Search

AimsThe aim of this study is to evaluate the clinical results of operative intervention for femoral metastases which were selected based on expected survival and to discuss appropriate surgical strategies.MethodsFrom 2002 to 2017, 148 consecutive patients undergoing surgery for femoral metastasis were included in this study. Prognostic risk assessments were performed according to the Katagiri and revised Katagiri scoring system. In general, the low-risk group underwent resection and reconstruction with endoprosthetic replacement (EPR), while the high-risk group underwent internal fixation (IF) and radiation therapy. For the intermediate-risk group, the operative choice depended on the patient’s condition, degree of bone destruction, and radio-sensitivity. Overall survival, local failure, walking ability, and systemic complications were evaluated.ResultsA total of 83 patients underwent EPR (low-risk, 23%; intermediate-risk, 60%; high-risk, 17%) and 65 patients underwent IF (low-risk, 0%; intermediate-risk, 32%; high-risk, 68%). The one-year survival rate was 71% for EPR and 15% for IF (p < 0.001). The one-year local failure-free survival was 93% for EPR and 67% for IF, and the two-year and five-year local failure-free survival for EPR were both 88% (p = 0.016). Although the ambulatory rate was 99% for EPR and 60% for IF, the median time to ambulation was shorter in the IF (EPR, 28 days, interquartile range (IQR) 25 to 35; IF, 23 days, IQR 18 to 28; p < 0.001) The cause of non ambulation was mainly due to progression of cancer (89%). The rate of systemic complications was comparable between the two groups (EPR, 18%; IF, 22%; p = 0.598).ConclusionSelective use of EPR where survival is expected to be good offers correspondingly good long-term results. IF is less invasive with shorter treatment period, which is beneficial for patients with short-term expected survival. Prognosis is an important indicator in selecting operative procedures for femoral metastasis. Cite this article: Bone Joint J 2020;102-B(3):285–292

Pro-gastrin-releasing peptide (ProGRP) is an established tumor marker of small cell lung cancer. The purpose of this study was to determine if ProGRP could serve as a tumor marker for the Ewing sarcoma family of tumors (ESFTs). Sixteen patients with ESFTs (mean age 32 years) were included in this study. As a control group, 42 patients with other tumor types that clinically or pathologically mimic ESFTs were also analyzed. Pre-treatment serum ProGRP and neuron-specific enolase (NSE) levels, the relationships between these levels, and tumor volume were investigated. In addition, serial changes in the serum or plasma ProGRP (6 patients) and NSE levels (5 patients) were measured over the course of treatment. Pre-treatment serum ProGRP levels were higher than the normal range in 8 of 16 patients; for these eight patients, ProGRP levels positively correlated with tumor volume (R = 0.99). In the control group, ProGRP levels were within the normal range, except for the two patients. Changes in ProGRP levels during treatment were consistent with tumor volume. Serum NSE levels were elevated in 14 of 16 patients with ESFTs and 8 of 42 patients with other tumor types. The range of NSE elevation was much smaller compared to that of ProGRP. Our data indicate that ProGRP is superior to NSE in terms of specificity. Serum ProGRP levels were elevated in half of the patients with ESFTs and reflected therapeutic response. ProGRP is a reliable tumor marker for the diagnosis of ESFTs and evaluation of treatment response.

We analyzed 428 femoral metastases initially treated with radiotherapy between 2002 and 2011 to clarify the clinical details of post-irradiation fractures of femoral metastasis. Patients included 161 men and 167 women, with a mean age of 62 years. Fracture incidence, fracture site, fracture risk based on X-ray images before radiotherapy, and interval from completion of radiotherapy to fracture occurrence were assessed. In addition, 24 pathological specimens obtained during 27 surgeries for these fractures were examined. Fractures occurred in 7.7% of 428 femoral metastases (total 33: 28 actual fractures and five virtual fractures with progressive pain and bone destruction). The fracture rate was 7.8% in the proximal femur and 1.5% in the shaft (P = 0.001). Fractures occurred a median of 4.4 months after radiotherapy, with 39.4% occurring within 3 months and 63.6% within 6 months. Among femurs with high fracture risk according to Harrington’s criteria or Mirels’ score, the fracture rate was 13.9% and 11.8%, respectively. Viable tumor cells were detected in all five patients with painful virtual fracture, in 85.7% of femurs with actual fractures that occurred within 3 months, and in only 25.0% of actual fractures occurring after 3 months. Post-irradiation fractures of femoral metastasis most frequently occurred within 3 months after radiotherapy, and were more common in the peritrochanteric area than in the shaft. Radiological evidence of impending fracture did not correlate with a high fracture rate. Actual fractures occurring after more than 3 months were likely caused by post-irradiation fragility of the femur, without viable tumor cells.

