Neural-cadherin (N-cadherin) is one of the most important molecules involved in tissue morphogenesis, wound healing, and the maintenance of tissue integrity. Recently, the cleavage of N-cadherin has become a focus of attention in the field of cancer biology. Cadherin and their ectodomain proteolytic shedding play important roles during cancer progression. The aims of this study are to investigate the serum soluble N-cadherin (sN-CAD) levels in patients with malignant bone and soft tissue tumors, and to evaluate the prognostic significance of the sN-CAD levels.
We examined the level of serum sN-CAD using an ELISA in 80 malignant bone and soft tissue tumors (bone sarcoma, n = 23; soft tissue sarcoma, n = 50; metastatic cancer, n = 7) and 87 normal controls. The mean age of the patients was 51 years (range, 10–85 years) and the mean follow-up period was 43 months (range, 1–115 months).
The median serum sN-CAD level was 1,267 ng/ml (range, 135–2,860 ng/ml) in all patients. The mean serum sN-CAD level was 1,269 ng/ml (range, 360–2,860 ng/ml) in sarcoma patients, otherwise 1,246 ng/ml (range, 135–2,140 ng/ml) in cancer patients. The sN-CAD levels in patient were higher than those found in the controls, who had a median serum level of 108 ng/ml (range, 0–540 ng/ml). The patients with tumors larger than 5 cm had higher serum sN-CAD levels than the patients with tumors smaller than 5 cm. The histological grade in the patients with higher serum sN-CAD levels was higher than that in the patients with lower serum sN-CAD levels. A univariate analysis demonstrated that the patients with higher serum sN-CAD levels showed a worse disease-free survival rate, local recurrence-free survival rate, metastasis-free survival rate, and overall survival rate compared to those with lower serum sN-CAD levels. In the multivariate analysis, sN-CAD was an independent factor predicting disease-free survival.
sN-CAD is a biomarker for malignant bone and soft tissue tumors, and a potentially valuable pre-therapeutic prognostic factor in patients with bone and soft tissue sarcoma.
Sarcoma; Cadherin; Prognosis; Shedding; Biomarker
Here, a case of Ewing’s sarcoma family of tumors (ESFT) of the femur with an unusual clinical course is reported. At 20 years of age, the patient had undergone curettage of a bone tumor of the right femur which was diagnosed as ESFT. One cycle of chemotherapy with vincristine and cyclophosphamide and radiotherapy for a total dose of 40 Gy was administered. The patient did not develop any recurrence or metastases for the following 18 years, in spite of the inadequacy of the initial treatment. At 38 years of age, he was referred to our institution with right thigh pain that had persisted for several months. Radiographs and magnetic resonance imaging findings showed a mass lesion in his proximal femur extending to the soft tissue. An open biopsy was performed and the lesion was diagnosed as recurrence of ESFT, although a molecular biological investigation did not reveal any expression of the characteristic fusion genes that have previously been reported. The patient received standard multimodal therapy employing standard combination chemo-therapy for ESFT and wide surgical excision. The patient has been disease-free for 9 years since the treatment. This patient may have a rare subtype of ESFT with an unknown chromosomal translocation and relatively non-aggressive biological behavior.
Ewing’s sarcoma; recurrence; unusual clinical course
Studies have shown that ischemia-reperfusion (I/R) produces free radicals leading to lipid peroxidation and damage to skeletal muscle. The purposes of this study were 1) to assess the histological findings of gastrocnemius muscle (GC) and tibialis anterior muscle (TA) in I/R injury model mice, 2) to histologically analyze whether a single pretreatment of edaravone inhibits I/R injury to skeletal muscle in murine models and 3) to evaluate the effect of oxidative stress on these muscles.
C57BL6 mice were divided in two groups, with one group receiving 3 mg/kg intraperitoneal injections of edaravone (I/R + Ed group) and the other group receiving an identical amount of saline (I/R group) 30 minutes before ischemia. Edaravone (3-methy-1-pheny1-2-pyrazolin-5-one) is a potent and novel synthetic scavenger of free radicals. This drug inhibits both nonenzymatic lipid peroxidation and the lipoxygenase pathway, in addition to having potent antioxidant effects against ischemia reperfusion. The duration of the ischemia was 1.5 hours, with reperfusion at either 24 or 72 hours (3 days). Specimens of gastrocnemius (GC) and anterior tibialis (TA) were removed for histological evaluation and biochemical analysis.
