KDM2B-Rearranged Soft Tissue Sarcomas Expand the Concept of BCOR-Associated Sarcoma.

Sarcomas with BCOR genetic alterations (BCOR-associated sarcomas) represent a recently recognized family of soft tissue and bone tumors characterized by BCOR fusion, BCOR internal tandem duplication, or YWHAE::NUTM2B fusion. Histologically, the tumors demonstrate oval to spindle cell proliferation in a variably vascular stroma and overexpression of BCOR and SATB2. Herein, we describe 3 soft tissue sarcomas with KDM2B fusions that phenotypically and epigenetically match BCOR-associated sarcomas. The cases included 1 infant, 1 adolescent, and 1 older patient. All tumors showed histologic findings indistinguishable from those of BCOR-associated sarcomas and were originally diagnosed as such based on the phenotype. However, none of the tumors had BCOR or YWHAE genetic alterations. Instead, targeted RNA sequencing identified in-frame KDM2B::NUTM2B, KDM2B::CREBBP, and KDM2B::DUX4 fusions. KDM2B fusions were validated using reverse-transcription PCR, Sanger sequencing, and in situ hybridization assays. Genome-wide DNA methylation analysis matched all 3 tumors with BCOR-associated sarcomas using the Deutsches Krebsforschungszentrum (DKFZ) classifier and t-distributed stochastic neighbor embedding analysis. One localized tumor showed a flat genome-wide copy number profile, and the patient remained disease-free after treatment. The other tumors showed multiple copy number alterations, including MDM2/CDK4 amplification and/or CDKN2A/B loss, and both tumors metastasized, leading to the patient's death in one of the cases. When tested using KDM2B immunohistochemistry, all 3 KDM2B-rearranged sarcomas showed diffuse strong staining, and all 13 sarcomas with BCOR genetic alterations also demonstrated diffuse, strong, or weak staining. By contrast, among 72 mimicking tumors, only a subset of synovial sarcomas showed focal or diffuse weak KDM2B expression. In conclusion, our study suggests that KDM2B-rearranged soft tissue sarcomas belong to the BCOR-associated sarcoma family and expand its molecular spectrum. This may be related to the known molecular relationship between KDM2B and BCOR in the polycomb repressive complex 1.1. Immunohistochemical analysis of KDM2B is a potentially valuable diagnostic tool for BCOR-associated sarcomas, including those with KDM2B rearrangement.

Perioperative Adriamycin plus ifosfamide vs. gemcitabine plus docetaxel for high-risk soft tissue sarcomas: randomised, phase II/III study JCOG1306.

BACKGROUND: This randomised phase II/III trial aimed to determine whether perioperative chemotherapy with gemcitabine plus docetaxel (GD) is non-inferior to the standard Adriamycin plus ifosfamide (AI) in terms of overall survival (OS) in patients with soft tissue sarcoma (STS). METHODS: Patients with localised high-risk STS in the extremities or trunk were randomised to receive AI or GD. The treatments were repeated for three preoperative and two postoperative courses. The primary endpoint was OS. RESULTS: Among 143 enrolled patients who received AI (70 patients) compared to GD (73 patients), the estimated 3-year OS was 91.4% for AI and 79.2% for GD (hazard ratio 2.55, 95% confidence interval: 0.80-8.14, P = 0.78), exceeding the prespecified non-inferiority margin in the second interim analysis. The estimated 3-year progression-free survival was 79.1% for AI and 59.1% for GD. The most common Grade 3-4 adverse events in the preoperative period were neutropenia (88.4%), anaemia (49.3%), and febrile neutropenia (36.2%) for AI and neutropenia (79.5%) and febrile neutropenia (17.8%) for GD. CONCLUSIONS: Although GD had relatively mild toxicity, the regimen-as administered in this study-should not be considered a standard treatment of perioperative chemotherapy for high-risk STS in the extremities and trunk. CLINICAL TRIAL REGISTRATION: jRCTs031180003.

Systemic inflammation response index (SIRI) as a predictive factor for overall survival in advanced soft tissue sarcoma treated with eribulin.

