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.

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.

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.

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.

A simple performance test for quantifying the severity of cervical myelopathy.

We evaluated 30 patients with cervical myelopathy before and after decompressive surgery and compared them with 42 healthy controls. All were asked to grip and release their fingers as rapidly as possible for 15 seconds. Films recorded with a digital camera were divided into three files of five seconds each. Three doctors independently counted the number of grip and release cycles in a blinded manner (N1 represents the number of cycles for the first five-second segment, N2 for the second and N3 for the third). N1 [corrected] N2 and N3 of the pre-operative group were significantly fewer than those of the control group, and the post-operative [corrected] group's results were significantly fewer [corrected] than those of the pre-operative group. In the control group, the numbers decreased significantly with each succeeding five-second interval (fatigue phenomenon). In the pre-operative myelopathy group there was no significant difference between N1 and N2 (freezing phenomenon). The 15-second test is shown to be reliable in the quantitative evaluation of cervical myelopathy. Although it requires a camera and animation files, it can detect small changes in neurological status because of its precise and objective nature.

C3-6 laminoplasty takes over C3-7 laminoplasty with significantly lower incidence of axial neck pain.

Five-lamina (C3-7) procedure is the most popular cervical laminoplasty and there have been no studies on the most appropriate number of laminae to be opened. We prospectively reduced the range of laminoplasty from C3-7 to C3-6 in 2002 and compared the outcome of C3-6 laminoplasty (n=37) to that of C3-7 laminoplasty (n=28). In both groups, neurological gain was satisfactory, radiographic changes were minimal, and postoperative MRI indicated sufficient expansion of the dura and the spinal cord. Average operating period was significantly shorter, and length of the operative wound was significantly less in the C3-6 group than in the C3-7 group. Postoperative axial neck pain was significantly rarer after C3-6 laminoplasty than after C3-7 laminoplasty (5.4% vs. 29%, P=0.015). Due to its simplicity and various benefits, C3-6 laminoplasty is a promising alternative to conventional C3-7 laminoplasty for treatment of multisegmental compression myelopathy.

Radiographic analysis of lumbar spine for low-back pain in the general population.

We sought to demonstrate a correlation between low-back pain (LBP) and the plain radiographic findings of the lumbar spine in the general population based on an analysis of 838 persons, 387 of whom presented with complaints of low-back pain. The incidence of intervertebral narrowing and irregular ossification of the vertebral end-plate image increased consistently with age and was higher in the presence of LBP in any age or gender group. Multiregression analysis was performed with the imaging factors as multivariates. As a result, multiregression equations with irregular ossification of the vertebral end-plate image, intervertebral narrowing, spondylolisthesis and abnormal lumbar lordotic angle combined as variates showed the highest significance as predictors of a relationship with LBP. The discrimination analysis was performed using the linear discriminant function, resulting in a true discrimination rate of 65%. Plain radiography of the lumbar spine is thus significant as it provides information which can be evaluated as meaningful findings in the investigation of LBP. In addition, while the significance can be increased by considering multiple factors, it is important to understand the limits of the accuracy of this prediction.

Phylogenetic relationship of six Glycyrrhiza species based on rbcL sequences and chemical constituents.

The nucleotide sequences of ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit gene (rbcL) of Glycyrrhiza glabra, G. uralensis, G. inflata, G. echinata, G. macedonica and G. pallidiflora have been determined to construct their phylogenetic tree. Based on these sequences, the six Glycyrrhiza species were divided into two groups: three, G. glabra, G. uralensis, and G. inflata, which produce glycyrrhizin as a major saponin, and the others, G. echinata, G. macedonica and G. pallidiflora, which produce macedonoside C as a major saponin. Among the three glycyrrhizin-producing species, only two nucleotide substitutions were observed between the rbcL sequences of G. glabra and G. uralensis, and the sequence of G. uralensis was identical to that of G. inflata, indicating that G. uralensis and G. inflata are closely related. Among the three macedonoside C-producing species, only one nucleotide substitution was observed between those of G. echinata and G. macedonica, indicating that these two species are also closely related.

