Prognosis Of Soft Tissue Sarcomas Research Articles

Early Lymph Node Metastasis May Predict Poor Prognosis in Soft Tissue Sarcoma.

Background Lymph node metastasis (LNM) is a relatively rare event in soft tissue sarcoma. An association between the timing of LNM detection and patient prognosis is presently unknown. Patients and Methods We retrospectively analyzed the clinicopathological features of 33 patients with LNM between 2001 and 2015. Analysis of the timing of LNM diagnosis was grouped according to patients presenting LNM in either <8 months (the median time from primary tumor diagnosis to LNM) or ≥8 months after primary tumor diagnosis. Results A relationship between the primary tumor size and the timing of the LNM was not significantly found (Rs = 0.0088, p=0.96). Sixteen patients had an LNM detection duration of <8 months, and 17 patients had a duration of ≥8 months. The 5-year survival for patients with an LNM detection duration of <8 months and ≥8 months was 19% and 71%, respectively (p=0.0016). There were 19 patients with pulmonary metastases. Among them, there were 13 patients with a duration of primary tumor diagnosis to LNM of <8 months and 6 with a duration of ≥8 months (p=0.01). Conclusion Early LNM (<8 months) may predict poor prognosis in soft tissue sarcoma.

The impact of antecedent primary malignancy in soft tissue sarcoma patients.

It is unclear whether antecedent primary malignancies (APMs) have any negative impact on the prognosis of soft tissue sarcoma (STS). We retrospectively reviewed STS patients with APMs (STS-APM) and compared their survival to those of STS only (STS-O). Twenty-one cases of STS-APM from 2008 to 2017 in our institution were analyzed. One hundred and seventy cases of STS-O at the same period were compared as a control group. Overall survival was estimated using Kaplan-Meier survival curves and prognostic factors were analyzed using logistic regression analyses and contingency table analyses. As the final status of STS-APM patients, 12 patients were in disease-free survival, 5 were alive with disease, 3 have died of disease, and 1 has died of another disease. There was no case that died of APM. The 5-year overall survival rates were 88% in STS-APM and 78% in STS-O, showing no statistical significant ( p = 0.65). The 5-year overall survival rates in each stage of STS-APM and STS-O were 100/100% in stage I, 100/85% in stage II, 86/72% in stage III, and the 3-year overall survival rates were 67/51% in stage IV, with no statistical significance. With regard to prognostic factor, histological grade of STS was the only significant factor. Although antecedent radiotherapy tended to show a high odds ratio, the association was not statistically significant. Antecedent chemotherapy did not show any estimated prognostic risk. Our study suggested that APM in STS patient would not be a negative prognostic factor.

Correlation of p16 and nm23-H1 expression levels with incidence and prognosis of soft tissue sarcoma.

The expression levels of p16 and nm23-H1 genes in soft tissue sarcoma (STS) were evaluated to investigate correlation of the expression levels with the incidence and prognosis of STS. Tumor tissues and para-carcinoma normal tissues were collected from 64 STS patients. The messenger ribonucleic acid (mRNA) expression levels of p16 and nm23-H1 in the tissues were detected via reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and the protein expression levels of p16 and nm23-H1 in tissues were detected using immunohistochemistry. Spearman's correlation analysis was used for the correlation between expression levels of p16 and nm23-H1 in STS tissues and the correlation between p16 and nm23-H1 mRNA and protein expression. Moreover, the correlation of p16 and nm23-H1 expression levels in tumor tissues with pathological parameters and prognosis of STS patients were analyzed combined with clinical data. Results of RT-qPCR showed that mRNA expression levels of p16 and nm23-H1 in tumor tissues of STS patients were significantly lower than those in para-carcinoma normal tissues (P<0.01). Results of immunohistochemistry showed that the positive expression rates of p16 and nm23-H1 in tumor tissues of STS patients (43.75 and 39.06% respectively) were significantly lower than those in para-carcinoma normal tissues (85.93 and 89.06% respectively). The expression of p16 and nm23-H1 mRNA was positively correlated with protein expression levels. There was a positive correlation between the expression levels of p16 and nm23-H1 in tumor tissues of STS patients. The negative expression of p16 in tumor tissues of STS patients correlated with tumor size, tumor metastasis and clinical staging, and the negative expression of nm23-H1 correlated with tumor metastasis and clinical staging. The overall 5-year survival rate of patients was 54.68%, and the prognosis of patients with positive expression levels of p16 and nm23-H1 was better. Univariate survival analyses revealed that p16 and nm23-H1 were influencing factors of the overall survival rate of STS patients. p16 and nm23-H1 expression in STS is low, and their expression levels are closely related to the pathological parameters and prognosis of STS patients, so they can serve as reference indexes for prognosis estimation of STS.

