Macrophages play a leading role in determining the direction of astrocytic migration in spinal cord injury via ADP-P2Y1R axis.

After spinal cord injury (SCI), inflammatory cells such as macrophages infiltrate the injured area, and astrocytes migrate, forming a glial scar around macrophages. The glial scar inhibits axonal regeneration, resulting in significant permanent disability. However, the mechanism by which glial scar-forming astrocytes migrate to the injury site has not been clarified. Here we show that migrating macrophages attract reactive astrocytes toward the center of the lesion after SCI. Chimeric mice with bone marrow lacking IRF8, which controls macrophage centripetal migration after SCI, showed widely scattered macrophages in injured spinal cord with the formation of a huge glial scar around the macrophages. To determine whether astrocytes or macrophages play a leading role in determining the directions of migration, we generated chimeric mice with reactive astrocyte-specific Socs3 -/- mice, which showed enhanced astrocyte migration, and bone marrow from IRF8 -/- mice. In this mouse model, macrophages were widely scattered, and a huge glial scar was formed around the macrophages as in wild-type mice that were transplanted with IRF8 -/ bone marrow. In addition, we revealed that macrophage-secreted ATP-derived ADP attracts astrocytes via the P2Y1 receptor. Our findings revealed a mechanism in which migrating macrophages attracted astrocytes and affected the pathophysiology and outcome after SCI.

Glial scar survives until the chronic phase by recruiting scar-forming astrocytes after spinal cord injury.

Spinal cord injury (SCI) causes reactive astrogliosis, the sequential phenotypic change of astrocytes in which naïve astrocytes (NAs) transform into reactive astrocytes (RAs) and subsequently become scar-forming astrocytes (SAs), resulting in glial scar formation around the lesion site and thereby limiting axonal regeneration and motor/sensory functional recovery. Inhibiting the transformation of RAs into SAs in the acute phase attenuates the reactive astrogliosis and promotes regeneration. However, whether or not SAs once formed can revert to RAs or SAs is unclear. We performed selective isolation of astrocytes from glial scars at different time points for a gene expression analysis and found that the expression of Sox9, an important transcriptional factor for glial cell differentiation, was significantly increased in chronic phase astrocytes (CAs) compared to SAs in the sub-acute phase. Furthermore, CAs showed a significantly lower expression of chondroitin sulfate proteoglycan (CSPG)-related genes than SAs. These results indicated that SAs changed their phenotypes according to the surrounding environment of the injured spinal cord over time. Even though the integrin-N-cadherin pathway is critical for glial scar formation, collagen-I-grown scar-forming astrocytes (Col-I-SAs) did not change their phenotype after depleting the effect of integrin or N-cadherin. In addition, we found that Col-I-SAs transplanted into a naïve spinal cord formed glial scar again by maintaining a high expression of genes involved in the integrin-N-cadherin pathway and a low expression of CSPG-related genes. Interestingly, the transplanted Col-I-SAs changed NAs into SAs, and anti-ß1-integrin antibody blocked the recruitment of SAs while reducing the volume of glial scar in the chronic phase. Our findings indicate that while the characteristics of glial scars change over time after SCI, SAs have a cell-autonomous function to form and maintain a glial scar, highlighting the basic mechanism underlying the persistence of glial scars after central nervous system injury until the chronic phase, which may be a therapeutic target.

Clinical features and outcomes of spine surgery in patients with ankylosing spondylitis.

OBJECTIVES: The study aimed to comprehend the clinical features and outcomes of surgical treatments for spinal disorders in patients with ankylosing spondylitis. METHODS: This retrospective study enrolled patients with ankylosing spondylitis who underwent spine surgery between 2000 and 2019 in our facility. RESULTS: Thirteen patients with ankylosing spondylitis underwent spine surgeries. The mean age was 56.2 years, and the mean disease duration was 25.1 years at the time of surgery. Nine patients had vertebral fracture, two had kyphotic deformity, and two had myelopathy due to the spinal ligament ossification. Fracture cases included five patients with secondary pseudarthrosis/delayed palsy due to conservative treatment failure. Spinal fixation was performed in all patients. Pedicle subtraction osteotomy for kyphosis and laminectomy for myelopathy were also conducted. All patients improved after surgeries. One patient with kyphotic deformity underwent additional surgery of bilateral hip prosthesis, which resulted in better spine alignment. Four cases of perioperative complications were observed. CONCLUSION: Myelopathy was newly found as the aetiology requiring surgery in patients with ankylosing spondylitis. This summarized case series could help physicians to identify patients with surgically treatable spinal disorders among patients with ankylosing spondylitis.

