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Undifferentiated pleomorphic sarcoma (UPS) is associated with poor prognosis. Recently, signal regulatory protein alpha (SIRPα), which is the immune checkpoint of macrophages, and T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT), which is the immune checkpoint of T cells and natural killer cells, have been considered as potential targets for cancer immunotherapy. This study aimed to assess the value of SIRPα and TIGIT as prognostic factors of UPS.The cBio Cancer Genomics Portal was used to analyze mRNA expression data of 50 UPS cases in the Cancer Genome Atlas. We retrieved 49 UPS cases and performed immunohistochemistry (IHC) to detect programmed death ligand 1 (PD-L1), SIRPα, CD68, CD163, TIGIT, CD155, and CD8.SIRPα was positively associated with CD163 (Pearson's r = 0.51, p = 0.0002) as per open access data and IHC of the cohort (p = 0.002), which revealed that SIRPα-positive macrophage infiltration was higher in UPS cells with ≥ 1% PD-L1 expression than that in UPS cells with 1% PD-L1 expression (p = 0.047). TIGIT was positively correlated with PD-L1 (r = 0.54, p 0.0001) and CD8A (r = 0.98, p 0.0001). In 35 of 49 cases, IHC revealed high levels of TIGIT expression on tumor cells. Furthermore, TIGIT expression on tumor cells was negatively correlated with CD155-positive (p = 0.0144) and CD8-positive (p = 0.0487) cell infiltration. Survival analysis showed that the high degree of SIRPα-positive macrophage infiltration was associated with poor overall survival and metastasis (p 0.0001, p = 0.0006, respectively).SIRPα-positive macrophages infiltrated UPS cells, which predicted poor prognosis. High TIGIT expression on tumor cells was associated with decreased levels of tumor-infiltrating macrophages in UPS.

XLSX file - 9K, Multiivariate analysis for overall survival with p-AKT expression

PDF file - 3331K, Representative examples of Everolimus-induced change in the activation of the AKT/mTOR and MAPK pathways assessed by immunocytochemistry. Decreased p-S6RP and p-p70S6K expressions by Everolimus (30 nM, a dose achievable in humans by oral administration) are detected in the FU-SFT8611 and HS-Sch-2 cell lines. p-AKT, p-mTOR, p-MEK, and p-ERK1/2 expressions show no obvious effect of Everolimus administration. Note that Everolimus treatment decreases the number of viable cells.

XLSX file - 9K, A comparison of p-Akt, p-mTOR, p-S6RP, p-p70S6K and p-4E-BP1 expression results in all specimens

Purpose: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. MPNSTs occur frequently in patients with neurofibromatosis type 1 (NF1), in which NF1 gene deficiency leads to Ras hyperactivation. Ras activation causes the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and regulates cellular functions. However, the activation profiles of the AKT/mTOR and MAPK pathways in MPNSTs are poorly understood. The purposes of this study are to examine the correlation between the activation of these pathways and clinicopathologic or prognostic factors and to identify candidate target molecules in MPNST. Moreover, we assessed the antitumor effects of the inhibitor of candidate target.Experimental Design: Immunohistochemistry was conducted to evaluate the activation profiles of AKT/mTOR and MAPK pathways using 135 tumor specimens. Immunohistochemical expressions were confirmed by Western blotting. Then, an in vitro study was conducted to examine the antitumor effect of the mTOR inhibitor on MPNST cell lines.Results: Phosphorylated-AKT (p-AKT), p-mTOR, p-S6RP, p-p70S6K, p-4E-BP1, p-MEK1/2, and p-ERK1/2 expressions were positive in 58.2%, 47.3%, 53.8%, 57.1%, 62.6%, 93.4%, and 81.3% of primary MPNSTs, respectively. Positivity for each factor showed no difference between NF1-related and sporadic MPNSTs. Univariate prognostic analysis revealed that p-AKT, p-mTOR, and p-S6RP expressions were associated with poor prognosis. Furthermore, activation of each p-mTOR and p-S6RP was an independent poor prognostic factor by multivariate analysis. mTOR inhibition by Everolimus showed antitumor activity on MPNST cell lines in vitro.Conclusion: mTOR inhibition is a potential treatment option for both NF1-related and sporadic MPNSTs. Clin Cancer Res; 19(2); 450–61. ©2012 AACR.

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PDF file - 182K, The Kaplan-Meier curves for overall survival according to p-p70S6K, p-4E-BP1, p-MEK1/2, and p-ERK1/2 expressions. Immunoreactivity for p-p70S6K, p-4E-BP1, p-MEK1/2, and p-ERK1/2 fails to show a significant difference in overall survival. p values are shown at the top right of each figure.

PDF file - 328K, A case of MPNST (left) arising from neurofibroma (right) in patients with neurofibromatosis type 1. Most MPNST cells are positive for p-AKT, p-mTOR, p-S6RP, p-p70S6K, and p-4E-BP1. Meanwhile, most tumor cells in the neurofibroma area are negative for them. NF: neurofibroma.

PDF file - 268K, Western blotting (WB) for p-AKT, (total) AKT, p-mTOR, (total) mTOR, p-S6RP, p-p70S6K, p-MEK1/2, and p-ERK1/2 using frozen tumor samples and corresponding normal tissue. Positive or negative staining (P: positive; N: negative) on immunohistochemistry (IHC) is shown above each band to be compared with the WB results. The expression levels in WB correspond closely to those in IHC. p-AKT, p-mTOR, and p-p70S6K show stronger expression in tumor samples than in normal tissue in both NF1-related (Case 1, 2 and 3) and sporadic (Case 4 and 5) MPNSTs, while this tendency was not apparent for p-MEK1/2 and p-ERK1/2.

