PRRX1-TOP2A interaction is a malignancy-promoting factor in human malignant peripheral nerve sheath tumours.

BACKGROUND: Paired related-homeobox 1 (PRRX1) is a transcription factor in the regulation of developmental morphogenetic processes. There is growing evidence that PRRX1 is highly expressed in certain cancers and is critically involved in human survival prognosis. However, the molecular mechanism of PRRX1 in cancer malignancy remains to be elucidated. METHODS: PRRX1 expression in human Malignant peripheral nerve sheath tumours (MPNSTs) samples was detected immunohistochemically to evaluate survival prognosis. MPNST models with PRRX1 gene knockdown or overexpression were constructed in vitro and the phenotype of MPNST cells was evaluated. Bioinformatics analysis combined with co-immunoprecipitation, mass spectrometry, RNA-seq and structural prediction were used to identify proteins interacting with PRRX1. RESULTS: High expression of PRRX1 was associated with a poor prognosis for MPNST. PRRX1 knockdown suppressed the tumorigenic potential. PRRX1 overexpressed in MPNSTs directly interacts with topoisomerase 2 A (TOP2A) to cooperatively promote epithelial-mesenchymal transition and increase expression of tumour malignancy-related gene sets including mTORC1, KRAS and SRC signalling pathways. Etoposide, a TOP2A inhibitor used in the treatment of MPNST, may exhibit one of its anticancer effects by inhibiting the PRRX1-TOP2A interaction. CONCLUSION: Targeting the PRRX1-TOP2A interaction in malignant tumours with high PRRX1 expression might provide a novel tumour-selective therapeutic strategy.

Dedifferentiation in low-grade osteosarcoma: a Japanese Musculoskeletal Oncology Group (JMOG) study.

BACKGROUND: Low-grade osteosarcomas, namely parosteal osteosarcoma (POS) and low-grade central osteosarcoma (LGCOS), occasionally dedifferentiate into high-grade malignancy, referred to as dedifferentiation in low-grade osteosarcoma (DLOS). This study aimed to elucidate the clinicopathologic features of DLOS, which are poorly described to date due to the extreme rarity of the disease. METHODS: A total of 33 patients with DLOS were included. Clinical characteristics, including the diagnostic accuracy of tumor biopsy, multimodal treatments, and clinical course, were retrospectively reviewed. Univariate analysis was performed to identify prognostic factors associated with overall survival (OS) and metastasis-free survival (MFS). RESULTS: The tumor subtypes comprised 10 cases (30.3%) of LGCOS and 23 cases (69.7%) of POS. The timing of dedifferentiation was synchronous in 25 (75.8%) and metachronous in 8 (24.2%) patients. The rates of preoperative diagnosis of DLOS were 40.0% and 65.4% for core needle biopsy and incisional biopsy, respectively. All patients underwent surgery and 25 patients received perioperative chemotherapy. Of the 13 patients who received neoadjuvant chemotherapy, 11 exhibited a poor histological response. The 5-year OS and MFS rates were 88.1% and 77.7%, respectively. Univariate analysis revealed that local recurrence was associated with poor OS (P < 0.01) and MFS (P < 0.01). Perioperative chemotherapy did not affect OS or MFS. CONCLUSIONS: The diagnostic accuracy of tumor biopsy for DLOS was lower than that for bone sarcomas, as reported previously. In contrast to conventional osteosarcomas with high chemosensitivity, both histological responses and survival analysis revealed low efficacy of chemotherapy for DLOS.

Pregnancy and Lactation-Associated Osteoporosis Successfully Treated with Romosozumab: A Case Report.

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare type of premenopausal osteoporosis that occurs mainly in the third trimester or immediately after delivery; one of its most common symptoms is back pain caused by a vertebral fracture. The pathogenesis of PLO is unclear, and there is no accepted consensus regarding the treatment of PLO. Although treatments with drugs such as bisphosphonate, strontium ranelate, denosumab, and teriparatide were reported, there is no report of a patient with PLO treated with romosozumab. We present the first case of a patient with PLO treated with romosozumab following 4-month teriparatide treatment. A 34-year-old primiparous and breastfeeding Japanese woman experienced severe low back pain 1 month postdelivery. She was diagnosed with PLO on the basis of low bone marrow density (BMD) and multiple vertebral fractures with no identified cause of secondary osteoporosis. She was treated with teriparatide injection for 4 months, but the treatment was discontinued because of the patient feeling severe nausea after every teriparatide injection and the appearance of new vertebral fractures. Thereafter, we used romosozumab for 12 months. After the romosozumab treatment, her BMD was increased from the baseline by 23.6% at L1-L4, 6.2% at the femoral neck, and 11.2% at the total hip. Treating PLO with 12-month romosozumab after 4 months of teriparatide injection remarkably increased the BMD of the lumbar spine, femoral neck, and total hip without subsequent fracture. Romosozumab has potential as a therapeutic option to improve the BMD and reduce the subsequent fracture risk of patients with PLO.

