Common variant in 6q26-q27 is associated with distal colon cancer in an Asian population.

BACKGROUND AND AIM: Colorectal cancer (CRC) is a multifactorial disease with both environmental and genetic factors contributing to its development. The incidence of CRC is increasing year by year in Japan. Patients with CRC in advanced stages have a poor prognosis, but detection of CRC at earlier stages can improve clinical outcome. Therefore, identification of epidemiologial factors that influence development of CRC would facilitate the prevention or early detection of disease. METHODS: To identify loci associated with CRC risk, we performed a genome-wide association study (GWAS) for CRC and sub-analyses by tumour location using 1583 Japanese CRC cases and 1898 controls. Subsequently, we conducted replication analyses using a total of 4809 CRC cases and 2973 controls including 225 Korean subjects with distal colon cancer and 377 controls. RESULTS: We identified a novel locus on 6q26-q27 region (rs7758229 in SLC22A3, p = 7.92 × 10⁻9, OR of 1.28) that was significantly associated with distal colon cancer. We also replicated the association between CRC and SNPs on 8q24 (rs6983267 and rs7837328, p = 1.51 × 10⁻8 and 7.44 × 10⁻8, ORs of 1.18 and 1.17, respectively). Moreover, we found cumulative effects of three genetic factors (rs7758229, rs6983267, and rs4939827 in SMAD7) and one environmental factor (alcohol drinking) which appear to increase CRC risk approximately twofold. CONCLUSIONS: We found a novel susceptible locus in SLC22A3 that contributes to the risk of distal colon cancer in an Asian population. These findings would further extend our understanding of the role of common genetic variants in the aetiology of CRC.

Significant reduction in the incidence of C5 palsy after cervical laminoplasty using chilled irrigation water.

AIMS: The aim of this study was to determine whether chilled irrigation saline decreases the incidence of clinical upper limb palsy (ULP; a reduction of one grade or more on manual muscle testing; MMT), based on the idea that ULP results from thermal damage to the nerve roots by heat generated by friction during bone drilling. METHODS: Irrigation saline for drilling was used at room temperature (RT, 25.6°C) in open-door laminoplasty in 400 patients (RT group) and chilled to a mean temperature of 12.1°C during operations for 400 patients (low-temperature (LT) group). We assessed deltoid, biceps, and triceps brachii muscle strength by MMT. ULP occurring within two days post-operatively was categorised as early-onset palsy. RESULTS: The incidence of ULP (4.0% vs 9.5%, p = 0.003), especially early-onset palsy (1.0% vs 5.5%, p < 0.001), was significantly lower for the LT group than for the RT group. Multivariate analysis indicated that RT irrigation saline use, concomitant foraminotomy, and opened side were significant predictors for ULP. DISCUSSION: Using chilled irrigation saline during bone drilling significantly decreased the ULP incidence, particularly the early-onset type, and shortened the recovery period for ULP. Chilled irrigation saline can thus be recommended as a simple method for preventing ULP. TAKE HOME MESSAGE: Chilled irrigation during laminoplasty reduces C5 palsy.

Runx1 repression by histone deacetylation is critical for Setbp1-induced mouse myeloid leukemia development.

Abnormal activation of SETBP1 through overexpression or missense mutations is highly recurrent in various myeloid malignancies; however, it is unclear whether such activation alone is able to induce leukemia development. Here we show that Setbp1 overexpression in mouse bone marrow progenitors through retroviral transduction is capable of initiating leukemia development in irradiated recipient mice. Before leukemic transformation, Setbp1 overexpression significantly enhances the self-renewal of hematopoietic stem cells (HSCs) and expands granulocyte macrophage progenitors (GMPs). Interestingly, Setbp1 overexpression also causes transcriptional repression of critical hematopoiesis regulator gene Runx1 and this effect is crucial for Setbp1-induced transformation. Runx1 repression is induced by Setbp1-mediated recruitment of a nucleosome remodeling deacetylase (NuRD) complex to Runx1 promoters and can be reversed by treatment with histone deacetylase (HDAC) inhibitors Entinostat and Vorinostat. Moreover, treatment with these inhibitors caused efficient differentiation of Setbp1 activation-induced leukemia cells in vitro, and significantly extended the survival of mice transplanted with such leukemias, suggesting that HDAC inhibition could be an effective strategy for treating myeloid malignancies with SETBP1 activation.