BACKGROUND: Eribulin is a tubulin and microtubule-targeting drug that has clinical benefit in overall survival (OS) for patients with advanced soft tissue sarcoma. Eribulin's efficacy has been confirmed in several clinical trials, although no clinically useful biomarkers have been identified. We therefore sought to clarify the predictive factor of eribulin treatment, while focusing on systemic inflammation and immune response values. METHODS: This study included 33 advanced STS patients treated with eribulin between March 2016 and September 2019. We evaluated the associations of clinical factors influencing the efficacy of eribulin treatment and systemic inflammatory and immune response, including the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the lymphocyte-to-monocyte ratio (LMR), the systemic inflammation response index (SIRI), and the prognostic nutrition index (PNI), with progression-free survival (PFS) and OS using the Kaplan-Meier method and log-rank test. RESULTS: NLR, LMR, PLR, SIRI, and PNI were unassociated with PFS. Compared with patients with SIRI <1.5, those with an SIRI ≥1.5 had a significantly shorter OS [median OS 15 months (95% confidence interval [CI] 8-not reached) vs. 7 months (95% CI 3-14), P = 0.04]. Moreover, the PFS tended to be shorter for patients with SIRI ≥1.5 who received chemotherapy after eribulin treatment than in those with SIRI >1.5 [median PFS 92.5 days (95% CI 27-204) vs. 133 days (95% CI 36-507), P = 0.08]. CONCLUSIONS: High SIRI values may predict poorer overall survival and the efficacy of subsequent drugs after eribulin treatment among patients with advanced soft tissue sarcoma.

Prognosis and surgical outcome of soft tissue sarcoma with malignant fungating wounds.

OBJECTIVE: Malignant fungating wounds are ulcerating tumors that infiltrate the overlying skin. Little evidence exists regarding the prognosis or treatment of malignant fungating wound in soft tissue sarcoma. This study aimed to reveal the prognosis and outcome of surgical treatment of malignant fungating wound in soft tissue sarcoma. METHODS: We retrospectively reviewed 26 patients with malignant fungating wound in high-grade soft tissue sarcoma between 2005 and 2018. The patients' characteristics, treatments, surgical wound complications, local recurrences and prognoses were analyzed. Overall survival was analyzed using the Kaplan-Meier method and compared with that of the control cohort, consisting of 236 consecutive patients with non-malignant fungating wound high-grade soft tissue sarcoma treated during the same period. RESULTS: Among the 26 patients, undifferentiated pleomorphic sarcoma was the most common subtype. Twenty-three patients, including 20 (87%) and 3 (13%), underwent limb-salvage surgery and amputation, respectively. Among the 20 patients who underwent limb-salvage surgery, 4 (20%) had surgical wound complications, which required additional surgical procedures. Excluding the patients who underwent palliative surgery, local recurrence occurred in 2 patients (11%). The 5-year overall survival rate for all high-grade malignant fungating wound and non-malignant fungating wound patients was 26.0 and 67.3% (P < 0.0001), respectively. CONCLUSIONS: Malignant fungating wounds in soft tissue sarcoma were significantly associated with a poor prognosis; however, the incidence of surgical complications and local recurrence after limb-salvage surgery was comparable to that of general soft tissue sarcoma cases. Limb-salvage surgery should be considered, if possible, to preserve the patient's quality of life because of the dismal prognosis of patients with malignant fungating wound in soft tissue sarcoma.

Identification of a Novel MAN1A1-ROS1 Fusion Gene Through mRNA-based Screening for Tyrosine Kinase Gene Aberrations in a Patient with Leiomyosarcoma.