Talipes Equinus Deformity Caused by Fibrous Gastrocnemius Muscle Contracture After Direct Contusion in Football Players: Report of Two Cases.

Two main causes of gastrocnemius contracture have been considered: 1) congenital deformities in pediatric patients, such as limb-length discrepancy, cerebral palsy, flatfoot, and clubfoot; and 2) secondary conditions such as immobilization for trauma or a nonfunctional limb. Talipes equinus deformity caused by fibrous gastrocnemius contracture after a direct muscle contusion is extremely rare. We describe 2 cases of talipes equinus deformity caused by fibrous gastrocnemius muscle contracture after a direct contusion in football players. Both of the players had a talipes equinus deformity with a severe restriction of ankle dorsiflexion, and a cord-like structure was observed at the proximal part of the lateral gastrocnemius head. Both patients' histological examinations revealed fibrous tendon-like tissue within the structure. After discission of the cord-like structures, the restriction of ankle dorsiflexion was completely resolved, and the patients were able to fully return to playing football without any discomfort in their calves.

Functional genomics identifies AMPD2 as a new prognostic marker for undifferentiated pleomorphic sarcoma.

Soft-tissue sarcomas are rare, heterogeneous, and often aggressive mesenchymal cancers. Many of them are associated with poor outcome, partially because biomarkers that can identify high-risk patients are lacking. Studies on sarcomas are often limited by small sample-sizes rendering the identification of biomarkers difficult when focusing on individual cohorts. However, the increasing number of publicly available 'omics' data opens inroads to overcome this obstacle. Here, we combine transcriptome analyses, immunohistochemistry, and functional assays to show that high adenosine monophosphate deaminase 2 (AMPD2) is a robust prognostic biomarker for worse outcome in undifferentiated pleomorphic sarcoma (UPS). Gene expression and survival data for UPS from two independent studies were subjected to survival association-testing. Genes, whose high expression was significantly correlated with worse outcome in both cohorts, were considered as biomarker candidates. The best candidate, AMPD2, was validated in a tissue microarray. Analysis of DNA copy-number data and matched transcriptomes indicated that high AMPD2 expression is significantly correlated with gains at the AMPD2 locus. Gene set enrichment analyses of AMPD2 co-expressed genes in both transcriptome datasets suggested that AMPD2-high UPS are enriched in tumorigenic signatures. Consistently, knockdown of AMPD2 by RNA interference in an UPS cell line inhibited proliferation in vitro and tumorigenicity in vivo. Collectively, we provide evidence that AMPD2 may serve as a biomarker for outcome prediction in UPS. Our study exemplifies how the integration of 'omics' data, immunohistochemistry, and functional experiments can identify novel biomarkers even in a rare sarcoma, which may serve as a blueprint for biomarker identification for other rare cancers.

Various checkpoint molecules, and tumor-infiltrating lymphocytes in common pediatric solid tumors: Possibilities for novel immunotherapy.

Long-term survival rates for pediatric patients with cancer have significantly improved, but novel approaches are desired for those with refractory/relapsed solid tumors. Recently, programed cell death-1/programed cell death-ligand-1 blockade has emerged as an effective option for many intractable cancers. However, not all patients show objective response to such therapy. On the other hand, several other checkpoint pathways, including Herpes virus entry mediator (HVEM)/B- and T-lymphocyte attenuator (BTLA), galectin-9 (GAL9)/T-cell immunoglobulin and mucin domain-3 (TIM3), and major histocompatibility complex class II (MHC-II)/lymphocyte activation gene-3 (LAG3), also regulate immune responses in the tumor microenvironment and may be alternative targets for novel immune therapies. In this study, we examined 65 common pediatric solid tumors and characterized the expression of Herpes virus entry mediator, GAL9, and MHC-II on tumor cells and their corresponding receptors B- and T-lymphocyte attenuator, TIM3, and LAG3, respectively, on tumor-infiltrating lymphocytes (TILs) with immunohistochemistry. Whereas the expression of GAL9 and MHC-II was limited, 73% of rhabdomyosarcomas and 100% of osteosarcomas expressed moderate to high levels of Herpes virus entry mediator on the tumor. TILs were detected in all tumor samples except one osteosarcoma. Interestingly, 45% of rhabdomyosarcomas, and 45% of osteosarcomas expressed moderate to high levels of both Herpes virus entry mediator on the tumor cells and B- and T-lymphocyte attenuator on the TILs. Results showed that a subset of pediatric solid tumors expressed tumor-associated checkpoint molecules, and TILs expressed corresponding receptors for these checkpoint molecules. Thus, immunogenic environments may be created, and checkpoint blockade may induce favorable immune responses.