Postoperative cervical pseudomeningocele with herniation of the spinal cord.

STUDY DESIGN: This is a report of a patient in whom spinal cord herniation into a pseudomeningocele resulted in progressive myelopathy. OBJECTIVE: To describe the outcome of a 59-year-old man who visited Osaka University Hospital complaining of gait disturbance. He had undergone cervical laminectomy to resect a spinal cord tumor 14 years previously. SUMMARY OF BACKGROUND DATA: Pseudomeningocele is an extremely rare condition and can be overlooked. In addition, cord herniation into the pseudomeningocele rarely can be diagnosed before surgical exploration. Our patient represents the first case we are aware of in which magnetic resonance imaging could clearly demonstrate not only the pseudomeningocele, but the herniation of the cord into the cyst. METHODS: Magnetic resonance imaging was used for preoperative and postoperative investigation. RESULTS: The pseudomeningocele was resected to improve the neurologic status of the patient. During the operation, the herniated cord was successfully reduced into the original subarachnoid space by the release of adhesion. Most symptoms subsided soon after surgery. Magnetic resonance imaging could delineate not only the cyst and cord herniation, but the medullary pathology. The distribution of high-intensity areas on T2-weighted images suggested the cord damage. CONCLUSION: Magnetic resonance imaging revealed not only the cyst and cord herniation, but medullary pathology, too.

Neck and shoulder pain after laminoplasty. A noticeable complication.

STUDY DESIGN: The authors retrospectively analyzed the prevalence and features of neck and shoulder pain (axial symptoms) after anterior interbody fusion and laminoplasty in patients with cervical spondylotic myelopathy. OBJECTIVES: To reveal the difference in prevalence of postoperative axial symptoms between anterior interbody fusion and laminoplasty and to clarify the pathogenesis of axial symptoms after laminoplasty. SUMMARY OF BACKGROUND DATA: Outcome of the cervical surgery is evaluated on neurologic status alone; axial symptoms after laminoplasty rarely have been investigated. Such symptoms, however, are often severe enough to interfere with a person's daily activity. METHODS: Ninety-eight patients had surgery for their disability secondary to cervical spondylotic myelopathy. Of those patients, 72 had laminoplasty, and 26 had anterior interbody fusion. The presence or absence of axial symptoms was investigated before and after surgery. The duration, severity, and laterality of symptoms were also recorded. RESULTS: The prevalence of postoperative axial symptoms was significantly higher after laminoplasty than after anterior fusion (60% vs. 19%; P < 0.05). In 18 patients (25%) from the laminoplasty group, the chief complaints after surgery were related to axial symptoms for more than 3 months, whereas in the anterior fusion group, no patient reported having such severe pain after surgery. CONCLUSIONS: The prevalence and severity of axial symptoms after laminoplasty proved to be higher and more serious than has been believed. Such symptoms should be considered in the evaluation of the outcome of cervical spinal surgery.

Cineradiographic motion analysis of atlantoaxial instability in os odontoideum.

Cineradiography was used to study six patients with os odontoideum. Atlantoaxial kinematics was analyzed with the relative motion of the atlas on the axis. In all cases, the tracing of the anterior arch was straight in the sagittal plane, whereas the posterior arch moved in two different configurations: straight and S-shaped. In cases of S-shaped configurations, the anterior translation occurred in the neutral position. Such translation could threaten the stability of the atlantoaxial complex fixed with posterior wiring because circumferential wires allow the laminas to rotate in the sagittal direction. In patients with os odontoideum, pathomechanics of the atlantoaxial joint should be examined with cineradiography in order biomechanically to determine the soundest fixation.

Neurologic complications of surgery for cervical compression myelopathy.

