Hideki Murata

RADIOTHERAPY FOR PATIENTS WITH METASTASES TO THE SPINAL COLUMN: A REVIEW OF 603 PATIENTS AT SHIZUOKA CANCER CENTER HOSPITAL

PURPOSE Long- and short-course radiotherapy have similar outcomes in the treatment of spinal metastases. Long-course radiotherapy is recommended for patients with good predicted survival to reduce the risk of in-field recurrence, whereas short-course radiotherapy is used for those with poor predicted survival. Therefore, prediction of prognosis and local control is required for selecting the optimal course of radiotherapy. METHODS AND MATERIALS The subjects were 603 patients with spinal metastases who received radiotherapy at the Shizuoka Cancer Center Hospital between September 2002 and February 2007. Factors associated with survival and local control were retrospectively investigated by multivariate analyses. Local recurrence was defined as regrowth within the irradiated field or exacerbation of symptoms such as pain and motor deficits. RESULTS Of the 603 patients, 555 (92%) were followed for 12 months or until death. The survival rates after 6, 12, and 24 months were 50%, 32%, and 19%, respectively, with a median survival of 6.2 months. The median survival periods after long- and short-course radiotherapy were 7.9 and 1.8 months, respectively. In multivariate analysis, primary tumor site, good performance status, absence of previous chemotherapy, absence of visceral metastasis, single bone metastasis, younger age, and nonhypercalcemia were associated with good survival. The local control rates after 6, 12, and 24 months were 91%, 79%, and 69%, respectively, and non-mass-type tumor, breast cancer, and absence of previous chemotherapy were predictors of good local control. CONCLUSIONS Identification of factors associated with good local control and survival may allow selection of an optimal radiotherapy schedule for patients with spinal metastases.

New prognostic factors and scoring system for patients with skeletal metastasis.

The aim of this study was to update a previous scoring system for patients with skeletal metastases, that was proposed by Katagiri et al. in 2005, by introducing a new factor (laboratory data) and analyzing a new patient cohort. Between January 2005 and January 2008, we treated 808 patients with symptomatic skeletal metastases. They were prospectively registered regardless of their treatments, and the last follow‐up evaluation was performed in 2012. There were 441 male and 367 female patients with a median age of 64 years. Of these patients, 749 were treated nonsurgically while the remaining 59 underwent surgery for skeletal metastasis. A multivariate analysis was conducted using the Cox proportional hazards model. We identified six significant prognostic factors for survival, namely, the primary lesion, visceral or cerebral metastases, abnormal laboratory data, poor performance status, previous chemotherapy, and multiple skeletal metastases. The first three factors had a larger impact than the remaining three. The prognostic score was calculated by adding together all the scores for individual factors. With a prognostic score of ≥7, the survival rate was 27% at 6 months, and only 6% at 1 year. In contrast, patients with a prognostic score of ≤3 had a survival rate of 91% at 1 year, and 78% at 2 years. Comparing the revised system with the previous one, there was a significantly lower number of wrongly predicted patients using the revised system. This revised scoring system was able to predict the survival rates of patients with skeletal metastases more accurately than the previous system and may be useful for selecting an optimal treatment.

Associations between microRNA expression and mesenchymal marker gene expression in glioblastoma

The subclassification of glioblastoma (GBM) into clinically relevant subtypes using microRNA (miRNA)- and messenger RNA (mRNA)-based integrated analysis has been attempted. Because miRNAs regulate multiple gene-signaling pathways, understanding miRNA-mRNA interactions is a prerequisite for understanding glioma biology. However, such associations have not been thoroughly examined using high-throughput integrated analysis. To identify significant miRNA-mRNA correlations, we selected and quantified signature miRNAs and mRNAs in 82 gliomas (grade II: 14, III: 16, IV: 52) using real-time reverse-transcriptase polymerase chain reaction. Quantitative expression data were integrated into a single analysis platform that evaluated the expression relationship between miRNAs and mRNAs. The 21 miRNAs include miR-15b, -21, -34a, -105, -124a, -128a, -135b, -184, -196a-b, -200a-c, -203, -302a-d, -363, -367, and -504. In addition, we examined 23 genes, including proneural markers (DLL3, BCAN, and OLIG2), mesenchymal markers (YKL-40, CD44, and Vimentin), cancer stem cell-related markers, and receptor tyrosine kinase genes. Primary GBM was characterized exclusively by upregulation of mesenchymal markers, whereas secondary GBM was characterized by significant downregulation of mesenchymal markers, miR-21, and -34a, and by upregulation of proneural markers and miR-504. Statistical analysis showed that expression of miR-128a, -504, -124a, and -184 each negatively correlated with the expression of mesenchymal markers in GBM. Our functional analysis of miR-128a and -504 as inhibitors demonstrated that suppression of miR-128a and -504 increased the expression of mesenchymal markers in glioblastoma cell lines. Mesenchymal signaling in GBM may be negatively regulated by miR-128a and -504.