Elastic shell theory for plant cell wall stiffness reveals contributions of cell wall elasticity and turgor pressure in AFM measurement.

The stiffness of a plant cell in response to an applied force is determined not only by the elasticity of the cell wall but also by turgor pressure and cell geometry, which affect the tension of the cell wall. Although stiffness has been investigated using atomic force microscopy (AFM) and Young's modulus of the cell wall has occasionally been estimated using the contact-stress theory (Hertz theory), the existence of tension has made the study of stiffness more complex. Elastic shell theory has been proposed as an alternative method; however, the estimation of elasticity remains ambiguous. Here, we used finite element method simulations to verify the formula of the elastic shell theory for onion (Allium cepa) cells. We applied the formula and simulations to successfully quantify the turgor pressure and elasticity of a cell in the plane direction using the cell curvature and apparent stiffness measured by AFM. We conclude that tension resulting from turgor pressure regulates cell stiffness, which can be modified by a slight adjustment of turgor pressure in the order of 0.1 MPa. This theoretical analysis reveals a path for understanding forces inherent in plant cells.

Analysis of factors influencing patient satisfaction after total hip arthroplasty in a Japanese cohort: the significant effect of postoperative physical activity.

[Purpose] To determine patient satisfaction after total hip arthroplasty in a Japanese cohort and to identify factors that significantly influence patient satisfaction. [Participants and Methods] This study included 285 patients who underwent primary total hip arthroplasty for osteoarthritis. Postoperative satisfaction, Oxford hip score, short form-12 mental component summary score, and University of California Los Angeles activity score were investigated. Muscle strength and daily step counts were determined using a hand-held dynamometer (µ-Tas F1) and activity monitor (ActivPAL) in 89 and 26 patients, respectively. Factors associated with postoperative satisfaction, Oxford hip score-activities of daily living, and University of California Los Angeles activity score were identified. The relationship between the Oxford hip score-activities of daily living and daily step counts was examined. [Results] Overall, 94.7% of the patients reported satisfaction with total hip arthroplasty. The Oxford hip score-activities of daily living and University of California Los Angeles activity score were significantly associated with patient satisfaction. Younger age and hip abductor strength were significantly associated with a higher Oxford hip score-activities of daily living and University of California Los Angeles activity score. The average daily step count was significantly correlated with the Oxford hip score-activities of daily living. [Conclusion] Self-reported physical activity levels significantly influenced patient satisfaction and were correlated with objective muscle strength and daily step count measurements. These findings can guide total hip arthroplasty patient counseling on the importance of muscle strength and activity levels.

Long-term outcomes of spinal meningioma resection with outer layer of dura preservation technique.

Spinal meningioma is a common benign intradural spinal tumor. It has been reported that the local recurrence rate after surgical resection increases with longer follow-up duration. Simpson grade 1 resection could reduce the risk of recurrence, but this procedure needs dural reconstruction, which would cause cerebrospinal fluid (CSF) leakage or iatrogenic spinal cord injury. Saito et al. reported dura preservation technique to reduce the risk of CSF leakage, in which the meningioma together with the inner layer of the dura is removed and the outer layer is preserved for simple dural closure. The long-term outcomes with this technique have never been investigated. In this study, we retrospectively analyzed the data of 38 surgically treated patients (dura preservation technique, 12 patients; Simpson grade 2 resection, 26 patients) to assess the long-term recurrence rate (mean, 121.5 months; range, 60-228 months). The local recurrence rate in the dura preservation group was 8.3% (1 of 12 cases), which was similar to that in Simpson grade 2 resection group (2 of 26 cases [7.7%]). Although this case series did not indicate the significant difference in the recurrence rates between the dura preservation group and Simpson grade 2 group, we consider that this technique still has advantages for surgically less invasiveness in terms of dural reconstruction which is necessary for Simpson grade 1 and higher possibility of complete resection of tumors compared with Simpson grade 2 resection.