Neurologic complications resulting from surgery for 384 cases of cervical myelopathy (cervical soft disc herniation, spondylosis, ossification of the posterior longitudinal ligament) were reviewed. Surgical procedures performed included 134 anterior interbody fusions (Cloward or Robinson-Smith technique), 70 subtotal corpectomies with strut bone graft, 85 laminectomies, and 95 laminoplasties. Twenty-one patients (5.5%) sustained neurologic deterioration related to surgery. The deterioration was classified into two types on the basis of the neurologic signs observed: deterioration of spinal cord function or of nerve root function. Manifestations of the former varied from weakness of the hand to tetraparesis. Paralysis of the deltoid and biceps brachii muscles was an exclusive feature of deterioration in the nerve root group. Causes of this paralysis included malalignment of the spine related to graft complications, and a tethering effect on the nerve root following major shifting of the spinal cord after decompression. The causes of deterioration of the cord function included spinal cord injury during surgery, malalignment of the spine associated with graft complication, and epidural hematoma.

Lateral rhachotomy for thoracic spinal lesions.

Capener's "Lateral Rhachotomy" was modified by additional excision of the pedicle, articular facets, part of the lamina, and a posterior half of the vertebral bodies on one side through a transpleural approach to the thoracic spine, and a retroperitoneal approach to the lumbar spine. The aim was to excise a space-occupying lesion, which exists in front of the thoracic or lumbar spinal cord, safely. This modification enable the authors to expose more than 50% of the spinal canal, and decompress it from its anterior, lateral, and posterior compressing mass. The utmost important point of this procedure is the excision of the lesion under the direct visualization of the dura. In ossification of the posterior longitudinal ligament (OPLL), the dura is usually indented by the thick bony mass, and the lesion extends over a few segment with adhesion. Using "Modified Lateral Rhachotomy," it was possible to explore three or four vertebral levels in continuity through the same skin incision. In the present report, the authors described their "Modified Lateral Rhachotomy" procedure, and reviewed the case material.

Laminoplasty versus subtotal corpectomy. A comparative study of results in multisegmental cervical spondylotic myelopathy.

A comparative study of surgical results was used to determine the treatment of choice for multisegmental cervical spondylotic myelopathy. Forty-one patients who received subtotal corpectomy and strut grafting (SCS) and forty-two undergoing laminoplasty were followed up for at least 2 years after surgery. Regarding factors known to affect surgical prognosis (age at surgery, duration of symptoms, severity of neurologic deficit, anteroposterior canal diameter, transverse area of the cord at the site of maximum compression, number of levels involved), the two groups were statistically comparable with each other. The severity of neurologic deficits was assessed by the Japanese Orthopaedic Association scale. Results were evaluated in terms of postoperative score and recovery rate. The difference between the recovery rate and final score between the two groups was not statistically significant. Surgical complications were more frequent in the subtotal corpectomy and strut grafting group than in the laminoplasty group. The most frequent complications encountered in the subtotal corpectomy and strut grafting group were related to bone grafting. Spinal alignment worsened in six patients of the laminoplasty group, but none of them suffered from neurologic deterioration. Another disadvantage of subtotal corpectomy and strut grafting was the longer postoperative period of bed rest needed to secure graft stability. We conclude that laminoplasty should be the treatment of choice for multisegmental cervical spondylotic myelopathy when neurologic results, incidence of complications, and postoperative treatment are taken into consideration.

Vertebral body replacement with a ceramic prosthesis for metastatic spinal tumors.

STUDY DESIGN: This study retrospectively analyzed the clinical outcome of vertebral replacement surgery with our unique ceramic prosthesis for spinal metastases. OBJECTIVES: To indicate the results of vertebral replacement surgery with a ceramic prosthesis. SUMMARY OF BACKGROUND DATA: Spinal metastasis often involves the vertebral bodies, of which abnormal fracture causes intractable pain and paresis. For such conditions, laminectomy or irradiation can have no effect because they do not improve spinal stability. Autogenous bone or bone cement are not durable materials, and fatigue fracture of the implanted material occasionally occurs. We developed a simple prosthesis made of alumina ceramic, a bioinert material, to replace the affected vertebrae. There has not been such a large study to assess vertebral replacement surgery with a ceramic prosthesis. METHODS: From 1972 to 1993, 90 ceramic prostheses were used in 84 patients with spinal metastasis, and the average follow-up period was 26.2 months. The primary tumor was thyroid cancer in 13 patients, breast cancer in 12, multiple myeloma in eight, renal cell cancer in eight, gastrointestinal cancer in eight, and lung cancer in eight. The clinical symptoms were assessed before and after surgery, and the maintenance of operative gain was investigated. RESULTS: Pain relief was achieved in 94%, motor function improved in 81%, and ambulation recovered in 64%. There were no serious complications associated with the procedure, and the operative benefit was maintained until the terminal stage in the vast majority of patients. CONCLUSIONS: In selected patients, vertebral replacement using our prosthesis proved to be a useful procedure, effectively managing the severe spinal pain or neurologic deficits associated with vertebral body destruction.