Intraneural lipomatous tumor of the median nerve: Three case reports with a review of literature

INTRODUCTION Intraneural lipoma and fibrolipomatous hamartoma of the nerve are rare soft tissue tumors that most commonly occur in the forearm and the wrist, and particularly within the median nerve. When the lesions are large enough, they may cause progressive compression neuropathy. They are distinct entities each other with different clinical and radiological findings and thereby need different surgical treatments. PRESENTATION OF CASE We report here 3 cases of intraneural lipomatous tumors of the median nerve (1 case of intraneural lipoma and 2 cases of fibrolipomatous hamartoma). DISCUSSION All patients were surgically treated successfully with complete excision for intraneural lipoma and with carpal tunnel releases for the both fibrolipomatous hamartomas. CONCLUSION A careful preoperative planning is necessary for the optimal treatment by distinguishing whether it is a resectable or non-resectable tumor based on the clinical and radiological findings, because they have characteristic findings each other.

A comprehensive analysis identifies BRAF hotspot mutations associated with gliomas with peculiar epithelial morphology.

Brain tumors harbor various BRAF alterations, the vast majority of which are the BRAF kinase‐activating V600E mutation. BRAF mutations are most frequently detected in certain subtypes of low‐grade glioma, such as pilocytic astrocytoma (PA), pleomorphic xanthoastrocytoma (PXA), ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNT). However, it is unclear whether gliomas harboring BRAF mutations can be invariably regarded as these glioma subtypes or their derivatives. To address this question, we analyzed 274 gliomas in our institutional case series. We performed high‐resolution melting analyses and subsequent direct Sanger sequencing on DNA isolated from snap‐frozen tumor tissues. As expected, BRAF mutations were detected in the aforementioned low‐grade gliomas: in 4/27 PAs, 2/3 PXAs, 4/8 GGs, and 1/6 DNTs. In addition to these gliomas, 1/2 astroblastomas (ABs) and 2/122 glioblastomas (GBs) harbored BRAF mutations. Pathological investigation of the two GBs revealed that one was a GB displaying epithelial features that presumably arose from a precedent GG, whereas the other GB, which harbored a rare G596 A mutation, showed marked epithelial features, including astroblastic rosettes. Our results indicate that in addition to being present in established BRAF‐associated gliomas, BRAF mutations might be associated with epithelial features in high‐grade gliomas, including sheet‐like arrangement of polygonal tumor cells with a plump cytoplasm and astroblastic rosettes, and thus could potentially serve as a genetic marker for these features.

Precise Detection of IDH1/2 and BRAF Hotspot Mutations in Clinical Glioma Tissues by a Differential Calculus Analysis of High-Resolution Melting Data.

High resolution melting (HRM) is a simple and rapid method for screening mutations. It offers various advantages for clinical diagnostic applications. Conventional HRM analysis often yields equivocal results, especially for surgically obtained tissues. We attempted to improve HRM analyses for more effective applications to clinical diagnostics. HRM analyses were performed for IDH1R132 and IDH2R172 mutations in 192 clinical glioma samples in duplicate and these results were compared with sequencing results. BRAFV600E mutations were analyzed in 52 additional brain tumor samples. The melting profiles were used for differential calculus analyses. Negative second derivative plots revealed additional peaks derived from heteroduplexes in PCR products that contained mutations; this enabled unequivocal visual discrimination of the mutations. We further developed a numerical expression, the HRM-mutation index (MI), to quantify the heteroduplex-derived peak of the mutational curves. Using this expression, all IDH1 mutation statuses matched those ascertained by sequencing, with the exception of three samples. These discordant results were all derived from the misinterpretation of sequencing data. The effectiveness of our approach was further validated by analyses of IDH2R172 and BRAFV600E mutations. The present analytical method enabled an unequivocal and objective HRM analysis and is suitable for reliable mutation scanning in surgically obtained glioma tissues. This approach could facilitate molecular diagnostics in clinical environments.

