Protocol for treating lumbar spinal canal stenosis with a combination of ultrapurified, allogenic bone marrow-derived mesenchymal stem cells and in situ-forming gel: a multicentre, prospective, double-blind randomised controlled trial.

INTRODUCTION: In patients with combined lumbar spinal canal stenosis (LSCS), a herniated intervertebral disc (IVD) that compresses the dura mater and nerve roots is surgically treated with discectomy after laminoplasty. However, defects in the IVD after discectomy may lead to inadequate tissue healing and predispose patients to the development of IVD degeneration. Ultrapurified stem cells (rapidly expanding clones (RECs)), combined with an in situ-forming bioresorbable gel (dMD-001), have been developed to fill IVD defects and prevent IVD degeneration after discectomy. We aim to investigate the safety and efficacy of a new treatment method in which a combination of REC and dMD-001 is implanted into the IVD of patients with combined LSCS. METHODS AND ANALYSIS: This is a multicentre, prospective, double-blind randomised controlled trial. Forty-five participants aged 20-75 years diagnosed with combined LSCS will be assessed for eligibility. After performing laminoplasty and discectomy, participants will be randomised 1:1:1 into the combination of REC and dMD-001 (REC-dMD-001) group, the dMD-001 group or the laminoplasty and discectomy alone (control) group. The primary outcomes of the trial will be the safety and effectiveness of the procedure. The effectiveness will be assessed using visual analogue scale scores of back pain and leg pain as well as MRI-based estimations of morphological and compositional quality of the IVD tissue. Secondary outcomes will include self-assessed clinical scores and other MRI-based estimations of compositional quality of the IVD tissue. All evaluations will be performed at baseline and at 1, 4, 12, 24 and 48 weeks after surgery. ETHICS AND DISSEMINATION: This study was approved by the ethics committees of the institutions involved. We plan to conduct dissemination of the outcome data by presenting our data at national and international conferences, as well as through formal publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCT2013210076.

Status of the Current Treatment Options and Potential Future Targets in Uterine Leiomyosarcoma: A Review.

Uterine leiomyosarcoma (uLMS) is the most common subtype of mesenchymal tumors in the uterus. This review aims to summarize the current standard therapies and the molecular properties of uLMS for novel molecular-targeted therapies. Although 65% of uLMS cases are diagnosed in stage I, the 5-year overall survival rate is less than 60%. The only effective treatment for uLMS is complete and early resection, and chemotherapy is the main treatment for unresectable advanced or recurrent cases. No chemotherapy regimen has surpassed doxorubicin monotherapy as the first-line chemotherapy for unresectable advanced or recurrent cases in terms of overall survival in phase 3 trials. As a second-line treatment, pazopanib, trabectedin, and eribulin are used, but their therapeutic effects are not sufficient, highlighting the urgent need for development of novel treatments. Recent developments in gene analysis have revealed that homologous recombination deficiency (HRD), including breast cancer susceptibility gene 2 (BRCA2) mutations, are frequently observed in uLMS. In preclinical studies and several case series, poly(adenosine diphosphate-ribose)polymerase inhibitors showed antitumor effects on uLMS cell lines with BRCA2 mutations or HRD and in recurrent or persistent cases of uLMS with BRCA2 mutations. Thus, HRD, including BRCA mutations, may be the most promising therapeutic target for uLMS.

Lipid Droplet Accumulation Independently Predicts Poor Clinical Prognosis in High-Grade Serous Ovarian Carcinoma.

High-grade serous ovarian carcinoma (HGSOC) is an epithelial cancer that accounts for most ovarian cancer deaths. Metabolic abnormalities such as extensive aerobic glycolysis and aberrant lipid metabolism are well-known characteristics of cancer cells. Indeed, accumulation of lipid droplets (LDs) in certain types of malignant tumors has been known for more than 50 years. Here, we investigated the correlation between LD accumulation and clinical prognosis. In 96 HGSOC patients, we found that high expression of the LD marker adipophilin was associated with poor progression-free and overall survival (p = 0.0022 and p = 0.014, respectively). OVCAR-3 ovarian carcinoma cells accumulated LDs in a glucose-dependent manner, which suggested the involvement of aerobic glycolysis and subsequently enhanced lipogenesis, with a result being LD accumulation. The acyl-CoA: cholesterol acyltransferase 1 inhibitor K604 and the hydroxymethylglutaryl-CoA reductase inhibitor pitavastatin blocked LD accumulation in OVCAR-3 cells and reduced phosphorylation of the survival-related kinases Akt and ERK1/2, both of which have been implicated in malignancy. Our cell-based assays thus suggested that enhanced aerobic glycolysis resulted in LD accumulation and activation of survival-related kinases. Overall, our results support the idea that cancers with lipogenic phenotypes are associated with poor clinical prognosis, and we suggest that adipophilin may serve as an independent indicator of a poor prognosis in HGSOC.