Mechanical measurement of gravitropic bending force in pea sprouts.

Environmental stimuli such as gravity and light modify the plant development to optimize overall architecture. Many physiological and molecular biological studies of gravitropism and phototropism have been carried out. However, sufficient analysis has not been performed from a mechanical point of view. If the biological and mechanical characteristics of gravitropism and phototropism can be accurately grasped, then controlling the environmental conditions would be helpful to control the growth of plants into a specific shape. In this study, to clarify the mechanical characteristics of gravitropism, we examined the transverse bending moment occurring in cantilevered pea (Pisum sativum) sprouts in response to gravistimulation. The force of the pea sprouts lifting themselves during gravitropism was measured using an electronic balance. The gravitropic bending force of the pea sprouts was in the order of 100 Nmm in the conditions set for this study, although there were wide variations due to individual differences.

Surgery-related predictable risk factors influencing postoperative clinical outcomes for thoracic myelopathy caused by ossification of the posterior longitudinal ligament: a multicenter retrospective study.

OBJECTIVE: Compression of the spinal cord by thoracic ossification of the posterior longitudinal ligament (T-OPLL) often causes severe thoracic myelopathy. Although surgery is the most effective treatment for T-OPLL, problems associated with surgical intervention require resolution because surgical outcomes are not always favorable, and a small number of patients experience deterioration of their neurological status after surgery. The aim of the present study was to examine the surgery-related risk factors contributing to poor clinical outcomes for myelopathy caused by T-OPLL. METHODS: Data were extracted from the records of 55 patients with thoracic myelopathy due to T-OPLL at institutions in the Fukuoka Spine Group. The mean follow-up period was 5.3 years. Surgical outcomes were assessed using the Japanese Orthopaedic Association (JOA) scale. To investigate the definitive factors associated with surgical outcomes, univariate and multivariate regression analyses were performed with several patient-related and surgery-related factors, including preoperative comorbidities, radiological findings, JOA score, surgical methods, surgical outcomes, and complications. RESULTS: Neurological status improved in 33 patients (60.0%) and deteriorated in 10 patients (18.2%) after surgery. The use of instrumentation was significantly associated with an improved outcome. In the comparison of surgical approaches, posterior decompression and fusion resulted in a significantly higher neurological recovery rate than did anterior decompression via a posterior approach and fusion or decompression alone. It was also found that postoperative neurological status was significantly poorer when there were fewer instrumented spinal levels than decompression levels. CSF leakage was a predictable risk factor for deterioration following surgery. CONCLUSIONS: It is important to identify preventable risk factors for poor surgical outcomes for T-OPLL. The findings of the present study suggest that intraoperative CSF leakage and a lower number of instrumented spinal fusion levels than decompression levels were exacerbating factors for the neurological improvement in T-OPLL surgery.

Prone position surgery for a professional sumo wrestler with thoracic ossification of the posterior longitudinal ligament resulting in intraoperative brachial plexus injury by hypertrophic pectoral muscles.

Surgery in the prone position is associated with a variety of complications due to the positioning, including the widely recognized peripheral nerve compression injuries and brachial plexus neuropathy. Previous studies have reported that thin body habitus is a predisposing risk factor for the compressive peripheral nerve injuries due to the prone position surgery. However, prone-position-related brachial plexus injury in patients who are overweight due to hypertrophic muscles have never been reported. Here we report a case of a professional sumo wrestler with severe thoracic ossification of the posterior longitudinal ligament (OPLL). Thoracic OPLL was successfully treated by posterior spinal fusion and decompression surgery. Despite a preoperative simulation and intraoperative inspection of the patient's surgical positioning, he suffered from bilateral upper extremity paralysis immediately after the surgery. Postoperative axillary MRI image revealed a high-intensity area on both sides of his pectoral muscles and axillary fossa, which implied that the pectoral muscles between the ribs and chest pad were pushed out toward the axillary fossa, resulting in compressive brachial plexus injury. His upper extremity motor paralysis was fully recovered in 6 months, but he still has mild tingling sensation even after 12 months of his surgery. In conclusion, overweight patients with hypertrophic muscles pose a risk for brachial plexus entrapment injury by pectoral muscles during prone-position surgery, and therefore it would be more effective to use a wide chest pad to reduce the pressure on the pectoral muscles to prevent it from being pushed out toward the axillary fossa.