We herein report the effectiveness of contralateral osteotomy of the pedicle and posterolateral elements for en bloc resection (COPPER) of paraspinal and spinal tumours. This surgical method allows for complete resection of the localized tumour in the lateral posterior lesion without removing the entire vertebral body, as in total en bloc spondylectomy. Complete resection of paraspinal and spinal tumours is challenging for spinal surgeons because of anatomical complexities. Although the COPPER method has been introduced as a less invasive surgical procedure for wide resection of spinal tumours, no studies have reported the usefulness of this technique. We identified three patients with paraspinal or spinal tumours who underwent wide resection using the COPPER method and reviewed their clinical, radiological, and pathological outcomes. In all cases, we resected the spinal and paraspinal tumours extending to the anterior column and extravertebral component using the modified COPPER method. All patients underwent en bloc resection with a negative margin. We report three cases of spinal and paraspinal tumours extending to the anterior column and extravertebral component.

In rare cases, giant cell tumor of bone (GCTB) can undergo primary or secondary malignant transformation to malignant giant cell tumor of bone (MGCTB), but the details of the molecular alterations are still unclear. The present study aimed to elucidate the clinicopathologic and molecular features of MGCTBs based on immunohistochemistry, fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) of nine MGCTBs (five primary and four secondary). Seven (78%) of 9 MGCTBs were immunohistochemically positive for H3.3 G34W. In two (22%) patients, although GCTB components were focally or diffusely positive for H3.3 G34W, their malignant components were entirely negative for H3.3 G34W, which was associated with heterozygous loss of H3F3A by FISH. NGS on four MGCTBs revealed pathogenic mutations in TP53 (n = 3), EZH2 (n = 1) and several other genes. Immunohistochemical analysis of the nine MGCTBs confirmed the p53 nuclear accumulation (n = 5) and loss of H3K27me3 expression (n = 3) and showed that they were mutually exclusive. In addition, four (80%) of five cases of pleomorphic or epithelioid cell-predominant MGCTBs were positive for p53, while three (75%) of four cases of spindle cell-predominant MGCTBs were negative for trimethylation at lysine 27 of histone 3 (H3K27me3). The results suggested that p53 alteration and dysfunction of histone methylation as evidenced by H3K27me3 loss may play an important role in the malignant progression of GCTB, and might contribute to the phenotype-genotype correlation in MGCTB. The combined histologic, immunohistochemical and molecular information may be helpful in part for the diagnosis of challenging cases.

BACKGROUND: Dedifferentiated chondrosarcoma (DDCS) is an aggressive bone tumour with a poor prognosis and no effective treatment. Because changes in DNA methylation play critical roles in DDCS, we explored the roles that DNA methylation plays in oncogenesis to potentially identify an effective epigenetic treatment. METHODS: We identified genes downregulated in DDCS vs. conventional chondrosarcoma (CCS) due to DNA methylation using in silico analysis. The results were validated in DDCS clinical samples, and the molecular functions of the genes of interest were investigated in multiple chondrosarcoma cell lines (NDCS-1, SW1353, and OUMS-27). The therapeutic effect of decitabine, a DNA methyltransferase inhibitor, was evaluated in vitro and in vivo. RESULTS: PRKCZ was specifically downregulated by DNA methylation in DDCS. Overexpression of PRKCZ decreased the proliferation of NDCS-1 and SW1353 cells. PRKCZ directly bound to and activated ATM, which was followed by phosphorylation of CHK2 and subsequent apoptosis. Decitabine increased PRKCZ expression through de-methylating the promoter region of PRKCZ, which activated the ATM/CHK2 pathway and inhibited cell proliferation by inducing apoptosis. CONCLUSIONS: Increased DNA methylation and reduced expression of PRKCZ prevents apoptosis via inactivation of the ATM/CHK2 pathway in DDCS. Decitabine-induced expression of PRKCZ represents a promising therapy for DDCS.

Introduction: Radiation-associated sarcoma (RAS) is one of the most life-threatening complications associated with the treatment of malignant neoplasms. Because all RAS patients have a history of radiotherapy, there have been no effective treatment options when RAS is not completely resected. Methods: We retrospectively reviewed 20 RAS patients, including 4 unresectable cases treated by carbon ion radiotherapy (CIRT). Results: The primary diseases targeted by radiotherapy included malignant lymphoma (n = 4), cervical cancer (n = 3), pharyngeal cancer (n = 3), breast cancer (n = 2), lung cancer (n = 1), rectal cancer (n = 1), maxillary cancer (n = 1), synovial sarcoma (n = 1), and benign neoplasms (n = 4). The histological diagnoses of RAS included osteosarcoma (n = 8), leiomyosarcoma (n = 3), undifferentiated pleomorphic sarcoma (n = 3), rhabdomyosarcoma (n = 1), angiosarcoma (n = 1), malignant peripheral nerve sheath tumor (n = 1), spindle cell sarcoma NOS (n = 1), and sarcoma not further specified (n = 2). The median survival time from the diagnosis of RAS was 26 months. Eleven patients underwent surgery. Five of these patients achieved a continuous disease free (CDF) status or showed no evidence disease. Four patients underwent CIRT. One of these patients with leiomyosarcoma achieved a CDF status, and the other patient with osteosarcoma achieved a partial response. On the other hand, 2 patients experienced grade 3 toxicities that required surgical treatment. Conclusion: RAS originates from various types of diseases that are treated by radiotherapy and shows diverse pathological features. Complete resection achieves a good prognosis. CIRT can be an effective and feasible option for unresectable RAS.

