Molecular profiling of bone remodeling occurring in musculoskeletal tumors.

Musculoskeletal malignancy is often accompanied by aberrant bone remodeling, leading to tumor cell invasion into skeletal tissues and causing severe pain. BMPs, FGF-2, and RANKL have been identified as promising regulators in physiological bone remodeling. In this study, we explored the expressional profile of BMPs, FGF-2, and RANKL in 1361 patients with 22 varieties of musculoskeletal tumors. Notably, the expression of FGF-2 and RANKL was under detected in all patients. Among BMP1 to BMP15, we found that BMP1, BMP2, BMP4, BMP5, BMP6, and BMP7 were prevalent. In comparison with normal bones, osteosarcoma highly expressed BMP1, BMP2, BMP4, and BMP7 with statistical significance. Synovial sarcoma upregulated BMP4, BMP5, and BMP7; rhabdomyosarcoma increased BMP1 and BMP4; and alveolar soft part sarcoma upregulated BMP1, BMP4, and BMP7. To visualize the BMP-oriented interactions in a bone tumor microenvironment, we have developed novel software that analyzes numerous cell-to-cell and ligand-to-receptor interactions, that is, Environmentome, delineating that osteosarcoma-secreted BMP-4 and synovial sarcoma-secreted BMP7 potently interact with osteoblasts, osteocytes, osteoclast precursors, and mature osteoclasts. Specifically, quantification analysis revealed that the relationship between osteosarcoma and mature osteoclast/precursor, BMP4-BMPR2 and BMP4-ACVR2A interactions were most potent. Regarding the association between osteosarcoma and osteocyte/osteoblast, BMP4-ACVR1 and BMP4-BMPR2 were the key interactions. In the connection between synovial sarcoma and mature osteoclast/precursor, BMP7-ACVR2A and BMP7-BMPR2 interactions were most remarkable. With regard to the cellular link between synovial sarcoma and osteocyte/osteoblast, BMP7-BMPR2 was identified as a potent interaction. In conclusion, our new outlook suggests delivering the pathological events that clinically underlie behind severe skeletal pain or fracture in musculoskeletal tumors.

Satisfaction After Joint-preservation Surgery in Patients With Musculoskeletal Knee Sarcoma Based on Various Scores.

BACKGROUND/AIM: At our institute, we prioritize joint-preservation whenever possible in cases of musculoskeletal knee sarcoma. This study aimed to evaluate patient satisfaction after joint-preservation surgery using different scales. PATIENTS AND METHODS: Surveys were mailed to 62 patients with musculoskeletal knee sarcoma. We analyzed the responders' data based on the Musculoskeletal Tumor Society (MSTS) score, Toronto Extremity Salvage Score (TESS), and three component scores (physical, mental, and role/social) of the 36-Item Short-Form Health Survey according to whether they belonged to patients in the joint-preservation or in the joint-replacement groups. RESULTS: The survey response rate was 67.7%. MSTS and TESS scores were higher in the patients in the joint-preservation group than in the joint-replacement group, although the differences lacked statistical significance. CONCLUSION: Better physical outcomes improve patient satisfaction, as demonstrated by the high satisfaction in the group with joint-preservation.

Determining Patient Satisfaction and Treatment Desires in Patients With Musculoskeletal Sarcoma of the Knee After Joint-preservation Surgery Using a Questionnaire Survey.

BACKGROUND/AIM: For cases of musculoskeletal sarcoma of the knee presenting to our institute, we prioritize joint preservation whenever possible. To investigate patient satisfaction and desire for joint preservation, a questionnaire survey was performed. PATIENTS AND METHODS: Surveys were mailed to 62 patients with musculoskeletal sarcoma of the knee. Responses concerning the patient and their families' satisfaction were evaluated on a 5-point Likert scale and their priorities for the surgery were noted as well. RESULTS: The survey response rate was 67.7%. All but one person were above neutral for the 5-point Likert scale. Overall, the first priority was tumor removal followed by preservation of function. CONCLUSION: Patients identified tumor removal as their first priority, which could increase satisfaction. Following that, better preservation of function could also increase patient satisfaction. Joint-preservation was consistent with these priorities.

Long period of relative quiescence in distal-type epithelioid sarcoma of the forearm with recurrence after surgery: A case report.