BACKGROUND: Soft tissue sarcomas are a heterogeneous group of rare malignant tumors. Advanced soft tissue sarcomas have a poor prognosis, and effective systemic therapies have not been established. Tyrosine kinases are increasingly being used as therapeutic targets for a variety of cancers and soft tissue sarcomas. Although complex karyotype sarcomas typically tend to carry more potentially actionable genetic alterations than do translocation-associated sarcomas (fusion gene sarcomas), based on our database review, we found that leiomyosarcoma and malignant peripheral nerve sheath tumors have lower frequencies of potential targets than other nontranslocation soft tissue sarcomas. We theorized that both leiomyosarcoma and malignant peripheral nerve sheath tumors might be included in any unique translocations. Furthermore, if tyrosine kinase imbalances, especially fusion genes, occur in patients with leiomyosarcomas and malignant peripheral nerve sheath tumors, tyrosine kinase inhibitors might be a drug development target for this sarcoma. In this study, we used a tyrosine kinase screening system that could detect an imbalance in mRNA between 5'- and 3'-sides in tyrosine kinase genes to identify potential novel therapeutic tyrosine kinase targets for soft tissue sarcomas. QUESTIONS/PURPOSES: (1) Are there novel therapeutic tyrosine kinase targets in tumors from patients with soft tissue sarcomas that are detectable using mRNA screening focusing on imbalance expressions between the 5' and 3' end of the kinase domain? (2) Can potential targets be verified by RNA sequencing and reverse transcription PCR (RT-PCR)? (3) Will potential fusion gene(s) transform cells in in vitro assays? (4) Will tumors in mice that have an identified fusion gene respond to treatment with a therapeutic drug directed at that target? METHODS: We used mRNA screening to look for novel tyrosine kinase targets that might be of therapeutic potential. Using functional assays, we verified whether the identified fusion genes would be good therapeutic candidates for soft tissue sarcomas. Additionally, using in vivo assays, we assessed whether suppressing the fusion's kinase activity has therapeutic potential. Study eligibility was based on a patient having high-grade spindle cell and nontranslocation sarcomas, including leiomyosarcoma, malignant peripheral nerve sheath tumor, and high-grade myxofibrosarcoma. Between 2015 and 2019, of the 172 patients with soft tissue sarcomas treated with surgical resection at Juntendo University Hospital, 72 patients had high-grade nontranslocation sarcomas. The analysis was primarily for leiomyosarcoma and malignant peripheral nerve sheath tumors, and there was a limitation of analysis size (reagent limitations) totaling 24 samples at the start of the study. We collected additional samples from a sample bank at the Tokyo Medical and Dental University to increase the number of sarcomas to study. Therefore, in this study, a total of 15 leiomyosarcoma samples, five malignant peripheral nerve sheath tumors samples, and four high-grade myxofibrosarcoma samples were collected to achieve the sample size of 24 patients. To identify tyrosine kinase fusion genes, we designed a NanoString-based assay (NanoString Technologies Inc, Seattle, WA, USA) to query the expression balances regarding transcripts of 90 tyrosine kinases at two points: the 5' end of the kinase domain and within the kinase domain or 3' end of the kinase domain. The tumor's RNA was hybridized to the NanoString probes and analyzed for the expression ratios of outliers from the 3' to 5' end of the kinase domain. Presumed novel fusion events in these positive tumors that were defined by NanoString-based assays were confirmed tyrosine kinase fusion genes by RNA sequencing and confirmatory RT-PCR. Functional analyses consisting of in vitro and in vivo assays were also performed to elucidate whether the identified tyrosine kinase gene fusions were associated with oncogenic abilities and drug responses. RESULTS: We identified aberrant expression ratios regarding the 3' to 5' end of the kinase domain ratios in ROS1 transcripts in a leiomyosarcoma in a 90-year-old woman. A novel MAN1A1-ROS1 fusion gene was identified from her thigh tumor through RNA sequencing, which was confirmed with real-time PCR. In functional assays, MAN1A1-ROS1 rearrangement revealed strong transforming potential in 3T3 cells. Moreover, in an in vivo assay, crizotinib, a ROS1 inhibitor, markedly inhibited the growth of MAN1A1-ROS1 rearrangement-induced transformed cells in a dose-dependent manner. CONCLUSION: We conducted tyrosine kinase screening to identify new therapeutic targets in soft tissue sarcomas. We found a novel MAN1A1-ROS1 fusion gene that may be a therapeutic target in patients with leiomyosarcoma. This study demonstrates that the mRNA screening system may aid in the development of useful therapeutic options for soft tissue sarcomas. CLINICAL RELEVANCE: If novel tyrosine fusions such as MAN1A1-ROS1 fusion can be found in sarcomas from other patients, they could offer avenues for new molecular target therapies for sarcomas that currently do not have effective chemotherapeutic options. Therefore, the establishment of a screening system that includes both genomic and transcript analyses in the clinical setting is needed to verify our discoveries and take the developmental process of treatment to the next step.

Pretreatment serum C-reactive protein is a significant prognostic factor in patients with soft tissue metastases.

BACKGROUND: Soft tissue metastasis is rarer than bone metastasis. Patients with soft tissue metastasis generally have a dismal prognosis. The treatment for metastatic lesions is sometimes difficult, because the prognostic factors of patients with soft tissue metastasis remain unelucidated. Therefore, this study aimed to identify these prognostic factors. METHODS: Thirty-one patients with soft tissue metastasis were included in the study. We evaluated associations of overall survival with clinical parameters and inflammatory markers using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Twelve patients received surgery for soft tissue metastasis, while radiation therapy was performed in six cases. The median overall survival after the detection of soft tissue metastasis was 11 months. Univariate analysis revealed that detection of soft tissue metastasis after the multidisciplinary treatment (P = 0.01); solitary metastasis (P = 0.0003); and pretreatment C-reactive protein (CRP) level < 0.4 mg/dL (P < 0.0001), white blood cell count < 8500 × 103/µL (P = 0.0003), and neutrophil-to-lymphocyte ratio < 5 (P = 0.02) were significant good prognostic factors. Multivariate analysis revealed that a CRP value < 0.4 mg/dL (P = 0.07) and solitary metastasis (P = 0.09) were possible significant predictors of survival. Furthermore, in case of CRP levels <0.4 mg/dL and metastatic tumor resection, patients had a good prognosis; however, when the CRP levels increased to 0.4 mg/dL and above, patients had a poor prognosis, irrespective of tumor resection. CONCLUSIONS: CRP is potentially useful for determining the indication of radical metastasectomy in soft tissue metastasis.