Co-expression Network Analysis Identifies Four Hub Genes Associated With Prognosis in Soft Tissue Sarcoma.

Background: Soft tissue sarcomas (STS) are heterogeneous tumors derived from mesenchymal cells that differentiate into soft tissues. The prognosis of patients who present with an STS is influenced by the regulation of a complex gene network.Methods: Weighted gene co-expression network analysis (WGCNA) was performed to identify gene modules associated with STS (Samples = 156).Results: Among the 11 modules identified, the black and blue modules were highly correlated with STS. However, using preservation analysis, the black module demonstrated low preservation, therefore the blue module was chosen as the module of interest. Furthermore, a total of 20 network hub genes were identified in the blue module, 12 of which were also hub nodes in the protein-protein interaction network of the module genes. Following additional verification, 4 of 12 genes (RRM2, BUB1B, CENPF, and KIF20A) demonstrated poorer overall survival and disease-free survival rate in the test datasets. In addition, gene set enrichment analysis (GSEA) demonstrated that samples with a high level of blue module eigengene (ME) were enriched in cell cycle and metabolism associated signaling pathways.Conclusion: In summary, co-expression network analysis identified four hub genes associated with prognosis for STS, which may diminish the prognosis by influencing cell cycle and metabolism associated signaling pathways.

LAG-3 expression on tumor-infiltrating T cells in soft tissue sarcoma correlates with poor survival.

ObjectiveTo elucidate the role and prognostic significance of lymphocyte activation-gene-3 (LAG-3) in soft tissue sarcoma (STS).MethodsThe expression of LAG-3 in patient and matched normal blood samples was analyzed by flow cytometry. The localization and prognostic values of LAG-3+ cells in 163 STS patients were analyzed by immunohistochemistry. In addition, the expression of tumor-infiltrating CD3+ T, CD4+ T, and CD8+ T cells and their role in the prognosis of STS were evaluated by immunohistochemistry. The effect of LAG-3 blockade was evaluated in an immunocompetent MCA205 fibrosarcoma mouse model. ResultsPeripheral CD8+ and CD4+ T cells from STS patients expressed higher levels of LAG-3 than those from healthy donors. LAG-3 expression in STS was significantly associated with a poor clinical outcome (P = 0.038 ) and was correlated with high pathological grade (P < 0.001), advanced tumor stage ( P = 0.016). Additionally, LAG-3 expression was highly correlated with CD8+ T-cell infiltration (r = 0.7034, P < 0.001). LAG-3 was expressed in murine tumor-infiltrating lymphocytes, and its blockade decreased tumor growth and enhanced secretion of interferon-gamma by CD8 + and CD4+ T cells. ConclusionsLAG-3 blockade may be a promising strategy to improve the effects of targeted therapy in STS.

Associations of clock genes polymorphisms with soft tissue sarcoma susceptibility and prognosis

