Cost of medical care for malignant brain tumors at hospitals in the Japan Clinical Oncology Group brain-tumor study group.

BACKGROUND: This study aimed to investigate what treatment are selected for malignant brain tumors, particularly glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL), in real-world Japan and the costs involved. METHODS: We conducted a questionnaire survey regarding treatment selections for newly diagnosed GBM and PCNSL treated between July 2021 and June 2022 among 47 institutions in the Japan Clinical Oncology Group-Brain Tumor Study Group. We calculated the total cost and cost per month of the initial therapy for newly diagnosed GBM or PCNSL. RESULTS: The most used regimen (46.8%) for GBM in patients aged ≤74 years was 'Surgery + radiotherapy concomitant with temozolomide'. This regimen's total cost was 7.50 million JPY (Japanese yen). Adding carmustine wafer implantation (used in 15.0%), TTFields (used in 14.1%), and bevacizumab (BEV) (used in 14.5%) to the standard treatment of GBM increased the cost by 1.24 million JPY for initial treatment, and 1.44 and 0.22 million JPY per month, respectively. Regarding PCNSL, 'Surgery (biopsy) + rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy' was the most used regimen (42.5%) for patients of all ages. This regimen incurred 1.07 million JPY per month. The three PCNSL regimens based on R-MPV therapy were in ultra-high-cost medical care (exceeding 1 million JPY per month). CONCLUSIONS: Treatment of malignant brain tumors is generally expensive, and cost-ineffective treatments such as BEV are frequently used. We believe that the results of this study can be used to design future economic health studies examining the cost-effectiveness of malignant brain tumors.

Axillary Artery Injury Associated with Dislocated or Displaced Proximal Humeral Fracture: A Report of 3 Cases.

CASE: (1) A 69-year-old man sustained a proximal humeral fracture-dislocation. During emergency surgery, copious bleeding occurred. A pseudoaneurysm was identified 30 days postoperatively. (2) A 69-year-old man sustained a proximal humeral fracture and axillary artery injury. Physical examination demonstrated a cold but pink hand. Hemiarthroplasty and bypass vein grafting were performed. (3) An 86-year-old woman sustained a proximal humeral fracture and axillary artery injury. Her hand had turned cold and pale. Reverse shoulder arthroplasty and bypass vein grafting were performed. CONCLUSION: In cases of proximal humeral fractures with significant displacement, concomitant axillary artery injury must be assessed and if there is a high index of suspicion, prompt advanced imaging is necessary.

Improvements in activities of daily living among patients with brain tumors are associated with age, baseline physical function, duration of rehabilitation, and tumor recurrence but not type.

Genetic testing has improved the accuracy of diagnosis of brain tumors, and treatment is now tailored to the type of brain tumor. In contrast, the factors that influence the improvement in independence in activities of daily living (ADLs) following rehabilitation have not been clarified, particularly the role of tumor type. In this retrospective cohort study of 358 participants, we analyzed changes in the Functional Independence Measure (FIM) from pre-rehabilitation to post-rehabilitation provided in an acute care hospital. Multiple regression was used to determine whether FIM gain is associated with age, gender, preadmission Karnofsky Performance Status (KPS), number of rehabilitation days, average duration of daily therapy (min/day), and tumor recurrence and type (WHO grade 1, 2, 3, and 4 gliomas; primary central nervous system lymphomas; and metastatic brain tumors). The results showed that older age (ß -0.183), tumor recurrence (ß -0.137), preadmission KPS < 80 (ß -0.180), and higher baseline total FIM score (ß -0.470) were associated with lower FIM gain whereas the average duration of daily therapy (ß 0.153) was associated with higher FIM gain. Brain tumor type was not associated with FIM gain. Improved independence in ADLs is more influenced by demographic, functional status, and treatment factors than differences in brain tumor type.

Recent advances in liquid biopsy of central nervous system lymphomas: case presentations and review of the literature.