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.

We conducted this study to clarify the current trends and healthcare resource usage in the treatment of inpatients with primary malignant brain tumors. The Diagnostic Procedure Combination (DPC) data of all inpatients treated between 2013 and 2014 in the 370 core and branch hospitals enrolled in the Japanese Neurosurgical Society training program were collected. DPC is a discharge abstract and administrative claims database of inpatients. We assessed 6,142 primary, malignant brain tumor patients. Patient information, diagnostic information, treatment procedure, and healthcare resource usage were analyzed. Chemotherapy was the most frequent treatment (27% of cases), followed by surgery (13%) and surgery + chemo-radiotherapy (11%). Temozolomide (TMZ), the most frequently used chemotherapeutic drug, was administered to 1,236 patients. Concomitant TMZ and radiotherapy was administered to 816 patients, and was performed according to the Stupp regimen in many cases. The mean length of hospital stay (LOS) was 16 days, and the mean medical cost was 1,077,690 yen. The average medical cost of TMZ-only treatment was 1,138,620 yen whilst it was 4,424,300 yen in concomitant TMZ patients. The LOS was significantly shorter in high-volume than in low-volume hospitals, and the medical cost was higher in hospitals treating 21–50 patients compared to those treating 1–10 patients. However, the direct medical cost of TMZ treatment was the same across different volume hospitals. This is the first report of current trends and healthcare resource usage in the treatment of primary malignant brain tumor inpatients in the TMZ era in Japan.

Skeletal-related events (SRE) are common in patients with renal cell carcinoma (RCC) that includes bone metastasis. The purpose of this study was to clarify the effectiveness of zoledronate with and without sunitinib, combined with radiotherapy, for the treatment of bone metastasis from RCC. We retrospectively analyzed 62 RCC patients with bone metastasis, who had been treated with radiotherapy at our institution. We divided the study cohort into two groups: patients treated with radiotherapy alone (RT; n = 27) and those treated with radiotherapy combined with zoledronate (RT + Z; n = 35). We investigated the overall survival and post-irradiation (PI)-SRE-free rate for each group, as well as the effect of sunitinib in the RT + Z treatment group. In addition, we determined treatment effectiveness by imaging assessments and relative response rates. There was no significant difference in the survival rates between the RT and RT + Z treatment groups (p = 0.11). However, the PI-SRE-free rate in the RT + Z group was significantly higher than that in the RT group (p = 0.02). The PI-SRE-free rate was significantly higher in patients who were treated with sunitinib after radiotherapy than in those who were treated without sunitinib (p = 0.03). However, there was no significant difference in the relative response rates, as assessed by imaging, in each group. Radiotherapy combined with zoledronate is an effective treatment for RCC with bone metastasis to prevent PI-SRE. Sunitinib may reduce PI-SRE if used after radiotherapy and combined with zoledronate.

Osteosarcoma is the second most common primary malignant bone tumor, after multiple myeloma. It typically affects the metaphyseal part of the long bones, with the knee being affected in almost 50 % of cases [1]. Osteosarcoma is usually treated with chemotherapy combined with wide resection. Currently, the 5-year survival rate is reported to be around 70 % [2, 3]. Osteosarcoma rarely arises in the pelvis, but when it does, it often brings about severe intractable pain. However, the clinical results of surgery for pelvic osteosarcoma are disappointing because of the serious functional disability after surgery and the low survival rate [2, 4, 5]. We herein report a case of large pelvic osteosarcoma that was successfully treated with repetitive intra-arterial chemotherapy combined with radiotherapy. It is more than 21 years from the first presentation and the patient has been disease free for the last 7 years. The patient was informed that the data concerning the case would be submitted for publication, and she consented. Case report

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.

