Fragment-Based Discovery of Allosteric Inhibitors of SH2 Domain-Containing Protein Tyrosine Phosphatase-2 (SHP2).

The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling and inhibit the proliferation of RTK-driven cancer cell lines. Here, we describe the first reported fragment-to-lead campaign against SHP2, where X-ray crystallography and biophysical techniques were used to identify fragments binding to multiple sites on SHP2. Structure-guided optimization, including several computational methods, led to the discovery of two structurally distinct series of SHP2 inhibitors binding to the previously reported allosteric tunnel binding site (Tunnel Site). One of these series was advanced to a low-nanomolar lead that inhibited tumor growth when dosed orally to mice bearing HCC827 xenografts. Furthermore, a third series of SHP2 inhibitors was discovered binding to a previously unreported site, lying at the interface of the C-terminal SH2 and catalytic domains.

TAS0728, A Covalent-binding, HER2-selective Kinase Inhibitor Shows Potent Antitumor Activity in Preclinical Models.

Activated HER2 is a promising therapeutic target for various cancers. Although several reports have described HER2 inhibitors in development, no covalent-binding inhibitor selective for HER2 has been reported. Here, we report a novel compound TAS0728 that covalently binds to HER2 at C805 and selectively inhibits its kinase activity. Once TAS0728 bound to HER2 kinase, the inhibitory activity was not affected by a high ATP concentration. A kinome-wide biochemical panel and cellular assays established that TAS0728 possesses high specificity for HER2 over wild-type EGFR. Cellular pharmacodynamics assays using MCF10A cells engineered to express various mutated HER2 genes revealed that TAS0728 potently inhibited the phosphorylation of mutated HER2 and wild-type HER2. Furthermore, TAS0728 exhibited robust and sustained inhibition of the phosphorylation of HER2, HER3, and downstream effectors, thereby inducing apoptosis of HER2-amplified breast cancer cells and in tumor tissues of a xenograft model. TAS0728 induced tumor regression in mouse xenograft models bearing HER2 signal-dependent tumors and exhibited a survival benefit without any evident toxicity in a peritoneal dissemination mouse model bearing HER2-driven cancer cells. Taken together, our results demonstrated that TAS0728 may offer a promising therapeutic option with improved efficacy as compared with current HER2 inhibitors for HER2-activated cancers. Assessment of TAS0728 in ongoing clinical trials is awaited (NCT03410927).

Morphology of the femoral insertion site of the medial patellofemoral ligament.

PURPOSE: The purpose of this study was to identify the femoral insertion of the medial patellofemoral ligament (MPFL) and related osseous landmarks. METHODS: A total of 31 unpaired human cadaveric knees were studied. The MPFL was identified, and the site of its femoral insertion was marked. Three-dimensional images were created, and the location and morphology of the femoral insertion of the MPFL and related osseous structures were analyzed. RESULTS: The MPFL was identified in all knees. The femoral insertion of the MPFL was elliptical in shape, and the mean surface area was 56.5 ± 16.9 mm(2). The characteristic features of the femoral insertion of the MPFL could not be identified, but the adductor tubercle was clearly identified in all knees. The centre of the femoral insertion of the MPFL was 10.6 ± 2.5 mm distal to the apex of the adductor tubercle on the long axis of the femur, and the position of the insertion site was consistent in all knees. CONCLUSION: The adductor tubercle was clearly identified as an osseous landmark. The femoral insertion of the MPFL was approximately 10 mm distal to the adductor tubercle. These findings may improve understanding of the anatomy of the femoral insertion of the MPFL and may assist surgeons in performing anatomical reconstruction.

Core Needle Percutaneous Transpedicular Vertebral Body Biopsy: A Study of 128 Cases.