Chondroblastoma (CB) is histologically characterized by oval to polygonal-shaped mononuclear neoplastic cells, multinucleated osteoclastic giant cells, and eosinophilic matrix with occasional calcification. Genetically, the majority of CBs harbor H3F3B p.K36M mutation. Despite the historical nomenclature, it has been reported that the matrix of CB is similar to osteoid rather than true cartilage; however, it remains unclear whether neoplastic cells in CB have the potential for osteoblastic differentiation. To clarify this issue, we immunohistochemically examined the expression of osteogenic and chondrogenic markers (SATB2, RUNX2, p63, and SOX9) as well as H3K36M mutant protein in 33 cases of CB. All 33 cases of CB were positive for H3K36M, while SATB2, RUNX2, p63, and SOX9 were expressed in 30/33 (91%), 33/33 (100%), 29/33 (88%), and 31/32 (97%) CB cases, respectively. Our immunohistochemical results suggest that neoplastic cells in CB frequently express both osteogenic and chondrogenic markers and may have an intermediate feature of osteoblastic and chondroblastic nature.

Chondrosarcoma is the second most common primary malignant bone tumor. In this multicenter study, we sought to evaluate the disease-specific survival (DSS) and disease-free survival (DFS), and prognostic factors in patients with dedifferentiated chondrosarcoma (DDCS) or grade 3 chondrosarcoma (G3CS) in Japan. We retrospectively investigated the treatment outcomes and prognostic factors in 62 patients with DDCS and 19 patients with G3CS at 15 institutions participating in the Japanese Musculoskeletal Oncology Group. We also clarified significant clinicopathological factors for oncological outcomes. In surgery for primary lesions aimed at cure, a histologically negative margin (R0) was obtained in 93% (14/15) of patients with G3CS and 100% (49/49) of patients with DDCS. The 5-year DSS was 18.5% in patients with DDCS and 41.7% in patients with G3CS (p = 0.13). Local control was obtained in 80% (12/15) and 79.6% (39/49) of patients with G3CS and DDCS in the primary lesion after surgery with a wide surgical margin, respectively. In multivariate analysis, stage and no treatment/palliative treatment for the primary lesion were independent prognostic factors for DSS of DDCS, and age and no treatment/palliative treatment for DSS of G3CS. The 5-year DFS rate was 22.8% in 26 patients with DDCS who did not receive adjuvant chemotherapy, and 21.4% in 14 patients who received adjuvant chemotherapy. The prognosis of DDCS remains poor, although R0 resection was carried out in most cases. Effective and/or intensive chemotherapeutic regimens or agents should be considered or developed for patients with high-grade chondrosarcoma, particularly for those with DDCS.

Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMT-MCT) causes tumor-induced osteomalacia (TIO). Most cases follow a benign clinical course, with rare occurrences of malignant transformation. We report a case of malignant PMT-MCT and review previous malignant cases to identify predictive factors for transformation. A 13-yr-old female, who presented with hypophosphatemic rickets, elevated serum intact fibroblast growth factor 23 (FGF23) levels, and a nodule in the back, received a diagnosis of TIO because of the benign PMT histopathology. After resection of the primary tumor, regular imaging analyses did not indicate any relapse. At 17 years of age, a tumor developed in the left leg and increased in size. The resected tumor showed a histopathology of pleomorphic sarcoma positive for the TP53 mutation. Despite amputation of the affected leg, the patient died due to multiple metastases at 18 years of age. A literature review revealed that 14 out of 15 reported malignant PMT-MCT tumors occurred in adults, and found no predictive factors for malignant transformation and treatment outcome. Changes in size or number of the tumors along with intact FGF23 levels have been considered as the only sign of malignant transformation. This pediatric case report and literature review indicate the need for prolonged regular monitoring for PMT-MCT.

Tyrosine kinase inhibitors (TKI) work against various types of cancer by inhibiting angiogenic signaling. Little is understood about the incidence, characteristics, and risk factors associated with thromboembolism induced by TKI in routine clinical practice. We retrospectively analyzed data derived from 29 patients with thyroid cancer or soft tissue sarcoma (STS) treated with lenvatinib (n=10) and pazopanib (n=19). Eight (arterial n=4; venous n=4) thromboembolic events developed in 6 (20%) patients. Thromboembolisms occurred during a mean of 149 (range, 42–847) days from starting TKI. The primary disease progressed in all patients with thromboembolism. The overall survival durations of patientswith and without improved thromboembolism were 572 [95% confidence interval (CI), 225– 918] and 176 (95% CI, 84–394) days, respectively, which did not significantly differ (P=0.33). Patients with and without improved thromboembolism survived after onset for 122 (95% CI, 71–173) versus 27 (95%CI, 21–42) days (P=0.049), which significantly differed. Univariate analysis and variate selection for multivariate analysis selected a history of thromboembolism as the most powerful risk factor for new thromboembolism. In summary, the frequency of thromboembolism in clinical practice was higher than that in previous clinical trials. Furthermore, a history of thromboembolism was a risk factor for the development of new thromboembolism in patients treated with TKI. Thromboembolism developed particularly as the primary disease progressed. Our findings require validation in a large-scale study.