SummaryPosterior reversible encephalopathy syndrome (PRES) is a clinical entity characterized by acute neurological symptoms such as severe headache, seizures, and visual disturbance, and by typical reversible lesion on brain magnetic resonance (MR) images. Since PRES is thought to be caused by vascular endothelial injury due to cytotoxic agents or acute systemic hypertension, the number of reports on PRES associated with angiogenesis inhibitors has been increasing. Although five cases that developed PRES due to pazopanib for renal cell carcinoma have already been reported, none of PRES due to pazopanib for soft-tissue sarcoma has been reported thus far. We describe a case of a 49-year-old woman with retroperitoneal soft-tissue sarcoma who developed PRES during pazopanib administration. Pazopanib at 800 mg/day was administered as her third-line treatment at relapse. After 38 days of pazopanib, she was admitted to our hospital with severe headache, vomiting, and systemic hypertension. The next day, she developed consciousness deterioration and visual disturbance together with exacerbated systemic hypertension. Brain MR images revealed hyper-intense signals on FLAIR sequences in the bilateral occipital lobes and the left thalamus. Intravenous nicardipine injection was immediately started to control her blood pressure and pazopanib was discontinued. Her symptoms gradually improved and disappeared on the fifth hospital day. After 2 weeks, hyper-intense signals on a FLAIR sequence disappeared completely. She restarted a low dose of pazopanib under good blood pressure control and experienced no subsequent recurrence of PRES.

The 2007 World Health Organization classification defined a new variant of glioblastoma (GBM) containing oligodendroglioma foci as GBM with an oligodendroglioma component (GBMO), which shows a favorable clinical outcome compared with "classic" GBM. However, all of the reported cases of GBMO have been adult cases, with no previous reports of pediatric cases. In this report, we demonstrated molecular characteristics of a pediatric GBMO case, showing aggressive clinical behavior with 8-month overall survival. The case showed neither isocitrate dehydrogenase 1/2 genes (IDH1/2) mutation nor 1p/19q co-deletion, a hallmark of oligodendroglioal tumors. In addition, microsatellite instability, leading to the putative mechanism of temozolomide (TMZ) resistance, was frequently detected. Molecular genetic analysis may provide critical prognostic and therapeutic insights, especially for the pediatric glioma containing oligodendroglioma components.

The purpose of this study was to investigate the differences between spinal metastasis and osteoporotic compression fractures on plain X-ray images, focusing on asymmetrical vertebral collapse and fracture level.This study included 180 patients with pathological collapse from spinal metastasis (188 vertebrae) who were treated at our institution and 70 patients (92 vertebrae) with osteoporotic compression fractures. Anteroposterior X-ray images of the lower thoracic and lumbar spine were evaluated for asymmetrical collapse deformity.Asymmetrical collapse was found in 134 vertebrae (71.3%) with metastasis, and in 20 osteoporotic vertebrae (21.7%); this difference was significant (p 0.0001). The asymmetrical collapse angle in spinal metastasis patients ranged from 0 to 18°, with a mean of 7.0 and a standard deviation (SD) of 4.5. In contrast, the asymmetrical collapse angle in patients with osteoporotic fractures ranged from 0 to 13°, with a mean of 3.1 and a SD of 2.8. The difference in collapse angle between the two groups was statistically significant (p 0.001). The cutoff value to suspect spinal metastasis was determined to be 5° or more (sensitivity 0.67, specificity 0.74). Fracture at Th10 or below L3 was found in 20.2% of spinal metastasis patients; only 3% of osteoporotic fractures occurred at these levels.Asymmetrical collapse with an angle of 5° or more and fractures at atypical levels on plain radiographs can be useful clues to spinal metastasis.

Squamous cell carcinoma (SCC) is a common skin cancer that may be associated with ultraviolet ray exposure, scarring due to a trauma or burn, or chronic osteomyelitis [1, 2]. SCC is usually treated by surgery. However, for SCC of the lower legs, surgery is sometimes problematic; indeed, tumour cells easily infiltrate the tibia due to a lack of protective fat buffer layer at the front of the lower leg. Amputation may be a safe method for resecting the tumour, and management of the wound after the [...]

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.

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.