Skeletal Metastasis of Unknown Primary Origin at the Initial Visit: A Retrospective Analysis of 286 Cases

Background Skeletal metastasis is a common metastatic event for several carcinomas, and the treatment for skeletal metastasis of unknown primary (SMUP) are a critical issue in cancer therapy. Making a diagnosis of the primary site is the most crucial step in the treatment of SMUP; however, the procedures are sometimes difficult and time-consuming, and the primary site often remains unknown. Therefore, to establish optimal diagnostic strategies and elucidate the overall survival rates of SMUP, we conducted this retrospective study. Methods We retrospectively analyzed the clinical data for 286 SMUP cases from a total of 2,641 patients with skeletal metastases who were treated between 2002 and 2014 at our initiations. Results The primary sites were identified in 254/286 patients (88.8%), while 32 (11.2%) primary sites were not detected by our diagnostic strategies. Lung cancer was identified in 72 (25.2%) cases, and was the most frequently observed primary lesion. The median survival time of the SMUP patients was 20.0 months, while the median survival times of solitary bone metastasis cases and multi-bone metastasis cases were 39.0 months and 16.0 months, respectively. The median survival times of prostate cancer cases was over 120 months, that of patients with primary lung cancers was 9.0 months and the median survival time of cases who were finally diagnosed with an unknown primary was 11.0 months. Conclusions We believe that our study would contribute to establishing an optimal strategy for diagnosing the primary site in SMUP patients, and our data provide definite indications for the survival times for different SMUP situations.

Reirradiation of spinal metastases with intensity-modulated radiation therapy: an analysis of 23 patients

This study aimed to evaluate the efficacy and safety of reirradiation with intensity-modulated radiation therapy (IMRT) for spinal metastases. We retrospectively analyzed 23 patients with spinal metastases who underwent IMRT reirradiation between December 2006 and July 2013. We evaluated the spinal radiation doses during the first and second radiation therapy courses, the interval between the courses, and the clinical outcomes after reirradiation, including skeletal-related events, local control rates (LCRs), overall survival (OS), and toxicities. The median time from the first irradiation to reirradiation was 13 months (range, 2–75 months). The median reirradiation dose delivered to 90% of the planning target volume was 24.5 Gy in 5 fractions (range, 14.7–50 Gy in 3–25 fractions). Nineteen patients experienced pain at reirradiation, and 15 of these attained pain relief. Two of the three patients with paresis in the upper or lower extremities upon initiation of reirradiation demonstrated improvement. Local progression was identified in four patients. The median time to local progression was 37 months. The 1- and 2-year LCRs after reirradiation were 88% and 75%, respectively. The 1- and 2-year OS rates after reirradiation were 45% and 20%, respectively, with a median OS of 12 months. No late toxicities occurred. In conclusion, spinal metastasis reirradiation using IMRT appears safe; pain relief and paresis improvement and/or prevention can be expected, along with a reduced risk of radiation-induced toxicity, especially in the spinal cord.

A case of primary extracranial meningioma of the forearm with bone invasion

We report here a rare case of primary extracranial meningioma in a 73-year-old woman with an asymptomatic mass located in the left distal-dorsal forearm. MRI revealed the lesion to be poorly circumscribed and unclear, with iso-signal intensity to muscle on T1 and with a relatively high signal intensity on T2-weighted imaging. The histopathology of the specimen from incision biopsy was typical of meningioma, showing bland spindle cell proliferation with a whorling pattern. Immunohistochemically, the tumor cells were positive for epithelial membrane antigen and vimentin, and negative for S-100 expression.

Solitary fibrous tumor in the pelvis: induced hypoglycemia associated with insulin-like growth factor II.

Solitary fibrous tumors (SFTs) are uncommon neoplasms of mesenchymal origin. SFT was first described in a patient with a distinctive pleural lesion by Klemperer in 1931 [1]. SFTs most commonly occur in the pleura; however, they have been reported to develop in extrapleural sites, for example intracranial lesions, the kidneys, the retroperitoneum, and the extremities [2, 3]. Histologically, SFTs are composed of areas of fibroblast-like spindle cell proliferation within a hemangiopericytomatous pattern. Overall, 15–20 % of SFTs behave aggressively; long-term followup is therefore, necessary [2, 4]. It has been reported that 4–11 % of cases of SFT are associated with hypoglycemia caused by excessive secretion of insulin-like growth factor (IGF)-II by tumors [5, 6]. The primary choice of therapy for SFTs is local resection, which leads to complete remission of hypoglycemia [7]. However, some cases of SFT are inoperable because of large size and/or inaccessible location of the tumor. In these instances, chemotherapy or radiation therapy can be performed for local control; however, no treatment has been established for such cases. In this article, we report a case of SFT in the pelvis associated with a hypoglycemic attack that was successfully treated with intra-arterial chemotherapy and concurrent radiotherapy. The patient was informed that data concerning her case would be submitted for publication, and she consented.