BACKGROUND: Epithelioid sarcoma (ES) is a rare malignant mesenchymal tumor that only accounts for 0.6% to 1.0% of all cases of sarcomas. ES with a relative quiescent state of more than 10 years is extremely rare.Here, we present a rare case of ES in the forearm of a 17-year-old girl. The patient had a congenital mass in her forearm that measured approximately 1cm; it grew rapidly starting 5 years ago. The mass was not treated until last year when she underwent the first surgery. The mass was located in the middle and lower part of the left forearm and involved the dorsal muscle group, intermuscular space, and subcutaneous tissues without clear boundaries.The patient underwent surgery, and the tumor recurred twice within 1 year postoperatively. METHODS: The tumor samples were examined via hematoxylin-eosin (HE) and immunohistochemistry staining. RESULTS: Histopathologically, the tumor comprised large polygonal epithelioid cells with abundant eosinophilic cytoplasm arranged in cell nests. Central necrosis and focal myxoid change could be seen in the tumor tissues. Immunostaining showed that the tumor cells were positive for CD34, CK, EMA, and vimentin but negative for CD31, S-100, and INI-1. CONCLUSION: Based on these findings, the tumor was diagnosed as ES of distal form. Distal-type ES could have a long period of relative quiescence, after which it could grow rapidly and relapse multiple times over a short duration.

Bladder cancer: overview and disease management. Part 1: non-muscle-invasive bladder cancer.

Part 1 of this two-part article provides an overview of bladder cancer and discusses its management. Since publication of a previous article entitled 'Understanding the role of smoking in the aetiology of bladder cancer' ( Anderson, 2009 ), the author has received many requests for an update. This article provides an overview of bladder cancer and its current management practices, underlining the continued role of smoking as the predominant risk factor in the disease's development. The management of bladder cancer is governed by specific guidelines. Management of non-muscle-invasive cancers, including surgical intervention with transurethral resection, and intravesical therapy using chemotherapy and immunotherapy agents, is discussed. Cystectomy (removal of the bladder), is sometimes necessary. Treatments are effective in reducing tumour recurrence, but the effects of the risks and side-effects on the individual's quality of life can be significant. The prevalence of bladder cancer, and the nature of its management make this cancer one of the most expensive for the NHS to treat. The effectiveness of health promotional strategies in increasing peoples' awareness of their risk of developing the disease, and in enabling them to change long-term health behaviours is discussed. The role of the multidisciplinary team is explored, along with that of the uro-oncology cancer nurse specialist. Part 2 will consider the management of muscle-invasive and metastatic bladder cancer.

Interleukin-6, C/EBP-ß and PPAR-γ expression correlates with intramuscular liposarcoma growth in mice: The impact of voluntary physical activity levels.

IL-6 is an axial cytokine overexpressed in cancer to promote growth and increase resistance to anti-cancer therapies. As the application of IL-6-targeting therapies are still limited, alternative non-aggressive and adjuvant approaches, like physical activity (PA) could be useful to reverse IL-6 effects. To get more insights into liposarcoma (LS) pathophysiology, we investigated potential molecular links between IL-6 and LS growth and we tested the impact of PA on such mechanism in an orthotopic model of intramuscular LS. Initially active nude mice have received an intramuscular injection of either human SW872 cells or vehicle, then were respectively randomized into voluntary-active or inactive mice with open or restricted access to activity-wheels. We found that LS-bearing mice exhibited ∼6 fold increase in circulating IL-6 comparing to controls, with a concomitant decrease in hepatic drug-metabolizing enzymes expression. Circulating IL-6 levels were positively correlated with intra-tumor IL-6 expression (r = 0.85, P < 0.01). Interestingly, intra-tumor IL-6, C/EBP-α/ß and PPAR-γ expression were correlated together and with greater tumor mass and autophagy markers, notably, GABARAPL-1. Intriguingly, we found that maintaining a spontaneous PA after tumor injection did not reduce the levels of IL-6, but even enhanced tumor growth, induced body weight loss and increased the risk of developing lung metastasis. Our findings suggest that (1) IL-6, C/EBP-ß and PPAR-γ exert a potential role in promoting growth of dedifferentiated LS and (2) that PA failed to mechanistically interfere with these factors, but enhanced LS growth via other independent-mechanisms. The preclinical data reported here could be helpful in the sub-molecular classification of LS patients to improve diagnosis and design a low-risk treatment. Circulating IL-6 could serve as an indicator for treatment follow-up and, perhaps, for infra-radiologic LS relapses.

Reliability and Validity of the Musculoskeletal Tumor Society Scoring System for the Upper Extremity in Japanese Patients.