Surgical biopsy is the gold standard for diagnosing central nervous system (CNS) lymphomas. However, reliable liquid biopsy methods for diagnosing CNS lymphomas have quickly developed and have been implicated in clinical decision-making. In the current report, we introduce two patients for whom liquid biopsy was essential for diagnosing CNS lymphomas and discuss the rapidly growing applications of this technology.

Successful Multimodal Treatment of Intracranial Growing Teratoma Syndrome with Malignant Features.

Molecular analysis of the growing teratoma syndrome has not been extensively studied. Here, we report a 14-year-old boy with a growing mass during treatment for a mixed germ cell tumor of the pineal region. Tumor markers were negative; thus, growing teratoma syndrome was suspected. A radical resection via the occipital transtentorial approach was performed, and histopathological examination revealed a teratoma with malignant features. Methylation classifier analysis confirmed the diagnosis of teratoma, and DMRT1 loss and 12p gain were identified by copy number variation analysis, potentially elucidating the cause of growth and malignant transformation of the teratoma. The patient remains in remission after intense chemoradiation treatment as a high-risk germ cell tumor.

Missense mutation of NRAS is associated with malignant progression in neurocutaneous melanosis.

Neurocutaneous melanosis (NCM) is a rare congenital neurocutaneous syndrome characterized by congenital melanocytic nevus of skin and abnormal proliferation of leptomeningeal melanocytes. Early acquisition of post-zygotic somatic mutations has been postulated to underlie the pathogenesis of NCM. The pathogenesis of NCM remains to be fully elucidated, and treatment options have not been established. Here, we report for the first time, multiregional genomic analyses in a 3-year-old autopsied girl with leptomeningeal melanomatosis associated with NCM, in which a ventriculo-peritoneal (VP) shunt was inserted for the treatment of hydrocephalus. The patient expired six months after the onset due to respiratory failure caused by abdominal dissemination via VP shunt. We performed multiregional exome sequencing to identify genomic differences among brain and abdominal tumors, nevus, and normal tissues. A total of 87 somatic mutations were found in 71 genes, with a significantly large number of gene mutations found in the tumor site. The genetic alterations detected in the nevus were only few and not shared with other sites. Three mutations, namely GNAQ R183Q, S1PR3 G89S and NRAS G12V, considered pathogenic, were found, although S1PR3 mutations have not been previously reported in melanocytic tumors. GNAQ and S1PR3 mutations were shared in both tumor and normal sites. Moreover, the mutant allele frequencies of the two mutations were markedly higher in tumor sites than in normal sites, with copy-neutral loss-of-heterozygosity (CN-LOH) occurring in tumor. NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discovering novel driver mutations associated with tumorigenesis and targeted therapy.

Multi-omics analyses of choroid plexus carcinoma cell lines reveal potential targetable pathways and alterations.

PURPOSE: Choroid plexus carcinomas (CPCs) are extremely rare brain tumors and carry a dismal prognosis. Treatment options are limited and there is an urgent need to develop models to further research. In the present study, we established two CPC cell lines and performed multi-omics analyses. These cell lines serve as valuable models to propose new treatments in these rare but deadly brain tumors. METHODS: Multi-omic profiling including, (i) methylation array (EPIC 850 K), (ii) whole genome sequencing (WGS), (iii) CANCERPLEX cancer genome panel testing, (iv) RNA sequencing (RNA-seq), and (v) proteomics analyses were performed in CCHE-45 and NGT131 cell lines. RESULTS: Both cell lines were classified as methylation class B. Both harbored pathogenic TP53 point mutations; CCHE-45 additionally displayed TP53 loss. Furthermore, alterations of the NOTCH and WNT pathways were also detected in both cell lines. Two protein-coding gene fusions, BZW2-URGCP, and CTTNBP2-ERBB4, mutations of two oncodrivers, GBP-4 and KRTAP-12-2, and several copy number alterations were observed in CCHE-45, but not NGT131. Transcriptome and proteome analysis identified shared and unique signatures, suggesting that variability in choroid plexus carcinoma tumors may exist. The discovered difference's importance and implications highlight the possible diversity of choroid plexus carcinoma and call for additional research to fully understand disease pathogenesis. CONCLUSION: Multi-omics analyses revealed that the two choroid plexus carcinoma cell lines shared TP53 mutations and other common pathway alterations and activation of NOTCH and WNT pathways. Noticeable differences were also observed. These cell lines can serve as valuable models to propose new treatments in these rare but deadly brain tumors.