Phase II trial of pazopanib in patients with metastatic or unresectable chemoresistant sarcomas: A Japanese Musculoskeletal Oncology Group study.

Alveolar soft part sarcoma (ASPS), epithelioid sarcoma (ES), and clear cell sarcoma (CCS) are known to be chemoresistant tumors. The aim of this study was to investigate the effect of pazopanib on these chemoresistant tumors. This study is designed as a single-arm, multicenter, investigator-initiated phase II trial. Patient enrollment was undertaken between July 2016 and August 2018 at 10 hospitals participating in the Japanese Musculoskeletal Oncology Group. The primary end-point is the CBR (CBR, including complete or partial response and stable disease) at 12 weeks after treatment with pazopanib according to RECIST. Eight patients were enrolled within the period. The histological subtypes were 5 ASPS, 2 ES, and 1 CCS. The median follow-up period was 22.2 (range, 4.9-24.9) months. All patients initially received pazopanib 800 mg once daily. The CBRs were 87.5% (7 of 8) and 75.0% (6 of 8) according to RECIST and Choi criteria at 12 weeks after pazopanib treatment, respectively. The CBRs at 12 weeks according to RECIST were 80.0%, 100.0%, and 100.0% in ASPS, ES, and CCS, respectively. Partial response was observed in 1 ASPS according to RECIST and 3 ASPS and 1 ES according to Choi criteria at 12 weeks after pazopanib treatment. This study documented antitumor activity of pazopanib, especially in ASPS. These results support the frontline use of pazopanib for ASPS. Prospective data collection is desired using both RECIST and Choi criteria for these rare chemoresistant tumors.

Skeletal muscle measurements predict surgical wound complications but not overall survival in patients with soft tissue sarcoma.

BACKGROUND: It is unknown whether sarcopenia influences treatment outcome in patients with soft tissue sarcoma. Herein, we aimed to elucidate the impact of sarcopenia on sarcoma treatment. METHODS: A total of 163 soft tissue sarcoma patients were included. Skeletal muscle measures were calculated using computed tomography images. Skeletal muscle area (SMA) and density (SMD) at the L3 level were extracted, and SMA was normalized by height as skeletal muscle index (SMI). The skeletal muscle gauge (SMG) was calculated by multiplying SMD × SMI. The relationship of skeletal muscle measures and clinical factors to wound complications and prognosis was evaluated, and classification and regression tree (CART) analysis was used to develop classification models for risk groups of surgical wound complications. RESULTS: Thirty-three patients developed wound complications. In univariate analysis, age (P = 0.0022), tumour location of adductor compartment of the thigh (P = 0.0019), operating time (P = 0.010), blood loss (P = 0.030), SMD (P = 0.0004) and SMG (P = 0.0001) were significantly correlated with complications. In multivariate analysis, lower SMG was an independent risk factor (P = 0.031, OR = 3.27). CART analysis classified three risk groups of surgical wound complications by SMG, age, tumour location and operating time, and area under the receiver operating characteristic curve (AUROCC) was 0.75. SMG was not associated with prognosis in univariate analysis (P = 0.15). CONCLUSIONS: The SMG does not affect overall survival but predicts surgical wound complications.

Osteosarcoma in patients over 50 years of age: Multi-institutional retrospective analysis of 104 patients.