Objective The aim of this study was to investigate the efficacy and safety of tranexamic acid in patients undergoing surgery for bone and soft tissue tumors. Methods Data were retrospectively collected from 454 consecutive patients with bone and soft tissue tumors who underwent open biopsy, marginal resection, curettage or wide resection between January 2017 and December 2018. We performed propensity score matching of patients who received tranexamic acid with those who did not. The primary outcome variables were intra-operative, peri-operative and estimated blood loss (IBL, PBL and EBL, respectively). Results Tranexamic acid (+) and tranexamic acid (−) groups were defined according to whether patients received tranexamic acid or not. Among the 454 patients, open biopsy was performed in 102, marginal resection in 175, curettage in 54 and wide resection in 123. Intra-operative blood loss was significantly lower in the tranexamic acid (+) group than in the tranexamic acid (−) group for both marginal and wide resection (marginal resection: 17.3 vs. 70.3 g, respectively, P = 0.045; wide resection: 128.8 vs. 273.1 g, respectively, P = 0.023). Peri-operative blood loss and estimated blood loss were also significantly lower in the tranexamic acid (+) group for wide resection (peri-operative blood loss: 341.5 vs. 686.5 g, respectively, P = 0.0039; estimated blood loss: 320.7 vs. 550.6 ml, respectively, P = 0.030). No venous thromboembolism occurred in either group. Conclusion This study suggests that TXA administration safely and effectively reduces blood loss, in particular for wide resection, with no increase in the rate of adverse events.

Periosteal chondrosarcoma is an extremely rare malignant cartilage-forming tumour that originates from the periosteum and occurs on the surface of bone. Often, it is difficult to distinguish periosteal chondrosarcoma from other tumours, and reports in the literature are scarce. This study aims to investigate the characteristics of periosteal chondrosarcoma, focusing particularly on medullary invasion. Among 33 periosteal cartilaginous tumours, seven patients with pathologically proven periosteal chondrosarcoma were identified retrospectively. The average tumour size was 5.4 cm in the long axis; two tumours were smaller than 3.0 cm. Six tumours were resected with a wide margin, and the remaining tumour had a marginal margin. Histology revealed that six tumours (85.7%) had invaded the medullary cavity; three of these did not show invasion into the medullary cavity on MRI evaluation. Neither local recurrence nor metastasis was observed among these patients. The frequency of invasion of the medullary cavity was higher than that reported previously. The recommended treatment for periosteal chondrosarcoma is resection with an adequate margin. Therefore, surgeons should consider the possibility of medullary invasion when attempting to achieve a histologically negative margin, even if the tumour does not show invasion into the medullary cavity on MRI.

Denosumab is a game-changing drug for giant cell tumor of bone (GCTB); however, its clinical biomarker regarding tumor ossification of GCTB has not been elucidated. In this study, we investigated the relationship between Wnt/β-catenin signaling and the ossification of GCTB and evaluated whether endogenous nuclear β-catenin expression predicted denosumab-induced bone formation in GCTB. Genuine patient-derived primary GCTB tumor stromal cells exhibited osteoblastic characteristics. Identified osteoblastic markers and nuclear β-catenin translocation were significantly upregulated via differentiation induction and were inhibited by treating with Wnt signaling inhibitor, GGTI-286, or selective Rac1-LEF inhibitor, NSC23766. Furthermore, we reviewed the endogenous ossification and nuclear β-catenin translocation of 86 GCTB clinical samples and elucidated that intra-tumoral ossification was significantly associated with the nuclear translocation. Three-dimensional quantitative analyses (n = 13) of tumoral CT images have revealed that the nuclear β-catenin translocation of naïve GCTB samples was significantly involved with the denosumab-induced tumor ossification. Our findings suggest a close relationship between the nuclear β-catenin translocation and the osteoblastic differentiation of GCTB. Investigations of the nuclear β-catenin in naïve GCTB samples may provide a promising biomarker for predicting the ossification of GCTB following denosumab treatment.

BackgroundDenosumab is a game-changing drug for giant cell tumor of bone (GCTB); however, its clinical biomarker in terms of post-administration ossification of the tumors has not been elucidated. The aims of this study were to investigate the relationship between Wnt/β-catenin signaling and the ossification of GCTB and to evaluate whether endogenous nuclear β-catenin expression predicted denosumab-induced bone formation in GCTB. MethodsWe established cultures of patient-derived primary GCTB stromal cells (pGCTB-SCs) and assessed the osteoblastic characteristics of pGCTB-SCs using cytochemical staining, optical density method (405 nm), and immunocytochemistry. Several mRNA expressions of osteoblastic markers (ALP, collagen type Ⅰ alpha 1 (COL1A1), integrin-binding sialoprotein (IBSP), runt-related transcription factor2 (RUNX2), and bone gamma-carboxyglutamate protein (BGLAP) was also investigated using quantitative real-time PCR (qRT-PCR) analysis. The impact on nuclear β-catenin translocation (NBT) by differentiation-induction was evaluated using Western blotting and immunocytochemistry. Wnt signaling inhibitor, GGTI-286, and selective Rac1 inhibitor, NSC23766, were added with OGM to evaluate the essential role of NBT. Furthermore, the distribution of endogenous NBT and the relationship with the tumoral ossification were assessed. Its predictability for the ossification in GCTB was also evaluated using a nuclear β-catenin labeling index (NBLI) of clinical samples (n = 86) and quantitative analyses of CT images.ResultspGCTB-SCs significantly expressed the osteoblastic markers with osteogenic medium (OGM) in a time-dependent manner (P < 0.0001, vs. vehicle). NBT was upregulated within 12 hours after OGM treatment. In addition, decreasing NBT by treatment with 40μM GGTI-286 significantly abolished the osteoblastic differentiation of pGCTB-SCs (P < 0.0001, vs. OGM). The selective Rac1 inhibitor, NSC23766, also suppressed the OGM-induced osteoblastic differentiation and NBT in pGCTB-SCs. Furthermore, in GCTB clinical samples, the NBTs were significantly associated with the tumor ossification following denosumab treatment (P = 0.003 for entire and peripheral tumor, and P = 0.02 for intra-tumor of GCTB) as well as endogenous intra-tumoral ossification. ConclusionsIn summary, our findings suggest a close relationship between the NBT and the osteoblastic differentiation of GCTB. Investigations of NBTs in naïve GCTB samples will provide a promising biomarker for predicting the ossification of GCTB following denosumab treatment.

