Activity of Cabazitaxel in Metastatic or Inoperable Locally Advanced Dedifferentiated Liposarcoma: A Phase 2 Study of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG).

Importance: Treatment options for patients with unresectable and/or metastatic dedifferentiated liposarcoma (DDLPS) are limited. New drugs are required. Objective: To assess whether cabazitaxel demonstrated sufficient antitumor activity in patients with metastatic or inoperable locally advanced DDLPS to justify further investigation in a phase 3 setting. Design, Setting, and Participants: This international multicenter, open-label single-arm phase 2 trial was conducted at 10 institutions in 4 European countries from March 2015 to March 2019. Eligible patients had to have metastatic or locally advanced histologically proven DDLPS with evidence of disease progression within the past 6 months and had to have received no more than 1 previous line of chemotherapy. Interventions: After mandatory central review of tumor blocks, if the DDLPS diagnosis was confirmed, patients started treatment within 72 hours after registration. Cabazitaxel was administered at a dose of 25 mg/m2 IV infusion over 1 hour every 21 days until intolerance, progression, or withdrawal of consent. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) rate at 12 weeks per RECIST 1.1. Based on a Simon 2-stage design, at least 4 of 17 (stage 1) and 11 of 37 (stage 2) eligible and evaluable patients who were progression free at 12 weeks were needed. The final analysis report was completed on November 17, 2021. Results: Forty patients were registered, with 2 patients being ineligible. The number of cycles ranged from 1 to 30, with a median of 5; 26 patients (65%) received at least 4 cycles of cabazitaxel. Progression-free survival at 12 weeks was 55%, achieving the primary study end point. At a median follow-up of 21.6 months, median PFS was 6 months and median OS 21 months. Response rate (RR) was 8% with 1 clinical response (CR) and 2 partial responses (PR). Twenty-three (60.5%) patients had a stable disease (SD). Disease control (PR+SD) was achieved in 26 patients (68%). Conclusions and Relevance: This nonrandomized phase 2 clinical trial met its primary end point, with 21 of 38 patients (55%) being progression free at 12 weeks. These results suggest important activity of cabazitaxel in patients with metastatic or inoperable locally advanced DDLPS. The drug is worth being further studied in these tumors in a phase 3 setting.

Nanoparticle albumin-bound paclitaxel and PD-1 inhibitor (sintilimab) combination therapy for soft tissue sarcoma: a retrospective study.

BACKGROUND: There is increasing evidence that combination therapy with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and programmed cell death protein 1 (PD-1) inhibitor is safe and efficacious in treating many types of malignant tumors. However, clinical data demonstrating the effect of this treatment combination for patients with metastatic soft tissue sarcoma (STS) are currently limited. METHODS: The clinical data of patients with metastatic STS who received nab-paclitaxel plus PD-1 inhibitor (sintilimab) therapy between January 2019 and February 2021 were retrospectively analyzed. The effectiveness and safety of the combined treatment were evaluated in terms of the median progression-free survival (PFS), estimated using the Kaplan-Meier method. The univariate Cox proportional hazards model was used to analyze the relationship between clinicopathological parameters and PFS. All statistical analyses were two-sided; P < 0.05 was considered statistically significant. RESULTS: A total of 28 patients treated with nab-paclitaxel plus sintilimab were enrolled in this study. The objective response rate was 25%, the disease control rate was 50%, and the median PFS was 2.25 months (95% CI = 1.8-3.0 months). The most common grade 1 or 2 adverse events (AEs) were alopecia (89.3%; 25/28), leukopenia (25.0%; 7/28), fatigue (21.4%; 6/28), anemia (21.4%; 6/28), and nausea (21.4%; 6/28). The most common grade 3 AEs were neutropenia (10.7%; 3/28) and peripheral neuropathy (10.7%; 3/28). No grade 4 AEs were observed. Among the present study cohort, patients with angiosarcoma (n = 5) had significantly longer PFS (P = 0.012) than patients with other pathological subtypes, including undifferentiated pleomorphic sarcoma (n = 7), epithelioid sarcoma (n = 5), fibrosarcoma (n = 4), synovial sarcoma (n = 3), leiomyosarcoma (n = 2), pleomorphic liposarcoma (n = 1), and rhabdomyosarcoma (n = 1); those who experienced three or more AEs had significantly longer median PFS than those who experienced less than three AEs (P = 0.018). CONCLUSION: Nab-paclitaxel plus PD-1 inhibitor is a promising treatment regimen for advanced STS. Randomized controlled clinical trials are required to further demonstrate its efficacy and optimal application scenario.