Reliable detection of genetic alterations in cyst fluid DNA for the diagnosis of brain tumors.

PURPOSE: Liquid biopsy of cyst fluid in brain tumors has not been extensively studied to date. The present study was performed to see whether diagnostic genetic alterations found in brain tumor tissue DNA could also be detected in cell-free DNA (cfDNA) of cyst fluid in cystic brain tumors. METHODS: Cyst fluid was obtained from 22 patients undergoing surgery for a cystic brain tumor with confirmed genetic alterations in tumor DNA. Pathological diagnoses based on WHO 2021 classification and diagnostic alterations in the tumor DNA, such as IDH1 R132H and TERT promoter mutation for oligodendrogliomas, were detected by Sanger sequencing. The same alterations were analyzed by both droplet digital PCR (ddPCR) and Sanger sequencing in cyst fluid cfDNA. Additionally, multiplex ligation-dependent probe amplification (MLPA) assays were performed to assess 1p/19q status, presence of CDKN2A loss, PTEN loss and EGFR amplification, to assess whether differentiating between astrocytomas and oligodendrogliomas and grading is possible from cyst fluid cfDNA. RESULTS: Twenty-five genetic alterations were found in 22 tumor samples. All (100%) alterations were detected in cyst fluid cfDNA by ddPCR. Twenty of the 25 (80%) alterations were also detected by Sanger sequencing of cyst fluid cfDNA. Variant allele frequency (VAF) in cyst fluid cfDNA was comparable to that of tumor DNA (R = 0.62, Pearson's correlation). MLPA was feasible in 11 out of 17 (65%) diffuse gliomas, with close correlation of results between tumor DNA and cyst fluid cfDNA. CONCLUSION: Cell-free DNA obtained from cyst fluid in cystic brain tumors is a reliable alternative to tumor DNA when diagnosing brain tumors.

Risk Factors for Reintubation After Anterior Cervical Spine Surgery: Comparative Study of Patients With Cervical Spine Trauma and Patients With Cervical Degenerative Disease.

STUDY DESIGN: Single-center retrospective study. OBJECTIVES: The aim was to compare the postoperative outcomes of anterior cervical spine surgery (ACSS) in patients with and without cervical spine trauma. SUMMARY OF BACKGROUND: Few papers have addressed airway obstruction after anterior ACSS for patients with cervical spine trauma. This study aimed to compare airway obstruction after ACSS between patients with cervical degenerative disorders and cervical spine injuries and identify the risk factors for unplanned postoperative reintubation. MATERIALS AND METHODS: Seventy-seven patients who underwent ACSS were enrolled in this retrospective study. There were 52 men and 25 women, with a mean age of 60.3±15.5 years old. The causes of surgery were as follows: 24 cervical spine fractures or dislocations, 12 spinal cord injuries without bony fracture, 19 disc herniations, and 22 myelopathies. The patients' characteristics, operative data, and risk factors for unplanned reintubation within 5 days postoperatively were analyzed using medical records. RESULTS: Postoperative reintubation was performed in 3 patients (3.9%), all of whom suffered trauma. We further examined risk factors for reintubation in patients in the trauma group. There was no significant difference between the reintubation (R) and nonreintubation (non-R) groups in age, sex, body mass index, amount of blood loss and operation time, preoperative paralysis severity, and the number of fused segments. Patients in group R had significantly higher rates of severe anterior element injury (100% vs. 27.3%, P=0.0011). Airway obstruction due to laryngopharyngeal edema and swelling was confirmed by laryngoscopy and computed tomography images. CONCLUSIONS: Unplanned reintubation after ACSS occurred at a higher rate in trauma patients than in patients with degenerative disorders. Our results suggested that the severe damage to the anterior element of the cervical spine was associated with postoperative reintubation. EVIDENCE LEVEL: Level IV.