Chondrosarcoma is the second most common malignant bone tumor. It is characterized by low vascularity and an abundant extracellular matrix, which confer these tumors resistance to chemotherapy and radiotherapy. There are currently no effective treatment options for relapsed or dedifferentiated chondrosarcoma, and new targeted therapies need to be identified. Isocitrate dehydrogenase (IDH) mutations, which are detected in ~50% of chondrosarcoma patients, contribute to malignant transformation by catalyzing the production of 2-hydroxyglutarate (2-HG), a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Mutant IDH inhibitors are therefore potential novel anticancer drugs in IDH mutant tumors. Here, we examined the efficacy of the inhibition of mutant IDH1 as an antitumor approach in chondrosarcoma cells in vitro and in vivo, and investigated the association between the IDH mutation and chondrosarcoma cells. DS-1001b, a novel, orally bioavailable, selective mutant IDH1 inhibitor, impaired the proliferation of chondrosarcoma cells with IDH1 mutations in vitro and in vivo, and decreased 2-HG levels. RNA-seq analysis showed that inhibition of mutant IDH1 promoted chondrocyte differentiation in the conventional chondrosarcoma L835 cell line and caused cell cycle arrest in the dedifferentiated JJ012 cell line. Mutant IDH1-mediated modulation of SOX9 and CDKN1C expression regulated chondrosarcoma tumor progression, and DS-1001b upregulated the expression of these genes via a common mechanism involving the demethylation of H3K9me3. DS-1001b treatment reversed the epigenetic changes caused by aberrant histone modifications. The present data strongly suggest that inhibition of mutant IDH1 is a promising therapeutic approach in chondrosarcoma, particularly for the treatment of relapsed or dedifferentiated chondrosarcoma.

To evaluate the clinical outcome of combination of carbon-ion radiotherapy with separation surgery (CIRT-SS) in patients with primary spinal/paraspinal sarcoma (PSPS) and epidural spinal cord compression (ESCC). CIRT-SS was performed in 11 consecutive patients. Patients treated in the primary and salvage settings were categorized into Group A (n = 8) and Group B (n = 3), respectively. Clinical results and imaging findings were collected, with a particular focus on ESCC grade, treatment-associated adverse events (AEs), and the locoregional control (LRC) rate and overall survival (OS). The median follow-up period from the start of CIRT-SS was 25 months (7–57 months). ESCC was improved by SS in all cases. No patients exhibited radiation-induced myelopathy (RIM), but three developed Grade 3 vertebral compression fracture (VCF) during follow-up. Locoregional recurrences were observed in four patients [Group A: 1 (12.5%), Group B: 3 (100%)]. Over the entire follow-up period, three patients developed distant metastases and two patients died. The 2-year LRC rate and OS were 70% and 80%, respectively. CIRT-SS in the primary setting achieved acceptable LRC and OS without RIM in patients with PSPS and with ESCC. VCF was the most frequent AE associated with CIRT-SS.

Background Soft tissue sarcomas arise in the deep sites of the buttocks and lower extremities. Since a tourniquet is not applied during surgery for soft tissue sarcomas at such sites, excessive intraoperative blood loss may occur. Various devices, including LigaSure™ (Medtronic, Dublin, Ireland), are used as electrothermal bipolar vessel sealers. However, its clinical relevance in soft tissue sarcomas surgery remains unclear. This study aimed to assess the effectiveness of LigaSure™ in soft tissue sarcomas surgery. Methods This study included 168 patients who underwent surgeries for soft tissue sarcomas in the deep sites in the buttocks and lower extremities between January 2004 and March 2018. The primary outcome was intraoperative blood loss, and secondary outcomes were surgery duration, wound complications, perioperative haemoglobin concentrations and intraoperative blood transfusion. To reduce selection biases, propensity score matching was applied. We defined the matched cases wherein LigaSure™ was used as the ‘using group’ and the other matched cases as the ‘non-using group’. Outcomes were compared between both groups. Results From each group, 35 cases were selected using propensity score matching. The intraoperative blood loss was significantly smaller statistically in the using group (181.5 ± 240.4 ml vs. 394.7 ± 547.3 ml, respectively; P = 0.041). The duration of operation was longer in the using group (189.9 ± 97.6 min vs. 140.6 ± 75.7 min, respectively; P = 0.007). There were no significant differences in other outcomes. Conclusion By using LigaSure™ for soft tissue sarcomas occurring in the buttocks and lower extremities, we observed a trade-off between reduced intraoperative blood loss and longer operative time.