Mesenchymal chondrosarcoma: A Japanese Musculoskeletal Oncology Group (JMOG) study on 57 patients.

BACKGROUND: This study aimed to elucidate the clinical features and prognostic factors of mesenchymal chondrosarcoma (MCS) and investigate optimal treatment strategies. METHODS: Data from 57 patients with MCS were collected from a Japanese Musculoskeletal Oncology Group (JMOG) and retrospectively analyzed. RESULTS: Data from 29 males and 28 females were collected. Primary tumor sites were the head and neck (7 patients), trunk (35 patients), and extremities (15 patients). The tumors originating in the trunk were significantly associated with a worse OS compared with those originating at the other sites in all patients and those with localized disease (P = 0.020 and P = 0.019, respectively). In patients with localized disease, the tumors originating in the head and neck were significantly associated with better OS and MFS compared with those originating in the trunk (P = 0.024 and P = 0.014, respectively). Positive surgical margin was significantly correlated with the worse LRFS (P = 0.018). Adjuvant chemotherapy exhibited a clear trend toward improved OS when MCS was localized in the trunk or extremities (P = 0.057). CONCLUSIONS: Adequate surgery is considered to be the mainstay of treatment for localized MCS. Prognosis was different depending on the site of tumor origin.

Phosphorylation of STAT3 in Undifferentiated Pleomorphic Sarcoma Is Correlated with a Favorable Prognosis.

OBJECTIVE: The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a role in various biological processes. Phosphorylated STAT3 (p-STAT3) functions as a transcriptional factor, and suppressor of cytokine signaling 3 (SOCS3) is a potential inhibitor of STAT3. Here, we analyzed the status of the JAK-STAT pathway in undifferentiated pleomorphic sarcoma (UPS). METHODS: We performed immunohistochemistry in 79 samples of UPS and Western blotting in 10 frozen samples. We also examined alterations in protein expression in the JAK-STAT pathway after the inhibition of phosphorylated Akt (p-Akt) or extracellular signal-regulated kinase (p-Erk) in vitro. RESULTS: Immunohistochemically, p-STAT3 and SOCS3 were positive in 59.7 and 55.8%, respectively. Positivity for p-STAT3 was significantly correlated with a better prognosis (p = 0.0006) and negatively with SOCS3 expression (p = 0.0223). Positivity for SOCS3 was significantly correlated with a worse prognosis (p = 0.0001). Western blotting analysis revealed that p-STAT3 expression was lower in tumor than in normal tissue. In vitro results demonstrated that there was no detectable change in the expression of p-STAT3 regardless of the status of p-Akt or p-Erk. CONCLUSION: p-STAT3 may be a useful prognostic factor for UPS.

Osteochondroma of the Tibial Sesamoid: A Case Report and Review of the Literature.

Osteochondroma, one of the most common benign bone tumors, frequently occurs in the metaphysis of the long bones. We report an extremely rare case of osteochondroma that occurred in the tibial sesamoid. The patient was a 62-year-old Japanese male. He presented with a 1-year history of pain and a hard mass on the plantar aspect of the right forefoot sole. The osteochondroma protruded toward the sole from the tibial sesamoid, leading to pain on weightbearing. After tibial sesamoidectomy, the patient's symptoms were eliminated, and no pain or complications such as hallux valgus occurred after the surgery. Although a potential risk exists of postoperative hallux valgus deformity, tibial sesamoidectomy seems to be an appropriate surgical option for both osteochondroma and bizarre parosteal osteochondromatous proliferation to avoid residual pain or local recurrence.

Missed causative tumors in diagnosing tumor-induced osteomalacia with (18)F-FDG PET/CT: a potential pitfall of standard-field imaging.