Clinical, imaging, and molecular features of radiation-induced glioblastomas developing more than 20 years after radiation therapy for intracranial germinomatous germ cell tumor: illustrative cases.

BACKGROUND: Germinomatous germ cell tumor is highly sensitive to chemoradiotherapy; patients are expected to survive for decades. Many radiation-induced malignant gliomas (RIMGs) occur >10 years after radiotherapy. Standard therapy for RIMGs has not been established because of the lesion's rarity, the patient's shorter survival period, and the risk of radiation necrosis by repeat radiation. OBSERVATIONS: Two patients, a 32-year-old man and a 50-year-old man, developed glioblastomas more than 20 years after radiation monotherapy for germinoma with or without mature teratoma. The first patient showed a tumor in the left frontotemporal region with disseminated lesions and died 2 months after partial resection of the tumor without responding to the chemotherapy with temozolomide and bevacizumab. Methylation classifier analysis classified the pathology as closest to diffuse pediatric-type high-grade glioma, Rtk1 subtype. The second patient showed a tumor mass in the brainstem and left cerebellar peduncle, which worsened progressively during chemotherapy with temozolomide and bevacizumab. The tumor transiently responded to stereotactic radiotherapy with the CyberKnife. However, the patient died of RIMG recurrence-related aspiration pneumonia 11 months after the biopsy. Methylation classifier analysis classified the pathology as closest to infratentorial pilocytic astrocytoma. LESSONS: Chemoradiotherapy may improve the survival of patients with RIMGs. Furthermore, molecular features may influence the clinical, locoregional, and pathological features of RIMG.

Risk Factors for the Incidence of the Volar Lunate Facet Fragments in Distal Radius Fractures.

Background The volar lip of the distal radius is the key structure for wrist joint stability. Rigid fixation of the volar lunate facet (VLF) fragment is difficult because of its unique anatomy, and a high rate of postoperative displacement was demonstrated. Purposes The aim of the study is to identify risk factors for VLF in distal radius fractures (DRFs) and to reconsider the important point for primary fixation. Patients and Methods One hundred fifty-five patients who underwent open reduction and internal fixation for an DRF were included and classified into one of the following two groups: VLF(+)or VLF(-). Demographic data, including age, sex, body mass index (BMI), laterality, trauma mechanism, and AO Foundation/Orthopaedic Trauma Association (AO/OTA) classification were recorded. Several parameters were investigated using wrist radiographs of the uninjured side and computed tomography scans of the injured side. Univariate and multivariate logistic regression analyses were performed to evaluate the risk factors for VLF. Results There were 25 patients in the VLF(+) group and 130 patients in the VLF(-) group. The incidence of VLF was 16.1%. The VLF(+) group tended to have a higher BMI and higher energy trauma mechanism. The odds ratio for the sigmoid notch angle (SNA), volar tilt (VT), and lunate facet curvature radius (LFCR) were 0.84, 1.32, and 0.70, respectively, with multivariate analysis, which was significant. A smaller SNA, larger VT, and smaller LFCR are potential risk factors for VLF. Conclusion Over-reduction of the VT at primary fixation should be avoided because it could place an excess burden on the VLF and cause subsequent postoperative fixation failure and volar carpal subluxation. Level of Evidence IV.

Preoperative Lower-Limb Muscle Predictors for Gait Speed Improvement after Total Hip Arthroplasty for Patients with Osteoarthritis.

