Jun Suenaga

Gamma Knife surgery for metastatic brain tumors from primary breast cancer: treatment indication based on number of tumors and breast cancer phenotype

OBJECT The goal of this study was to analyze prognostic factors for local tumor control and survival and indications for initial treatment with the Gamma Knife in patients with up to 10 metastatic brain tumors from primary breast cancer. METHODS Outcomes were retrospectively reviewed in 101 women with a total of 600 tumors, who underwent Gamma Knife surgery (GKS) for metastatic brain tumors between April 1992 and December 2008 at 1 institution. The inclusion criteria were up to 10 brain metastases, maximum diameter of tumor < 3 cm, and total tumor volume < 15 cm(3). The exclusion criteria were poor systemic condition, presence of carcinomatous meningitis, and previous whole brain radiation treatment and/or craniotomy. RESULTS The mean tumor volume at GKS was 3.7 cm(3) (range 0.016-14.3 cm(3)). The mean margin dose was 19 Gy (range 8-30 Gy). Neuroimaging showed that the local tumor growth control rate was 97%, and the tumor response rate was 82.3%. Larger tumor volume (p = 0.001) and lower margin dose (p = 0.001) were significant adverse prognostic factors for local tumor growth control according to a multivariate analysis. The number of brain metastatic lesions was 4 or fewer in 76 patients and 5 or more in 25 patients. The median overall survival time was 13 months. Multivariate analysis revealed that the presence of extracranial metastases (p = 0.041) and lesions that were not the human epidermal growth factor receptor-2 (HER2)-positive type (p = 0.001) were significant adverse prognostic factors for overall survival. The number of brain metastases was not statistically significant, except for a single metastasis. The median new lesion-free survival time after initial GKS was 9 months. Five or more lesions at initial GKS (p = 0.007) and younger patient age (p = 0.008) reduced survival significantly. The prevention of neurological death after GKS was 93.9% at 1 year, and a lower Karnofsky Performance Scale score (p = 0.009) was the only unfavorable factor. Median overall survival associated with the HER2-positive phenotype was significantly longer than survival associated with the other phenotypes (luminal and triple-negative). There were no statistically significant differences between the 3 breast cancer phenotypes for the incidence of new brain metastases after initial GKS. CONCLUSIONS Initial GKS resulted in excellent local tumor control rates, which were associated with prolonged survival and a low risk of neurological death for patients with up to 10 metastatic brain tumors from primary breast cancer. The authors recommend periodic clinical and neuroradiological follow-up examinations after GKS in patients with 5 or more lesions at initial GKS, because they carry a high risk of development of new brain metastases, and in patients with the HER2-positive phenotype, because they tend to have a favorable prognosis in overall survival. Last, the authors recommend additional GKS or whole-brain radiation treatment for salvage treatment if new brain metastases occur.

Gamma Knife surgery for brain metastases from colorectal cancer: Clinical article

OBJECT The outcomes after Gamma Knife surgery (GKS) were retrospectively analyzed in patients with brain metastases from radioresistant primary colorectal cancer to evaluate the efficacy of GKS and the prognostic factors for local tumor control and overall survival. METHODS The authors reviewed the medical records of 152 patients with 616 tumors. The group included 102 men and 50 women aged 35-85 years (mean age 64.4 years), who underwent GKS for metastatic brain tumors from colorectal cancer between April 1992 and September 2008 at Yokohama Rosai Hospital. RESULTS The mean prescription dose to the tumor margin was 18.5 Gy (range 8-30 Gy). The mean tumor volume at GKS was 2.0 cm(3) (range 0.004-10.0 cm(3)). The primary tumors were located in the colon in 88 patients and the rectum in 64. The median interval between the diagnosis of primary lesions and the diagnosis of brain metastases was 27 months (range 0-180 months). The median neuroradiological follow-up period after GKS was 3 months (mean 6.4 months, range 1-93 months). The local tumor growth control rate, based on MR imaging, was 91.2%. The significant factors for unfavorable local tumor growth control, based on multivariate analysis, were larger tumor volume (p = 0.001) and lower margin dose (p = 0.016). The median overall survival time was 6 months. Lower Karnofsky Performance Scale (KPS) score (p = 0.026) and the presence of extracranial metastases (p = 0.004) at first GKS were significantly correlated with poor overall survival period in multivariate analysis. The cause of death was systemic disease in 112 patients and neurological disease in 13 patients. Leptomeningeal carcinomatosis was significantly correlated with a shorter duration of neurological survival in multivariate analysis (p < 0.0001). CONCLUSIONS Gamma Knife surgery is effective for suppression of local tumor growth in patients with brain metastases from radioresistant colorectal primary cancer. Therefore, clinical and radiological screening of intracranial metastases for patients with lower KPS scores and/or the presence of extracranial metastases as well as follow-up examinations after GKS for brain metastases should be performed periodically in patients with colorectal cancer, because the neurological prognosis is improved by initial and repeat GKS for newly diagnosed or recurrent tumors leading to a prolonged high-quality survival period.

Surgical treatment for late complications following gamma knife surgery for arteriovenous malformations.