Does hip center location affect the recovery of abductor moment after total hip arthroplasty?

BACKGROUND: In total hip arthroplasty (THA), placing the cup in an anatomic position is not always possible in case of deformities related to developmental dysplasia of the hip (DDH). Thus far, the influence of a hip center on the abductor moment after THA has not been clearly elucidated. Therefore, we performed a retrospective study to assess (1) how abductor muscle moment recovers postoperatively in THA and (2) whether acetabular cup position affects the recovery of abductor moment. HYPOTHESIS: A high hip center affects the recovery of abductor moment of a dysplastic hip after THA. PATIENTS AND METHODS: We evaluated 100 patients, who underwent unilateral primary THA, at 12 months postoperatively. The study included 86 women and 14 men, with a mean age of 65.5±9.9 years (range, 40 to 86 years). Patients with secondary osteoarthritis due to DDH were included (Crowe 1: 76; Crowe 2: 15, Crowe 3:9, and Crowe 4: none). A cementless straight stem was implanted in all hips. Hip abductor moment was measured using a belt-stabilized hand-held dynamometer. The ratio of moment of the affected side to that of the contralateral side was calculated as moment ratio. The horizontal and vertical centers of rotation (H-COR and V-COR) (with respect to the inter teardrop line) and vertical shift (V-shift) (difference in V-COR between the affected hip and the contralateral normal hip) were determined. RESULTS: At 6 and 12 months postoperatively, the abductor moment ratios were 95.1 and 94.7%, respectively. Significant negative correlation was observed between the postoperative abductor moment ratio and V-COR at 6 months postoperatively (r=-0.2436, p=0.0238). Significant delay in the recovery of abductor moment ratio was observed in the groups with higher hip center (V-shift>15mm) (odds ratio=12.7; 95% CI: 2.11-232.1, p=0.0034) at 6 months postoperatively, which was fully recovered at 12 months postoperatively. DISCUSSION: Superior placement of a hip center, more than 15mm above the true hip center, delayed the recovery of abductor muscle moment after THA. LEVEL OF EVIDENCE: III, retrospective comparative study.

Class III ß-Tubulin Overexpression Induces Chemoresistance to Eribulin in a Leiomyosarcoma Cell Line.

Eribulin is a new drug to treat soft tissue sarcoma (STS) that exerts antitumor activity by binding to microtubules. The prognosis of STS is poor, and eribulin is expected to improve the treatment outcome. We observed several cases that exhibited resistance to eribulin and developed an eribulin-resistant leiomyosarcoma cell line to investigate the mechanism of resistance. The IC50 of eribulin was 125 times higher in the resistant cell line than in the parental cell line, and eribulin did not induce G2/M arrest in resistant cells. The resistant cell line showed increased expression of MDR1 transcript, but protein levels and functional analysis results were similar to the parental cell line. We found that class III ß-tubulin (TUBB3) was overexpressed in the resistant cell line, and siRNA knockdown of TUBB3 partially recovered sensitivity to eribulin. TUBB3 expression in clinical samples varied, suggesting that TUBB3 has the potential to be a biomarker for selection of anticancer drugs and may be a target for overcoming resistance to eribulin.

Correction: Hypoxia-inducible factor 1 alpha is a poor prognostic factor and potential therapeutic target in malignant peripheral nerve sheath tumor.

[This corrects the article DOI: 10.1371/journal.pone.0178064.].