Standardization of evaluation method and prognostic significance of histological response to preoperative chemotherapy in high-grade non-round cell soft tissue sarcomas.

BACKGROUND: Preoperative chemotherapy is widely applied to high-grade localized soft tissue sarcomas (STSs); however, the prognostic significance of histological response to chemotherapy remains controversial. This study aimed to standardize evaluation method of histological response to chemotherapy with high agreement score among pathologists, and to establish a cut-off value closely related to prognosis. METHODS: Using data and specimens from the patients who had registered in the Japan Clinical Oncology Group study, JCOG0304, a phase II trial evaluating the efficacy of perioperative chemotherapy with doxorubicin (DOX) and ifosfamide (IFO), we evaluated histological response to preoperative chemotherapy at the central review board. RESULTS: A total of 64 patients were eligible for this study. The percentage of viable tumor area ranged from 0.1% to 97.0%, with median value of 35.7%. Regarding concordance proportion between pathologists, the weighted kappa coefficient (κ) score in all patients was 0.71, indicating that the established evaluation method achieved substantial agreement score. When the cut-off value of the percentage of the residual tumor area was set as 25%, the p-value for the difference in overall survival showed the minimum value. Hazard ratio of the non-responder with percentage of the residual tumor < 25%, to the responder was 4.029 (95% confidence interval 0.893-18.188, p = 0.070). CONCLUSION: The standardized evaluation method of pathological response to preoperative chemotherapy showed a substantial agreement in the weighted κ score. The evaluation method established here was useful for estimating of the prognosis in STS patients who were administered perioperative chemotherapy with DOX and IFO. TRIAL REGISTRATION: UMIN Clinical Trials Registry C000000096. Registered 30 August, 2005 (retrospectively registered).

Clinicopathologic and survival correlates of embryonal rhabdomyosarcoma driven by RAS/RAF mutations.

Embryonal rhabdomyosarcoma (ERMS) is the most common subtype of rhabdomyosarcoma (RMS). Among RMS subtypes, ERMS is associated with a favorable outcome with an overall survival of 70% at 5 years for localized disease. The molecular profile of ERMS is heterogeneous, including mostly point mutations in various genes. Therapeutic strategies have remained relatively consistent irrespective of the molecular abnormalities. In this study, we focus on a homogeneous RAS/RAF mutated ERMS subset and correlate with clinicopathologic findings. Twenty-six cases (16 males and 10 females) were identified from screening 98 ERMS, either by targeted DNA sequencing (MSK-IMPACT) or by Sanger sequencing. Fourteen (54%) cases had NRAS mutations, 6 (23%) had KRAS mutations, 5 (19%) had HRAS mutations, and 1 case (4%) had BRAF mutation. Median age at diagnosis was 8 years (range 1-70) with two-thirds occurring in the children. Tumor sites varied with H&N and GU sites accounting for 62% of cases. RAS isoform hot spot mutations predominated: NRAS p.Q61K (57%), KRAS p.G12D (67%), and HRAS (codons 12, 14, and 61). Additional genetic abnormalities were identified in 85% of the RAS-mutated cases. At last follow-up, 29% of patients died of disease and 23% were alive with disease. The 3-year and 5-year survival rates were 75% and 61% respectively. In conclusion, RAS mutations occur in 27% of ERMS, with NRAS mutations encompassing half of the cases. Overall RAS-mutant RMS does not correlate with age or site, but most tumors show an undifferentiated and spindle cell morphology.

Neoadjuvant radiation for cutaneous and soft tissue angiosarcoma.