This model of I/R injury was highly reproducible in histologic muscle damage. In the histologic damage score, the mean muscle fibers and inflammatory cell infiltration in the I/R + Ed group were significantly less than the corresponding values of observed in the I/R group. Thus, pretreatment with edaravone was observed to have a protective effect on muscle damage after a period of I/R in mice. In addition, the mean muscle injury score in the I/R + Ed group was also significantly less than the I/R group. In the I/R + Ed group, the mean malondialdehyde (MDA) level was lower than in the I/R group and western-blotting revealed that edaravone pretreatment decreased the level of inducible nitric oxide synthase (iNOS) expression.
Edaravone was found to have a protective effect against I/R injury by directly inhibiting lipid peroxidation of the myocyte by free radicals in skeletal muscles and may also reduce the secondary edema and inflammatory infiltration incidence of oxidative stress on tissue.
Ischemia-reperfusion injury; Skeletal muscle; Free radical scavenger; Edaravone; iNOS
Platelet-rich plasma (PRP) is a fraction of plasma in which several growth factors are concentrated at high levels. The active soluble releasate isolated following platelet activation of PRP (PRP-releasate) has been demonstrated to stimulate the metabolism of IVD cells in vitro. The in vivo effect of PRP-releasate on degenerated IVD remains unknown. The purpose of this study was to determine the reparative effects of autologous PRP-releasate on degenerated intervertebral discs (IVDs).
To induce disc degeneration, New Zealand white rabbits (n = 12) received anular puncture in two noncontiguous discs. Autologous PRP and PPP (platelet-poor plasma) were isolated from fresh blood using two centrifugation techniques. Four weeks after the initial puncture, releasate isolated from clotted PPP or PRP (PPP- or PRP-releasate), or phosphate-buffered saline (PBS; control) was injected into the punctured discs. Disc height, magnetic resonance imaging (MRI) T2-mapping and histology were assessed.
Anular puncture produced a consistent disc narrowing within four weeks. PRP-releasate induced a statistically significant restoration of disc height (PRP vs. PPP and PBS, P<0.05). In T2-quantification, the mean T2-values of the nucleus pulposus (NP) and anulus fibrosus (AF) of the discs were not significantly different among the three treatment groups. Histologically, the number of chondrocyte-like cells was significantly higher in the discs injected with PRP-releasate compared to that with PBS.
The administration of active PRP-releasate induced a reparative effect on rabbit degenerated IVDs. The results of this study suggest that the use of autologous PRP-releasate is safe and can lead to a clinical application for IVD degeneration.
This longitudinal study aimed to identify risk factors for the incidence and progression of radiographic knee osteoarthritis (OA). We examined the inhabitants of Miyagawa village aged ≥65 years every two years between 1997 and 2007. Anteroposterior radiographs of both knees were graded for OA using the Kellgren-Lawrence (K/L) grading system. Knee OA was defined as grade ≥2. We recorded the incidence of knee OA among participants in whom both knees changed from K/L grades 0 or 1 to ≥2 over a four-year follow-up period. We also recorded the progression of knee OA using this threshold among patients in whom one or both knees changed from K/L grades 2 or 3 to any higher grade over the follow-up period. Baseline data obtained from standard questionnaires, physical findings and X-rays included age, gender, body mass index (BMI), osteoporosis, Heberden’s nodes, knee range of motion (ROM), knee pain and cigarette smoking. The rates of incidence and progression of knee OA among 360 participants (241 women, 119 men) who fulfilled the study criteria were 4.0 and 6.0% per year, respectively. Female gender (odds ratio [OR] 2.849, 95% confidence interval [CI] 1.170–6.944) and high BMI (OR 1.243, 95% CI 1.095–1.411) were significantly associated with the incidence of knee OA, and restricted knee ROM (OR 0.941, 95% CI 0.892–0.992) was significantly associated with knee OA progression. Patients with a low knee ROM relative to grade of radiographic knee OA require more careful follow-up than those with a higher ROM.