STUDY DESIGN: We report an accurate technique for percutaneous transpedicular core needle biopsy of vertebral body lesions, and evaluate its effectiveness for histologic diagnosis retrospectively. OBJECTIVE: The purpose of this study is to evaluate the effectiveness and accuracy of this method retrospectively. SUMMARY OF BACKGROUND DATA: Better knowledge of vertebral pedicle morphometry has led to the development of transpedicular fixation techniques in spinal surgery. After experience with these techniques, we have been performing percutaneous transpedicular vertebral body core needle biopsies (transpedicular biopsy) for histologic diagnosis since 1993. METHODS: A total of 128 patients who had undergone transpedicular biopsy for T1-L5 vertebral body lesions were evaluated. The biopsies were carried out under local anesthesia, except in children, for whom general anesthesia was used. Biopsy specimens were obtained by passing 8 or 11 G needle biopsy instruments percutaneously through the pedicle into the site of the lesion under C-arm fluoroscopy guidance. Histologic analyses were performed, and the accuracy and effectiveness of this technique were evaluated. RESULTS: The pathologic evaluations were definitive in 120 patients (93.8%) and not diagnostic in 8. The accuracy of the results differed among the diagnostic categories. Diagnostic accuracy was 78.6% for primary neoplasms and 97.0% for metastatic neoplasms. There was a significant difference in the diagnostic criteria and spinal segment. True positive rate was higher in the thoracic spine (92.2%) than that of lumbar spine (76.6%). CONCLUSIONS: Transpedicular biopsy is a useful procedure for evaluation of thoracic and lumbar vertebral body lesions.

Limb function after excision of a deltoid muscle sarcoma.

BACKGROUND: Limb function after excision of deltoid muscle sarcomas has not been thoroughly investigated, although a large defect of soft tissue often causes some degree of dysfunction after wide excision. We formulated a hypothesis that the limb functional results depend on the volume of the excised deltoid muscle and examined the clinical outcomes in patients with a sarcoma in the deltoid muscle treated by surgical resection. METHODS: The clinical outcomes of 8 patients with a malignant soft tissue tumor in the deltoid muscle were retrospectively reviewed. The following items were evaluated: type of excision of the deltoid muscle, including total excision, subtotal excision, and partial excision; surgical margins; reconstruction procedure used; postoperative complications; local recurrence; metastasis; survival; and functional results (determined by the Musculoskeletal Tumor Society scoring system). RESULTS: After surgical resection, reconstruction in 6 of 8 patients was performed by pedicled latissimus dorsi musculocutaneous or muscle flap or pedicled trapezius musculocutaneous flap. Two patients did not undergo reconstruction because skin closure was possible. The partial excision group had a Musculoskeletal Tumor Society score of 100.0%, and the subtotal excision case and the total excision group had scores of 76.6% and 82.2%, respectively. None of the patients has demonstrated any evidence of local recurrence. CONCLUSION: We conclude that the functional results may depend on the volume of the excised deltoid muscle. Latissimus dorsi and trapezius musculocutaneous flaps were found to be useful for covering a defect of the deltoid muscle, although these flaps did not contribute to function of the shoulder.

Age-related effects of major and trace element concentrations in rat liver and their mutual relationships.

The concentrations of 22 major and trace elements in livers from rats aging from 5 to 113 weeks old were determined. The rats investigated were the same rats previously reported with respect to 29 elements in bones (femur) and 26 elements in kidneys. The samples were decomposed with high-purity nitric acid and hydrogen peroxide. Seven elements (Na, Mg, P, K, Ca, Fe and Zn) were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES), and 15 elements (Mn, Co, Cu, As, Se, Rb, Sr, Mo, Cd, Sn, Sb, Cs, Ba, Pb and Bi) were determined by inductively coupled plasma mass spectrometry (ICP-MS). Analysis of variance (ANOVA) for age variations indicated that the concentrations of many elements, such as Mg, P, K, Mn, Fe, Cu, Zn, Sr, Mo and Cd, were almost constant across the ages of the rats with the exception of 5 weeks old (p > 0.05). Arsenic, Pb and Bi showed significant increasing trends, while Na and Co showed decreasing trends (p < 0.01). Selenium showed a decreasing trend except at the initial stage of 5-9 weeks old. Calcium, Rb, Sn, Sb, Cs and Ba showed significant age-related variations, but their patterns were not monotonic. The liver clearly contrasts with the kidneys, in which many elements showed significant age-related variations with increasing trends. The concentration ranges of Mg, P, K, Mn, Cu, Zn, and Mo were controlled within 15% across all ages of rats. The homeostasis of the aforementioned elements may be well established in the liver. The toxic elements, such as Cd, Pb and Bi, showed a narrow concentration range among age-matched rats.