BACKGROUND AND OBJECTIVES: Neoadjuvant radiation (NRT) is frequently utilized in soft tissue sarcomas to increase local control. Its utility in cutaneous and soft tissue angiosarcoma remains poorly defined. METHODS: This retrospective cohort study was performed using the National Cancer Database (2004-2016) evaluating patients with clinically localized, surgically resected angiosarcomas. Factors associated with receipt of NRT in the overall cohort and margin positivity in treatment naïve patients were identified by univariate and multivariable logistic regression analyses. Survival was assessed using Kaplan-Meier analysis. RESULTS: Of 597 patients, 27 (4.5%) received NRT. Increasing age (odds ratio [OR] 0.95, p = 0.025), tumor size more than or equal to 5 cm (OR 3.16, p = 0.02), and extremity tumor location (OR 3.99, p = 0.04) were associated with receipt of NRT. All patients who received NRT achieved an R0 resection (p = 0.03) compared with 17.9% of patients without NRT. Factors associated with risk of margin positivity included tumor size more than or equal to 5 cm (OR 1.85, p = 0.01), and head/neck location (OR 2.24, p = 0.006). NRT was not significantly associated with improved survival (p = 0.21). CONCLUSIONS: NRT improves rates of R0 resection but is infrequently utilized in cutaneous and soft tissue angiosarcoma. Increased usage of NRT, particularly for patients with lesions more than or equal to 5 cm, or head and neck location, may help achieve complete resections.

A comparison of clinical outcomes between additional excision after unplanned and planned excisions in patients with soft-tissue sarcoma of the limb : a propensity matching cohort study.

AIMS: Patients with soft-tissue sarcoma (STS) who undergo unplanned excision (UE) are reported to have worse outcomes than those who undergo planned excision (PE). However, others have reported that patients who undergo UE may have similar or improved outcomes. These discrepancies are likely to be due to differences in characteristics between the two groups of patients. The aim of the study is to compare patients who underwent UE and PE using propensity score matching, by analyzing data from the Japanese Bone and Soft Tissue Tumor (BSTT) registry. METHODS: Data from 2006 to 2016 was obtained from the BSTT registry. Only patients with STS of the limb were included in the study. Patients with distant metastasis at the initial presentation and patients with dermatofibrosarcoma protuberans and well-differentiated liposarcoma were excluded from the study. RESULTS: A total of 4,483 patients with STS of the limb were identified before propensity score matching. There were 355 patients who underwent UE and 4,128 patients who underwent PE. The five-year disease-specific survival (DSS) rate was significantly better in the patients who received additional excision after UE than in those who underwent PE. There was no significant difference in local recurrence-free survival (LRFS) between the two groups. After propensity score matching, a new cohort of 355 patients was created for both PE and UE groups, in which baseline covariates were appropriately balanced. Reconstruction after tumour excision was frequently performed in patients who underwent additional excision after UE. There were no significant differences in DSS and LRFS between the patients who underwent PE and those who had an additional excision after UE. CONCLUSION: Using propensity score matching, patients with STS of the limb who underwent additional excision after UE did not experience higher mortality and local failure than those who underwent PE. Reconstruction may be necessary when additional excision is performed. Cite this article: Bone Joint J 2021;103-B(12):1809-1814.

Brain Metastasis in Soft Tissue Sarcoma at Initial Presentation.

BACKGROUND/AIM: Brain metastasis is a rare condition among patients with soft tissue sarcoma (STS), and its precise incidence remains unclear. The aim of this study was to investigate which patients should be screened for brain metastasis. PATIENTS AND METHODS: We identified all patients with STS diagnosed between 2010 and 2015 in the SEER database. Incidence of brain metastasis at initial presentation and higher incidence of brain metastasis by histological subtype were investigated. In addition, risk factors for brain metastasis were examined. RESULTS: A total of 26,676 patients were included for analysis, of whom 162 patients (0.6%) had brain metastasis. Alveolar soft part sarcoma (6.3%), malignant hemangioendothelioma (3.1%) and malignant schwannoma (2.6%) showed higher incidence of brain metastasis. Deep-rooted tumor, trunk tumor, and histological high-grade tumor tended to show higher incidence of brain metastasis. CONCLUSION: Risk factors for brain metastasis were deep location, trunk development and histologically high-grade tumor, or specific histological subtypes.