Does Participation in Sports Affect Osteoarthritic Progression After Periacetabular Osteotomy?

BACKGROUND: Periacetabular osteotomy (PAO) is an effective treatment for symptomatic acetabular dysplasia. However, whether postoperative participation in sports leads to progression of the Kellgren-Lawrence (KL) grade of osteoarthritis (OA) in these patients is unclear. PURPOSE: To investigate (1) participation in sports before and after PAO and (2) whether postoperative participation in sports leads to progression of the KL grade. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: The authors retrospectively reviewed data on 161 patients (183 hips) who underwent PAO for symptomatic acetabular dysplasia with preoperative KL grade 1 or 2 between 1998 and 2011. The mean age at the time of surgery was 42.0 ± 10.9 years (range, 12-64 years), and the mean follow-up duration was 100 months (range, 13-180 months). Data included participation in sports, the University of California, Los Angeles (UCLA) activity scale score, age at the time of surgery, body mass index, follow-up duration, history of treatment for developmental hip dislocations, Merle d'Aubigné-Postel score, Oxford Hip Score, center-edge angle, and KL grade. Univariate and multivariate analyses were applied to determine which factors were associated with progression to KL grade 3 or 4 after PAO. RESULTS: The number of patients who participated in sports significantly increased from 50 (31.1%) preoperatively to 89 (55.3%) postoperatively. The mean UCLA score significantly increased from 4.7 ± 2.1 preoperatively to 5.5 ± 2.0 postoperatively. The KL grade progressed to grade 3 or 4 in 16 hips, including 4 hips that underwent conversion to total hip arthroplasty. No significant differences were found in postoperative participation in sports (89 hips [53.3%] vs 11 hips [68.8%], respectively; P = .24) and the UCLA score (5.6 ± 2.0 vs 5.1 ± 2.0, respectively; P = .30) between hips with KL grade 1 or 2 and KL grade 3 or 4. A multivariate analysis revealed that no factors, including postoperative participation in sports, were significantly associated with progression to KL grade 3 or 4. CONCLUSION: Postoperative participation in sports after PAO did not significantly and negatively influence progression of the KL grade at midterm follow-up.

Hypoxia-inducible factor 1 alpha is a poor prognostic factor and potential therapeutic target in malignant peripheral nerve sheath tumor.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. Hypoxia-inducible factor 1 (HIF-1) plays a crucial role in the cellular response to hypoxia and regulates the expression of multiple genes involved in tumor progression in various cancers. However, the importance of the expression of HIF-1α in MPNSTs is unclear. METHODS: The expression of HIF-1α was examined immunohistochemically in 82 MPNST specimens. Cell culture assays of human MPNST cells under normoxic and hypoxic conditions were used to evaluate the impact of anti-HIF-1α-specific siRNA inhibition on cell survival. A screening kit was employed to identify small molecules that inhibited HIF-1α. RESULTS: The nuclear expression of HIF-1α was positive in 75.6% of MPNST samples (62/82 cases). Positivity for HIF-1α was a significant poor prognostic factor both in univariate (P = 0.048) and multivariate (P ≤ 0.0001) analyses. HIF-1α knockdown abrogated MPNST cell growth, inducing apoptosis. Finally, chetomin, an inhibitor of HIF-1α, effectively inhibited the growth of MPNST cells and induced their apoptosis. CONCLUSION: Inhibition of HIF-1α signaling is a potential treatment option for MPNSTs.

Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110alpha inhibitors.

We have previously reported the imidazo[1,2-a]pyridine derivative 4 as a novel p110alpha inhibitor; however, although 4 is a potent inhibitor of p110alpha enzymatic activity and tumor cell proliferation in vitro, it is unstable in solution and ineffective in vivo. To increase stability the pyrazole of 4 was replaced with a hydrazone and a moderately potent p110alpha inhibitor 7a was obtained. Subsequent optimization of 7a afforded exceptionally potent p110alpha inhibitors, including 8c and 8h, with IC(50) values of 0.30 nM and 0.26 nM, respectively; to the best of our knowledge, these compounds are the most potent PI3K p110alpha inhibitors reported to date. Compound 8c was also stable in solution and exhibited significant anti-tumor effectiveness in vivo.

Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110alpha inhibitors.

3-{1-[(4-Fluorophenyl)sulfonyl]-1H-pyrazol-3-yl}-2-methylimidazo[1,2-a]pyridine, 2a, was discovered in our chemical library as a novel p110alpha inhibitor with an IC(50) of 0.67microM, through screening in a scintillation proximity assay. Optimization of the substituents of 2a increased the p110alpha inhibitory activity by more than 300-fold (2g: IC(50)=0.0018microM). Further structural modification of 2g afforded thiazole derivative 12, which has potent p110alpha inhibitory activity (IC(50) of 0.0028microM) and is highly selective for p110alpha over other PI3K isoforms. Compound 12 also inhibited serum-induced cell proliferation of A375 and HeLa cells in vitro with IC(50) values of 0.14microM and 0.21microM, respectively, and suppressed tumor growth by 37% in a mouse HeLa xenograft model when dosed intraperitoneally at 25mg/kg. These results suggest that selective p110alpha inhibitors may have potential as cancer therapeutic agents.

Nuclear beta-catenin correlates with cyclin D1 expression in spindle and pleomorphic sarcomas but not in synovial sarcoma.

Nuclear beta-catenin staining in soft tissue sarcomas (STSs) has been shown to correlate with tumor progression as assessed by proliferative activity or poor prognosis. Frequent activation of Wnt signaling pathway has been also shown in synovial sarcoma (SS), suggesting a specific role of this pathway in SS. We examined roles of nuclear beta-catenin staining within soft tissue sarcomas. Immunohistochemical detection of nuclear beta-catenin accumulation correlated with cyclin D1 overexpression in spindle cell and pleomorphic sarcomas (P = .037), and the expression of these proteins evenly distributed throughout each section. In some cases, strong beta-catenin nuclear staining was observed in highly pleomorphic and mitotic cells. Furthermore, tumors with nuclear beta-catenin accumulation showed statistically significant increasing cyclin D1 mRNA expression level compared with those without (P = .023). Cyclin D1 mRNA expression levels were statistically higher in tumors with cyclin D1 overexpression than in tumors without (P = .037), suggesting that cyclin D1 overexpression is due to transcriptional activation. However, these correlations could not be detected in SS. In biphasic SS, beta-catenin nuclear staining was observed in spindle cells, whereas cyclin D1 nuclear staining was seen in glandular areas where beta-catenin kept membranous expression. Mutations in exon 3 of the beta-catenin gene and in the mutation cluster region of adenomatous polyposis coli gene were absent in this series of cases. Thus, cyclin D1 could be considered as one of the targets of the nuclear beta-catenin in spindle cell and pleomorphic sarcomas. A possible association between beta-catenin accumulation and spindle cell morphogenesis may exist in SS.

Prognostic significance of dysadherin expression in epithelioid sarcoma and its diagnostic utility in distinguishing epithelioid sarcoma from malignant rhabdoid tumor.