The authors present an extremely rare case of a fibrotic nodule arising from the cerebellopontine (CP) angle. A 57-year-old male had suffered from hearing disturbance and tinnitus for several years. Computed tomography revealed a high-density mass in the left CP angle with little enhancement after intravenous administration of contrast media. Magnetic resonance imaging (MRI) showed a very hypointense mass on T2-weighted imaging. T1-weighted MRI with gadolinium revealed very faint, delayed enhancement of the tumor. The patient underwent surgical resection of the tumor. Histopathologically the lesion comprised entirely fibrotic tissue consisting of thick collagenous fibers and sclerosing blood vessels with a few intervening viable cells with, partly, the immunophenotype of arachnoid cells. Intracranial fibrotic nodules are extremely rare. This tumor, however, had some radiological features similar to those of other, more common, tumors for example meningiomas or solitary fibrous tumors; it was, therefore, difficult to distinguish it from the others. It is believed that intracranial fibrotic nodules usually have benign, non-neoplastic characteristics, although their natural history is not yet fully understood. It is, therefore, necessary to be able to perform a differential diagnosis that will distinguish this rare condition from other intracranial fibrous neoplasms that occasionally have malignant features.

INTRODUCTIONIntraneural 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 CASEWe report here 3 cases of intraneural lipomatous tumors of the median nerve (1 case of intraneural lipoma and 2 cases of fibrolipomatous hamartoma).DISCUSSIONAll patients were surgically treated successfully with complete excision for intraneural lipoma and with carpal tunnel releases for the both fibrolipomatous hamartomas.CONCLUSIONA 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.

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.

A 74-year-old man suffered sudden loss of consciousness at home. Computed tomography revealed severe subarachnoid hemorrhage and an unusual posterior cerebral artery (PCA) aneurysm with vertebrobasilar dolichoectasia (VBD). The aneurysm was located in the right hypothalamus. VBD associated with a distal lesion makes endovascular treatment difficult because of the elongation and tortuosity of the access route. However, endovascular coil embolization was successful for the present ruptured PCA aneurysm with VBD.

Summary We report the case of a 39-year-old man with a dermatofibrosarcoma protuberans (DFSP) on the right shoulder. A wide surgical excision of the tumour was performed, creating a 12-cm-wide defect. An anterolateral thigh flap created from two semicircular skin paddles was harvested and the two skin paddles were slid towards each other to cover the circular defect. The sliding technique is a useful design that preserves the suprafascial plexus and enables a single perforator to supply two split-skin paddles. Using this design, the donor site can be closed primarily without requiring a skin graft. This technique can be applied to other free flaps to reconstruct wide defects after the resection of cancers.

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.

Background Solitary bone only metastasis (SBOM) is a rare condition in which metastasis is limited to a single skeletal lesion originating from a previously treated or controllable primary lesion. The study objective was to evaluate the clinical features and survival regarding this rare condition and to clarify its treatment strategy. Methods A total of 1453 patients with bone metastasis registered in our hospital database were enrolled. To assess the primary and/or metastatic lesion we used plain X-ray images, CT, MRI and FDG-PET scans as well as bone scans. Results Among the patients, only 27 (1.8%) had SBOM. The primary cancers responsible for SBOM were lung in seven patients, breast in five, kidney in four, prostate in two, uterus in two and other types in seven. Treatment of SBOM involved resection in four patients, radiotherapy only in 17, radiotherapy in combination with zoledronate in six and chemotherapy with zoledronate in one. Local recurrence did not develop in the four cases treated with resection. However, in-field recurrence was found in 4 of 22 (18%) patients who underwent radiotherapy. All three patients who received >40 Gy did not develop in-field recurrence. The overall and event free survival rates at 5 years were 63% and 41%, respectively. Conclusions Solitary bone only metastasis should be treated with wide resection or long-course radiotherapy at doses 40–50 Gy to achieve long lasting local tumor control.