OBJECTIVE: We describe herein two tumor-induced osteomalacia (TIO) cases for whom the causative lesions, located in their popliteal fossa, that were not identified in the standard field of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT), which usually images only the head, trunk, and proximal parts of the extremities. CLINICAL PRESENTATION AND INTERVENTION: A 47 years old Japanese man with multiple pathological fractures due to osteomalacia, accompanied by muscle weakness, hypophosphatemia, and an elevation of alkaline phosphatase (ALP) was referred to our hospital. A (18)F-FDG PET/CT scan was performed, but no (18)F-FDG uptake was detected in the standard field of imaging. Magnetic resonance imaging revealed a small subcutaneous tumor (1.9×1.2×0.6cm) of the left posteriomedial knee, displaying uniform enhancement on gadolinium-enhanced T1-weighted fat-suppression imaging. The tumor was resected widely and diagnosed as phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT). The other patient was a 31 years old Japanese woman with multiple pathological fractures, hypophosphatemia and elevated of ALP and was referred to our hospital on suspicion of TIO. Although the causative lesion was not identified in the standard field of (18)F-FDG PET/CT, (18)F-FDG uptake (SUVmax 2.9) was detected on the right knee in the additional whole-body (18)F-FDG PET/CT. Magnetic resonance imaging revealed a soft-tissue tumor (6.4×4.1×2.9cm) in the right posterior knee. Following biopsy, the tumor was marginally resected, and was pathologically diagnosed as PMTMCT. CONCLUSION: Once patients are suspected to have TIO, a whole-body nuclear imaging study such as (18)F-FDG PET/CT should be performed, in order not to miss the hidden causative tumor, especially occurring in the distal extremities.

Elevated expression of HSP90 and the antitumor effect of an HSP90 inhibitor via inactivation of the Akt/mTOR pathway in undifferentiated pleomorphic sarcoma.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a heterogeneous tumor group, and little is known about molecular target therapy for UPS. Heat shock protein 90 (HSP90) is an expressed chaperone that refolds certain denatured proteins under stress conditions. One of these proteins is Akt. The disruption of Akt signaling plays an important role in tumor progression. The present study's purpose was to analyze the HSP90 expression, Akt/mTOR pathway activation and the correlation between HSP90 expression and its pathway activation in UPS. METHODS: The status of HSP90 and the profiles of the Akt/ mTOR pathway were assessed by immunohistochemistry in 79 samples of UPS, and these data were compared with clinicopathological and histopathological findings. The expressions of indicated proteins were assessed by Western blotting in five frozen samples. After treating UPS cells with the HSP90 inhibitor, we assessed the antitumor effect of the inhibitor. RESULTS: Immunohistochemically, phosphorylated Akt (p-Akt), p-mTOR, p-S6RP and p-4EBP were positive in 57.3, 51.9, 54.5 and 57.1% of the UPS samples, respectively. The expressions of those phosphorylated proteins were correlated with each other. HSP90 expression was elevated in 56.4% of the samples and was correlated with p-Akt, p-mTOR and p-S6RP. The immunohistochemical results were confirmed by Western blotting. The HSP90 inhibitor led to decreased viability and invasiveness of the cells and inactivated the AKT/mTOR pathway in vitro. CONCLUSION: Elevated expression of HSP90 is a poor-prognosis factor and is involved in the activation of the Akt/mTOR pathway in UPS. HSP90 inhibition is a potential treatment option for UPS.

Expression and regulation of toll-like receptors (TLRs) in human intervertebral disc cells.

PURPOSE: Although inflammatory processes play an essential role in painful intervertebral disc (IVD) degeneration, the underlying regulatory mechanisms are not well understood. This study was designed to investigate the expression, regulation and importance of specific toll-like receptors (TLRs)--which have been shown to play an essential role e.g. in osteoarthritis--during degenerative disc disease. METHODS: The expression of TLRs in human IVDs was measured in isolated cells as well as in normal or degenerated IVD tissue. The role of IL-1ß or TNF-α in regulating TLRs (expression/activation) as well as in regulating activity of down-stream pathways (NF-κB) and expression of inflammation-related genes (IL-6, IL-8, HSP60, HSP70, HMGB1) was analyzed. RESULTS: Expression of TLR1/2/3/4/5/6/9/10 was detected in isolated human IVD cells, with TLR1/2/4/6 being dependent on the degree of IVD degeneration. Stimulation with IL-1ß or TNF-α moderately increased TLR1/TLR4 mRNA expression (TNF-α only), and strongly increased TLR2 mRNA expression (IL-1ß/TNF-α), with the latter being confirmed on the protein level. Stimulation with IL-1ß, TNF-α or Pam3CSK4 (a TLR2-ligand) stimulated IL-6 and IL-8, which was inhibited by a TLR2 neutralizing antibody for Pam3CSK4; IL-1ß and TNF-α caused NF-κB activation. HSP60, HSP70 and HMGB1 did not increase IL-6 or IL-8 and were not regulated by IL-1ß/TNF-α. CONCLUSION: We provide evidence that several TLRs are expressed in human IVD cells, with TLR2 possibly playing the most crucial role. As TLRs mediate catabolic and inflammatory processes, increased levels of TLRs may lead to aggravated disc degeneration, chronic inflammation and pain development. Especially with the identification of more endogenous TLR ligands, targeting these receptors may hold therapeutic promise.