Resection Status Does Not Impact Recurrence in Well-Differentiated Liposarcoma of the Extremity.

BACKGROUND: Well-differentiated liposarcoma (WDLPS) is a low-grade soft tissue sarcoma with a propensity for local recurrence. The necessity of obtaining microscopically free surgical margins (R0) to minimize local recurrence is not clear. This study evaluates recurrence-free survival (RFS) of extremity WDLPS in relation to resection margin status. METHODS: A retrospective review of adult patients with primary extremity WDLPS at seven US institutions from 2000 to 2016 was performed. Patients with recurrent tumors or incomplete resection (R2) were excluded. Clinicopathologic factors were analyzed to assess impact on local RFS. RESULTS: 97 patients with primary extremity WDLPS were identified. The majority of patients had deep, lower extremity tumors. Mean tumor size was 18.2±8.9cm. Patients were treated with either radical (76.3%) or excisional (23.7%) resections; 64% had R0 and 36% had microscopically positive (R1) resection margins. Ten patients received radiation therapy with no difference in receipt of radiation between R0 vs R1 groups. Thirteen patients (13%) developed a local recurrence with no difference in RFS between R0 vs R1 resection. Five-year RFS was 59.5% for R0 vs 85.2% for R1. Only one patient died of disease after developing dedifferentiation and distant metastasis despite originally having an R0 resection. DISCUSSION: In this large multi-institutional study of surgical resection of extremity WDLPS, microscopically positive margins were not associated with an increased risk of recurrence. Positive microscopic margin resection for extremity WDLPS may yield similar rates of local control while avoiding a radical approach to obtain microscopically negative margins.

The effect of adjuvant chemotherapy on the survival of patients with high-risk soft tissue sarcomas: Single center experience.

PURPOSE: To evaluate the effect of adding adjuvant ifosfamide/doxorubicin combination chemotherapy (CTX) to adjuvant radiotherapy (RT) on the survival in patients with surgically treated high-risk soft tissue sarcomas (STSs). METHODS: The study included 69 patients (group A) receiving adjuvant RT and 74 patients (group B) receiving adjuvant CTX after adjuvant RT. RESULTS: The median relapse-free survival (RFS) was 18.2 months (95% CI, 11.9-43.4) in group A and 27.2 months (95% CI, 17.6-36.8) in group B (p = 0.004). The median overall survival (OS) was 45.6 months (95% CI, 26.4-64.8) in group A and 110.1 mo (95% CI, 44.3-175.8) in group B (p = 0.007). Receiving adjuvant CTX was an independent predictive factor for both RFS [HR: 0.482, (0.307-0.757), p = 0.002) and OS (HR: 0.549, [0.348-0.867], p = 0.010). CONCLUSION: There are conflicting literature data regarding the survival benefit of adjuvant CTX for surgically treated STSs. However, appropriate patient selection may provide a significant survival benefit in RFS and OS with CTX in the adjuvant treatment of high-risk STSs.

Reirradiation in Conservative Salvage of Recurrent Soft-tissue Sarcoma: An Analysis of Treatment Efficacy and Toxicities.

OBJECTIVE: Compared with radical resection alone, perioperative radiation therapy (RT) combined with neurovascular preserving surgery is the standard for the management of virgin soft-tissue sarcomas. Yet, the optimal management of a local recurrence remains unclear. We report outcomes of patients with locally recurrent soft-tissue sarcoma treated with resection and reirradiation at the University of Florida. MATERIALS AND METHODS: We reviewed the records of patients treated with primary conservative surgery and radiation for soft-tissue sarcoma followed by salvage resection and reirradiation for a local recurrence at our institution. RESULTS: We analyzed 23 patients treated between 1976 and 2014 (median follow-up, 46 mo). Tumor sites included: proximal extremity, 11 patients; trunk, 6; distal extremity, 5; and head and neck, 1. All patients had conservative gross total resection of their recurrent tumor, without amputation. For reirradiation, 16 patients received external-beam RT alone, 6 received external-beam RT and brachytherapy, and 1 received brachytherapy alone. Two patients received chemotherapy. After retreatment, the 5-year overall survival, cause-specific survival, local control, and distant control rates were 39%, 42%, 46%, and 60%, respectively. Ten patients experienced local recurrences, 1 experienced regional recurrence, and 9 developed distant metastases. Retreatment-related complications ranged from delayed wound healing to limb amputation; 8 patients required amputation. Only 3 patients remained disease-free at last follow-up. No statistically significant associations were found between treatment factors (eg, RT dose) and local control. CONCLUSIONS: Achieving local control of recurrent soft-tissue sarcoma is challenging. Treatment with reoperation and reirradiation can lead to debilitating complications affecting function and quality of life.