Background Undifferentiated pleomorphic sarcoma (UPS) is a sarcoma with a poor prognosis. A clinical trial, SARC028, revealed that treatment with anti-PD-1 drugs was effective against UPS. Studies have reported that UPS expresses PD-L1, sometime strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained still unclear. CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a novel regulator of PD-L1 expression. The positive relationship between PD-L1 and CMTM6 has been reported in several studies. The aim of this study was to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6. Materials and methods Fifty-one primary UPS samples were subjected to CMTM6 and PD-L1 immunostaining. CMTM6 expression was assessed using proportion and intensity scores. CMTM6 gene copy number was also evaluated using a real-time PCR-based copy number assay. We also analyzed the mRNA expression and copy number variation of PD-L1 and CMTM6 in The Cancer Genome Atlas (TCGA) data. Results TCGA data indicated that the mRNAs encoded by genes located around 3p22 were coexpressed with CMTM6 mRNA in UPS. Both proportion and intensity scores of CMTM6 positively correlated with strong PD-L1 expression (≥ 50%) (both p = 0.023). CMTM6 copy number gain increased CMTM6 expression. Patients with UPS with a high CMTM6 intensity score had worse prognosis for overall survival. Conclusions CMTM6 expression was significantly correlated with PD-L1 expression. CMTM6 expression induced strong PD-L1 expression (≥ 50%). CMTM6 copy number gain promoted CMTM6 expression and increased PD-L1 expression in UPS.

Undifferentiated pleomorphic sarcoma (UPS) is a sarcoma with a poor prognosis. A clinical trial, SARC028, revealed that treatment with anti-PD-1 drugs was effective against UPS. Studies have reported that UPS expresses PD-L1, sometimes strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained unclear. CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a novel regulator of PD-L1 expression. The positive relationship between PD-L1 and CMTM6 has been reported in several studies. The aim of this study was thus to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6 in this disease. Fifty-one primary UPS samples were subjected to CMTM6 and PD-L1 immunostaining. CMTM6 expression was assessed using proportion and intensity scores. CMTM6 gene copy number was also evaluated using a real-time PCR-based copy number assay. We also analyzed the mRNA expression and copy number variation of PD-L1 and CMTM6 in The Cancer Genome Atlas (TCGA) data. TCGA data indicated that the mRNAs encoded by genes located around 3p22 were coexpressed with CMTM6 mRNA in UPS. Both proportion and intensity scores of CMTM6 positively correlated with strong PD-L1 expression (≥ 50%) (both p = 0.023). CMTM6 copy number gain increased CMTM6 expression. Patients with UPS with a high CMTM6 intensity score had a worse prognosis for overall survival. UPS showed variation in CMTM6 copy number and CMTM6 expression. CMTM6 expression was significantly correlated with PD-L1 expression, especially with strong PD-L1 expression.

Study Design: Retrospective diagnostic analysis. Objectives: To establish a new predictor of surgical outcome after surgery for intradural extramedullary spinal tumor (IDEMT) in the thoracic spine, we introduced shape factor (SF), a mathematical description of the morphology of the spinal cord. SF was calculated by dividing object area by the square of perimeter. Materials and Methods: Forty-three consecutive patients with IDEMT, detected by magnetic resonance imaging at the thoracic level with myelopathic signs, were included. Preoperative transverse cross-sectional area (CSA) and perimeter of the spinal cord (perimeter) at the level of maximal compression were measured. SF was calculated as 4π × CSA/(perimeter)2. The association between clinicoradiological factors and surgical outcome of IDEMT was statistically analyzed. Results: Mean CSA, perimeter, and SF were 27.8 ± 15.8 mm2, 28.8 ± 6.1 mm, and 0.385 ± 0.14, respectively. A histogram distribution revealed that perimeter and SF, but not CSA, fit the normal distribution. The patients were subdivided into 2 groups according to postoperative modified Japanese Orthopedic Association Score (mJOA). [group F (favorable): n = 32, mJOA ≥ 9; group UF (unfavorable): n = 11, mJOA < 9). Group UF had significantly lower mean CSA and SF. In univariate analysis of possible predictive factors for IDEMT surgery, greater age, lower preoperative mJOA, and lower SF were significantly associated with unfavorable outcome. In multivariate analysis, lower SF was the only significant predictor of postoperative outcome (odds ratio = 2.66, 95% CI 1.10–6.39, p = 0.0115). Conclusion: Measurements of CSA and perimeter, followed by calculation of SF, may provide valuable quantitative information for the outcome of surgery for IDEMT.

Doxorubicin is a first-line therapy for patients with unresectable advanced soft tissue sarcoma (STS). However, because of cardiotoxicities, it is not used for patients with cardiac problems. Eribulin has exhibited efficacy for advanced STS in second- or later-line treatments. In the present study, we retrospectively analyzed the efficacy and safety of first-line eribulin therapy for patients with advanced STS unable to receive doxorubicin. Six of 28 patients who received eribulin as any line treatment received eribulin as a first-line treatment. The reasons for avoiding doxorubicin were as follows: cardiac problems for four patients and advanced age for two. Median progression-free survival (PFS) of the patients who received eribulin as first-line and, second or later-line therapy were 9.7 months (95% CI: 1.0-not reached) and 3.9 months (95% CI: 2.7–5.9), which were not significantly different. The reasons for discontinuation of eribulin were disease progression and adverse events (2 fatigue and 1 neuropathy) for three patients each. No treatment-related cardiotoxicity was observed. The findings of this study indicated that eribulin exhibits meaningful efficacy for the patients with contraindications for doxorubicin as a first-line treatment without cardiac adverse events. However, appropriate safety management is necessary because older patients are typically among those intolerable of doxorubicin.