Phylogenetic relationship of Glycyrrhiza plants based on rbcL sequences.

The nucleotide sequences of the ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit gene (rbcL) of Glycyrrhiza glabra, G. uralensis, G. inflata, G. echinata, and G. pallidiflora have been determined to construct the phylogenetic tree. In the phylogenetic tree based on the rbcL sequences, the five Glycyrrhiza species were divided into two groups: the three glycyrrhizin-producing species G. glabra, G. uralensis, and G. inflata; and the two glycyrrhizin-nonproducing species G. echinata and G. pallidiflora. Among the three glycyrrhizin-producing species, only two nucleotide substitutions were observed between the rbcL sequence of G. glabra and G. uralensis, and the sequence of G. uralensis was identical to that of G. inflata, indicating that the three glycyrrhizin-producing species are closely related.

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.

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.

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.

Suppression of pulmonary metastasis by angiogenesis inhibitor TNP-470 in murine osteosarcoma.

We treated a murine osteosarcoma cell line, LM8, which preferentially metastasizes to the lungs, with a new angiogenesis inhibitor, TNP-470, to evaluate the efficacy of this compound in the suppression of pulmonary metastasis of osteosarcoma. In an in vivo experiment, tumor cells were inoculated i.v. into C3H mice, and TNP-470 or vehicle alone (control group) was administered s.c. every day for 3 weeks. In the TNP-470-treated groups, both the number of pulmonary metastatic nodules and the lung wet weight were significantly reduced in a dose-dependent manner. Similarly, vascular density in the metastatic tumors estimated by immunohistochemical staining with anti-von-Willebrand factor antibody as an endothelial marker were significantly reduced. No severe side-effects were found. In an in vitro experiment, viable tumor cells were counted after 3 days' treatment with TNP-470. The 50% inhibitory concentration was 0.6 ng/ml for LM8, which was more sensitive than other tumor cells previously reported. Our results show that TNP-470 suppresses the pulmonary metastasis of LM8 and suggest that both its anti-angiogenic activity and cytostatic activity towards LM8 are responsible for the antitumor effect.

Orthopaedic management of spinal metastases.

Spinal metastases result in severe spinal pain, neurologic deficits, or both. These symptoms usually are caused by spinal instability, in which conservative therapy can have no effect, and surgical treatment is required to restabilize the destroyed spinal segments. Surgical indications are instability of the spine, pain and/or paresis resistant to radiation therapy, acute progressing paresis, and unknown histologic diagnosis. There are 2 surgical approaches for vertebral metastases: prosthetic replacement and posterior stabilization. Single or 2 consecutive diseased vertebrae should be treated with replacement surgery. In this series, excellent surgical outcome was attained with this procedure, and surgical benefit was maintained until the terminal stage of each patient. Multiple vertebral metastases are treated with posterior stabilization using various instrumentation systems that provide rigid stabilization. To choose the most appropriate procedure for each patient, the local condition of the lesion and general status of the patient, including prediction of life expectancy, should be evaluated fully. Spinal metastases develop early and are not terminal events. Therefore, not only palliative treatment but also surgical intervention should be considered for spinal metastases when indicated.

The risk of cancer in rheumatoid patients in Japan.

In order to clarify the risk of cancer development in patients with rheumatoid arthritis (RA), the incidence of malignant tumors during a follow-up period was investigated in RA patients at the Center for Adult Diseases, Osaka, Japan. Six hundred and fifty-five eligible rheumatoid patients (131 males, 524 females) who were admitted to our institute between 1980 and 1989 were matched against the files of the Osaka Cancer Registry. Among them, a total of 26 patients (5 males, 21 females) were noted to have developed some kinds of cancer. The female RA patients demonstrated a significantly higher incidence of all cancers than the general population, with an observed/expected (O/E) ratio of 1.71 (95% confidence interval = 1.06-2.62). Cancer of the buccal cavity/pharynx and thyroid cancer also showed a higher incidence in female RA patients, with O/E ratios of 12.93 and 2.74, respectively.