BACKGROUND: Primary osteosarcoma in elderly patients are rare malignant tumors. Its optimal treatment has not yet been determined. METHODS: This retrospective study included 104 patients aged >50 years with resectable, non-metastatic osteosarcoma treated by the members of the Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group. The effects of adjuvant chemotherapy were estimated by comparing outcomes in patients who received surgery plus chemotherapy with those who underwent surgery alone. RESULTS: Median age at presentation was 59 years. Neoadjuvant and adjuvant chemotherapy was administered to 83 (79.8%) patients. Patients who underwent surgery plus chemotherapy and those who underwent surgery alone had 5-year overall survival (OS) rates of 68.6% and 71.7%, respectively (p = 0.780), and 5-year relapse free survival (RFS) rates of 48.2% and 43.6%, respectively (p = 0.64). Univariate analysis showed that resection with wide margins was significantly correlated with better prognosis. CONCLUSIONS: The addition of chemotherapy to surgery did not improve OS or RFS in patients aged >50 years with resectable, non-metastatic osteosarcoma. Surgery with wide margins was only significantly prognostic of improved survival. The effect of chemotherapy in elderly osteosarcoma patients was unclear.

Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations.

Tenosynovial giant cell tumor (TSGCT) is a rare neoplasm. Although surgical resection is the widely accepted primary treatment for TSGCT, recurrences are frequent, and patients' joint function may be severely compromised. Previous studies reported that CSF1-COL6A3 fusion genes were identified in approximately 30% of TSGCTs. The aim of our study was to comprehensively clarify the genomic abnormalities in TSGCTs. We performed whole exome sequencing in combination with target sequence validation on 34 TSGCT samples. RNA sequencing was also performed on 18 samples. RNA sequencing revealed fusion transcripts involving CSF1, including novel CSF1-VCAM1, CSF1-FN1 and CSF1-CDH1 fusions, in 13/18 (72%) cases. These fusion genes were validated by chromogenic in situ hybridization. All CSF1 fusions resulted in the deletion of CSF1 exon 9, which was previously shown to be an important negative regulator of CSF1 expression. We also found that 12 (35%) of the 34 TSGCT samples harbored CBL missense mutations. All mutations were detected in exons 8 or 9, which encode the linker and RING finger domain. Among these mutations, C404Y, L380P and R420Q were recurrent. CBL-mutated cases showed higher JAK2 expression than wild-type CBL cases (p = 0.013). CSF1 fusion genes and CBL mutations were not mutually exclusive, and both alterations were detected in six of the 18 (33%) tumors. The frequent deletion of CSF1 exon 9 in the fusion transcripts suggested the importance of this event in the etiology of TSGCT. Our results may contribute to the development of new targeted therapies using JAK2 inhibitors for CBL-mutated TSGCT.

H3K27me3 deficiency defines a subset of dedifferentiated chondrosarcomas with characteristic clinicopathological features.

Dedifferentiated chondrosarcoma is a rare bone sarcoma, whose genetic background remains incompletely understood. Mutations in SUZ12 or EED, which encode polycomb repressive complex 2 (PRC2) components, and resulting deficiency in H3K27me3 are characteristic features of the majority of malignant peripheral nerve sheath tumors. Here, we investigated H3K27me3 and PRC2 status in dedifferentiated chondrosarcoma. Among 19 evaluable dedifferentiated chondrosarcoma cases, six (32%) showed immunohistochemical loss of H3K27me3 only in the dedifferentiated component, whereas the well-differentiated component retained H3K27me3. H3K27me3-deficient dedifferentiated chondrosarcoma occurred in two men and four women with a median age of 66. All of these tumors affected bones of the upper half of the body, with the ribs being preferentially involved, which represented a significantly different distribution compared to that in the 13 H3K27me3-intact dedifferentiated chondrosarcomas. H3K27me3-deficient dedifferentiated chondrosarcomas were histologically different from H3K27me3-intact dedifferentiated chondrosarcomas, as the former invariably demonstrated dedifferentiated histology with a striking similarity to classic malignant peripheral nerve sheath tumor, comprising sweeping to swirling fascicles of relatively uniform spindle cells. Heterologous rhabdomyoblastic differentiation, the focal presence of grade 3 chondrosarcoma histology, and a cartilaginous component in the metastatic sites were exclusively seen in some cases of H3K27me3-deficient dedifferentiated chondrosarcoma. In all three H3K27me3-deficient dedifferentiated chondrosarcomas that contained focal grade 3 histology, dedifferentiated components did not juxtapose to the grade 3 areas but transitioned abruptly from the grade 1-2 components. Targeted next generation sequencing, which was successfully performed on four H3K27me3-deficient dedifferentiated chondrosarcomas, identified an IDH2 mutation in one case and COL2A1 truncations in three cases. The dedifferentiated areas of three cases harbored SUZ12 or EED alterations, which were absent in the well-differentiated component, suggesting a role for PRC2 aberrations in dedifferentiation. H3K27me3 deficiency defines a novel subset of dedifferentiated chondrosarcoma that requires recognition because of its diagnostic and potential clinical implications.