BackgroundDysfunction of the circadian clock and polymorphisms of some circadian genes have been linked to cancer development and progression. We investigated the relationship between circadian genes germline variation and susceptibility or prognosis of patients with soft tissue sarcoma.Patients and methodsWe considered the 14 single nucleotide polymorphisms (SNPs) of 6 core circadian genes that have a minor allele frequency > 5% and that are known to be associated with cancer risk or prognosis. Genotyping was performed by q-PCR. Peripheral blood and clinic-pathological data were available for 162 patients with liposarcoma or leiomyosarcoma and 610 healthy donors. Associations between the selected clock genes polymorphisms and sarcoma susceptibility or prognosis were tested assuming 3 models of inheritance: additive, recessive and dominant. Subgroup analysis based on sarcoma histotype was performed under the additive genetic model. Multivariate logistic regression and multivariate Cox proportional hazard regression analyses were utilized to assess the association between SNPs with patient susceptibility and survival, respectively. Pathway variation analysis was conducted employing the Adaptive Rank Truncated Product method.ResultsSix out of the 14 analyzed SNPs were statistically significantly associated with susceptibility or prognosis of soft tissue sarcoma (P < 0.05). The present analysis suggested that carriers of the minor allele of the CLOCK polymorphism rs1801260 (C) or of PER2 rs934945 (T) had a reduced predisposition to sarcoma (26% and 35% respectively with the additive model) and liposarcoma (33% and 41% respectively). The minor allele (A) of NPAS2 rs895520 was associated with an increased predisposition to sarcoma of 33% and leiomyosarcoma of 44%. RORA rs339972 C allele was associated with a decreased predisposition to develop sarcoma assuming an additive model (29%) and leiomyosarcoma (36%). PER1 rs3027178 was associated with a reduced predisposition only in liposarcoma subgroup (32%). rs7602358 located upstream PER2 was significantly associated with liposarcoma survival (HR: 1.98; 95% CI 1.02–3.85; P = 0.04). Germline genetic variation in the circadian pathway was associated with the risk of developing soft tissue sarcoma (P = 0.035).ConclusionsGenetic variation of circadian genes appears to play a role in the determinism of patient susceptibility and prognosis. These findings prompt further studies to fully dissect the molecular mechanisms.

Class III β-Tubulin Overexpression Induces Chemoresistance to Eribulin in a Leiomyosarcoma Cell Line.

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.

The use of apatinib combined with chemotherapy in treating soft tissue sarcoma.

e23524 Background: Soft tissue sarcomas (STS) are rare and aggressive malignancies that develop from the mesenchymal tissue. Despite advances in treatment methods, the prognosis of STS is very poor. Targets therapy combined with chemotherapy is very popular in recent years. Apatinib, a small molecule vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, plays antiangiogenic and antitumor roles. Methods: Three patients of STS were treated with apatinib combined with chemotherapy from Feb. 2016 to Sep. 2016, as detailed in the Table. The dose of apatinib was 250mg/d. Chemotherapy regimen was ifosfamide combined with pirarubicin or gemcitabine combined with carboplatin/DDP. Next generation sequence (NGS) was used to test the gene change of tumor. Results: The characteristics of patients are shown in the Table, all patients show partial response to apatinib combined with chemotherapy. Moreover, the three patients have achieved progression-free survival of 14, 9 and 11 months, respectively, which were much better than previous reported (about 6 months). The main toxicities were tolerable. The gene test showed many genes change, which were members of tumor angiogenesis pathway, including AKT1, MAP2K2, KRAS and PIK3CA. Conclusions: The results of NGS showed that there were many tumor angiogenesis related genes change in STSs. Apatinib as VEGFR-2 TKI, combined with chemotherapy could prolong the PFS, improve the quality of life. Apatinib may provide an additional option for the treatment of STS. Characteristics Patient 1 Patient 2 Patient 3 Age, years 32 27 18 Sex Female Female Female Primary tumor position Left nose Right thigh Left cheek Pathologic type Fibromyxoid sarcoma Angiosarcoma Rhabdomyosarcoma Stage of treatment with apatinib Locally advanced Lung and brain metastasis Locally advanced Treatment line 1 Surgery Surgery Ifosfamide and pirarubicin + Apatinib Treatment line 2 Second surgery + chemotherapy Pazopanib Treatment line 3 Ifosfamide and pirarubicin + Apatinib Gemcitabine and carboplatin/DDP+Apatinib PFS of Apatinib 14 months 9 months 11 months

Combined Use of the Neutrophil-Lymphocyte and Platelet-Lymphocyte Ratios as a Prognostic Predictor in Patients with Operable Soft Tissue Sarcoma.

