown some efficacy. Advances in irradiation technology, neuroimaging, and adjuvant treatment are needed to enhance the efficacy of stereotactic radiosurgery for recurrent glioblastoma and reduce the morbidity associated with irradiation.
Extensive surgical removal of tumor tissue can contribute to longer survival for patients with gliomas. Intraoperative magnetic resonance (iMR) imaging is important for safe and maximal resection of brain tumors. A new operating room equipped with a 1.5-T MR imaging system and neuronavigation opened at Yamagata University Hospital in 2008. Using this new suite, we have safely treated over 200 cases. Use of iMR imaging improved glioma resection rates in 25 (34%) of 73 cases, and gross total resection was achieved in 48 patients (66%). Motor evoked potential (MEP) monitoring was performed in combination with iMR imaging for 32 gliomas. MEP monitoring was successful in 30 cases (94%). Transient decreases in MEP amplitude were seen in two patients. One patient showed transient motor weakness and another showed improvement of motor function. The iMR imaging system provides useful information for tumor resection that allows intraoperative modification of surgical strategies. Combining MEP monitoring with iMR imaging appears to offer the most effective method for safe glioma surgery near eloquent areas.
The usefulness of rapid growth hormone (GH) measurement was retrospectively evaluated as an indicator of total tumor removal during surgery and compared with several reported criteria in 252 acromegalic patients who underwent transsphenoidal surgery at Toranomon Hospital between 2006 and 2008. GH levels were measured in blood samples obtained before surgery, at the start of tumor removal, and every 20 minutes thereafter until 20 minutes after total tumor removal as judged by the operator. Intraoperative GH dynamics were compared between 201 patients fulfilling the Cortina consensus criteria (successful group) and 37 patients who did not (unsuccessful group). Among several criteria indicating total tumor removal, only the ratio of serum GH level 20 minutes after the end of tumor removal to GH level at the end of tumor excision was significantly different between the groups; a reduction ratio of 65% was the most appropriate cut-off value based on sensitivity (59.2%) and specificity (59.5%). The ratio of GH level 20 minutes after the end of tumor removal/GH level at the end of tumor excision was the most reliable index to judge tumor removal during surgery, but this index is neither necessary nor sufficient and should be used as one of the indicators to judge complete tumor removal during surgery.
Reliable prognostic parameters indicating progression in residual pituitary adenoma after surgery are necessary. The World Health Organization classification of tumors of endocrine organs defines atypical pituitary adenomas as tumor with Ki-67 labeling index higher than 3%, excessive p53 immunoreactivity, and increased pleomorphism. The real value of Ki-67 labeling index correlating with tumor progression is controversial. We investigated the relationship between positive labeling for MIB-1 and clinical features of 39 patients with pituitary adenomas with and without rapid re-growth after initial surgery. Ki-67 expression revealed pituitary adenomas with progression (re-growth within 5 years after initial surgery) had a mean proliferation index of 3.66 ± 3.00% (mean ± standard deviation [SD], n = 12), which was significantly higher than in tumors without progression of 1.89 ± 1.25% (mean ± SD, n = 27) (p < 0.05, Mann-Whitney test). Receiver operating characteristic analysis showed a threshold level of Ki-67 expression greater than 2.0% predicts progression with high specificity. Younger patients had higher MIB-1 index and more progression (p < 0.05). Adenomas with cavernous sinus invasion, functioning adenomas, and giant adenomas had higher MIB-1 index (p < 0.05). There was no significant correlation between tumor size or cavernous sinus invasion and progression. More completely removed tumors were less progressive. A threshold of 2% for the MIB-1 labeling index predicts higher risk of progression of residual adenomas after surgery, so shorter interval of follow-up neuroimaging, and early initiation of adjuvant therapy might be required.