Miliary cerebrospinal lesions caused by Nocardia beijingensis in an immunocompetent patient.

The genus Nocardia usually infect immunocompromised patients. Pulmonary nocardiosis is the most common Nocardia-induced infection while central nervous system (CNS) is the most common extrapulmonary site to develop nocardial disease. Approximately 54 % cases of previously reported nocardial brain abscesses were solitary lesions, while 38 % cases had multiple lesions; but miliary-like ring enhancing lesions have not been reported previously. We present a case of immunocompetent patient with miliary-like cerebrospinal lesions caused by Nocardia beijingensis. A 68-year-old Japanese man presented with acute-onset headache, vomiting, and progressive disturbance of consciousness. A contrasted magnetic resonance imaging (MRI) scan showed countless miliary-like ring-shaped enhancing lesions on the patient's whole brain, brain stem, and cervical spinal cord. A brain biopsy was performed and Kinyoun stain suggested that the brain lesions were abscesses caused by Nocardia species. 16S ribosomal RNA sequencing identified Nocardia beijingensis as the causative microorganism. The trimethoprim/sulfamethoxazole regimen was continued for 7 months and the patient showed good improvement with recovery of consciousness. Clinical manifestation of Nocardia beijingensis infection is poorly studied. Further cases are needed to be accumulated.

Assessment of the Passive Tension of the First Dorsal Interosseous and First Lumbrical Muscles Using Shear Wave Elastography.

PURPOSE: Quantitative evaluation of passive tension of the intrinsic muscles of the hand is necessary to assess contracture of the intrinsic muscles accurately. The aim of this study was to evaluate the shear modulus, which is related to passive muscle tension, of the first dorsal interosseous (FDI) and first lumbrical (FL) muscles using shear wave elastography. METHODS: Subjects were 18 healthy males. The shear modulus of the FDI and FL muscles was assessed at several proximal interphalangeal (PIP), distal interphalangeal (DIP), metacarpophalangeal (MCP), and wrist joint positions. The position in which the MCP joint was flexed 60° past 0° with PIP-DIP joint extension and that in which the MCP joint was extended 30° past 0° with PIP-DIP joint flexion were respectively defined as the slack and stretched positions. We analyzed whether the shear modulus was affected by finger position (slack or stretched), wrist position (30° flexion past 0° and 30° extension past 0°), and muscle (FDI or FL). RESULTS: Shear modulus in the stretched position was significantly higher than that in the slack position. The shear modulus of the FL muscle at 30° wrist extension was significantly higher than that at 30° flexion. The shear modulus of the FL muscle was significantly higher than that of the FDI muscle in the stretched position with the wrist at 30° flexion and extension, and in the slack position with the wrist at 30° extension. CONCLUSIONS: The shear modulus of the FDI and FL muscles increased with MCP joint extension and PIP-DIP joint flexion. The difference in the muscle characteristics between the FDI and FL muscles should be considered when evaluating or treating contractures of the intrinsic muscles. CLINICAL RELEVANCE: Shear wave elastography can evaluate the condition of the intrinsic muscles of the hand quantitatively.

Enantio- and diastereoselective hetero-Diels-Alder reactions between 2-aza-3-silyloxy-1,3-butadienes and aldehydes catalyzed by chiral dirhodium(II) carboxamidates.

The first catalytic asymmetric hetero-Diels-Alder reaction between 2-aza-3-silyloxy-1,3-butadienes and aldehydes is described. With dirhodium(II) tetrakis[N-benzene-fused-phthaloyl-(S)-piperidinonate], Rh(2)(S-BPTPI)(4), the cycloaddition reaction proceeded exclusively in an endo mode to give all-cis-substituted 1,3-oxazinan-4-ones in high yields with up to 98% ee.