The concentrations of major and trace elements in rat kidney: aging effects and mutual relationships.

The concentrations of 26 major to trace elements in rat kidneys aging from 5 to 113 weeks old were determined. The rats investigated were the same rats used previously reported to have 29 elements in bones (femurs). The samples were decomposed by high purity nitric acid and hydrogen peroxide. Eight elements (Na, Mg, Si, P, K, Ca, Fe and Zn) were determined using inductively coupled plasma atomic emission spectrometry (ICP-AES) and 18 elements (Mn, Co, Ni, Cu, As, Se, Rb, Sr, Mo, Cd, Sn, Sb, Cs, Ba, Tl, Pb, Bi and U) were determined using inductively coupled plasma mass spectrometry (ICP-MS). The aging effects on the concentrations of these elements and mutual elemental relationships were investigated. Analysis of variance (ANOVA) for age variations indicated that the concentrations of P, K, Mn and Mo were almost constant across the age of rats (p>0.3). The concentration of many elements such as Na, Mg, Ca, Fe, Co, Cu, Zn, As, Se, Cd, Sn, Sb, Tl, Pb and Bi, showed significant increasing trends (p<0.01) with different patterns. Rubidium, Cs, Pb and Bi showed significant age variations but not monotonic trends. Silicon, Ni, Sr, Ba and U showed large concentration scatterings without any significant trends (p>0.01). The metabolism of these elements may not be well established in the kidney. Many toxic elements such as As, Cd, Sn, Pb and Bi showed a narrow concentration range among age-matched rats. The kidney may have established metabolic mechanisms to confine or accumulate these toxic elements even though their concentrations are very low (e.g., 10 ngg(-1) of Cd). These elements also closely coupled with Fe. A cluster analysis was performed using an elemental correlation matrix and indicated that these elements, including Fe, formed a cluster. However, another cluster analysis using "an aging effect eliminated" elemental correlation showed different clustering in which the Fe, Cd cluster disappeared.

Force on the sacrococcygeal and ischial areas during posterior pelvic tilt in seated posture.

BACKGROUND: Most posture problems encountered in persons who use wheelchairs in a seated posture for extended periods are related to sacral sitting due to posterior pelvic tilt. Posterior pelvic tilt places pressure and shearing force on the sacrococcygeal area that can lead to pressure ulcers, but the relationship between pelvic tilt and force applied to the sacrococcygeal and ischial tuberosity areas has not yet been investigated. OBJECTIVE: To investigate the relationships of posterior pelvic tilt in a seated posture with vertical force and horizontal force on the sacrococcygeal and ischial tuberosity areas. STUDY DESIGN: Repeated measures design. METHODS: Thirty male and female subjects aged ≥60 years sat in a measurement chair at varying pelvic tilt angles, and force on the sacrococcygeal and ischial tuberosity areas was measured. RESULTS: The pressure on the sacrococcygeal area increased with pelvic tilt in all subjects, with vertical force averaging 19% of the body weight at a pelvic tilt angle of 30°. The horizontal force on the sacrococcygeal area increased in 93% of the subjects, with an average increase equal to 3% of the body weight. CONCLUSIONS: We confirmed changes in vertical and horizontal forces on the sacrococcygeal and ischial tuberosity areas with a change in seated posture (pelvic tilt). CLINICAL RELEVANCE: We propose guidelines for rehabilitation practitioners working with wheelchair users to suggest improved ways of sitting in wheelchairs that avoid pelvic tilt angles that might promote pressure ulcers on the buttocks.