Os odontoideum with posterior atlantoaxial instability.

Nine patients who had os odontoideum with posterior atlantoaxial instability are reviewed. Three parameters were measured on the lateral radiographs: the distance from the os odontoideum to the spinous process of the axis in extension (Dext), the distance from the os odontoideum to the posterior arch of the atlas (Datl), and the degree of instability (Inst). Patients were classified into four groups: Group I, local symptoms (N = 3); Group II, transient myelopathy (N = 0); Group III, progressive myelopathy (N = 6); and Group IV, cerebral symptoms (N = 0). The development of cervical myelopathy was not related to degree of instability but to distance from the os to the spinous process of the axis (Dext). Dext was more than 16 mm in Group I and less than or equal to 16 mm in Group III. Five of six patients in Group III underwent myelography. Based on myelographic findings, Group III was further subdivided into two groups, Group IIIA (N = 2) and Group IIIB (N = 3), according to the following characteristics: In Group IIIA, the distance from the os to the posterior arch of the atlas was more than 13 mm, and the spinal cord was impinged between the os odontoideum and the lamina of the axis in extension and reduced in flexion. In Group IIIB, Datl was less than or equal to 13 mm, and the spinal cord was compressed at the level of the atlas during flexion and extension. Stenotic Datl of 13 mm or less specifically defined severe cervical myelopathy. Surgical treatment for cervical myelopathy in os odontoideum with posterior instability is suggested as follows: in the absence of canal stenosis of the atlas (Group IIIA), atlantoaxial fusion in a reduced position is indicated; when associated with canal stenosis of the atlas (Group IIIB), laminectomy of the atlas followed by occiput-to-C2 arthrodesis is indispensable.

Motion analysis of the cervical spine in athetoid cerebral palsy. Extension-flexion motion.

Frequently instability and premature onset of spondylosis of the cervical spine are found in athetoid cerebral palsy (CP) patients. These structural abnormalities appear to be related to athetoid motion of the neck in CP. Through motion analysis, the authors aimed to clarify the abnormalities of cervical motion that could precipitate structural abnormalities. The gross characteristic feature of cervical motion in athetoid CP is "whip movement." Both velocity and acceleration during extension-flexion motion were greater than in normal subjects, especially at the upper cervical levels. Also, a sudden increase in velocity and acceleration occurred during rapid motions at certain levels, followed by a larger range of motion of the cervical spine. Such kinematic abnormalities were thought to generate a greater shearing force and bending moment exerted on the corresponding cervical articulations-discs and facets. Olisthetic instability often accompanied disc degeneration at the upper cervical levels. A large range of extension--flexion motion of the cervical spine, analogous to a cantilever, caused a repeated bending moment of extraordinary magnitude and was regarded as a precipitative factor for disc degeneration and osteophytosis common at the middle and lower levels of the disc.

Unstable cervical spine in athetoid cerebral palsy.