Dysadherin is a cancer-associated cell membrane glycoprotein, which downregulates E-cadherin and promotes metastasis. We studied the clinicopathological features in 72 cases of epithelioid sarcoma and in six cases of malignant rhabdoid tumor, and also assessed the immunohistochemical expression of dysadherin, E-cadherin and MIB-1 in epithelioid sarcoma and malignant rhabdoid tumor cases. In addition, we compared dysadherin mRNA expression between epithelioid sarcoma and malignant rhabdoid tumor cell lines, using RT-PCR and real-time quantitative RT-PCR analysis. Immunohistochemical dysadherin expression was more frequently observed in proximal-type epithelioid sarcoma (71%) in comparison with distal-type epithelioid sarcoma (36%) (P = 0.037). Furthermore, seven proximal-type epithelioid sarcoma cases mimicking malignant rhabdoid tumor (histologically classified as the large cell type, accompanied by frequent rhabdoid cells and located in deep soft tissue) were all positive for dysadherin (100%), whereas dysadherin expression was not detected at all in any of the true six malignant rhabdoid tumors (0%). Cell lines established from proximal-type epithelioid sarcoma revealed significantly higher levels of dysadherin mRNA expression, compared with the levels seen in malignant rhabdoid tumor cell lines by real-time quantitative RT-PCR (P = 0.0433). Epithelioid sarcoma patients with dysadherin expression survived for a significantly shorter time than those without dysadherin expression (P = 0.001). In multivariate analysis, dysadherin immunopositivity (P = 0.0004) was one of the two independent adverse prognostic factors. We conclude that dysadherin expression in epithelioid sarcoma is a significant poor prognostic factor and that it is a powerful diagnostic marker for distinguishing epithelioid sarcoma, including the proximal-type epithelioid sarcoma, from malignant rhabdoid tumor. In epithelioid sarcoma, especially in proximal-type epithelioid sarcoma, increased cell disadhesion and motility by dysadherin plays an important role to acquire aggressive biological behavior. However, in malignant rhabdoid tumor, cell growth cycle that is regulated by hSNF5/INI1 gene seems to be critical to lethal biological behavior rather than dysadherin.

Malignant perivascular epithelioid cell tumor of the colon: report of a case with molecular analysis.

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm, and malignant cases are extremely rare. A case of malignant PEComa arising in the colon is described herein. The patient was a 43-year-old Japanese woman without a history of tuberous sclerosis complex. The tumor occurred in the abdominal cavity attached to the serosal side of the descending colon. Histologically, the tumor consisted of sheets or closely packed nests of epithelioid cells with clear or eosinophilic cytoplasms. The tumor cells were positive for HMB-45 but negative for S-100 protein and cytokeratins by immunohistochemical staining. Ki-67 labeling index was 2.9%. Peritoneal dissemination of tumor occurred at 20 months and the patient died of tumor at 38 months after the initial operation. This was considered to be a case of malignant PEComa, based on the histological and clinical features. Tumor cells showed overexpression of cyclin D1 but lacked the loss of heterozygosity of the TSC1 and TSC2 genes. The result suggests that the overexpression of cyclin D1 may play an important role in the tumorigenesis of PEComa. Because PEComas can behave in an aggressive manner, careful follow up is warranted.

DNA hypermethylation status of multiple genes in soft tissue sarcomas.

The aberrant methylation of promoter CpG islands is known to be a major inactivation mechanism of tumor-related genes. To determine the clinicopathological significance of gene promoter methylation in soft tissue sarcomas, we examined the promoter methylation status of 10 tumor-related genes in 65 soft tissue sarcomas and 19 adjacent non-neoplastic tissues by methylation-specific PCR. The methylation frequencies of tumor-related genes tested in soft tissue sarcomas were 17 (26%) for RASSF1A, 11 (17%) for DAP kinase, 10 (15%) for MGMT, nine (14%) for GSTP1, eight (12%) for PTEN, six (9%) for p16 and hMLH1, five (8%) for hMSH2, two (3%) for p14, and one (2%) for RB. Promoter methylation of these genes was not recognized in non-neoplastic tissues. All those cases of soft tissue sarcoma that had MGMT methylation, with the exception of one case of malignant peripheral nerve sheath tumor, showed large tumor size (> or = 10 cm) or recurrence. Moreover, eight of 10 cases with MGMT methylation revealed high American Joint Committee on Cancer stage. Seven of 10 cases (70%) with MGMT methylation showed a loss of MGMT expression by immunohistochemistry. In addition, MGMT methylation status had a statistically significant correlation with a loss of MGMT expression (P=0.014). In conclusion, although methylation of tumor-related genes was a relatively rare event in soft tissue sarcomas, methylation was tumor-specific. Of 10 tumor-related genes, cases with MGMT methylation had a tendency to be aggressive behavior. Moreover, MGMT methylation was closely associated with a loss of MGMT expression. Although our findings need to be extending to a large series, promoter methylation of tumor-related genes is likely to have an association with the pathogenesis of soft tissue sarcomas. Furthermore, MGMT methylation may be associated with tumor aggressiveness and the inactivation of MGMT gene.