Background: Preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are associated with poor prognosis in soft tissue sarcoma (STS). The aim of the present study is to determine whether the combination of NLR and PLR (CNP) can better predict patient survival after resection for STS.Methods: We included 310 STS patients in this retrospective study. Preoperative CNP was calculated as follows: patients with both elevated NLR (>2.51) and PLR (>191.1) were given a score of 2; patients showing an increase in one or neither were allocated a score of 1 or 0, respectively.Results: Cut-off values of 2.51 and 191.1 were defined as elevated NLR and PLR, respectively. Elevated CNP was significantly associated with older age (P=0.034), larger tumor size (P=0.025), deeper tumor location (P=0.044), higher tumor grade (P=0.028), a more advanced stage according to the American Joint Committee on Cancer (AJCC) (P=0.005), shorter overall survival (OS) (P=0.000) and shorter disease-free survival (DFS) (P=0.000). Multivariate analysis indicated CNP but not NLR or PLR to be an independent prognostic factor for OS and DFS (P=0.000 and P=0.001, respectively).Conclusions: Preoperative CNP is associated with tumor progression and can be considered an independent marker of postoperative survival in patients with STS.

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

Background:Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well-documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial.Methods:Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1α, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan–Meier and Cox regression.Results:Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44–3.59, P<0.001). Hypoxia-inducible factor-1α and GLUT1 were not prognostic. Carbonic anhydrase IX remained prognostic in multivariable analysis.Conclusions:The VorteX-Biobank contains tissue with linked outcome data and is an important resource for research. This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker. However, overlap between single marker positivity was poor and future work will develop an STS hypoxia gene signature to account for tumour heterogeneity.

Fungation in soft tissue sarcomas is associated with poor survival.

Whilst much is known on the multiple variables associated with a poor prognosis in soft tissue sarcomas, little evidence exists on the impact of fungation at the time of presentation. The aim of this study was to assess the impact of fungation on overall and disease free survival in soft tissue sarcomas. The study comprised a retrospective review of all patients presenting with a soft tissue sarcoma between 1996 and 2014 managed at a single institution. Over the 18-year study period, 2661 patients were diagnosed with a STS. Eighty-six patients (3.2%) presented with a fungating tumour. The five year survival for all patients with a fungating sarcoma was 15.5% (95% confidence interval: 4.6-26.4), which compared to 65.6% (95% confidence interval 63.2-67.8%) (p=0.0001) for non-fungating tumours. The incidence of metastasis at presentation in the non-fungating tumour group was 11.3% of patients, compared to 20.0% in those with a fungating tumour (p=0.0113). Factors associated with a poor prognosis in the fungating group included size, grade and tumour-type, patient age, tumour depth, and metastases at presentation. As an independent risk factor, tumour fungation was associated with a poor prognosis when compared to non-fungating tumours. The rate of limb sacrifice as primary treatment was higher in the fungating group (23% versus 73%). In spite of this, the incidence of local recurrence was higher in the fungating group (20% versus 16.5%). Fungation is associated with a poor prognosis with a high incidence of metastases at presentation and a high rate of local recurrence. As an independent variable, fungation confers a poor prognosis when compared to non-fungation in soft tissue sarcomas.

Prognostic value of the C-reactive protein/Albumin Ratio (CAR) in patients with operable soft tissue sarcoma.

BackgroundThe preoperative C-reactive protein/Albumin ratio (CAR) is valuable for predicting the prognosis of patients with various types of cancers. The aim of the present study is to investigate the prognostic value of the preoperative CAR and compare it with other systemic inflammatory response markers in patients with soft tissue sarcoma (STS).MethodsThis retrospective study included 206 patients with STS. The optimal cutoff value of the CAR was determined by receiver operating characteristic (ROC) analysis. The impact of the CAR and other clinicopathological features on overall survival (OS) and disease-free survival (DFS) was evaluated using univariate and multivariate Cox regression analyses. Kaplan-Meier survival analyses were used to compare groups classified by the CAR. Additionally, the area under the receiver operating characteristic curve (AUC) was used to compare the predictive ability of the CAR, high-sensitivity modified Glasgow prognostic score (Hs-mGPS), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR).ResultsThe optimal cut-off value of the CAR was 0.1035 according to the ROC analysis. An increased CAR (≥0.1035) was significantly associated with older age, larger tumor size, deep tumor location, higher tumor grade and more advanced American Joint Committee on Cancer (AJCC) stage (all P<0.05). Patients with an elevated CAR (≥0.1035) exhibited a shorter median survival time and lower 5-year OS rate than those with a CAR<0.1035 (68.2 vs 115.8 months, P = 0.000; 44.6% vs 80.9%, P = 0.000, respectively). The results of a multivariate analysis indicated that the CAR (Hazard ratio (HR) 2.47, 95% confidence interval (CI) 1.47-4.14, P = 0.001) was an independent prognostic factor for OS along with tumor grade (P<0.05). Additionally, the CAR exhibited a greater AUC value (0.662) than the NLR and PLR, but the value was equal to the Hs-mGPS.ConclusionsThe preoperative CAR is an independent prognostic factor predicting prognosis in STS and exhibits superior prognostic ability compared to the established inflammation-based prognostic indices.