Factors affecting prognosis and treatment strategies in metastatic soft tissue sarcomas: twenty years of experience.

OBJECTIVE: In this study, we aimed to reveal the general clinicopathological features, treatment features, and factors that could predict overall survival in metastatic soft tissue sarcomas, a very rare and heterogeneous disease group. PATIENTS AND METHODS: This study was a retrospective cohort study. Patients monitored with metastatic soft tissue sarcoma between January 2001 and January 2021 were evaluated retrospectively. Patients aged 18 years and over, histopathologically diagnosed with metastatic STS, and unsuitable for operations, such as local curative surgery or metastasectomy, were included in the study. RESULTS: A total of 179 patients in the metastatic stage and monitored in our center were included in the study. The median follow-up period was 8.4 months (IQR, 3.4-14.4). 58 (32.4%) patients were de-novo metastatic, and 121 (67.6%) patients developed metastasis later. The median age was 53.2 (Range: 18.8-87.6 years), and 101 (56.4%) patients were male. The most common primary location was the lower extremity (87) (48.6%). The most common histological subtypes were synovial sarcoma (38) (21.2%), pleomorphic sarcoma (37) (20.7%), and liposarcoma (26) (14.5%). The majority were grade 3 tumors (n=131, 73.2%). Having ECOG PS 2-3 (HR=2.829, 95% CI 1,667-4.800, p<0.001), having tumor grade as 3 (HR=1.748, 95% CI 1.150-2.656, p<0.009), receiving palliative chemotherapy (HR=0.294, 95% CI 0.144-0.600, p<0.001), and receiving two or more lines of chemotherapy among those palliative receivers (HR=2.505 95% CI 1.696-3.700, p<0.001) were independent predictive factors of mortality. CONCLUSIONS: Survival in metastatic soft tissue sarcoma is better in patients with good ECOG performance status, low tumor grades, and who have received palliative chemotherapy. Receiving more than one line of palliative systemic treatment for progressive disease improves survival.

CHIR99021, trough GSK-3ß Targeting, Reduces Epithelioid Sarcoma Cell Proliferation by Activating Mitotic Catastrophe and Autophagy.

Epithelioid sarcoma (ES) is a rare disease representing <1% of soft tissue sarcomas. Current therapies are based on anthracycline alone or in combination with ifosfamide or other cytotoxic drugs. ES is still characterized by a poor prognosis with high rates of recurrence. Indeed, for years, ES survival rates have remained stagnant, suggesting that conventional treatments should be revised and improved. New therapeutic approaches are focused to target the key regulators of signaling pathways, the causative markers of tumor pathophysiology. To this end, we selected, among the drugs to which an ES cell line is highly sensitive, those that target signaling pathways known to be dysregulated in ES. In particular, we found a key role for GSK-3ß, which results in up-regulation in tumor versus normal tissue samples and associated to poor prognosis in sarcoma patients. Following this evidence, we evaluated CHIR99021, a GSK-3 inhibitor, as a potential drug for use in ES therapy. Our data highlight that, in ES cells, CHIR99021 induces cell cycle arrest, mitotic catastrophe (MC) and autophagic response, resulting in reduced cell proliferation. Our results support the potential efficacy of CHIR99021 in ES treatment and encourage further preclinical and clinical studies.

Regional variation in the survival of patients with a soft-tissue sarcoma of the extremity and trunk wall under a centralized care system : what has been the impact of national policies in the UK?