Malignant soft tissue tumors of the foot are extremely rare and thus can be prematurely excised without appropriate preoperative evaluation. The present study compares adverse effects between unplanned and planned surgical excisions.
We retrospectively reviewed the clinical records, radiographs, pathology reports and pathological specimens of 14 consecutive patients with soft tissue sarcoma of the foot among 592 with sarcomas between 1973 and 2009. We then compared the incidence and clinical outcomes after unplanned (UT; n = 5) and planned (PT; n = 9) surgical excisions of foot sarcomas.
The most frequent diagnosis was synovial sarcoma (n = 4; 28.6%). The overall 5-year survival rates of the PT and UT groups were 65.6% and 60.0%, respectively, and the event-free 5-year survival rates were 63.5% and 40.0%, respectively. Event-free and overall survival rates did not significantly differ between the two groups. However, tumors were significantly larger in the PT group than in the UT group (p < 0.05).
Unplanned resection lead to a relatively worse prognosis and a likelihood of recurrence despite additional resections. We recommend that soft tumors of the foot should only be excised after appropriate preoperative evaluation regardless of the size of the tumor.
Numerous studies have reported the survival of metastatic sarcoma patients who have undergone either a lung metastasectomy or chemotherapy. However, little is known with regards to the clinical course of patients with bone or soft tissue sarcomas who have succumbed to disease. This study aimed to analyze the metastatic patterns of sarcoma patients and to describe the clinical course after the detection of distant metastasis. We reviewed the clinical records of 255 patients with a diagnosis of sarcoma who were referred to our institution, and found 63 patients who succumbed due to metastasis. We examined the clinical features of the initially detected distant metastases, the subsequent clinical course up to the time of patient death and the survival time of patients who died of lung metastasis. Of the 63 patients who died of distant metastasis, 52 (83%) developed lung metastasis as the first metastatic site, while 22 (35%) developed extra-pulmonary metastasis. The majority (77%; 49 of 63 patients) died of primary metastasis. While all 18 bone sarcoma patients died of lung metastasis, 11 of the 45 soft tissue sarcoma patients died of extra-pulmonary metastasis. Six patients died of brain metastasis. The survival of the patients with lung metastasis was only approximately 6 months following the cessation of treatment, regardless of the type of treatment used. These results indicate that planned follow-up and treatment of sarcomas require a precise knowledge of tumor clinical behavior, particularly of the preponderant activity.
cause of death; metastasis; sarcoma
We describe the development of a new device that permits handy intraoperative measurement of lumbar segmental instability. The subjects comprised 80 patients with lumbar degenerative disease. Relationships between preoperative radiological assessments and extended distance as measured using our new device were investigated. Mean extended distance measured using the device was 3.7 ± 1.9 mm. Correlation coefficients between angular motion and extended distance, and translational motion and extended distance were 0.76 and 0.66, respectively, revealing significant positive relationships between these values (p < 0.01 each). The correlation coefficient between the intervertebral endplate angle on the flexion film and extended distance was −0.78, showing a significant negative relationship (p < 0.01). In conclusion, the device for intraoperative measurement of lumbar segmental instability that we have developed appears to permit simple measurement of intervertebral instability and provides operators with valuable information for selecting operative methods of spinal fusion or instrumentation.
Bone morphogenic proteins (BMPs) may have neurotrophic functions but there is limited evidence of these functions in the peripheral nervous system. We therefore investigated the expression of BMPs and BMP receptors (BMPRs) in normal and injured peripheral nerves. In 10 of 15 Sprague-Dawley rats, a 3-mm segment of sciatic nerve was resected at the trifurcation in the thigh. One day (n = 5) and 7 days (n = 5) after transection, proximal and distal stumps were removed and immunohistochemically analyzed for BMP-2, -7, BMPR-1A, -1B, and -2. The other five animals served as normal controls. In normal nerves, BMP-2 expression was localized at Ranvier’s node, and BMP-7 and BMPR-1B were expressed in several axon-Schwann cell units, whereas other receptors were not expressed. After nerve transection, BMP-7 expression was upregulated at both proximal and distal stumps along with Schwann cell columns during Wallerian degeneration. BMPRs were also upregulated compared with the normal nerve. The upregulation in BMP expression after nerve transection suggests that BMPs may play a role in the healing response of the peripheral nerve.