BACKGROUND: The Musculoskeletal Tumor Society (MSTS) scoring system developed in 1993 is a widely used disease-specific evaluation tool for assessment of physical function in patients with musculoskeletal tumors; however, only a few studies have confirmed its reliability and validity. QUESTIONS/PURPOSES: The aim of this study was to validate the MSTS scoring system for the upper extremity (MSTS-UE) in Japanese patients with musculoskeletal tumors for use by others in research. Does the MSTS-UE have: (1) sufficient reliability and internal consistency; (2) adequate construct validity; and (3) reasonable criterion validity in comparison to the Toronto Extremity Salvage Score (TESS) or SF-36? METHODS: Reliability was performed using test-retest analysis, and internal consistency was evaluated with Cronbach's alpha coefficient. Construct validity was evaluated using a scree plot to confirm the construct number and the Akaike information criterion network. Criterion validity was evaluated by comparing the MSTS-UE with the TESS and SF-36. RESULTS: The test-retest reliability with intraclass correlation coefficient (0.95; 95% CI, 0.91-0.97) was excellent, and internal consistency with Cronbach's α (0.7; 95% CI, 0.53-0.81) was acceptable. There were no ceiling and floor effects. The Akaike Information Criterion network showed that lifting ability, pain, and dexterity played central roles among the components. The MSTS-UE showed substantial correlation with the TESS scoring scale (r = 0.75; p < 0.001) and fair correlation with the SF-36 physical component summary (r = 0.37; p = 0.007). Although the MSTS-UE showed slight correlation with the SF-36 mental component summary, the emotional acceptance component of the MSTS-UE showed fair correlation (r = 0.29; p = 0.039). CONCLUSIONS: We can conclude that the MSTS is not an adequate measure of general health-related quality of life; however, this system was designed mainly to be a simple measure of function in a single extremity. To evaluate the mental state of patients with musculoskeletal tumors in the upper extremity, further study is needed.

Electrophysiological features in dogs with peripheral nerve sheath tumors: 51 cases (1993-2010).

OBJECTIVE: To determine the electrophysiological changes in dogs with peripheral nerve sheath tumors (PNSTs), evaluate the prevalence of these changes, assess the correlation between spontaneous activity in epaxial muscles and proximal invasion by the tumor, and evaluate whether knowledge of electrophysiological changes could be helpful in the imaging diagnosis via CT or MRI. DESIGN: Retrospective case series. ANIMALS: 51 dogs with a histologic (n = 18) or a suspected (33) diagnosis of PNST. PROCEDURES: Clinical, postmortem, and histologic reports and details of electrodiagnostic procedures and CT or MRI reports were studied. Twenty-four CT and 6 MRI reports for dogs with PNSTs were reviewed by a single observer blinded to the diagnosis. RESULTS: Only 2 of the 51 dogs had no electrophysiological changes. The most commonly affected muscles were those innervated by the radial, ulnar, median, tibial-sciatic, and peroneal nerves. Abnormal spontaneous epaxial muscle activity was significantly more frequent in the group with foraminal or spinal invasion by the tumors. Knowledge of the electrophysiological changes increased diagnostic accuracy of CT. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that electrophysiological studies may be sensitive for the detection of PNST and helpful in the imaging diagnosis. Epaxial electromyographic abnormalities appeared to be predictive for intervertebral or vertebral canal invasion by PNSTs in dogs.

Platinum quantum dots and their cytotoxic effect towards myoblast cancer cells (C2C12).

The cytotoxic effect towards myoblast cancer cells (C3C12) of well-crystalline colloidal Pt quantum dots (QDs) was examined and presented in this paper. The Pt QDs were synthesized by facile colloidal process and characterized by transmission electron microscopy (TEM) and high-resolution TEM (HR-TEM), which confirmed that the QDs are prepared in high-density, possessing a well-crystalline structure. To examine the cytotoxicity, various doses of as-prepared QDs were treated with C2C12 myoblast cancer cells at different incubation intervals; 24, 48, 72, and 96 hours, and the viability of cells was analyzed with MTT assay. The detailed analyses revealed that in the presence of Pt-QDs, with increasing the incubation time, the number of cancer cells decreases. Moreover, with increasing concentration of Pt-QDs, the cancer cell death increases, confirming that the concentration of Pt-QDs has a significant role in controlling the number of cancer cells. The present research demonstrated that Pt-QDs can efficiently be used as anticancer agents.

Intramuscular metastasis of uterine cervix cancer on F-18 FDG PET/CT.