Proneural and mesenchymal are two subtypes of glioblastoma identified by gene expression profiling. In this study, the primary aim was to detect markers to develop a clinically applicable method for distinguishing proneural and mesenchymal glioblastoma. The secondary aims were to investigate the temporospatial dynamics of these markers and to explore the association between these markers and the expression of chromatin-modifying genes. One hundred thirty-three glioma samples (grade II: 14 samples, grade III: 18, grade IV: 101) were analyzed. We quantified the expression of 6 signature genes associated with proneural and mesenchymal glioblastoma by quantitative reverse transcription-polymerase chain reaction. We assigned proneural (PN) and mesenchymal (MES) scores based on the average of the 6 markers and calculated a predominant metagene (P-M) score by subtracting the MES from the PN score. We used these scores to analyze correlations with malignant transformation, tumor recurrence, tumor heterogeneity, chromatin-modifying gene expression, and HDAC7 expression. The MES score positively correlated with tumor grade, whereas the PN score did not. The P-M score was able to distinguish the proneural and mesenchymal subtypes. It was decreased in cases of tumor recurrence and malignant transformation and showed variability within a tumor, suggesting intratumoral heterogeneity. The PN score correlated with the expression of multiple histone-modifying genes, whereas the MES score was associated only with HDAC7 expression. Thus, we demonstrated a simple and straightforward method of quantifying proneural/mesenchymal markers in glioblastoma. Of note, HDAC7 expression might be a novel therapeutic target in glioblastoma treatment.

BACKGROUND: High-throughput gene expression studies on glioblastoma have identified proneural (PN) gene-expression type as the one characterized by a strong expression of neurogenesis-related genes. Although the PN type is generally associated with good prognosis, the clinical and biological significance of the PN type has not been completely elucidated. In the current study, we aimed to expound the biological significance of the PN subtype by quantifying its gene signature in glioblastoma, low-grade gliomas, and glioblastoma-derived cellular spheres. METHODS: To evaluate the PN gene-expression signature of all the glioma grades, we quantified the expression signature of 82 gliomas (grade II, 14 gliomas; III, 16; and IV, 52) by using real-time reverse transcription PCR. All samples had been assessed for IDH mutation and 1p/19q co-deletion. We characterized the PN signature by estimating the relative expression score of nine PN markers (DLL3, BCAN, OLIG2, NKX2.2, ASCL1, SOX2, ERBB3, NCAM1, and NCAM2) and eight mesenchymal (MES) markers (YKL-40, CD44, Vimentin, COL1A1, TRL2, TRL4, TRADD, and RELB). In addition, we evaluated the expression signature of five matched glioblastoma tissues and glioblastoma-derived cellular spheres. RESULTS: The PN gene-expression signature was higher in low-grade gliomas than that in glioblastoma. In the IDH-wild glioblastoma (n = 42), 19% of the tumor was characteristic of the PN type, while 32% was of the MES type. The overall survival time was not significantly different between two types. The analysis of five glioblastoma-derived spheres demonstrated that two of them showed the PN signature, and the remaining three showed the MES signature. Glioblastoma-derived spheres showed a different expression signature from that of the originating tumor. In particular, two spheres derived from the MES glioblastoma showed the PN signature after successful expansion as neurospheres, suggesting a conversion of the MES to PN type under proliferating conditions. CONCLUSIONS: The expression analysis of glioma tissues showed that the PN signature is displayed early in gliomagenesis, and is not specific to a subset of glioblastomas. Given that the MES to PN conversion is a frequent event under proliferating conditions, a display of the subtype-specific gene signature might be reversible phenomenon. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.

The most recent definition of glioblastoma with oligodendroglioma component (GBMO) assigned clinical significance to the observation of oligodendroglial foci within glioblastomas. However, the pathological mechanism of its histogenesis has not yet been determined. We report the genetic analysis of a GBMO case that evolved from an astrocyte lineage. A 37-year-old male underwent a third craniotomy for the removal of recurrent lesions of a secondary glioblastoma originating from a previous diffuse astrocytoma. The lesion in the right frontal lobe contained oligodendroglial foci within a glioblastoma background, while the remaining lesions showed only classic glioblastoma histology. Genetic analyses revealed distal 10q loss of heterozygosity (LOH) occurring de novo in the oligodendroglial tissue, as well as 10p, 17p LOH, and isocitrate dehydrogenase-1 gene (IDH1) mutations inherited from the previous lesions. The final recurrent glioblastoma underwent LOH on almost the entire of chromosome 10. Based on these results, the importance of an oligodendroglial component in glioblastomas may be limited.

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.