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.

Correlation Between Gait and Life Expectancy in Patients with Spinal Metastases.

BACKGROUND: Metastatic epidural spinal cord compression (MESCC) may lead to walking disability. The effect of regaining gait ability on the life expectancy of cancer patients is still unknown. To explore this issue, we evaluated the effect of gait ability recovery in nonambulatory patients after treatment for a metastatic spinal tumor. METHODS: In total, 105 patients who underwent surgery for MESCC between January 2006 and December 2016 and survived longer than 3 months were enrolled. All the patients were nonambulatory because of the MESCC and had undergone posterior decompression and fixation with intraoperative radiotherapy. At postoperative month 3, patients who had regained their gait ability were categorized as ambulatory and those who had not were categorized as nonambulatory. Age, sex, prognosis score (modified Bauer score), preoperative and postoperative Frankel grade scores, tumor origin site, Charlson comorbidity index, and survival time were compared between the groups. RESULTS: Seventy-two patients regained gait ability at postoperative month 3, and 33 patients did not. The modified Bauer score did not differ between the groups (P = 0.08); therefore, the presumptive life expectancy of the groups before treatment was not biased. The median survival time was significantly longer in the ambulatory group (610 days) than that in the nonambulatory group (181 days, P < 0.05). CONCLUSIONS: Patients who regained their gait ability after treatment for MESCC tended to live longer than those who did not, indicating that recovery of gait ability by patients with cancer is associated with improved life expectancy.

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.

Clinicopathologic Characterization of Epithelioid Hemangioendothelioma in a Series of 62 Cases: A Proposal of Risk Stratification and Identification of a Synaptophysin-positive Aggressive Subset.

Epithelioid hemangioendothelioma (EHE) is a rare vascular endothelial neoplasm with characteristic histology and distinctive fusion genes. Its clinical presentation and outcome are heterogeneous, and the determinants of survival are controversial. In this study, we aimed to identify clinicopathologic prognostic factors of EHE in a retrospective cohort of 62 cases with CAMTA1/TFE3/WWTR1 alterations. The tumors were of the CAMTA1 subtype for 59 cases, TFE3 subtype for 2 cases, and variant WWTR1 subtype (WWTR1-ACTL6A) for 1 case. Twenty-two tumors (35.5%) demonstrated atypical histology, defined by having at least 2 of the following 3 findings: high mitotic activity (>1/2 mm2), high nuclear grade, and coagulative necrosis. During a median follow-up of 34 months, 11 patients (18%) died, and the 5-year overall survival rate was 78.8%. Survival did not correlate with such clinical parameters as age, sex, tumor sites, multifocality, and multiorgan involvement. Conversely, based on both univariate and multivariate analyses, large tumor size (>30 mm) and histologic atypia were significantly associated with a shorter survival. A proposed 3-tiered risk assessment system using these 2 parameters significantly stratified the patients into low-risk, intermediate-risk, and high-risk groups with 5-year overall survival rates of 100%, 81.8%, and 16.9%, respectively (P<0.001). Four tumors (6.4%) expressed synaptophysin, which all belonged to the high-risk group and pursued an aggressive course. The present study demonstrated the independent prognostic significance of large tumor size and atypical histology in EHE, as well as the value of risk stratification using these 2 factors. Moreover, we revealed a small EHE subset with aberrant synaptophysin expression, which may have potential prognostic and diagnostic implications.

Comprehensive molecular and clinicopathological profiling of desmoid tumours.

Previous studies have not clearly identified a prognostic factor for desmoid tumours (DT). Whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) were performed in 64 cases of DT to investigate the molecular profiles in combination with the clinicopathological characteristics. CTNNB1 mutations with specific hotspots were identified in 56 cases (87.5%). A copy number loss in chromosome 6 (chr6) was identified in 14 cases (21.9%). Clustering based on the mRNA expression profiles was predictive of the patients' prognoses. The risk score generated by the expression of a three-gene set (IFI6, LGMN, and CKLF) was a strong prognostic marker for recurrence-free survival (RFS) in our cohort. In risk groups stratified by the expression of IFI6, the hazard ratio for recurrence-free survival in the high-risk group relative to the low-risk group was 12.12 (95% confidence interval: 1.56-94.2; p = 8.0 × 106). In conclusion, CTNNB1 mutations and a chr6 copy number loss are likely the causative mutations underlying the tumorigenesis of DT while the gene expression profiles may help to differentiate patients who would be good candidates for wait-and-see management and those who might benefit from additional systemic or radiation therapies.