Extraskeletal osteosarcoma (ESOS) occurs in approximately 1% of soft tissue sarcomas and 2–4% of all osteosarcomas. In particular, subcutaneous osteosarcoma is extremely rare, occurring in less than 10% of ESOS cases. This report presents a case of a subcutaneous tumor in the upper arm of a 79-year-old male. Imaging and pathological findings led to the conclusion that the soft tissue tumor should be diagnosed as subcutaneous osteosarcoma. Additionally, this case report documented the clinicopathological findings of the extraskeletal subcutaneous osteosarcoma in this case and discussed its clinical features by reviewing cases previously described in the literature.
osteosarcoma; subcutaneous tissue; extraskeletal
The anatomic femoral component and Harris-Galante porous II (HGPII) cup were developed to provide more reliable bone ingrowth. We performed 20 cementless total hip arthroplasties (THAs) with anatomic stem/HGPII cup with 22-mm head in 14 consecutive patients, and evaluated the clinical and radiological results for a mean follow-up of 12.8 years. The all-anatomically designed stem provided excellent clinical and radiographic results. Four acetabular components underwent revision: three for fracture of the locking mechanism and wear of the polyethylene liner and one for the locking mechanism failure with dislocation of the HGPII cup. The abduction angles of the four revised acetabular components were apparently higher. The survivorship 13 years after surgery was 78%. Our findings show good long-term results using the anatomic femoral component, while the HGPII cup combined with 22-mm head seems to have poor durability due to locking mechanism failure.
Osteoarthritis (OA) is a common disease that has a definite genetic component. Only a few OA susceptibility genes that have definite functional evidence and replication of association have been reported, however. Through a genome-wide association study and a replication using a total of ∼4,800 Japanese subjects, we identified two single nucleotide polymorphisms (SNPs) (rs7775228 and rs10947262) associated with susceptibility to knee OA. The two SNPs were in a region containing HLA class II/III genes and their association reached genome-wide significance (combined P = 2.43×10−8 for rs7775228 and 6.73×10−8 for rs10947262). Our results suggest that immunologic mechanism is implicated in the etiology of OA.
In a recent study, we demonstrated that a high-power flash wave light (FWL) from a xenon lamp exerted a stronger cytocidal effect against a mouse osteosarcoma cell line than continuous wave light (CWL) in photodynamic therapy with acridine orange (AO-PDT). Based on our in vitro results, we investigated the in vivo anti-tumor activity of AO-PDT using flash wave light from a xenon lamp in a mouse osteosarcoma model. Mouse osteosarcoma cells (LM8) were injected into the subcutaneous tissue of the back of C3H mice, and tumors that grew to approximately 3 mm in diameter were treated by AO-PDT using FWL. AO was administered by intravenous injection and 2 h later the entire body of the mouse was illuminated with FWL from a xenon lamp. Significant growth inhibition of the tumor xenografts was observed as compared with that in the control group, suggesting that AO-PDT with FWL may be useful in the treatment of osteosarcoma. An immunohistochemical study of the tumors treated by AO-PDT showed that the underlying mechanism of the tumor growth inhibition involved both apoptosis and necrosis. In conclusion, it appears that following the intravenous administration of AO, AO-PDT in combination with FWL exerts strong anti-tumor activity. Inhibitory effects against growth of the primary tumor in human patients with osteosarcoma as well as other musculoskeletal sarcomas were also observed.
osteosarcoma; acridine orange; photodynamic therapy; flash wave light; apoptosis
Leptomeningeal carcinomatosis occurs in patients with cancer at the rate of approximately 5%; it develops particularly in patients with breast cancer, lung cancer, melanoma, leukemia, or malignant lymphoma. We describe a rare case of leptomeningeal carcinomatosis in which spinal intradural squamous cell carcinoma with no lesions in the cerebral meninges and leptomeninx, was the primary lesion.