A pilot project for the Japan arthroplasty register.

BACKGROUND: National arthroplasty registers are valuable tools for reporting on an updated epidemiologic survey of arthroplasties and for evaluating the performance of implants and operative procedures through the early identification of failure risk factors. More than ten registers have been launched globally, but no national register has been reported in Asia. METHODS: In February 2006, a pilot project of the Japan Arthroplasty Register (JAR) for total hip arthroplasty (THA) and total knee arthroplasty/unicompartmental knee arthroplasty (TKA/UKA) was launched by the Japanese Orthopaedic Association (JOA). Data obtained include information about patients, primary and revision arthroplasty operative procedures, and implants and materials used. The JAR office accumulated and processed all data and reports annually. RESULTS: Up to May 2011, 83 of 130 hospitals nominated by the JOA (64 %) participated in the JAR pilot project. From 2006 to 2011, 33,080 data collection forms were submitted; 17,534 for THA and 17,269 for TKA/UKA. A brief summary of the annual report of the JAR is available from The Japanese Society for Replacement Arthroplasty web site at http://jsra.info/ . CONCLUSION: A national arthroplasty register is a useful tool for evaluating the outcomes of interventions and the materials used in arthroplasties and for providing rapid feedback to practitioners and patients about any failure of THA and TKA/UKA. As the first national arthroplasty register in Asia, the JAR will help guide the development of registers of arthroplasty characteristics specific to Asian populations.

Interleukin-6 upregulates expression of ADAMTS-4 in fibroblast-like synoviocytes from patients with rheumatoid arthritis.

AIM: A disintegrin-like and metalloproteinase with thrombospondin type 1 motif (ADAMTS)-4 and ADAMTS-5 play crucial roles in the cleavage of aggrecan. Several recent studies have demonstrated the effect of cytokines such as interleukin (IL)-1ß, tumor necrosis factor-α and transforming growth factor-ß on the expression of ADAMTS-4 and ADAMTS-5 in fibroblast-like synoviocytes (FLS). However, the effect of IL-6 remains unclear. The aim of this study is to investigate the expression of ADAMTS-4 and ADAMTS-5 in FLS of rheumatoid arthritis (RA) patients after IL-6 stimulation. METHOD: Immunohistochemical staining was performed to examine the expression and localization of ADAMTS-4 and ADAMTS-5 in RA synovium. FLS isolated from RA patients were stimulated by IL-6 and soluble IL-6 receptor (sIL-6R) in the presence or absence of anti-IL-6R antibody, and the expression levels of ADAMTS-4 and ADAMTS-5 messenger RNA (mRNA) were assessed using real-time polymerase chain reaction. Furthermore, the IL-6 signaling pathway for regulation of ADAMTS-4 and ADAMTS-5 was also examined. RESULTS: Staining for ADAMTS-4 and ADAMTS-5 was mainly observed in the sublining layer of synovial membrane and pannus. The expression of ADAMTS-4 mRNA was increased by IL-6/sIL-6R, whereas that of ADAMTS-5 was decreased. Anti-IL-6R antibody suppressed the effect of IL-6/sIL-6R. Mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) kinase (MEK)1/2 inhibitor U0126 inhibited the effect of IL-6/sIL-6R on ADAMTS-4 mRNA expression in FLS. Signal transducer and activator of transcription 3 (STAT3) inhibitor parthenolide inhibited the effect of IL-6/sIL-6R on ADAMTS-4, and downregulated ADAMTS-5 expression. CONCLUSION: These results suggest IL-6 may participate in cartilage destruction in RA as an inducer of ADAMTS-4 expression from FLS.

Aging effects of major and trace elements in rat bones and their mutual correlations.

