A unique hinge binder of extremely selective aminopyridine-based Mps1 (TTK) kinase inhibitors with cellular activity.

Mps1, also known as TTK, is a dual-specificity kinase that regulates the spindle assembly check point. Increased expression levels of Mps1 are observed in cancer cells, and the expression levels correlate well with tumor grade. Such evidence points to selective inhibition of Mps1 as an attractive strategy for cancer therapeutics. Starting from an aminopyridine-based lead 3a that binds to a flipped-peptide conformation at the hinge region in Mps1, elaboration of the aminopyridine scaffold at the 2- and 6-positions led to the discovery of 19c that exhibited no significant inhibition for 287 kinases as well as improved cellular Mps1 and antiproliferative activities in A549 lung carcinoma cells (cellular Mps1 IC50=5.3 nM, A549 IC50=26 nM). A clear correlation between cellular Mps1 and antiproliferative IC50 values indicated that the antiproliferative activity observed in A549 cells would be responsible for the cellular inhibition of Mps1. The X-ray structure of 19c in complex with Mps1 revealed that this compound retains the ability to bind to the peptide flip conformation. Finally, comparative analysis of the X-ray structures of 19c, a deamino analogue 33, and a known Mps1 inhibitor bound to Mps1 provided insights into the unique binding mode at the hinge region.

Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity.

Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.

Two-level ligamentum flavum hematoma in the lumbar spine. Case report.

Ligamentum flavum hematoma is a rare cause of spinal root or cord compression that usually occurs at a single level. No case of multiple-level ligamentum flavum hematoma has previously been reported. We report an extremely rare case of double, contiguous ligamentum flavum hematomas in the lumbar spine. A 71-year-old man with hypertension and degenerative lumbar scoliosis presented with pain and muscle weakness in the left lower extremity after physical exertion. Magnetic resonance imaging of the lumbar spine showed severe spinal stenosis caused by two-level ligamentum flavum hematoma (L3-L4 and L4-L5). Both hematomas were completely removed and the diagnosis was histologically confirmed. Symptoms completely resolved after surgery. Despite being extremely rare, ligamentum flavum hematoma with involvement of multiple levels may be observed.

Progressive myelopathy due to idiopathic intraspinal tumoral calcinosis of the cervical spine. Case report.

Tumoral calcinosis is a rare disorder that most often occurs in periarticular regions of the extremities. Here, the authors report on an extremely rare case of idiopathic intraspinal tumoral calcinosis of the cervical spine. This 54-year-old man presented with a 2-week history of progressive cervical myelopathy. Results of magnetic resonance imaging and computed tomography myelography of the cervical spine revealed an intraspinal calcified mass lesion posterior to the spinal cord at the C3-4 level, resulting in marked spinal cord compression. Spinal cord decompression and en bloc resection of the mass lesion were performed via a C-2 laminoplasty and C3-4 laminectomy. The mass was localized in the dura mater. Histologically, the lesion consisted of numerous nodules with amorphous calcified materials and a florid proliferation of multinucleated giant cells; that is, its histological characteristics were identical to those of tumoral calcinosis. The symptoms disappeared completely after surgery. In all previously reported cases of cervical tumoral calcinosis, the lesion was located in the paraspinal soft tissue, with bone and facet joint involvement. The present case is the first reported instance of cervical tumoral calcinosis localized only in the spinal canal.

Giant cell tumor of fifth lumbar vertebrae: two case reports and review of the literature.

BACKGROUND CONTEXT: complete or total en bloc spondylectomy has been recommended for giant cell tumors of the spine. Wide local resection of the fifth lumbar vertebra carries potential risks of major complications because of its anatomical features. Only nine cases of the giant cell tumors involving the fifth lumbar vertebra have been reported in the literature. PURPOSE: to present two cases of giant cell tumor of the fifth lumbar vertebra treated by single-stage combined anterior and posterior tumor resection over 7 years of follow-up. STUDY DESIGN: Case report and a review of literature. METHODS: A 33-year-old female and a 20-year-old female, each diagnosed with giant cell tumor of fifth lumbar vertebra, underwent single-stage tumor resection through a combined posterior and retroperitoneal anterior approach. RESULTS: The resection of the fifth lumbar vertebra was completed in the first case without major perioperative complications. In the second case, massive bleeding during the anterior procedure for resection of the vertebral body interrupted the total resection of the tumor, resulting in possible residual tumor which required adjuvant radiotherapy. The patients recovered both clinically and neurologically after the operation. Spinal reconstruction was maintained, and no recurrence of the tumor was evident at the 7-year and 8-year follow-up, respectively. CONCLUSION: There was no recurrence of the tumor after the combined single-stage anterior and posterior tumor resection and adjuvant radiotherapy for the second case for over 7 years follow-up. However, complete resection of the vertebra and tumor at the fifth lumbar vertebra is still challenging to accomplish.