A 64-year-old man complained of sacral pain. Although the patient was treated with analgesics, epidural block and nerve root block, sacral pain persisted. Since acute urinary retention occurred, he was operated on. The patient was diagnosed as having an intradural squamous cell carcinoma of unknown origin.
Since the patient presented with a slightly decreased level of consciousness 2 months after surgery, he was subjected to MRI scanning of the brain and spinal cord, which revealed disseminated lesions in the medulla oblongata. The patient died of pneumonia and sepsis caused by methicillin-resistant Staphylococcus aureus 5 months after surgery.
We report the first case of a patient with intradural squamous cell carcinoma with unknown origin that developed independently in the sacrum.
X-ray images of lumbar degenerative diseases often show not only claw osteophytes, but also pairs of osteophytes that form in a direction away from the adjacent disc. We have investigated the direction of the formation of anterior lumbar vertebral osteophytes across the lumbar vertebrae using a sufficient number of lumbar radiographs, because osteophytes images can provide essential information that will contribute to the understanding of the pathology and progress of lumbar spine degeneration.
The direction of the formation of 14,250 pairs of anterior lumbar vertebral osteophytes across the adjacent intervertebral discs in 2,850 patients who were all over 60 years old was investigated. Anterior lumbar vertebral osteophytes were distributed into six groups based on the direction of extension of each pair of osteophytes across the intervertebral disc space.
In L1–L2 and L2–L3, the number of patients classified into groups B (the pair of osteophytes extended in the direction of the adjacent disc) and C (almost complete bone bridge formation by a pair of osteophytes across the intervertebral disc space) was larger than that classified into group D (the pair of osteophytes extended in a direction away from the adjacent disc). In L3–L4, L4–L5 and L5-S1, the number of patients in group D was greater than that of patients belonging to groups B and C.
Our study showed that pairs of osteophytes frequently formed in the direction of the adjacent disc in the upper lumbar vertebrae (L1–L2 and L2–L3) and in the direction away from the adjacent disc in middle or lower lumbar vertebrae (L3–L4, L4–L5, and L5-S1).
There have been reports of serious complications associated with pedicle screw fixation, including nerve root injuries caused by accidental screw insertion. We have developed a new system of lumbar spinal instrumentation that we call Tadpole system®. The purposes of this report were to show the results of a biomechanical study and the short-term outcome of a clinical study, as well as to determine the usefulness of this system.
The Tadpole system® lumbar spinal fusion is a hook-and-rod system according to which the spine is stabilized using 2 sets of 2 spinous processes each that are held in place by 4 hooks tandemly connected to a rod. The biomechanical study was done using 5 human lumbar cadaveric spines, and the range of motion (ROM) was examined in a non-treatment model, an injured model, a pedicle screw fixation model and a Tadpole system® model. For the short-term clinical study the Tadpole system® was used in 31 patients, and the factors analyzed were operation time, time required for spinal instrumentation, amount of intraoperative bleeding, postoperative improvement rate of the Japanese Orthopaedic Association (JOA) score for lumbar spinal disorders, instrumentation failure, spinous process fracture, spinal fluid leakage, nerve root injury, postoperative infection, and bone fusion 2 years after the operation.
The ROM in the Tadpole system® model was slightly bigger than that in the pedicle screw fixation model, but smaller than that in the normal control model. These biomechanical data indicated that the Tadpole system® provided fairly good stability. The mean operation time was 79 min, the mean time required for spinal instrumentation was 8 min, and the mean amount of intraoperative bleeding was 340 mL. The mean postoperative improvement rate of JOA score was 70.9 ± 24.8%. Instrumentation failure (dislocation of a hook) occurred in one patient, and none of the patients developed spinous process fracture, spinal fluid leakage, nerve root injury, or postoperative infection. Two years after the operation, bone union was confirmed in 29 of the 31 patients (93.5%).