The concentrations of 29 major to trace elements in rat bones (femur) aging from 5 to 113 weeks old were determined. The samples were decomposed by high purity nitric acid and hydrogen peroxide. Nine elements (Na, Mg, P, K, Ca, Fe, Ni, Zn, and Sr) were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES) and 20 elements (Li, B, Al, V, Cr, Mn, Cu, As, Se, Rb, Mo, Ag, Cd, Sb, Cs, Ba, W, Tl, Pb, and U) were determined by inductively coupled plasma mass spectrometry (ICP-MS). Aging effects on these elements and mutual elemental correlations were investigated. The concentrations of Ca, P and Na increased in the initial stage of 5-17 weeks and then maintained constant values, whereas those of Mg, K, Mn, Sr and Ba showed decreasing trends of differing patterns. Furthermore, Cu, Zn and Mo showed increasing trends for a whole range of ages. Selenium showed a remarkable increasing trend with a factor of 10. The values of Na, Mg, P, K, Ca, Mn, Cu, Zn, Se and Mo in the age-matched rats distributed narrow ranges, indicating that the metabolism of these elements in bone was well-established. By contrast, those of Al, V, Ni, Ag, Cd, Sb, W, Tl, and U were distributed across a broad range. The metabolism of these elements was not well-established. A cluster analysis was performed using an elemental correlation matrix.

Anatomic double-bundle anterior cruciate ligament reconstruction restores patellofemoral contact areas and pressures more closely than nonanatomic single-bundle reconstruction.

PURPOSE: To investigate the effects of anterior cruciate ligament (ACL) deficiency and nonanatomic single-bundle (SB) and anatomic double-bundle (DB) ACL reconstruction on the contact characteristics of the patellofemoral (PF) joint. METHODS: By use of a materials testing system, 7 fresh-frozen human cadaveric knees were tested. The following states were tested: ACL-intact knee, nonanatomic SB ACL reconstruction, anatomic DB ACL reconstruction, and ACL-deficient knee. Hamstring autografts were used. PF contact pressures and areas were measured with pressure-sensitive film at 30°, 60°, and 90° of knee flexion with a constant 100-N load on the quadriceps tendon. RESULTS: The total contact area of ACL-deficient and nonanatomic SB ACL-reconstructed knees (123.8 ± 63.9 and 149.6 ± 79.3 mm(2), respectively) significantly decreased when compared with those of the intact knee (206.1 ± 83.6 mm(2)) at 30° of knee flexion. The lateral-facet peak pressure of ACL-deficient and nonanatomic SB ACL-reconstructed knees (1.12 ± 0.52 and 1.22 ± 0.54 MPa, respectively) significantly decreased when compared with those of the intact knee (0.68 ± 0.38 MPa) at 90° of knee flexion. Anatomic DB ACL reconstruction restored the contact pressures and areas to values similar to those of the intact knee (no significant difference). CONCLUSIONS: ACL deficiency resulted in a significant decrease in the total and medial PF contact areas and in an increase in the lateral PF contact pressure. Anatomic DB ACL reconstruction more closely restored normal PF contact area and pressure than did nonanatomic SB ACL reconstruction. CLINICAL RELEVANCE: Our findings suggest that the changes in the PF contact area and pressures in ACL deficiency and after nonanatomic SB ACL reconstruction may be one of the causes of PF osteoarthritis or other related PF problems found at long-term follow-up. Anatomic DB ACL reconstruction may reduce the incidence of PF problems by closely restoring the contact area and pressure.

Comparison of the volar locking plate and the bridging external fixator in the treatment of distal radius fracture based on range of wrist motion assessed by functional radiography.

BACKGROUND: The authors hypothesized that an external fixator (EF) could compromise ROM compared with a volar locking plate (VP) because of the longer duration of immobilization using a VP. Postoperative ROM were therefore compared between the EF and the VP, focusing on the movement of the radiocarpal (RC) and midcarpal (MC) joints evident on radiology. The clinical outcomes of the two methods were also evaluated. MATERIAL/METHODS: Functional radiographs were taken in active volar and dorsal flexions from both the injured and contralateral sides. Clinical outcomes in terms of grip strength, pulp pinch, Quick-DASH, and the modified Cooney evaluation were compared. RESULTS: The average wrist volar flexion angle was significantly smaller on the injured side in both groups, significantly so in the VP group. No significant differences were seen in clinical outcome. Although distinct restriction of the wrist volar flexion angle was seen in patients treated with the VP, the Quick-DASH and the modified Cooney evaluation showed no difference between these two groups. CONCLUSIONS: These results should be considered when performing surgical treatment for patients with distal radius fracture. These procedures should be adopted to complement each other according to local conditions and individual patient-related factors.