This study aimed to identify preoperative lower-limb muscle predictors for gait speed improvement after total hip arthroplasty (THA) with hip osteoarthritis. Gait speed improvement was evaluated as the subtraction of preoperative speed from postoperative speed. The preoperative muscle composition of ipsilateral hip abductors was evaluated using computed tomography. The females (n = 45) showed smaller total cross-sectional areas of the gluteal muscles than the males (n = 13). The gluteus maximus in the females showed lower lean muscle mass area (LMM) and higher ratios of the intramuscular fat area and the intramuscular adipose tissue area to the total muscle area (TM) than the males. Regression analysis revealed that LMM/TM of the glutei medius and minimus may correlate negatively with postoperative improvement in gait speed. Receiver operating characteristic curve analysis for prediction of minimum clinically important improvement in gait speed at ≥0.32 m/s resulted in the highest area under the curve for TM in the upper portion of the gluteus maximus with negative correlation. The explanatory variables of hip abductor muscle composition predicted gait speed improvement after THA more precisely in the females compared with the total group of both sexes. Preoperative muscle composition should be evaluated separately based on sex for the achievement of clinically important improvement in gait speed after THA.

Multidrug chemotherapy, whole-brain radiation and cytarabine therapy for primary central nervous system lymphoma in elderly patients with dose modification based on geriatric assessment: study protocol for a phase II, multicentre, non-randomised study.

INTRODUCTION: Multidrug chemoimmunotherapy with rituximab, high-dose methotrexate, procarbazine and vincristine (R-MPV) is a standard therapy for younger patients with primary central nervous system lymphoma (PCNSL); however, prospective data regarding its use in elderly patients are lacking. This multi-institutional, non-randomised, phase II trial will assess the efficacy and safety of R-MPV and high-dose cytarabine (HD-AraC) for geriatric patients with newly diagnosed PCNSL. METHODS AND ANALYSIS: Forty-five elderly patients will be included. If R-MPV does not achieve complete response, the patients will undergo reduced-dose, whole-brain radiotherapy comprising 23.4 Gy/13 fractions, followed by local boost radiotherapy comprising 21.6 Gy/12 fractions. After achieving complete response using R-MPV with or without radiotherapy, the patients will undergo two courses of HD-AraC. All patients will undergo baseline geriatric 8 (G8) assessment before HD-AraC and after three, five and seven R-MPV courses. Patients with screening scores of ≥14 points that decrease to <14 points during subsequent treatment, or those with screening scores <14 points that decrease from the baseline during subsequent treatment are considered unfit for R-MPV/HD-AraC. The primary endpoint is overall survival, and the secondary endpoints are progression-free survival, treatment failure-free survival and frequency of adverse events. The results will guide a later phase III trial and provide information about the utility of a geriatric assessment for defining chemotherapy ineligibility. ETHICS AND DISSEMINATION: This study complies with the latest Declaration of Helsinki. Written informed consent will be obtained. All participants can quit the study without penalty or impact on treatment. The protocol for the study, statistical analysis plan and informed consent form have been approved by the Certified Review Board at Hiroshima University (CRB6180006) (approval number: CRB2018-0011). The study is ongoing within nine tertiary and two secondary hospitals in Japan. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION: jRCTs061180093.

Correction loss following short-segment posterior fixation for traumatic thoracolumbar burst fractures related to endplate and intervertebral disc destruction.