AIMS: While a centralized system for the care of patients with a sarcoma has been advocated for decades, regional variations in survival remain unclear. The aim of this study was to investigate regional variations in survival and the impact of national policies in patients with a soft-tissue sarcoma (STS) in the UK. METHODS: The study included 1,775 patients with a STS who were referred to a tertiary sarcoma centre. The geographical variations in survival were evaluated according to the periods before and after the issue of guidance by the National Institute for Health and Care Excellence (NICE) in 2006 and the relevant evolution of regional management. RESULTS: There had been a significant difference in survival between patients referred from the North East, North West, East Midlands, West Midlands, South West, and Wales in the pre-NICE era (five-year disease-specific survival (DSS); South West, 74% vs North East, 47% (p = 0.045) or West Midlands, 54% (p = 0.049)), which was most evident for patients with a high-grade STS. However, this variation disappeared in the post-NICE era, in which the overall DSS for high-grade STS improved from 47% to 68% at five years (p < 0.001). Variation in the size of the tumour closely correlated with the variation in DSS, and the overall size of the tumour and incidence of metastasis at the time of diagnosis also decreased after the national policies were issued. CONCLUSION: The survival of patients with a STS improved and regional variation corrected after the introduction of national policies, as a result of a decreasing size of tumour and incidence of metastasis at the time of diagnosis, particularly in patients with a high-grade STS. This highlights the positive impact of national guidelines on regional variation in the presentation, management, and outcome in patients with a STS. Cite this article: Bone Joint J 2021;103-B(9):1541-1549.

Preoperative versus Post-operative Radiotherapy for Extremity Soft tissue Sarcoma: a Systematic Review and Meta-analysis of Long-term Survival.

BACKGROUND: The role of perioperative radiotherapy in the management of resectable extremity soft tissue sarcoma (ESTS) is widely recognised for local tumour control, wound complications (WC) and long-term function. However, debate continues regarding its implications on long-term survival. This study aimed to determine whether the timing of perioperative radiotherapy affects long-term survival outcomes in adults with ESTS. METHODS: A systematic literature search of MEDLINE, EMBASE, Web of Science and Cochrane was performed. The primary outcome measure was the pooled hazard ratio (HR) at 95% confidence intervals. Secondary outcomes and subgroup analyses were presented as cumulative odds ratios (OR). A random-effects, generic inverse variance method and sensitivity analysis were performed to minimise heterogeneity. RESULTS: Six studies (n = 4192 patients) were identified. Time-to-event analysis demonstrated a statistically significant advantage in post-operative radiotherapy for overall survival (HR 1.15 and p = 0.05). Combined HRs for disease-free (1.25 and p = 0.22) and disease-specific (1.06 and p = 0.43) survival also favoured post-operative radiotherapy but did not achieve statistical significance. Post-operative radiotherapy was shown to confer an overall (OR 1.19 and p = 0.01), disease-free (OR 1.19 and p = 0.01) and disease-specific (OR 1.19 and p = 0.01) survival advantage on subgroup analysis. This survival benefit was best observed at three years in the disease-free survival comparison (OR 1.55 and p = 0.003). Preoperative radiotherapy was associated with more WC (OR 2.74 and p<0.00001). CONCLUSIONS: Pooled analysis of published literature suggests that post-operative radiotherapy confers a significant long-term survival advantage with fewer WC. Further large multicentre randomised controlled trials with long-term follow-up are required to determine the optimal perioperative radiotherapy regime in adult ESTS.

Analysis of clinical factors associated with survival in patients with soft-tissue sarcoma receiving trabectedin.

Soft-tissue sarcomas (STSs) are a heterogeneous group of rare malignancies. Treatment for advanced STS usually starts with anthracycline-based therapies, with no clear sequence for further treatment. A preferred option is trabectedin, especially for liposarcoma and leiomyosarcoma (L-sarcoma). However, due to severe side effects and few clinical trials, further research of the parameters affecting survival is necessary for the optimal selection of patients. We retrospectively analyzed 73 consecutive patients with STS treated with trabectedin at the University Hospital Centers at Zagreb and Osijek from 2014 to 2021. Our primary goals were evaluating factors affecting progression-free survival (PFS) and overall survival (OS). The median PFS and OS for trabectedin were 3.6 months and 13.7 months, respectively. Patients with L-sarcoma exhibited longer PFS and a trend towards longer OS compared to those with non-L-sarcoma. However, these effects were primarily a result of the myxoid liposarcoma subtype, which exhibited a median PFS of 21.1 months and a median OS of 33.3 months, both significantly longer compared to non-myxoid L-sarcoma. Additionally, patients with three or more sites of metastases exhibited shorter median PFS (3.1 months vs. 3.6 months) and OS (5.7 months vs. 23.8 months) compared to only one metastatic site. There was no correlation between the PFS values of trabectedin and pazopanib and no difference in survival, regardless of the treatment sequence. Trabectedin treatment yields the greatest survival benefit in patients with myxoid liposarcoma and low metastatic burden, whereas the additional use of pazopanib provides further clinical benefit, regardless of treatment sequence.