Characterization of human synovial fluid cells of 26 patients with osteoarthritis knee for cartilage repair therapy.

AIM: To investigate the possibility of chondrogenic differentiation and cartilage repair of synovial fluid cells of osteoarthritis (OA) knee. METHODS: Synovial fluids from 26 patients with OA knee were aspirated from each knee joint and cultured in vitro. The morphology of cultured synovial fluid cells, cell proliferation rate, the phenotype, and chondrogenic differentiation were analyzed in in vitro. Also, human autologous synovial fluid cells were transplanted to OA cartilage, and the cells were traced in ex vivo. RESULTS: In 19 of 26 materials, the cells proliferated satisfactorily. The cell proliferation in six materials was very slow and one material contaminated. Culture-expanded synovial fluid cells had a fibroblastic morphology and the phenotype was negative for CD10, CD14, and CD45, and positive for CD13, CD44, and CD105. Pellet culture of synovial fluid cells showed chondrogenic differentiation. In the ex vivo study, autologous transplanted synovial fluid cells were observed in repaired or enhanced regenerative cartilage areas and showed a tendency to infiltrate the original degenerative cartilage of OA. CONCLUSIONS: This study proved the possibility of chondrogenic differentiation of synovial fluid cells of OA knee joints despite the pathologic environment within a diseased joint. Synovial fluid cells were actually heterogeneous cells but they showed chondrogenic differentiation, similar to that of bone marrow-derived mesenchymal progenitor cells (BMMPCs). The Ex vivo study suggested that synovial fluid cells had a tendency to adhere to OA degenerative cartilage in humans.

Clinical findings of hibernoma of the buttock and thigh: rare involvements and extremely high uptake of FDG-PET.

BACKGROUND: Hibernoma is a rare adipose tissue tumor of the soft tissue and the term is derived from the histological similarities to the brown fat found in hibernating animals. It usually occurs in the interscapular area, back, and neck and a few cases have been reported in the buttock or thigh. CASE REPORT: Two cases are presented, one of which had a lesion in the buttock and the other a lesion in the thigh. The lesion in the buttock extended into the pelvis. CT and MR findings suggested liposarcoma in both cases, but the uptake was extremely intense on 18F-FDG-PET in one case. This was not typical of liposarcoma and suggestive of hibernoma. Biopsy specimens revealed a proliferation of adipose cells with vacuolated granular eosinophilic cytoplasm. No cellular atypia or mitotic figures were observed in either case. A marginal excision was performed in one case and an intralesional excision in the other. There were no signs of local recurrence at the final follow-up. CONCLUSIONS: While occurrences in the buttock or thigh are exceedingly rare, hibernoma should be included in the differential diagnosis of an adipose tissue tumor in the thigh, even though the imaging findings mimic liposarcoma. 18F-FDG-PET may be a very meaningful technique to differentiate hibernoma from liposarcoma. A correct diagnosis should be established to prevent over-surgery.

Methods of reconstruction for bone defect after tumor excision: a review of alternatives.

Bone defect is a common problem encountered in the treatment of musculoskeletal tumor surgery. Allograft is a commonly used technique to reconstruct a large osseous defect following tumor excision in the United States and some European countries, and relatively good results have been reported because of its biologic nature. However, with the use of an allograft, there are concerns of transmission of infectious diseases, immunological reactions, and social or religious refusal in some regions in the world. Under these circumstances, vascularized autogenous fibular or iliac bone grafts are commonly used techniques and bone lengthening techniques using external fixation have been reported recently. These procedures utilize viable bone. In addition to these procedures, some biological reconstructive techniques utilizing nonviable bone have been performed as surgical alternatives for allografts using treated recycling bone including irradiated or pasteurized resected bone graft and reconstruction using an autograft containing tumor treated by liquid nitrogen. Although each technique has its proper advantages and disadvantages, the clinical results are similar to the allograft, and numerous techniques are now available as reasonable alternatives for allografts.