The manifestations and pathomechanism of cervical instability of the athetoid neck in cerebral palsy (CP) patients was clarified in this study by means of static and dynamic x-ray analysis. Instability was defined as follows: 1) listhesis indicating anterior or posterior slip of more than 3 mm and/or 2) sagittal rotation between two vertebrae beyond the normal range measured by Penning. Cervical instability fitting this definition mainly took place in the upper and middle cervical disc levels, such as C3-4, C4-5, and/or occasionally C5-6. These coincide with the disc levels adjacent to the apex of the lordotic curve and/or those around the transitional vertebrae between the two reversed curves that render the cervical spine S-shaped in athetoid CP. A large facet angle at the apex vertebra facilitated anterior and/or posterior listhesis of the vertebrae. Conversely, a sudden decrease in the facet angle around the transitional vertebra in S-shaped curves precipitated deflection of the spine and increased sagittal rotation at this level. In addition to these structural abnormalities, rapid and repetitious neck movements seemed to accelerate the progression of cervical instability in athetoid CP patients.

Intraoperative measurement of lumbar spinal instability.

To justify lumbar fusion or stabilization, a quantitative assessment and definition of spinal instability are essential. To quantify spinal instability, the tensile stiffness of a motion segment (vertebra-disc-vertebra) was measured with a spinal distractor during spinal decompression surgery. Stiffness was indicated by the relationship between load and displacement between the two adjacent spinous processes where a vertebral spreader was suspended. A load-displacement curve was recorded at each step of surgical decompression and fixation while the motion segment was being distracted at a constant speed. The device used for measuring stiffness of a spinal motion segment is a lumbar spinal spreader with a load strain gauge and a displacement transducer. The stiffness of a spinal motion segment was reduced as disc degeneration developed. Degenerative spondylolisthetic discs showed the least stiffness (lowest, 3.9 N/mm; average, 5.4 N/mm). The stiffness of herniated discs, however, was relatively greater (average, 11.8 N/mm). The stiffness of normal motion segments was greater than affected segments. If the stiffness of a motion segment before decompression was graded as 100, it was reduced to 82% after partial laminectomy and facetectomy and to 65% after discectomy on average. After interbody fusion by iliac bone graft, it increased to 133% and to 184%, after Luque fixation.

Multiple mechanisms deregulate EZH2 and histone H3 lysine 27 epigenetic changes in myeloid malignancies.

Polycomb repressive complex 2 (PRC2) is involved in trimethylation of histone H3 lysine 27 (H3K27), chromatin condensation and transcriptional repression. The silencing function of PRC2 complex is mostly attributed to its intrinsic activity for methylating H3K27. Unlike in B-cell lymphomas, enhancer of zeste homolog 2 (EZH2) mutations in myeloid malignancies are inactivating/hypomorphic. When we assessed the mutational status in myeloid malignancies (N=469 cases examined), we found EZH2 and EED/SUZ12 mutations in 8% and 3.3% of cases, respectively. In addition to mutant cases, reduced EZH2 expression was also found in 78% cases with hemizygous deletion (-7/del7q cases involving EZH2 locus) and 41% of cases with diploid chromosome 7, most interestingly cases with spliceosomal mutations (U2AF1/SRSF2 mutations; 63% of cases). EZH2 mutations were characterized by decreased H3K27 trimethylation and increased chromatin relaxation at specific gene loci accompanied by higher transcriptional activity. One of the major downstream target is HOX gene family, involved in the regulation of stem cell self-renewal. HOXA9 was found to be overexpressed in cases with decreased EZH2 expression either by EZH2/spliceosomal mutations or because of -7/del7q. In summary, our results suggest that loss of gene repression through a variety of mutations resulting in reduced H3K27 trimethylation may contribute to leukemogenesis.

Potential risk of thermal damage to cervical nerve roots by a high-speed drill.

Using the transverse processes of fresh porcine lumbar spines as an experimental model we evaluated the heat generated by a rotating burr of a high-speed drill in cutting the bone. The temperature at the drilled site reached 174 degrees C with a diamond burr and 77 degrees C with a steel burr. With water irrigation at a flow rate of 540 ml/hr an effective reduction in the temperature was achieved whereas irrigation with water at 180 ml/hr was much less effective. There was a significant negative correlation between the thickness of the residual bone and the temperature measured at its undersurface adjacent to the drilling site (p < 0.001). Our data suggest that tissues neighbouring the drilled bone, especially nerve roots, can be damaged by the heat generated from the tip of a high-speed drill. Nerve-root palsy, one of the most common complications of cervical spinal surgery, may be caused by thermal damage to nerve roots arising in this manner.