Absence of H3F3A mutation in a subset of malignant giant cell tumor of bone.

Giant cell tumor of bone typically involves the epiphysis of the long bones of skeletally mature patients. It is genetically characterized by highly recurrent and specific mutations of the H3F3A gene, which encodes histone H3.3. The most common mutation H3F3A G34W can readily be detected by a recently developed mutation-specific antibody. Giant cell tumor of bone rarely transforms to a sarcoma (malignant giant cell tumor of bone), which has not been genetically characterized in detail. We studied seven clinicopathologically defined malignant giant cell tumors, as well as two H3F3A-mutant bone sarcomas without giant cell tumor histology using a combination of clinicopathological, immunohistochemical, and molecular methods (Sanger sequencing + pyrosequencing or next generation sequencing). The cases included five men and four women, with a median age at initial diagnosis of 27 years. The two H3F3A G34W-positive sarcomas without giant cell tumor histology involved the subarticular epiphyseal sites, suggesting relatedness with giant cell tumor of bone. In two of the seven clinicopathologically defined malignant giant cell tumor cases, the sarcoma tissue showed the H3F3A G34W mutation. However, in the remaining five cases, in contrast to their associated H3F3A G34W-mutant giant cell tumor, the sarcoma lacked the H3F3A G34W mutation, either entirely or sub-clonally in the samples tested. This discordant mutation status was confirmed in all instances by immunohistochemistry and sequencing. A FISH analysis suggested that the absence of the H3F3A G34W mutation may be related to deletion of the H3F3A gene. Therefore, we have demonstrated that H3F3A G34W mutation, a critical driver in giant cell tumor, is absent in a subset of malignant giant cell tumor of bone. This novel recurrent phenomenon has potential biological and diagnostic implications, and further study is required to better characterize this progression pathway and understand its mechanism.

Body composition as a predictor of toxicity after treatment with eribulin for advanced soft tissue sarcoma.

BACKGROUND: Despite the clinical benefits of eribulin on overall survival of advanced soft tissue sarcoma (STS) patients, treatment-related toxicity reduces their QOL. Body composition metrics (BCMs) are associated with poor outcome and drug toxicities in several cancers. This study investigated whether BCMs could predict drug toxicity occurrence in advanced STS patients treated with eribulin. METHODS: This study included 23 advanced STS patients treated with eribulin between March 2016 and April 2018. BCMs were evaluated using a CT scan obtained within 1 month before or after treatment initiation. The relationship of BCMs and other clinical factors was evaluated and CART analysis used to develop classification models for risk groups of drug toxicity. RESULTS: Sixteen patients (69.6%) experienced any grade 3/4 toxicity. Eleven patients (47.8%) developed G4 hematologic toxicity, which was significantly higher in those with low skeletal muscle gauge (SMG) (P = 0.02) and low pretreatment neutrophil count (P = 0.0002). Six patients (26.1%) had grade 3/4 non-hematologic toxicity, and was higher in those with low SMG (P = 0.004), and low serum albumin level (P = 0.02). Five patients with high BMI (P = 0.03) experienced febrile neutropenia (FN) and low pretreatment neutrophil count (P = 0.02). CART analysis classified three risk groups, and area under the receiver operating characteristic curve (AUROCC) was 0.92, 0.88, 0.92 in G4 hematologic AE, G3/4 non-hematologic AE, FN, respectively. CONCLUSIONS: SMG is a significant predictive factor of eribulin drug toxicity in advanced STS patients. Risk classification of drug toxicity through combining predictive factors, could improve the therapeutic strategy used in chemotherapy.

Predictive factors for complications after surgical treatment for schwannomas of the extremities.

BACKGROUND: Schwannomas are well-encapsulated, benign neoplasms, and enucleation is a standard operation procedure. The incidence of neurological complications after surgical treatment for schwannomas of the extremities varies, and there is no consensus concerning predictive factors for complications. The aim of this study was to elucidate predictive factors for complications after surgical treatment of schwannomas that develop in the major nerves of the extremities. METHODS: A total of 139 patients with 141 schwannomas arising in major nerves were retrospectively analyzed. Data regarding preoperative clinical features, the postoperative neurological complications, and clinical course of complications, with a median follow-up period of 2 months (range, 0.5-96), were obtained. Predictive factors for complications were statistically analyzed. RESULTS: Postoperative complications occurred in 49 lesions (34.8%), including 42 with sensory disturbance and 8 with motor weakness. In univariate analysis, older age, tumors originating from the upper extremity, and major motor nerve involvement were associated with a higher complication rate (p = 0.03, p = 0.003, and p = 0.001, respectively). In multivariate analysis, major motor nerve involvement was an independent predictive factor for postoperative complications (p = 0.03). Almost all complications gradually improved, but 6 out of 8 patients with motor weakness did not show full recovery at the final follow-up. CONCLUSIONS: Schwannomas originating from major motor nerves can lead to a higher risk for postoperative complications.