We report F-18 FDG PET/CT images of biopsy-proven intramuscular metastasis from primary uterine cervix cancer. A 70-year-old woman was admitted because of a mass in the left axilla. She was diagnosed with uterine cervix cancer and underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic node dissection and received adjuvant chemotherapy and radiation therapy 9 years ago. Magnetic resonance imaging showed a large soft tissue mass in the intramuscular region of the left axilla. The mass showed intense F-18 FDG uptake with a central necrotic portion on F-18 FDG PET/CT. Hypermetabolic lymph nodes were also noted in the left axilla, interpectoral, and left supraclavicular areas. Additionally, several hypermetabolic nodules were noted in both lungs. The lesion in the left axilla was excised and the pathologic results were consistent with metastasis from uterine cervix cancer.

Predictors of outcome of non-muscle-invasive and muscle-invasive bladder cancer.

Bladder cancer is a major cause of morbidity and mortality. At initial diagnosis, 75% of patients present with non-muscle-invasive disease and 25% of patients have muscle-invasive or metastatic disease.Patients with noninvasive disease suffer from a high rate of recurrence and 10-30% will have disease progression. Patients with muscle-invasive disease are primarily treated with radical cystectomy, but frequently succumb to their disease despite improvements in surgical technique. In non-muscle-invasive disease, multiplicity, tumor size, and prior recurrence rates are the most important predictors for recurrence, while tumor grade, stage, and carcinoma in situ are the most important predictors for progression. The most common tool that clinicians use to predict outcomes after radical cystectomy is still the tumor-node-metastasis (TNM) staging system, with lymph node involvement representing the most important prognostic factor. However, the predictive accuracy of staging and grading systems are limited, and nomograms incorporating clinical and pathologic factors can improve prediction of bladder cancer outcomes. One limitation of current staging is the fact that tumors of a similar stage and grade can have significantly different biology. The integration of molecular markers, especially in a panel approach, has the potential to further improve the accuracy of predictive models and may also identify targets for therapeutic intervention or patients who will respond to systemic therapies.

Interstitial fluid pressure and vascularity of intradermal and intramuscular human tumor xenografts.

PURPOSE: High interstitial fluid pressure (IFP) in tumors has been shown to be associated with poor prognosis. Mechanisms underlying the intertumor heterogeneity in IFP were investigated in this study. METHODS AND MATERIALS: A-07 melanoma xenografts were transplanted intradermally or intramuscularly in BALB/c nu/nu mice. IFP was measured in the center of the tumors with a Millar catheter. Tumor blood perfusion and extracellular volume fraction were assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The necrotic fraction, vascular density, and vessel diameters of the tumors were determined by image analysis of histological preparations. RESULTS: Significant intertumor heterogeneity in IFP, blood perfusion, and microvascular morphology was observed whether the tumors were transplanted intradermally or intramuscularly. High IFP was mainly a consequence of high resistance to blood flow caused by low vessel diameters in either transplantation site. IFP decreased with increasing blood perfusion in intradermal tumors and increased with increasing blood perfusion in intramuscular tumors, mainly because the morphology of the tumor microvasculature differed systematically between the two tumor models. CONCLUSION: The potential of DCE-MRI as a noninvasive method for assessing the IFP of tumors may be limited because any relationship between IFP and blood perfusion may differ with the tumor growth site.

Inhibitor of indoleamine-2,3-dioxygenase 1-methyl-D-tryptophan can stimulate the growth of immunogenic tumors.

We studied the effect of 1-methyl-D-tryptophan, an inhibitor of indoleamine-2,3-dioxygenase, on the growth of transplanted hepatocarcinoma-29 in C3HA mice. Hepatocarcinoma-29 transplanted into the thigh muscles undergoes immunological rejection in more than 50% non-syngeneic recipients. Chronic local administration of 1-methyl-D-tryptophan promotes progressive growth of the tumor in recipient mice leading to 100% animal death. The stimulating effect of 1-methyl-D-tryptophan on tumor growth is discussed.

Neuroendocrine tumor (carcinoid) metastatic to orbital extraocular muscle: case report and literature review.

PURPOSE: To report a patient who showed neuroendocrine tumor (carcinoid) metastasis to the medial rectus muscle and to review patients' characteristics of carcinoid metastases to the extraocular muscles. CASE: A 72-year-old woman, who initially presented with spindle-shaped enlargement of the right medial rectus muscle, was followed for 3 years with a diagnosis of orbital myositis. Initial biopsy of the medial rectus muscle showed inflammation only. She showed remission and exacerbation of right proptosis and eyelid swelling, which responded to oral and intravenous steroids. On the occasion of abdominal computed tomography for ischemic colitis, a large retroperitoneal mass was detected and diagnosed as well-differentiated neuroendocrine tumor. The gradual increase of the medial rectus muscle with optic nerve compression, and hence, visual reduction, prompted a second excisional biopsy of the medial rectus mass, which proved to be neuroendocrine tumor metastasis. Whole body 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography fused with computed tomography revealed abnormal uptake only in the right orbit (maximum standardized uptake value: SUVmax = 3.83), and the patient underwent radiation to the right orbit with the subsidence of the residual mass. RESULTS: The literature review found 15 patients, including this patient, with neuroendocrine tumor metastases to the extraocular muscles. Frequent symptoms and signs were diplopia, proptosis, and ocular motility limitation. CONCLUSIONS: Neuroendocrine tumor appears to have propensity to extraocular muscle metastases and its slow growth might pose difficulty in differential diagnoses of orbital myositis.