Dural substitute with polyglycolic acid mesh and fibrin glue for dural repair: technical note and preliminary results.

BACKGROUND: An ideal dural substitute that enables watertight closure, has sufficient strength, and can be absorbed without remnant materials that induce inflammation, adhesion, and infection is not available. The purpose of this study was to evaluate the efficacy of a bioabsorbable polyglycolic acid (PGA) mesh and fibrin glue as a substitute for dural repair. METHODS: Altogether, 10 patients with noted dural tears during extradural spinal surgery and 20 patients who underwent durotomy for intradural spinal surgery were included in this study. In a series of 20 consecutive cases, dural closure was performed by suture and fibrin glue. In the subsequent 10 consecutive patients, dural closure was performed by suture and fibrin glue with the use of absorbable PGA mesh. The medical records and magnetic resonance imaging (MRI) of the surgical site were retrospectively reviewed to evaluate the presence of a cerebrospinal fluid (CSF) fistula or leakage after the surgery. RESULTS: A CSF fistula occurred in five patients who underwent dural repair with fibrin glue alone, and postoperative MRI showed CSF leakage in two patients with incidental dural tears after laminectomy for ossification of ligamentum flavum. No CSF fistula was present in patients who underwent dural repair using PGA mesh and fibrin glue, and no adverse effects or complications were encountered postoperatively. Follow-up MRI revealed no evidence of CSF leakage around the reconstructed dura mater. CONCLUSIONS: The use of PGA mesh and fibrin glue for the repair of dura mater is a useful method of preventing CSF leakage in spinal surgery.

Chronic subdural hematoma coexisting with ligamentum flavum hematoma in the lumbar spine: a case report.

We present a case of a chronic spinal subdural hematoma combined with a ligamentum flavum hematoma in the lumbar spine treated surgically. An 83-year-old woman receiving antiplatelet medicine due to an angina suffered from pain in her lower extremity and gait disturbance after a backward fall. Radiological findings including magnetic resonance imaging (MRI) revealed hematoma in the ligamentum flavum at the level of L2 - L3 and a chronic subdural hematoma at the level from L3 to L5. Laminectomy through L2 to L5 was performed and a hematoma existing in the ligamentum flavum and cystic mass was removed. A chronic subdural hematoma was spontaneously evacuated after splitting of the dura mater and an intact arachnoid membrane was observed with no leakage of cerebrospinal fluid. Her clinical symptoms completely disappeared after surgery. To the best of our knowledge, this is the first case of combination of chronic subdural hematoma and ligamentum flavum hematoma in the lumbar spine treated by surgery. Chronic spinal subdural hematoma and hematoma in the ligamentum flavum should be considered as a cause of progressive nerve root compression in patients with anticoagulant therapy, and an appropriate pre-operative diagnosis would be needed to achieve complete decompression of subdural and epidural hematoma.

Clinical features of cauda equina tumors requiring surgical treatment.

In this study, we evaluated the clinical features of cauda equina tumors requiring surgical treatment. Medical records of 28 patients with cauda equina tumors (13 men and 15 women) undergoing surgical treatment were retrospectively reviewed. The majority of histological diagnoses indicated schwannoma (23 cases, 82%), and the remaining 5 indicated ependymoma, neurofibroma, meningioma, and ganglioneuroblastoma. In 86% of the cases, the initial symptom was pain in the lower back and/or lower extremities. Preoperatively, half of the patients had symmetrical pain in the lower back or lower extremities, severe pain in the supine position, or pain that was increased by coughing. One third of the patients needed morphine to control nocturnal pain. Tumor size, as determined by magnetic resonance imaging (MRI), correlated with preoperative symptom duration (r = 0.66, p < 0.001). These findings indicate that symmetrical lower back pain and/or pain that radiates to both lower extremities and increases in the supine position are characteristic of cauda equina tumors. The correlation between symptom duration and tumor size indicates that earlier diagnosis of this tumor is necessary. Earlier diagnosis based on these characteristic symptoms should make use of further examinations such as MRI.