Atypical Fracture of the Scapular Spine: A Case Report.

Atypical fractures are gaining attention as a severe potential side effect of long-term treatment with bone-modifying agents (e.g., bisphosphonate and denosumab) for osteoporosis. Most atypical fractures occur in weight-bearing bones; the femur is the most frequent site. Atypical fractures occurring in non-weight-bearing bones are extremely rare. We describe an atypical fracture of the scapular spine in a 92-year-old Japanese woman with osteoporosis who had been treated with minodronate for ~7 years. Although the dislocation of the fracture site remained after conservative treatment, there was no obstacle to her daily life.

Congenital incomplete duplication of lower extremity (polymelia) accompanied with anorectal malformation and unilateral deafness.

Polymelia (supernumerary limbs) is an extremely rare congenital condition in humans. Because congenital anorectal malformation is a relatively common complication of polymelia and it may require emergency surgery as in the present case, accompanying malformations must be investigated.

Reference values of lumbar spine range of motion by sex and age based on the assessment of supine trunk lateral bending-A preliminary study.

[Purpose] The purpose of this study was to clarify the preliminary reference values for the lumbar spine range of motion associated with lateral bending exercises by gender and age group. [Methods] Subjects were 82 volunteers without low back pain, including five males and five females in each age group from 16-19 to 80-89 years. All subjects underwent radiographs of the lumbar spine with lateral flexion; the range of lateral flexion of the vertebrae from T12 to the sacrum (ROLB) was measured twice by three observers. [Results] The ROLB of the entire T12-S1 of all subjects showed a significant negative correlation with age in both sexes (p < 0.01). The ROLB of the lumbar spine tended to be greater in females, with a statistically significant difference between those aged 16-19 and 70-79 (p < 0.05). Lateral flexion angles for each intervertebral segment were largest at L3-L4 and smallest at L5-S1 (0.7°). [Conclusion] Lumbar ROLB reference values were examined by gender and age group; ROLB was greatest in L3-L4, and ROLB tended to be lower in older age groups.

Rib stress fracture in a female athlete caused by bouncing the barbell in bench press exercise: A case report.

Rib stress fractures can occur in sports involving repetitive trunk muscle contractions. Few documented cases show rib fractures from repetitive upper-limb training. This report presents a case of a rib stress fracture from micro blunt trauma during bench press exercises. The patient was a 24-year-old elite female sprinter with a history of left navicular stress fracture and secondary amenorrhea treatment a year prior. She modified her bench press technique to involve bouncing the barbell on her rib cage. Within weeks, she experienced anterior chest pain, exacerbated by sneezing. Computed tomography revealed a fifth rib fracture with callus formation. After refraining from bench presses for 4 weeks, her chest pain subsided, allowing her to resume upper-limb training. When athletes performing bench press exercises experience chest pain, rib fractures should be considered, even without acute trauma. Additionally, research on the safety of the bouncing bench pressing technique is required.

Walking ability after resection of soft tissue sarcoma of the thigh and the sciatic nerve.

Walking ability may be fairly well maintained after sciatic nerve resection combined with wide resection of soft tissue sarcoma, therefore, surgeons should not hesitate to perform sciatic nerve resection to achieve an adequate surgical margin.

Case report: Atypical lipomatous tumor of the thigh in a four-year-old girl.

Atypical lipomatous tumors (ALTs) are locally aggressive adipocytic malignancies that frequently occur in middle-aged adults. We report the rare case of an ALT of the thigh that occurred in a 4-year-old girl. Since the tumor was initially diagnosed as a lipoblastoma by incisional biopsy, marginal resection was performed. Histopathological findings of the surgical specimen revealed the proliferation of mature and variously sized adipocytes, as well as ectopic ossification; these features differ from the typical findings of lipoblastoma. Immunohistochemical findings showed nuclear positivity for a murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) and negativity for pleomorphic adenoma gene 1 (PLAG1). Fluorescence in situ hybridization showed abnormal amplification of the MDM2 gene. The patient was thus finally diagnosed as having an ALT. No signs of local recurrence or metastasis were noted 1 year postoperatively. This case is instructive in the differential diagnosis of primary adipocytic tumors. Lipoblastomas are the most common adipocytic tumors in children, but if a tumor is located in the deep tissue or imaging findings are not typical, the possibility of ALT should be considered and immunohistochemistry for MDM2 and CDK4 should be added.