BACKGROUND: There has been widespread use of short-segment posterior fixation (SSPF) for traumatic thoracolumbar burst fractures. The relationship between the destruction of the vertebral endplate and adjacent disc and postoperative correction loss has been studied in only a few studies. This study investigated the risk factors for correction loss following SSPF. METHODS: Forty-eight patients (mean age 35.0 years) who underwent SSPF for thoracolumbar burst fractures were enrolled. The mean follow-up period was 25.7 months (12-98 months). The neurological status and postoperative back pain were assessed by the medical records. Segmental kyphotic angle (SKA) and anterior vertebral body height ratio (AVBHR) were measured radiographically to assess indirect vertebral body reduction and local kyphosis. Preoperative Sander's traumatic intervertebral disc lesion (TIDL) classification and AO classification were used to evaluate the severity of disc and vertebral endplate injury. The corrective loss was considered present if ΔSKA was ≥10°. A multivariate logistic regression analysis was performed to identify the risk factors associated with postoperative loss of correction. RESULTS: The fracture distribution was as follows: 10 at T12, 17 at L1, 10 at L2, 9 at L3, and 2 at L4. Vertebral fractures were classified in the following way: A3 in 13 patients, A4 in 11, B1 in 11, and B2 in 13. In 47 patients (98%), a union of the fractured vertebrae was achieved. SKA and AVBHR improved significantly after surgery from 11.6° to 3.5° and from 67.2 to 90.0%, respectively. However, the correction loss at follow-up was 10.4° and 9.7%, respectively. Twenty patients (42%) had severe TIDL (grade 3). Postoperative ΔSKA and ΔAVBHR were significantly higher in patients with TIDL grade 3 than with TIDL grade 0-2. The presence of cranial TIDL grade 3 and older age were significant risk factors for ΔSKA ≥10° on multivariate logistic regression analysis. All patients could walk at follow-up. TIDL grade 3 and ΔSKA ≥10° were associated with severe postoperative back pain. CONCLUSIONS: Risk factors for loss of correction after SSPF for thoracolumbar burst fractures were severe disc and endplate destruction at the time of injury and older age.

Preoperative three-dimensional multifusion imaging aiding successful microvascular decompression of a cerebellopontine angle lipoma: associated hemifacial spasm. Illustrative case.

BACKGROUND: Cerebellopontine angle (CPA) lipoma-associated hemifacial spasm (HFS) is rare. As the removal of CPA lipomas has a high risk of worsening the neurological symptoms, surgical exploration is warranted only in selected patients. Preoperative identification of the lipoma affected site of the facial nerve, and offending artery are crucial for patient selection and successful microvascular decompression (MVD). OBSERVATIONS: Presurgical simulation using three-dimensional (3D) multifusion imaging showed a tiny CPA lipoma wedged between the facial and auditory nerves, as well as an affected facial nerve by the anterior inferior cerebellar artery (AICA) at the cisternal segment. Although a recurrent perforating artery from the AICA anchored the AICA to the lipoma, successful MVD was achieved without lipoma removal. LESSONS: The presurgical simulation using 3D multifusion imaging could identify the CPA lipoma, affected site of the facial nerve, and offending artery. It was helpful for patient selection and successful MVD.

Elevated ratio of C-type lectin-like receptor 2 level and platelet count (C2PAC) aids in the diagnosis of post-operative venous thromboembolism in IDH-wildtype gliomas.

INTRODUCTION: Podoplanin (PDPN) is known to induce platelet aggregation via interacting with the C-type lectin-like receptor-2 on platelets and is involved in postoperative venous thromboembolism (VTE) formation. In this study, we investigate the correlation between soluble C-type lectin-like receptor (sCLEC-2) levels and PDPN expression in patients with high grade gliomas and the relationship between sCLEC-2 levels and the occurrence of VTE. MATERIALS AND METHODS: Forty-four patients harboring high grade gliomas, treated surgically at the Department of Neurosurgery, Niigata University from April 2018 to August 2020, were included. Patients with high grade gliomas were divided into isocitrate dehydrogenase (IDH)- wildtype and mutant groups, and the presence or absence of VTE and the intensity of PDPN by immunohistochemistry were confirmed. Platelet counts, as well as plasma sCLEC-2 and PDPN were measured in these patients. Furthermore, the levels of sCLEC-2 concentration were divided by the platelet count (C2PAC index) for comparison. RESULTS: IDH-wildtype glioma patients highly expressed PDPN (P < 0.001) compared to IDH-mutant glioma patients. In total, 9 (20.5 %) patients were diagnosed with VTE during the follow-up period, of which 8 patients harbored IDH-wildtype gliomas, and one patient an IDH-mutant glioma. Mean sCLEC-2 levels and C2PAC index in patients with IDH-wildtype gliomas were significantly higher than that of low or no PDPN expression group, which included patients with IDH-mutant gliomas (P = 0.0004, P = 0.0002). In patients with IDH-wildtype gliomas, the C2PAC index in patients with VTE was significantly higher than in patients without VTE (P = 0.0492). The optimal cutoff point of C2PAC for predicting VTE in IDH-wildtype glioma patients was 3.7 with a sensitivity of 87.5 % and specificity of 51.9 %. CONCLUSION: Platelet activation is strongly involved in the development of VTE in patients with IDH-wildtype high grade gliomas, and C2PAC index is a potential marker to detect VTE formation after surgery.