Japanese Orthopaedic Association Back Pain Evaluation Questionnaire. Part 3. Validity study and establishment of the measurement scale : Subcommittee on Low Back Pain and Cervical Myelopathy Evaluation of the Clinical Outcome Committee of the Japanese Orthopaedic Association, Japan.

BACKGROUND: The Japanese Orthopaedic Association decided to revise the JOA score for low back pain and to develop a new outcome measure. In February 2002, the first survey was performed with a preliminary questionnaire consisting of 60 evaluation items. Based on findings of that survey, 25 items were selected for a draft of the JOA Back Pain Evaluation Questionnaire (JOABPEQ). The second survey was performed to confirm the reliability of the draft questionnaire. This article further evaluates the validity of this questionnaire and establishes a measurement scale. METHODS: The subjects of this study consisted of 355 patients with low back disorders of any type (201 men, 154 women; mean age 50.7 years). Each patient was asked to fill in a self-administered questionnaire. Superficial validity was checked in terms of the completion rate for filling out the entire questionnaire. Factor analysis was then performed to evaluate the validity of the questionnaire and establish a measurement scale. RESULTS: As a result of the factor analysis, 25 items were categorized into five factors. The factors were named based on the commonality of the items: social function, mental health, lumbar function, walking ability, and low back pain. To establish a measurement scale for each factor, we determined the coefficient for each item so the difference between the maximum factor scores and minimum factor scores was approximately 100. We adjusted the formula so the maximum for each factor score was 100 and the minimum was 0. CONCLUSIONS: We confirmed the validity of the JOA Back Pain Evaluation Questionnaire and established a measurement scale.

Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ): part 4. Establishment of equations for severity scores. Subcommittee on low back pain and cervical myelopathy, evaluation of the clinical outcome committee of the Japanese Orthopaedic Association.

BACKGROUND: To establish a patient-oriented outcome measure for cervical myelopathy, a subcommittee of the Japanese Orthopaedic Association (JOA) developed a new scoring system to evaluate the overall clinical status of patients, which could be completed by patients themselves. The subcommittee completed three large-scale studies to select and modify questions derived from various preexisting outcome measures including Short Form-36, and then finalized and validated the questionnaire, which comprised 24 questions. METHODS: The finalized questionnaire was administered to 369 patients with cervical myelopathy due to disc herniation, spondylosis, or ossification of posterior longitudinal ligament by randomly selected board-certified spine surgeons. Patients with different severities of myelopathy were included to insure accuracy and responsiveness of this questionnaire against patients' different neurological status. RESULTS: Data of 236 patients were employed and were subjected to rigorous statistical analyses. There was no question that was difficult to answer and distribution of answers for each question was not concentrated to one choice, indicating the appropriateness of all 24 questions. Results of factor analysis suggested that the 24 questions could be divided into five different factors or functional domains. The factors were defined as follows: factor 1, lower extremity function; factor 2, quality of life; factor 3, cervical spine function; factor 4, bladder function; and factor 5, upper extremity function. Finally, equations that would yield scores for the five factors were assembled. The score to be used to represent the degree of patients' disability or status in each domain can be calculated by multiplying prefixed numbers of selected answers to questions by preassigned coefficients. Coefficients were defined to make the minimum score 0 and the maximum score 100. CONCLUSIONS: We have successfully established a questionnaire that is able to demonstrate the status of patients suffering cervical myelopathy from five different aspects represented by five intuitive numerical scores. The final issue to be confirmed is the responsiveness of this questionnaire to changes in patients' status after various surgical and nonsurgical treatments.