Tumor prostheses for the lower limb following resection of musculoskeletal tumors is useful limb salvage management, however, as compared with routine total joint replacement, an increased incidence of deep periprosthetic infection of tumor prosthesis has been observed. The risk factors for periprosthetic infection of tumor prosthesis remain unclear. This study examines the risk factors and outcomes of periprosthetic infection. This was a retrospective observational study including 121 patients (67 males and 54 females) who underwent tumor prosthesis of the lower limb after resection of musculoskeletal tumors between 1 January 2000 and 30 November 2018. Among a total of 121 tumor prostheses, 7 were total femurs, 47 were proximal femurs, 47 were distal femurs, and 20 were proximal tibias. The incidence of postoperative infection and its risk factors were analyzed. Forty-five patients (37%) had osteosarcoma, 36 patients (30%) had bone metastasis, and 10 patients (8%) had soft-tissue tumors invading the bone. The mean operating time was 229 min, and the mean follow-up duration was 5.9 years. Deep periprosthetic infection was noted in 14 patients (12%). In the multivariate analysis, the risk factors for postoperative infection were identified as being male (hazard ratio [HR], 11.2316, p = 0.0100), soft-tissue tumor (HR, 52.2443, p = 0.0003), long operation (HR, 1.0056, p = 0.0184), and radiotherapy (HR, 6.5683, p = 0.0476). The incidence of periprosthetic infection in our institution was similar to that of previous reports. Patients undergoing tumor prosthesis of the lower limb who were male, had a soft-tissue tumor, were predicted to have a long operation, and who underwent radiation, had an increased possibility of postoperative infection.

Introduction To investigate the clinical outcome and prognostic factors of malignant spinal dumbbell tumors (m-SDTs). Methods We retrospectively reviewed the clinical outcome of 22 consecutive cases of m-SDTs and analyzed the prognostic factors associated with worse outcome. Results Nineteen of the 22 cases were managed with surgery (86%), and gross total resection (GTR) was achieved in four cases (21%). The duration of overall survival (OS) ranged from 3 to 140 months, with a median survival time of 15.3 months. The 5 year OS rate was 55.6%. In multivariate analysis, histological subtype (high-grade malignant peripheral nerve sheath tumor) (hazard ratio [HR] 14.9, p = 0.0191), GTR (HR 0.07, p = 0.0343), and presence of local recurrences (HR 11.2, p = 0.0479) were significant and independent predictors of OS. Conclusions On the basis of clinical data, we propose that GTR and prevention of local recurrence may improve the clinical outcome of m-SDTs.

Osteosarcoma is an aggressive mesenchymal malignancy of the bone. Patient-derived models are essential tools for elucidating the molecular mechanisms associated with poor prognosis and the development of novel anticancer drugs. This study described the establishment of a patient-derived cancer model of osteosarcoma. Primary osteosarcoma tumor tissues were obtained from an osteosarcoma patient and inoculated in the skin of immunodeficient mice, followed by transplantation to other mice upon growth. Cells were maintained in monolayer cultures, and the capability of spheroid formation was assessed by seeding the cells on culture dishes. The invasion ability of cells was monitored by Matrigel assay, and genomic and proteomic backgrounds were examined by mass spectrometry. A cell line was established from patient-derived tumors and showed similar histology to that of the primary tumor tissue. Additionally, these cells formed spheroids on low-attachment tissue-culture dishes and exhibited invasive capabilities, and we confirmed that the genomic backgrounds were similar between patient-derived xenograft tumors and the cell line. Furthermore, the proteome of the patient-derived tumors and the cells exhibited similar, but not identical, patterns to that of the original tumor tissue. Our results indicated that this patient-derived xenograft model and cell line would be useful resources for osteosarcoma research.

Synovial sarcoma (SS) is a malignant soft tissue neoplasm harboring SS18-SSX fusion gene and is histologically characterized by spindle cells and epithelial components. Some investigations have demonstrated that desmoplastic reaction (DR) is an independent prognostic factor of cancers. However, it remains unknown whether DR is of predictive value for the prognosis of synovial sarcoma patients. Here, we reviewed the clinical and histological findings of 88 patients with SS. We defined DR as hyalinized collagenous structures and classified the degree of DR as follows: none, mild, moderate, and severe. Overall, 23 SS cases (24%) showed moderate or severe DR histologically. Statistically, the cases with moderate or severe degree of DR showed poorer prognosis than those with no or mild DR (local recurrence: P = 0.0059, distant metastasis: P = 0.0002, tumor death: P = 0.0382). The findings of the study suggest that the DR of synovial sarcoma could be an important prognostic factor.

Pazopanib, trabectedin, and eribulin are administered for the treatment of soft tissue sarcomas (STSs), however, there is little consensus on which agent should be preferentially used in a clinical setting. This study assessed whether peripheral immune-related markers served as a useful reference when selecting pazopanib, trabectedin, or eribulin. This study included 63 patients who were administered pazopanib, trabectedin, or eribulin for advanced STSs between March 2015 and December 2020. Patients were divided into three groups based on the first drug administered among these three drugs. Differences in overall survival (OS) or progression-free survival (PFS) among the three groups were analyzed. OS showed no significant differences among the drugs administered first. For patients with low neutrophil-to-lymphocyte ratio (NLR), the OS of patients administered pazopanib as the first choice was shorter than the others (hazard ratio [HR] = 9.53, 95% confidence interval [CI] = 1.94–18.13, p = 0.0018). In the low platelet-to-lymphocyte ratio (PLR) subgroup, the OS of the patients administered eribulin for the first choice was longer than that of the others (HR = 0.32, 95%CI = 0.10–0.98, p = 0.046). Therefore, NLR and PLR might be used as prognostic indicators to dictate whether STS patients receive pazopanib, trabectedin, or eribulin.