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.

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.

Nuclear expression of MDM2 in hibernoma: a potential diagnostic pitfall.

Hibernoma is a rare benign adipocytic tumor composed of a proliferation of brown and white fat cells varying in their proportions. The tumor may also contain fat cells resembling lipoblasts, which makes it difficult to distinguish it from atypical lipomatous tumor/well differentiated liposarcoma (ALT/WDLS). Although nuclear expressions of murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) are widely used as immunohistochemical surrogate markers for ALT/WDLS, the utility of these proteins in distinguishing between hibernoma and ALT/WDLS still remains to be elucidated. We evaluated immunohistochemical expressions of MDM2 and CDK4 in 10 hibernomas expressing uncoupling protein-1 (UCP-1), a mitochondrial protein transporter consistently expressed in brown fat cells, and lacking MDM2 gene amplification, which was analyzed by fluorescence in situ hybridization (FISH). In contrast to the data previously obtained, nuclear expression of MDM2 was observed in 100% (10/10 cases) of the hibernomas irrespective of the proportion of brown fat cells, whereas no cases were positive for CDK4. The tumors also showed almost concurrent expression of p53 (in 9/10 cases) and ubiquitin-specific-processing protease 7 (USP7) (in 10/10 cases), which deubiquitinates and stabilizes MDM2, potentially resulting in its nuclear expression without MDM2 gene amplification. MDM2 expression may thus be a diagnostic pitfall for hibernoma particularly in differentiating it from ALT/WDLS.

Renal Angiomyolipoma Mimicking a Well-Differentiated Retroperitoneal Liposarcoma.

A 37-year-old Burmese woman presented with an incidentally found retroperitoneal fat-containing tumor. The tumor was 9 cm in the longest diameter, surrounding the right kidney, and composed of homogenous adipose tissue with thickened septum-like structures and spotty nonadipose structures, which were enhanced on contrast-enhanced computed tomography and magnetic resonance imaging. The tumor did not show either a beak sign or synchronous angiomyolipoma-like lesion in the kidneys. The tumor had irregular septa, thin blood vessels, and spotty small soft-tissue nodules. The tumor did not contain any heterogeneously enhanced solid lesions suspicious for dedifferentiated liposarcomas. Based on these imaging findings, a clinical diagnosis of a well-differentiated liposarcoma was made. Under the consensus of a multidisciplinary cancer board, she was recommended to undergo core-needle biopsy to confirm the clinical diagnosis. However, she declined to undergo biopsy for financial reasons. She underwent kidney-sparing retroperitoneal tumor resection. Histopathologically, the tumor was an angiomyolipoma with positive immunostaining for HMB45 and Melan A. The present case suggests the importance of core-needle biopsy prior to surgical intervention for retroperitoneal fat-containing tumors.

Standard Treatment Remains the Recommended Approach for Patients with Bone Sarcoma Who Underwent Unplanned Surgery: Report from the Japanese Musculoskeletal Oncology Group.