Elderly and low Karnofsky performance status (KPS) patients have been excluded from most prospective trials. This retrospective study investigated glioblastoma treatment outcomes, including those of elderly and low KPS patients, and analyzed the prognostic factors using the medical records of 107 consecutive patients, 59 men and 48 women aged from 21 to 85 years (median 65 years), with newly diagnosed glioblastoma treated at our institute. There were 71 high-risk patients with age >70 years and/or KPS <70%. Based on the extent of resection, the patients were classified into 3 groups: more than subtotal resection (subtotal, n = 44), partial resection (partial, n = 29), and biopsy only (biopsy, n = 34). Median overall survival (OS) of all 107 patients was 13.5 months. Median OS was 13.2 months in the high-risk group. Median OSs were 15.8, 12.8, and 12.1 months in the subtotal, partial, and biopsy groups, respectively. Multivariate analysis of 73 patients in the subtotal and partial groups found age ≤65 years (p = 0.047), 60 Gy irradiation (p = 0.009), O6-methylguanine-deoxyribonucleic acid methyltransferase-negative (p = 0.027), and more than subtotal removal (p = 0.003) were significant prognostic factors. The median postoperative KPS score tended to be better than the preoperative score, even in the high-risk group. We recommend maximal safe resection for glioblastoma patients, even those with advanced age and/or with low KPS scores.
The present retrospective study evaluated the recurrence patterns after aggressive surgical removal of intracranial glioblastomas in 43 consecutive adult patients. The resection rate of the enhanced lesion on magnetic resonance imaging was 100% and 95-99% in 22 and 21 cases, respectively. All patients received postoperative fractionated radiotherapy (60 Gy in 30 fractions) with additional chemotherapy (25 cases) or vaccine therapy (18 cases). During follow-up (median 17 months), tumor recurrence was identified in 33 patients, most frequently regional within the wall of the resection cavity (20 cases). No clinical factor differed significantly between the groups of patients with regional or marginal tumor progression (N = 22) and patients with distant or multiple recurrences (N = 8). Progression-free survival did not differ significantly between these two groups (p = 0.27). However, overall survival was significantly longer (p = 0.04) in patients with regional or marginal tumor progression, and constituted 90% and 54% at 1 and 2 years after surgery, respectively, compared to 75% and 0% in patients with distant or multiple recurrences. Aggressive surgical resection and adjuvant management of intracranial glioblastoma may change its recurrence pattern. Tumor progression appears in the wall of the resection cavity or within 2 cm from its margin in approximately half of patients.
A 68-year-old man presented with severe conscious disturbance caused by pituitary apoplexy resulting in massive intracerebral hemorrhage (ICH). He had been periodically followed up for asymptomatic pituitary adenoma at another hospital for 8 years. Neuroimaging examination revealed pituitary apoplexy and massive ICH located in the left frontal lobe, and the ICH was directly connected to the intratumoral hemorrhage. The diagnosis was massive ICH from pituitary apoplexy. The patient underwent emergent evacuation of hematoma and removal of the pituitary adenoma via bi-frontal craniotomy. Postoperatively, he continued to exhibit deep consciousness disturbance and died 1 month after the operation. Pituitary apoplexy is usually characterized by intra-tumoral hemorrhage. The treatment strategy for asymptomatic pituitary adenoma is still controversial. This case shows that we should always consider the risk of pituitary apoplexy manifesting as ICH which may cause a fatal outcome.
Coexistence of brain tumors of different pathologies is rare, and the majority of the cases were related to genetic disorders or secondary tumors occurring after radiotherapy. A 73-year-old man was introduced to the outpatient department suffering from severe nausea and vertigo. Magnetic resonance imaging showed a cystic tumor in the left cerebellar hemisphere and another lesion in the sella turcica. There was no evident family history of von Hippel-Lindau (VHL) disease, and the systemic investigation failed to detect any other tumors or signs of VHL disease. Treatment was performed in two stages, and he was discharged with remaining slight ataxic gait. The diagnoses were cerebellar hemangioblastoma and pituitary null cell adenoma. Additional immunohistochemical investigation using VHL disease gene-related protein in both tumors showed minute granular positive staining in the cytoplasm of stromal cells in the former, and diffuse and strong granular cytoplasmic positive staining in the latter. Further analysis is required to confirm the true implication of the VHL gene mutation, and the possible involvement of VHL gene-related protein in the pathogenesis of these coexisting tumors.
A 68-year-old male presented with a very rare case of spindle cell oncocytoma (SCO), a recently identified very rare neoplasm of the anterior pituitary, manifesting as panhypopituitarism and visual field defect. The pituitary tumor with suprasellar extension was only partially resected via transsphenoidal surgery because of the tumor consistency and bleeding. Histological diagnosis was consistent with schwannoma. The tumor regrew and angiography revealed hypervascularity, so a transcranial approach was employed for the re-operation which only achieved partial resection because of intraoperative extensive bleeding. The tumor cells showed similar histological and immunohistochemical profiles to the previous specimen, but electron microscopy demonstrated that cytoplasm abundantly filled with mitochondria. The final diagnosis of SCO was established and the patient received postoperative conventional radiation therapy of 50 Gy. Only 15 cases of SCO have been reported, and the diagnosis was mistaken in many cases as schwannoma, oncocytic pituitary adenoma, or craniopharyngioma, and multiple surgeries followed by radiation therapy were required.