Purpose While radiotherapy is generally an acceptable treatment for metastatic spinal cord compression, surgical intervention is controversial due to the invasiveness and diversity of diseases in the patients being considered. The ideal treatment, therefore, depends on the situation, and the most acute treatment possible is necessary in patients presenting with myelopathy. We compared the neurological outcomes between radiotherapy and surgery in patients with metastatic spinal cord compression presenting with myelopathy. Methods A total 54 patients with metastatic spinal cord compression presenting with myelopathy treated in our institution between 2006 and 2016 were analyzed retrospectively. Twenty patients were selected by radiotherapy alone (radiation group), and 36 patients were selected by decompression and stabilization surgery with or without radiotherapy (surgery group). The neurological outcomes and complications were compared between the two treatment groups. Results Seven patients initially in the radiation group underwent surgery because of a substantial decline in their motor strength during radiotherapy. One of the remaining 13 patients (8%) in the radiation group and 30 of the 34 patients (88%) in the surgery group showed improvement in their neurological symptoms (P

Despite advances in our understanding of the underlying molecular drivers of sarcomas, few treatments are available with proven benefit for advanced metastatic sarcomas. Immunotherapy has value in this setting for some types of cancers, but sarcomas, with their multiplicity of rare types, have not been characterized in detail for their expression of targetable immune biomarkers. This study provides the most systematic evaluation to date of tumor-infiltrating lymphocytes and immune checkpoint biomarker expression in sarcomas. We examined by morphology and immunohistochemistry 1072 sarcoma specimens representing 22 types, in addition to 236 benign bone and soft-tissue tumors. Genomically-complex sarcoma types-those driven by mutations and/or copy-number alterations-had much higher numbers of tumor-infiltrating lymphocytes than translocation-associated sarcomas. Prior exposure to radiotherapy was associated with increased immune infiltrates. Higher lymphocytic infiltration was associated with better overall survival among the non-translocation-associated sarcomas. Expression of PD-1 and CD56 were associated with worse overall survival. LAG-3 and TIM-3, two emerging immune checkpoints, were frequently expressed in most sarcoma types. Indeed, most cases positive for PD-(L)1 coexpressed one or both of these novel biomarkers, providing a potential rationale in support for trials targeting LAG-3 and/or TIM-3 in conjunction with PD-1 inhibition.

Myxoid liposarcomas (MLSs) are genetically defined by the presence of DDIT3 gene fusions and most commonly arise in the extremities of young adults. Whether MLSs develop primarily in the retroperitoneum is controversial, and a recent retrospective study found no molecularly confirmed examples. Because MLSs tend to metastasize to deep soft tissues, purported examples of primary retroperitoneal lesions might represent distant metastasis, most commonly from extremities. In addition, well-differentiated or dedifferentiated liposarcomas, which are characterized by MDM2 amplifications, may exhibit prominent myxoid changes and mimic MLSs. Here, we document 5 cases of MLSs that originated in the retroperitoneum that were identified through critical clinicopathologic reevaluation. These cases accounted for 2.3% of 214 primary retroperitoneal liposarcomas and 3.2% of 156 MLSs in our database. They occurred in 3 men and 2 women with a median age of 32 years. All tumors were localized to the retroperitoneum at presentation, and no patient developed extra-abdominal recurrences during the clinical course (median, 50 mo). All 5 cases exhibited at least focal classic histologic findings. All harbored DDIT3 gene rearrangements, and none harbored MDM2 amplifications according to fluorescence in situ hybridization. This study demonstrates that primary MLSs can occur in the retroperitoneum, albeit rarely, and can be accurately diagnosed through combined clinicopathologic and molecular analysis.

Leiomyosarcoma (LMS) of soft tissue is a sarcoma with smooth-muscle differentiation, and conventional chemotherapy does not improve its outcome. The application of novel antitumor agents and precise prognostication has been demanded. The expression of the protein Forkhead box M1 (FOXM1), a member of the FOX family, is considered an independent predictor of poor survival in many cancers and sarcomas. However, the expression status of FOXM1 in LMS is poorly understood. The purposes of this study were to examine the correlation between the expression of FOXM1 and clinicopathologic or prognostic factors and to clarify the efficacy of FOXM1 target therapy in LMS. We evaluated the immunohistochemical expressions of FOXM1 using 123 LMS tumor specimens. Univariate and multivariate survival analyses revealed that FOXM1 expression was associated with poor prognosis in LMS. An in vitro study was then carried out to examine the antitumor effect of a FOXM1 inhibitor (thiostrepton) and siRNA on a novel LMS cell line, TC616. We also assessed the efficacy of the combined use of doxorubicin and thiostrepton. Thiostrepton showed dose-dependent antitumor activity and TC616 cells treated with the combination of thiostrepton and doxorubicin showed lower proliferation compared to those treated with either drug individually. FOXM1 interruption by siRNA decreased cell proliferation and increased chemosensitivity. In conclusion, FOXM1 has potential to be a therapeutic target for LMS.

Eribulin is a new drug to treat soft tissue sarcoma (STS) that exerts antitumor activity by binding to microtubules. The prognosis of STS is poor, and eribulin is expected to improve the treatment outcome. We observed several cases that exhibited resistance to eribulin and developed an eribulin-resistant leiomyosarcoma cell line to investigate the mechanism of resistance. The IC50 of eribulin was 125 times higher in the resistant cell line than in the parental cell line, and eribulin did not induce G2/M arrest in resistant cells. The resistant cell line showed increased expression of MDR1 transcript, but protein levels and functional analysis results were similar to the parental cell line. We found that class III β-tubulin (TUBB3) was overexpressed in the resistant cell line, and siRNA knockdown of TUBB3 partially recovered sensitivity to eribulin. TUBB3 expression in clinical samples varied, suggesting that TUBB3 has the potential to be a biomarker for selection of anticancer drugs and may be a target for overcoming resistance to eribulin.