BACKGROUND: The outcomes of unplanned surgery for bone sarcomas have not been frequently discussed. However, it is important to recognize patterns, treatment, and clinical outcomes of unplanned surgeries for patients with bone sarcomas. This multicenter study aimed to characterize the clinical outcomes of patients with bone sarcomas who underwent unplanned surgeries. PATIENTS AND METHODS: Data of 43 patients with bone sarcomas who underwent unplanned surgery between 2006 and 2017 were obtained from 23 hospitals in Japan. These included 18 cases of osteosarcoma, 9 of Ewing sarcoma, 8 of chondrosarcoma, and 6 of undifferentiated pleomorphic sarcoma. The study included 28 men and 15 women, with a mean age of 46 years. The mean follow-up duration was 59 months. RESULTS: The main primary tumor sites were the femur (n = 19), spine (n = 6), pelvis (n = 5), tibia (n = 3), and humerus (n = 3). The primary diagnoses were benign bone tumor (n = 24), trauma (n = 7), bone metastasis (n = 5), osteomyelitis (n = 4), degeneration (n=2), and unknown (n = 1). As unplanned surgeries, curettage, with or without bone graft, was performed in 26 patients; internal fixation was performed in 7; spinal surgery in 5; arthroplasty in 4; and arthroscopy in one. Thirty-eight patients received additional standard treatments. Thirty-four of these patients underwent surgical tumor resections, including amputation (n = 10), and the remaining 4 received radiotherapy or carbon ion radiotherapy as additional standard treatments. The 5-year disease-specific survival (DSS) rates in patients with osteosarcoma, Ewing sarcoma, and chondrosarcoma were 65.5%, 58.3%, and 72.9%, respectively. Twelve (27.9%) patients developed local recurrences (LR); among the total 43 patients studied, the 5-year DSS rates were significantly worse for those who developed LR compared to those who did not (p = 0.03). The 5-year DSS rates in patients with and without LR were 44% and 73.8%, respectively. CONCLUSION: We recommend that patients who have undergone unplanned surgery be administered standard treatment, including the option of amputation because herein, LR was shown to be a risk factor for decreased DSS.

Prediction of pathological fracture in patients with lower limb bone metastasis using computed tomography imaging.

Lower limb pathological fractures caused by bone metastases can severely impair activities of daily living, so recognizing fracture risk is essential. Medial cortical involvement (MCI) in the proximal femur has been demonstrated to affect bone strength in biomechanical studies, but it has not been investigated in real patients. Between 2012 and 2019, 161 bone metastases with computed tomography (CT) images were retrospectively examined. Twenty-nine fractures were observed including 14 metastases with pathological fractures at the first examination, and prophylactic surgery was performed for 50 metastases. We extracted clinicopathological data using CT images, including patient's background, MCI in the proximal femur, site, size, circumferential cortical involvement (CCI), pain, and nature of metastasis. Cox proportional hazard regression analyses were performed, and we created integer scores for predicting fractures. We revealed that MCI, CCI, lytic dominant lesion, and pain were significant factors by univariate analyses. By multivariable analysis, MCI and each 25% CCI were significant and integer score 1 was assigned based on hazard ratio. The full score was four points, with MCI in the proximal femur (one point) and ≥ 75% CCI (three points). With integer score two, sensitivity was 88.9% and specificity was 81.2% for predicting fracture within 60 days. In conclusion, MCI and CCI examined by CT images were the risk factors for pathological fracture. CCI ≥ 50% is a widely known risk factor, but in addition, it may be better to consider surgery if MCI in the proximal femur is observed in metastasis with 25-50% CCI.

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.

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.

Incidence of Unrecognized Incidental Durotomy during Surgery for Malignant Spinal Tumor.

INTRODUCTION: Cerebral spinal fluid leak from durotomy is a well-known risk with spinal surgeries. The aim of this study is to identify the incidence of unrecognized incidental durotomy during posterior surgery for spinal metastases and its risk factors. METHODS: Participants comprised 75 patients who underwent posterior spine surgery for spinal metastases between January 2012 and December 2016. Cases with apparent durotomy noticed intraoperatively were excluded. Unrecognized durotomy was diagnosed as the presence of wide subcutaneous fluid retention on magnetic resonance imaging at least 3 months postoperatively. For comparison, 50 patients who underwent cervical laminoplasty due to cervical spondylotic myelopathy were examined using the same method. We also examined correlations between occurrence of durotomy and patient characteristics such as age, type of tumor, location of tumor (ventral or dorsal), extent of tumor, and history of radiotherapy before surgery. RESULTS: Unrecognized durotomy occurred in 21 cases of spinal metastasis (26.7%) and in 1 case of cervical spondylotic myelopathy (2%), representing a significant difference between groups. Age, type of tumor, location of tumor, extent of tumor, and history of radiotherapy before surgery did not correlate significantly with occurrence of durotomy. No local trouble was observed in durotomy cases, except in one case with subcutaneous local infection. CONCLUSIONS: The incidence of unrecognized incidental durotomy is significantly higher during surgery for spinal metastases than that during surgery for degenerative disease.

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.

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.