A 15-year-old boy was referred to our hospital with a rare case of inflammatory pseudotumor (IP) in the lateral ventricle manifesting as complaints of headache and low-grade fever. Computed tomography and magnetic resonance imaging demonstrated a well-demarcated and enhanced tumorous lesion in the right lateral ventricle. Intraoperative findings showed a hard mass with feeding arteries from the choroid plexus around the foramen of Monro in the right lateral ventricle, although the mass was not attached to the wall of the lateral ventricle. The lesion was totally resected, and the histopathological diagnosis was IP. The present and previous cases suggest that good outcomes are obtained by surgical removal and treatment of hydrocephalus. IP should be considered in the differential diagnosis of hard tumorous lesions with good enhancement and no tumorous staining in the ventricle.
A 60-year-old male presented with a rare case of periventricular schwannoma. Imaging studies revealed a partially calcified, well-enhanced tumor in the periventricular area of the left frontal horn. The preoperative diagnosis was low grade glioma, but postoperative pathological findings revealed that the tumor was schwannoma. Most intraparenchymal schwannomas are benign, so total extirpation is usually curative. However, this uncommon neoplasm is difficult to distinguish from mimics, especially low grade gliomas, with only preoperative radiological findings or intraoperative pathological findings. Based on our experience and analysis of the characteristic radiological and pathological features in previous cases, we suggest that an accurate intraoperative diagnosis is possible. The key element is the combination of correct interpretation of the intraoperative pathology analysis and careful evaluation of the preoperative radiological studies. An appropriate intraoperative judgment is important, because the treatment, including the surgical management, would be totally different for schwannoma and glioma.
A 29-year-old woman in the 17th week of pregnancy presented with blurred vision and visual impairment of both eyes. Magnetic resonance imaging revealed a tuberculum sellae meningioma. Visual impairment progressively worsened, and surgical resection was performed in the 19th week of pregnancy without fetal heart monitoring. The intra- and postoperative courses were without complications. Her visual acuity and field almost fully recovered immediately after the operation. She delivered a healthy normal baby on the expected day.
A 71-year-old woman presented with a rare case of geriatric ependymoma originating from the fourth ventricle manifesting as progressive gait and memory disturbance. Imaging studies revealed an extraaxial mass in the fourth ventricle protruding into the right cerebellomedullary cistern, with concomitant obstructive hydrocephalus. Surgery achieved subtotal removal since the tumor tightly adhered to the right vestibular area of the fourth ventricular floor. The histological diagnosis was ependymoma, which was also confirmed by comparative genetic hybridization. Although she developed severe laryngeal edema and worsening of the hydrocephalus postoperatively which required additional treatment, she recovered with residual mild gait disturbance, and was transferred to a rehabilitation facility. Fourth ventricle ependymoma in the elderly is rare. Comparative genetic hybridization may be important in the diagnosis of geriatric ependymoma and in the choice for adjuvant therapy as well as in estimating the prognosis for patients with rare types of ependymoma.
Endoscope biopsy guided navigation for intra-parenchymal lesions is safe and effective, but determination of the entry point and trajectory of the endoscopic biopsy is less clear. We describe preoperative planning based on stereotactic methods, and achieving the plan using several techniques. The preoperative planning was based on stereotactic methods such as determining target, entry point, and trajectory. A transparent sheath was advanced under guidance of the navigation system and specimens collected under visual endoscopic monitoring. After collecting specimens, intraoperative magnetic resonance imaging was performed for confirming accurate sampling. Correct specimens were obtained in 6 cases as confirmed by intraoperative magnetic resonance imaging. The histological diagnoses were diffuse large B-cell type malignant lymphoma (n = 3), astrocytoma (n = 1), glioblastoma (n = 1), and inflammatory changes without neoplastic cells (n = 1). No postoperative intracranial hemorrhage or other operative complications occurred. Preoperative planning based on stereotactic methods and procedures guided by navigation systems can achieve endoscopic biopsy for intraparenchymal lesions safely and accurately.