Neutrophil-to-lymphocyte ratio after pazopanib treatment predicts response in patients with advanced soft-tissue sarcoma.

BACKGROUND: Pazopanib is a multi-tyrosine kinase inhibitor that is used to treat advanced soft-tissue sarcoma, and its efficacy has been confirmed in several clinical trials, although no clinically useful biomarkers have been identified. In other cancers, the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), and the lymphocyte-to-monocyte ratio (LMR) are associated with chemotherapy response and prognosis. Therefore, we aimed to evaluate the associations of pazopanib response with NLR, PLR, and LMR among patients with advanced soft-tissue sarcoma. METHODS: Data regarding NLR, PLR, and LMR were obtained for 25 patients who received pazopanib for soft-tissue sarcoma. The patients were categorized according to their values for NLR (≥3.8 vs. <3.8), PLR (≥230 vs. <230), and LMR (≥2.4 vs. <2.4), and we evaluated the associations of these markers with progression-free survival and overall survival using Kaplan-Meier curves and Cox proportional models. RESULTS: No significant differences in progression-free survival or overall survival were observed based on the pre-treatment NLR, PLR, and LMR values. However, decreased NLR values after treatment using pazopanib were independently associated with significantly prolonged progression-free survival (hazard ratio: 0.07, p = 0.001) and overall survival (hazard ratio: 0.17, p = 0.0006). CONCLUSIONS: Decreased NLR values after treatment using pazopanib may predict high efficacy and favorable outcomes among patients with advanced soft-tissue sarcoma.

Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2.

Notch signaling modulates skeletal formation and pathogenesis of osteoarthritis (OA) through induction of catabolic factors. Here we examined roles of Hes1, a transcription factor and important target of Notch signaling, in these processes. SRY-box containing gene 9 (Sox9)-Cre mice were mated with Hes1(fl/fl) mice to generate tissue-specific deletion of Hes1 from chondroprogenitor cells; this deletion caused no obvious abnormality in the perinatal period. Notably, OA development was suppressed when Hes1 was deleted from articular cartilage after skeletal growth in type II collagen (Col2a1)-Cre(ERT);Hes1(fl/fl) mice. In cultured chondrocytes, Hes1 induced metallopeptidase with thrombospondin type 1 motif, 5 (Adamts5) and matrix metalloproteinase-13 (Mmp13), which are catabolic enzymes that break down cartilage matrix. ChIP-seq and luciferase assays identified Hes1-responsive regions in intronic sites of both genes; the region in the ADAMTS5 gene contained a typical consensus sequence for Hes1 binding, whereas that in the MMP13 gene did not. Additionally, microarray analysis, together with the ChIP-seq, revealed novel Hes1 target genes, including Il6 and Il1rl1, coding a receptor for IL-33. We further identified calcium/calmodulin-dependent protein kinase 2δ (CaMK2δ) as a cofactor of Hes1; CaMK2δ was activated during OA development, formed a protein complex with Hes1, and switched it from a transcriptional repressor to a transcriptional activator to induce cartilage catabolic factors. Therefore, Hes1 cooperated with CaMK2δ to modulate OA pathogenesis through induction of catabolic factors, including Adamts5, Mmp13, Il6, and Il1rl1. Our findings have contributed to further understanding of the molecular pathophysiology of OA, and may provide the basis for development of novel treatments for joint disorders.

Prevalence and clinical outcomes of hip fractures and subchondral insufficiency fractures of the femoral head in patients with tumour-induced osteomalacia.