We conclude that this system is a useful, easy-to-use and safe spinal instrumentation technique for lumbar fusion surgery.
There has been only one report on the physical characteristics of patients with developmental cervical spinal canal stenosis. The objective of this consecutive clinical study was to identify the physical characteristics of patients with developmental cervical spinal canal stenosis. The subjects were 243 patients with cervical spine disease who received treatment in our department between April 2001 and March 2002. These patients were divided into two groups (the groups of patients with and without spinal canal stenosis) on the basis of their lateral cervical spine radiographs. The six items examined were height, weight, sitting height, inter inner canthal distance, upper arm length, and head circumference in each patient, and then their values were compared between the two groups. The mean inter inner canthal distance was 2.7 cm in the group of patients with spinal canal stenosis and 3.5 cm in the group of patients without spinal canal stenosis; a significant difference (P < 0.01) was observed. Regarding height, weight, sitting height, upper arm length, and head circumference, no significant difference was found while comparing the two groups. In conclusion, developmental cervical spinal canal stenosis seems to be highly likely in patients with smaller inter inner canthal distance.
Cervical spine; Spinal canal stenosis; Physical characteristics
The purpose of the present study was to clarify changes in the psychological state of mothers of patients with idiopathic scoliosis, and to clarify relationships between the psychological states of the mothers and patients. The Maudsley personality inventory (MPI) was administered to 30 patients with idiopathic scoliosis who underwent surgery and their mothers preoperatively and at about 1 year postoperatively. We investigated the relationships between preoperative MPI scores and postoperative scores in patients and their mothers, respectively, and the relationships between MPI scores for patients and mothers. The results of the present study revealed that patients became more extroverted following surgery, while mothers displayed reduced neurotic tendencies. In conclusion, the mothers of patients who undergo corrective treatment for scoliosis may have experienced a substantial psychological burden before surgery, and doctors who treat patients with scoliosis should bear this point in mind.
Scoliosis; Surgery; Parent–patient; Psychological characteristics
We administered the Maudsley Personality Inventory (MPI) preoperatively to 303 patients with spinal diseases about to undergo surgery. Patients younger than 20 years, patients previously treated in the Department of Psychiatry, and patients with poor postoperative results were excluded. Patients with N-scores (neuroticism scale) of 39 points or greater or L-scores (lie scale) of 26 points or greater were regarded as "abnormal." Based on clinical definitions we identified 24 "problem patients" during the course and categorized them as "Unsatisfied," "Indecisive," "Doctor shoppers," or "Distrustful." Preoperative MPI categorized 26 patients as abnormal; 22 patients categorized as abnormal became problem patients (p<0.001). MPI sensitivity and specificity was 84.6% and 99.3%, respectively. Preoperative MPI to patients with spinal disease was found to be useful in detecting problem patients.
Purpose. This paper reports the procedures and the clinical results of a series of surgical treatments for skeletal metastases from soft tissue sarcomas.
Subjects and methods. Surgical treatment of metastatic bony lesions from soft tissue sarcomas has been carried out over a 20 year period (1975–1996). Thirty-two patients developed skeletal metastases from soft tissue sarcomas, and 20 of these cases received surgical treatment. The 23 metastatic bony lesions in these 20 patients were treated using the following
surgical approaches: wide resection with prosthetic replacement in five lesions, wide or marginal resection without reconstruction in four lesions, intramedullarly nailing with curettage and methylmethacrylate cementation in four lesions, marginal resection of vertebral body with replacement by a ceramic prosthesis in three lesions, laminectomy in three lesions, intramedullarly nailing in two lesions, and curettage in two lesions.
Results. Relief of pain was achieved in 17 of the 20 patients. The ambulatory status of the patients with metastasis in the lower extremity or periacetabular region was significantly improved in nine of 10 cases. Seventeen patients died of disease, with a mean survival period of 17.9 months after surgery for metastasis.
Discussion. Although surgical treatment for skeletal metastases from soft tissue sarcomas cannot save the life of the patient, it can be of value in improving their well-being and overall quality of life. In these cases, surgical intervention may be more frequently indicated than in tumors with an osteoblastic or mixed pattern.