Association of preoperative muscle composition of the lower extremity with gait function after total knee arthroplasty.

BACKGROUND: Limitations of gait function persist in some patients with knee osteoarthritis after total knee arthroplasty. This study aimed to identify preoperative muscle composition variables of the operated limb associated with postoperative gait function. METHODS: Longitudinal data from 45 patients who underwent unilateral primary total knee arthroplasty were retrospectively analyzed. Timed Up-and-Go test and gait speed were measured preoperatively and at 3 and 6 months postoperatively. Preoperative muscle composition in the glutei medius and minimus, the quadriceps, the hamstrings, and combination of the hamstrings and quadriceps were evaluated by computed tomography. The area ratio of the individual muscle composition to the total muscle was calculated. The factors associated with Timed Up-and-Go test and gait speed were identified using stepwise regression analysis. RESULTS: Shorter Timed Up-and-Go test and faster gait speed at each time point correlated with higher lean muscle mass area of the total hamstrings, higher area ratio of lean muscle mass to the total hamstrings or to combination of the hamstrings and quadriceps, and lower area ratio of low density lean tissue or intramuscular adipose tissue to the total hamstrings. Shorter Timed Up-and-Go test at each time point also correlated with higher combined area of lean muscle mass of the hamstrings and quadriceps. Faster gait speed at each time point additionally correlated with lower area ratio of intramuscular fat to the total hamstrings and lower area ratio of lean tissue mass or intramuscular adipose tissue to combination of the hamstrings and quadriceps. Regression analysis using the significant muscle composition variables revealed that the area ratio of lean muscle mass to the total hamstrings was the only predictor of Timed Up-and-Go test and gait speed after operation. CONCLUSIONS: Preoperative area ratio of ipsilateral lean muscle mass to the total hamstrings could predict gait function after total knee arthroplasty.

Epigenetic upregulation of Schlafen11 renders WNT- and SHH-activated medulloblastomas sensitive to cisplatin.

BACKGROUND: Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma. METHODS: SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo. RESULTS: High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells. CONCLUSIONS: High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin.

Activation of STAT3 (signal transducer and activator of transcription 3) in synovial tissues from the hip joint in the early stage of rapidly destructive coxopathy.

Interleukin-6 signaling activates signal transducer and activator of transcription 3 (STAT3), resulting in matrix metalloproteinase-3 (MMP-3) production. The hip joints with rapidly destructive coxopathy (RDC) show rapid chondrolysis, probably by increased MMP-3. This study aimed to elucidate STAT3 activation in the synovial tissues with joint destruction in the early stage of RDC. Synovial tissues within 7 months from the disease onset were obtained from four RDC patients with femoral head destruction and high serum levels of MMP-3. RDC synovial tissues demonstrated the synovial lining hyperplasia with an increase of CD68-positive macrophages and CD3-positive T lymphocytes. STAT3 activation was found in the synovial tissues by immunohistochemistry using anti-phospho-STAT3 antibody. The majority of phospho-STAT3-positive cells were the synovial lining cells and exhibited negative expression of the macrophage or T cell marker. Treatment with CP690,550, a Janus Kinase inhibitor, resulted in a decrease in phospho-STAT3-positive cells, especially with high intensity, indicating effective suppression of STAT3 activation in RDC synovial tissues. Inhibitory effect of CP690,550 could work through the Janus Kinase/STAT3 axis in the synovial tissues in the early stage of RDC. Thus, STAT3 may be a potential therapeutic target for prevention of joint structural damage in RDC.