Improved prognosis in soft-tissue sarcoma of extremity and trunk wall

Background and purpose — Soft-tissue sarcoma (STS) is rare, with challenging individualized treatment, so diagnostics and treatment should be centralized. Historical controls are sometimes used for investigation of whether new diagnostic or therapeutic tools affect patient outcome. However, as yet unknown factors may affect the outcome. We investigated prognostic factors and prognosis in 2 nationwide cohorts of patients diagnosed with a local STS during the periods 1998–2001 and 2005–2010, with special interest in finding factors lying behind possible improvement of prognosis.Patients and methods — 2 cohorts of patients with STS of the extremities or trunk diagnosed during the periods 1998–2001 and 2005–2010 were retrieved from the nationwide Finnish Cancer Registry. Detailed information was gathered from patient files.Results — Compared to first cohort, a larger proportion of patients with inadequate surgery in the second cohort received radiation therapy, and both the local control rate and the sarcoma-specific survival rate improved in the second cohort. For sarcoma-specific survival, cohort (HR =0.6, 95% CI: 0.5–0.9), age, depth, grade, and margin were significant factors in multivariate analysis. For local control, cohort (HR =0.6, 95% CI: 0.5–0.9), age, and margin were significant in multivariate analysis.Interpretation — Known prognostic factors including type of treatment did not entirely explain the secular trend of continuous improvement in prognosis in STS. This illustrates the danger of using historical controls for investigation of whether new diagnostic or therapeutic tools have an effect on patient outcome.

Absence of progression, not extent of tumour shrinkage, defines prognosis in soft-tissue sarcoma – An analysis of the EORTC 62012 study of the EORTC STBSG

BackgroundAnthracycline-based chemotherapy remains the mainstay of first-line treatment in metastatic or advanced soft-tissue sarcoma (STS). Age, performance status, tumour histology and tumour grade are recognised prognostic factors; however, the prognostic value of tumour response and tumour shrinkage is ill-defined. MethodsPatients recruited to the European Organisation for Research and Treatment of Cancer 62012 trial with advanced intermediate or high-grade STS, who received at least one cycle of chemotherapy and one tumour assessment of response, were eligible for this study. Kaplan–Meier estimates of overall survival (OS) by tumour response were computed using a landmark approach after two, four, and six cycles of chemotherapy. The prognostic role of the kinetics of tumour response was analysed by Cox proportional hazards. ResultsThree hundred eighty-nine patients were included in this study. Compared to stable or responding patients, patients with progressive disease (PD) after two, four and six cycles of chemotherapy achieved a worse OS: hazard ratio [HR] 2.62 (95% confidence interval [CI] 1.72–4.00), p < 0.001; HR 2.23 (95% CI 1.4–3.56), p = 0.0001; and HR 3.16 (95% CI 1.96–5.08), p = 0.0001, respectively. However, patients with stable or responding disease achieved similar OS outcomes. Correspondingly, patients with an increase in tumour size by 10% or more correlated with a worse OS in Cox proportional hazard analysis. ConclusionsNo association between prognosis and amount of tumour shrinkage was detected. Interestingly, an increase in tumour size by at least 10% correlated with a worse OS, but re-defining PD as a ≥10% increase in tumour size did not translate into a better discrimination of survival outcomes for responders versus stable disease. Disease control rather than tumour response is a valuable end-point in advanced or metastatic STS receiving palliative anthracycline-based chemotherapy, supporting the use of time-to-event end-points in future STS trials.