Benign vs malignant soft tissue neoplasms: limitations of magnetic resonance imaging.

AIMS: Various features have been described in the literature to differentiate benign from malignant lesions. The aim of the present study was to study the accuracy of each of these features and that of magnetic resonance imaging (MRI) in diagnosing malignant lesions. MATERIALS AND METHODS: Fifty-five consecutive patients presenting with neoplastic (both benign and malignant) lesions diagnosed clinically and on ultrasound were studied and their MRI features were compared with the findings on surgical exploration and histopathologic examination. RESULTS: There were 32 (58%) benign and 23 (42%) malignant masses. Malignant masses were more common in patients older than 20 years (83%), and these had symptoms of less than 6 months duration (75%), as against benign lesions. The swelling was painful in 8 malignant masses and these were more common in the upper limbs (61%). Various features of malignant lesions were size more than 5 cm in 83%, change in signal intensity from homogenous on T1-weighted images to heterogenous on T2-weighted images in 74%, irregular margins in 74%, and heterogenous contrast enhancement in 91%. The accuracy of these features was 76%, 58%, 78%, and 60%, respectively. Most benign and malignant lesions were intramuscular in location. A significant number (38%) of benign lesions were located in the intermuscular facial plane. Definitive diagnosis was made in 42% of the lesions. CONCLUSIONS: MRI is an excellent modality for evaluating soft tissue neoplasms; however, prediction of a specific diagnosis and differentiation of malignant and benign lesions is not always possible.

Horner syndrome associated with contusion of the longus colli muscle simulating a tumor.

A 22-year-old man who was discovered unarousable after an accidental methadone overdose complained of worsening neck pain and left arm weakness over the next week. Examination disclosed a left Horner syndrome and a left brachial plexopathy. Imaging showed a left paraspinal mass adjacent to the sympathetic pathway at the fourth and fifth cervical vertebral levels with imaging features of a tumor. Biopsy was deferred. One month later, the imaging abnormality had nearly disappeared. In retrospect, it represented a contusion injury of the longus colli muscle, a finding not reported previously. Whether it caused the Horner syndrome or was merely a bystander in cervical neck trauma is uncertain. This abnormality should be recognized as a diagnostic confounder.

Patellofemoral knee pain in an adult with radiographic osteoarthritis and human immunodeficiency virus infection.

STUDY DESIGN: Resident's case problem. BACKGROUND: Kaposi's sarcoma (KS) is the most common form of cancer in patients with human immunodeficiency virus (HIV) infection. Although KS is often initially asymptomatic, this neoplasm may progress to affect multiple organ systems, including structures of the musculoskeletal system, which can produce symptoms similar to those associated with common orthopaedic conditions. This resident's case problem describes the evaluation and differential diagnosis of a 45-year-old male with HIV and KS, referred to physical therapy with an initial diagnosis of radiographic osteoarthritis (OA) and patellofemoral pain syndrome (PFPS) of the left knee. His primary complaint was knee pain during end range knee flexion. DIAGNOSIS: The history, systems review, and examination suggested a source of pain of a nonorthopaedic origin. Differential examination ruled out clinical OA, PFPS, ligament/cartilage derangement, and tendonitis. Avascular necrosis of the medial femoral condyle was also considered as a possible source of pain. Recent blood tests indicated a high viral load and low CD4 count, which might have increased susceptibility to opportunistic infections or KS tumor progression. The patient was referred back to his physician for additional follow-up. Magnetic resonance imaging (MRI) of the knees were consistent with a systemic inflammatory process such as KS. A true-cut biopsy was subsequently scheduled, which confirmed KS lesions at the left knee. DISCUSSION: Physical therapists who manage orthopaedic conditions should be aware of the disablement that may result from acquired immunodeficiency syndrome-related KS. A thorough joint-specific examination, with a broad differential diagnosis, should be employed for patients having known systemic diseases. LEVEL OF EVIDENCE: Differential diagnosis, level 4.