Background: To establish the surgical indications and strategy for late complications following gamma knife surgery (GKS) for arteriovenous malformations (AVMs). Methods: Ten male and 7 female patients aged 17–52 years (mean 28.0 years) were retrospectively identified among 686 patients who underwent GKS for AVM at our hospital. Ten patients showed cyst formation (group A), 2 patients had expanding hematoma (group B), and 5 patients had both cyst and expanding hematoma (group C). Results: The mean nidus volume was 10.1 ml (range 0.1–36 ml), and the mean prescription dose at the nidus margin was 19.9 Gy (range 18–28 Gy). Complete obliteration of the nidus was obtained in 12 patients, partial obliteration in 4, and no change in 1. Cyst formation (group A) was asymptomatic in 5 patients, and symptomatic in 5 patients, manifesting as headache, hemianopia, aphasia, and motor weakness. Expanding hematoma (groups B and C) was associated with surrounding brain edema and was symptomatic in all 7 patients. Cyst opening in 1 patient and placement of an Ommaya reservoir in 2 patients were necessary in group A. Both patients in group B underwent craniotomy. Four of the 5 patients in group C required craniotomy. Another patient in group C was lost to follow-up and the final outcome was unknown. Conclusions: Cyst formation is one of the late complications of GKS for AVM. Some cysts show spontaneous regression but others gradually increase in size and become symptomatic, although relatively large asymptomatic cysts are also known. Predicting the future course of a cyst is difficult. Surgery such as placement of an Ommaya reservoir should be considered for symptomatic cases. Expanding hematoma always increases in size and becomes symptomatic, so removal by craniotomy is necessary. Surrounding brain edema decreases rapidly after surgery and neurological symptoms quickly resolve.

Developmental changes in the expression pattern of the JNK activator kinase MUK/DLK/ZPK and active JNK in the mouse cerebellum

JNK is one of the key molecules regulating cell differentiation and migration in a variety of cell types, including cerebral cortical neurons. MUK/DLK/ZPK belongs to the MAP kinase-kinase-kinase class of protein kinases for the JNK pathway and is expressed predominantly in neural tissue. We have determined the expression pattern of MUK/DLK/ZPK and active JNK in the cerebellum at different stages of postnatal development. Quantitative analysis by Western blotting has showed that high expression levels of MUK/DLK/ZPK and active JNK are maintained during the postnatal development of the cerebellum, and that these levels decrease in the adult cerebellum. Immunohistochemical staining has revealed, however, that their distribution in the developing cerebellum is considerably different. Although active JNK is highly concentrated in the premigratory zone of the external germinal layer (EGL), high expression of MUK/DLK/ZPK has been observed in the molecular layer and in the premigratory zone. Neither the active JNK nor MUK protein has been detected in the proliferative zone of the EGL. These observations suggest that during the postnatal development of the cerebellum, the MUK-JNK signaling pathway contributes to the regulation of granule cell differentiation and migration; further, the activity of MUK/DLK/ZPK is tightly regulated by posttranslational mechanisms and by its expression level.

The interaction of Kinesin-1 with its adaptor protein JIP1 can be regulated via proteins binding to the JIP1-PTB domain

BackgroundThe regulatory mechanisms of motor protein-dependent intracellular transport are still not fully understood. The kinesin-1-binding protein, JIP1, can function as an adaptor protein that links kinesin-1 and other JIP1-binding “cargo” proteins. However, it is unknown whether these “cargo” proteins influence the JIP1–kinesin-1 binding.ResultsWe show here that JIP1–kinesin-1 binding in Neuro2a cells was dependent on conserved amino acid residues in the JIP1-phosphotyrosine binding (PTB) domain, including F687. In addition, mutation of F687 severely affected the neurite tip localization of JIP1. Proteomic analysis revealed another kinesin-1 binding protein, JIP3, as a major JIP1 binding protein. The association between JIP1 and JIP3 was dependent on the F687 residue in JIP1, and this association induced the formation of a stable ternary complex with kinesin-1. On the other hand, the binding of JIP1 and JIP3 was independent of kinesin-1 binding. We also show that other PTB binding proteins can interrupt the formation of the ternary complex.ConclusionsThe formation of the JIP1–kinesin-1 complex depends on the protein binding-status of the JIP1 PTB domain. This may imply a regulatory mechanism of kinesin-1-dependent intracellular transport.

Three-dimensional multimodality fusion imaging as an educational and planning tool for deep-seated meningiomas

Abstract Introduction: The utility of surgical simulation with three-dimensional multimodality fusion imaging (3D-MFI) has been demonstrated. However, its potential in deep-seated brain lesions remains unknown. The aim of this study was to investigate the impact of 3D-MFI in deep-seated meningioma operations. Material and Methods: Fourteen patients with deeply located meningiomas were included in this study. We constructed 3D-MFIs by fusing high-resolution magnetic resonance (MR) and computed tomography (CT) images with a rotational digital subtraction angiogram (DSA) in all patients. The surgical procedure was simulated by 3D-MFI prior to operation. To assess the impact on neurosurgical education, the objective values of surgical simulation by 3D-MFIs/virtual reality (VR) video were evaluated. To validate the quality of 3D-MFIs, intraoperative findings were compared. The identification rate (IR) and positive predictive value (PPV) for the tumor feeding arteries and involved perforating arteries and veins were also assessed for quality assessment of 3D-MFI. Results: After surgical simulation by 3D-MFIs, near-total resection was achieved in 13 of 14 (92.9%) patients without neurological complications. 3D-MFIs significantly contributed to the understanding of surgical anatomy and optimal surgical view (p < .0001) and learning how to preserve critical vessels (p < .0001) and resect tumors safety and extensively (p < .0001) by neurosurgical residents/fellows. The IR of 3D-MFI for tumor-feeding arteries and perforating arteries and veins was 100% and 92.9%, respectively. The PPV of 3D-MFI for tumor-feeding arteries and perforating arteries and veins was 98.8% and 76.5%, respectively. Conclusions: 3D-MFI contributed to learn skull base meningioma surgery. Also, 3D-MFI provided high quality to identify critical anatomical structures within or adjacent to deep-seated meningiomas. Thus, 3D-MFI is promising educational and surgical planning tool for meningiomas in deep-seated regions.