Extremity soft tissue sarcoma with multiple primary malignancies – Characteristics and outcome

BackgroundUnderstanding the incidence and characteristics of multiple primary malignancies (MPM) has implications for guiding appropriate treatment and surveillance of extremity soft tissue sarcoma (STS). ObjectivesWe sought to examine the incidence of MPM in STS (MPM-STS), and compare their clinicopathologic characteristics and survival to those with STS only. Methods585 patients who underwent surgery for extremity STS were reviewed. Logistic regression analyses to identify factors contributing to the development of MPMs and a 1:2 matched case–control analysis to compare survival outcome were performed. ResultsOf the 585 patients analyzed, 34 (6%) with MPM were identified. On univariate logistic regression analysis, older age (>49 years) at STS diagnosis (p = 0.008) and histologic types of undifferentiated pleomorphic sarcoma or myxofibrosarcoma (p = 0.033) were significant. In multivariate analysis, only older age at STS diagnosis remained significant (OR = 2.5, p = 0.029). Cancer-specific survival of the MPM-STS group was significantly lower than that of the STS-only group (p = 0.031). However, there was no significant difference in STS-specific survival between the two groups (p = 0.208). ConclusionOur study suggests that MPM is not uncommon in extremity STS and older age at STS diagnosis is associated with risk of MPM. Prognosis of STS in the MPM-STS group seems similar to that of the STS-only group.

3401 Absence of progression, not extent of remission defines prognosis in soft tissue sarcoma - an analysis of the EORTC 62012 study

3401 Absence of progression, not extent of remission defines prognosis in soft tissue sarcoma - an analysis of the EORTC 62012 study

Association of Short Duration From Initial Symptoms to Specialist Consultation With Poor Survival in Soft-Tissue Sarcomas

The association of symptom duration with survival remains controversial in soft-tissue sarcoma (STS). We determined whether the length from initial symptoms to specialist consultation affects prognosis in STSs. We retrospectively reviewed 152 primary STS patients (with 142 non-small round cell sarcomas) who consulted our specialist hospital. The factors that affected the length of the period from the initial symptoms to specialist consultation and the length of the delay at the clinic before specialist hospital referral were investigated. The relation between the length of the period from symptom onset and overall survival was also analyzed. Unplanned excision and superficial tumor were significantly associated with increasing duration from the initial symptoms to specialist hospital referral. Multivariate analysis revealed that tumors over 5 cm (P=0.002 and 0.005) and symptoms within 6 months (P=0.017 and 0.016) were independent poor prognostic factors of overall survival among the pretreatment factors when analyzing all and non-small round cell STSs. This is a first report to show the independent prognostic role of symptom duration in STSs on multivariate analysis. Considering the impact of symptom duration on survival in these heterogenous tumors, careful follow-up and consideration of treatment are necessary for patients with short symptom duration.

Obesity does not affect survival outcomes in extremity soft tissue sarcoma.

Obesity is a growing epidemic and has been associated with an increased frequency of complications after various surgical procedures. Studies also have shown adipose tissue to promote a microenvironment favorable for tumor growth. Additionally, the relationship between obesity and prognosis of soft tissue sarcomas has yet to be evaluated. We sought to assess if (1) obesity affects survival outcomes (local recurrence, distant metastasis, and death attributable to disease) in patients with extremity soft tissue sarcomas; and (2) whether obesity affected wound healing and other surgical complications after treatment. A BMI of 30 kg/m(2) or greater was used to define obesity. Querying our prospective database between 2001 and 2008, we identified 397 patients for the study; 154 were obese and 243 were not obese. Mean followup was 4.5 years (SD, 3.1 years) in the obese group and 3.9 years (SD, 3.2 years) in the nonobese group; the group with a BMI of 30 kg/m(2) or greater had a higher proportion of patients with followups of at least 2 years compared with the group with a BMI less than 30 kg/m(2) (76% versus 62%). Outcomes, including local recurrence, distant metastasis, and overall survival, were analyzed after patients were stratified by BMI. Multivariable survival models were used to identify independent predictors of survival outcomes. Wilcoxon rank sum test was used to compare continuous variables. Based on the accrual interval of 8 years, the additional followup of 5 years after data collection, and the median survival time for the patients with a BMI less than 30 kg/m(2) of 3 years, we were able to detect true median survival times in the patients with a BMI of 30 kg/m(2) of 2.2 years or less with 80% power and type I error rate of 0.05. Patients who were obese had similar survival outcomes and wound complication rates when compared with their nonobese counterparts. Patients who were obese were more likely to have lower-grade tumors (31% versus 20%; p = 0.021) and additional comorbidities including diabetes mellitus (26% versus 7%; p < 0.001), hypertension (63% versus 38%; p < 0.001), and smoking (49% versus 37%; p = 0.027). Regression analysis confirmed that even after accounting for certain tumor characteristics and comorbidities, obesity did not serve as an independent risk factor in affecting survival outcomes. Although the prevalence of obesity continues to increase and lead to many negative health consequences, it does not appear to adversely affect survival, local recurrence, or wound complication rates for patients with extremity soft tissue sarcomas. Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.