PURPOSE: Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome usually caused by phosphaturic mesenchymal tumours, leading to great distress due to bone pain and affecting quality of life (QoL). This study aimed to investigate the prevalence and clinical outcomes of hip fractures and subchondral insufficiency fractures (SIF) of the femoral head. METHODS: Twelve TIO patients were treated between January 2000 and December 2016 at our hospital. All underwent surgery for the tumour causing TIO, and complete removal of the tumour was accomplished in nine of 12 cases. Plain radiographs of the hip were obtained in all cases, and magnetic resonance imaging (MRI) was obtained from 15 hips representing eight patients before tumour removal. We evaluated the prevalence of hip fractures or SIF and their clinical outcomes. RESULTS: Hip fractures were observed in six of 12 cases, and the total number of fractures was nine, of which five were femoral neck, two were intertrochanteric and two were subtrochanteric fractures. Conservative treatment, regardless of complete remission of TIO, was successful except in one case with impending subtrochanteric fracture. SIFs were observed in 11 of 24 hips. Seven of 11 hips with SIF showed progression after surgery for tumour resection. CONCLUSIONS: Hip fractures and SIF are highly prevalent in TIO patients. Surgical and medical treatment for TIO is sufficient for treating hip fractures conservatively. However, SIF tends to show progression of femoral head collapse, serving as the main cause of pain after successful TIO treatment.

FOSL1 immunohistochemistry clarifies the distinction between desmoplastic fibroblastoma and fibroma of tendon sheath.

AIMS: Although desmoplastic fibroblastoma (DFB) and fibroma of tendon sheath (FTS) are well-established entities, they may show overlapping clinicopathological features. In addition, cytogenetic data showing a shared 11q12 rearrangement in a small number of cases suggest a close link between these entities. A recent microarray study revealed up-regulation of FOSL1 mRNA in DFBs with 11q12 rearrangement. The aim of this study was to clarify the relationship between DFB and FTS. METHODS AND RESULTS: We tested 42 cases diagnosed originally as either DFBs or FTSs for interobserver concordance based on the existing histological criteria and correlated the diagnosis with FOSL1 immunohistochemistry. In addition, FOSL1 gene status was determined by chromogenic in-situ hybridization (CISH). Using joint histological evaluation, 41 of 42 tumours were classified unanimously by three pathologists into 25 DFBs and 16 FTSs, whereas only one case received discordant opinions. Immunohistochemically, all DFBs showed diffuse, strong FOSL1 nuclear immunoreactivity (25 of 25, 100%), while none of the FTSs showed such overexpression. None of the selected 42 DFB mimics overexpressed FOSL1. FOSL1 was not rearranged in seven DFBs tested by CISH. CONCLUSIONS: We confirm here that DFB and FTS are two distinct entities that can be distinguished using the existing histological criteria. This distinction corresponds perfectly with FOSL1 immunohistochemical expression status, and diffuse strong FOSL1 expression specific to DFBs sharpens the border between the two categories. FOSL1 overexpression in DFB may not be caused directly by FOSL1 gene rearrangement. FOSL1 may also be a diagnostic aid for differentiating DFB from other histological mimics.

Neoadjuvant and adjuvant chemotherapy with modified mesna, adriamycin, ifosfamide, and dacarbazine (MAID) regimen for adult high-grade non-small round cell soft tissue sarcomas.

BACKGROUND: Good local control of high-grade non-small round cell soft tissue sarcomas (NSRCSTSs) has been achieved with significant advances in surgical techniques and radiotherapy. However, the role of chemotherapy remains controversial. Our aim was to investigate the efficacy, feasibility and adverse effects of neoadjuvant and adjuvant chemotherapy with modified mesna, adriamycin, ifosfamide and dacarbazine (MAID) regimen for NSRCSTSs. METHODS: We conducted a retrospective review of 40 consecutive patients (29 men, 11 women; median age 47 years) with high-grade NSRCSTSs treated in two referral centers between 2004 and 2009 (median follow-up 38.5 months). Patients with distant or nodal metastases at diagnosis were excluded. The regimen consisted of ifosfamide 2,500 mg/m(2)/6 h (days 1-3), mesna 2,500 mg/m(2)/6 h (days 1-3), tetrahydropyranyl adriamycin 20 mg/m(2)/0.5 h (days 1-3), and dacarbazine 300 mg/m(2)/1 h (days 1-3). RESULTS: Among the 26 evaluable patients, there were 8 with a partial response, 15 with stable disease, and 3 with progressive disease. Two- and 5-year overall survival rates were 92 and 86%, respectively, and corresponding disease-free survival rates were 80 and 77%. All relapses were metastases without local recurrence. Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 38, 18, and 21 patients, respectively. No serious infectious complications occurred due to the administration of granulocyte colony-stimulating factor and prophylactic antibiotics. No other life-threatening serious adverse events were observed. CONCLUSION: The modified MAID regimen achieved a better outcome with less serious adverse events than previously reported and is a potential option in the management of NSRCSTSs. Further evaluation with long-term follow-up is required.