High Expression of CD109 Antigen Regulates the Phenotype of Cancer Stem-Like Cells/Cancer-Initiating Cells in the Novel Epithelioid Sarcoma Cell Line ESX and Is Related to Poor Prognosis of Soft Tissue Sarcoma

Epithelioid sarcoma (ES) is a relatively rare, highly malignant soft tissue sarcoma. The mainstay of treatment is resection or amputation. Currently other therapeutic options available for this disease are limited. Therefore, a novel therapeutic option needs to be developed. In the present study, we established a new human ES cell line (ESX) and analyzed the characteristics of its cancer stem-like cells/cancer-initiating cells (CSCs/CICs) based on ALDH1 activity. We demonstrated that a subpopulation of ESX cells with high ALDH1 activity (ALDHhigh cells) correlated with enhanced clonogenic ability, sphere-formation ability, and invasiveness in vitro and showed higher tumorigenicity in vivo. Next, using gene expression profiling, we identified CD109, a GPI-anchored protein upregulated in the ALDHhigh cells. CD109 mRNA was highly expressed in various sarcoma cell lines, but weakly expressed in normal adult tissues. CD109-positive cells in ESX predominantly formed spheres in culture, whereas siCD109 reduced ALDH1 expression and inhibited the cell proliferation in vitro. Subsequently, we evaluated the expression of CD109 protein in 80 clinical specimens of soft tissue sarcoma. We found a strong correlation between CD109 protein expression and the prognosis (P = 0.009). In conclusion, CD109 might be a CSC/CIC marker in epithelioid sarcoma. Moreover, CD109 is a promising prognostic biomarker and a molecular target of cancer therapy for sarcomas including ES.

Tumor Infiltrating PD1-Positive Lymphocytes and the Expression of PD-L1 Predict Poor Prognosis of Soft Tissue Sarcomas

Recently, the possibility of PD1 pathway-targeted therapy has been extensively studied in various human malignant tumors. However, no previous study has investigated their potential application for soft-tissue sarcomas (STS). In this study, we evaluated the clinical impact of intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression in tumor cells in 105 cases of STS. Intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression were seen in 65% and 58% of STS, respectively. Both PD1-positivity and PD-L1 expression were significantly associated with advanced clinicopathological parameters such as higher clinical stage, presence of distant metastasis, higher histological grade, poor differentiation of tumor, and tumor necrosis. Moreover, both PD1-positivity and PD-L1 positivity were independent prognostic indicators of overall survival (OS) and event-free survival (EFS) of STS by multivariate analysis. In addition, the combined pattern of PD1- and PD-L1-positivity was also an independent prognostic indicator for OS and EFS by multivariate analysis. The patents with a PD1+/PD-L1+ pattern had the shortest survival time. In conclusion, this study is the first to demonstrate that the infiltration of PD1 positive lymphocytes and PD-L1 expression in STS cells could be used as novel prognostic indicators for STS. Moreover, the evaluation of PD1- and PD-L1-positivity in STS is also available as possible criteria for selection of patients suitable for PD1-based immunotherapy.