Poor Efficacy of Postoperative Radiotherapy in Infiltrative High-grade Soft Tissue Sarcomas.

BACKGROUND/AIM: We aimed to investigate the effectiveness of postoperative radiotherapy (RT) on local recurrence-free survival (LRFS) in high-grade infiltrative soft tissue sarcomas (STSs) and determine its prognostic factors. PATIENTS AND METHODS: This was a retrospective cohort study and included 132 patients with high-grade STSs. Patients were divided into two groups: Group RT (n=48) who underwent postoperative RT and Group No-RT (n=84) who underwent only surgery. We analysed 5-year LRFS and its prognostic factors between these groups. Furthermore, 5-year LRFS in infiltrative and non-infiltrative STSs were evaluated. RESULTS: Five-year LRFS was not significantly different in Group RT (83.6%) and Group No-RT (79.6%) (p=0.698). Overall, significant prognostic factors influencing LRFS were age at diagnosis (p=0.02) and tumour growth pattern (p=0.04). Postoperative RT was less effective in the infiltrative than in non-infiltrative pattern of STSs. CONCLUSION: Postoperative RT does not influence local recurrence outcomes in infiltrative STSs.

Immunohistochemical expression of cyclin-dependent kinase inhibitors p16 and p57 in rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a highly malignant cancer and is the most common soft tissue sarcoma in children and adolescents, but it is rare in adults (<1% of all adult malignancies). Altered expression and molecular abnormalities of cell-cycle-regulatory proteins are one of the most prominent features in RMS. Therefore, we evaluated the expression of cyclin-dependent kinase inhibitors p57 and p16, as well as p16 methylation status, along with clinicopathological characteristics and overall survival (OS) in RMS patients. This analysis was conducted on 23 pediatric and 44 adult patients. There was a male predominance in both groups and extremities were the most frequent tumor site. In adults, alveolar and pleomorphic types were almost equally represented. The majority of pediatric tumors were low grade, whereas, in adults, only one patient had a low-grade tumor. Seven pediatric (30.43%) and eight adult (18.18%) patients had a low p16 expression. The analysis of methylation status of the p16 promoter showed the presence of methylated allele only in one sample with pleomorphic histology. Six (26.1%) pediatric and 15 (34.1%) adult patients had low p57 expression, while in 17 (73.9%) pediatric and 29 (65.9%) adult patients it was assessed as high. Ninetyone percent of the pediatric patients and 32.6% of adults were alive at the end of the observational period. In adults, significant associations were found between OS and age (P = 0.020), gender (P = 0.027), tumor size (P < 0.001), lymph node status (P < 0.001), presence of metastases (P = 0.015), and p57 expression (P = 0.039). Stratification by histological type showed the correlation of low p57 expression (P = 0.030) and worse OS of patients with alveolar RMS. Univariate analysis identified age > 50 yrs. (HR 2.447), tumors > 5 cm (HR 21.31), involvement of regional lymph nodes (HR 3.96), the presence of metastases (HR 2.53), and low p57 expression (HR 2.11) as predictors of lower OS. Tumor size, regional lymph nodes involvement, and metastases were the independent predictors after multivariate analysis, while p57 did not predict OS in an independent way. In summary, although p57 was not confirmed to be an independent predictor of OS, our results indicate that its low expression may be the marker of aggressive phenotype and poor prognosis in adult RMS patients. Also, our findings suggest that epigenetic inactivation of p16 is not important in the pathogenesis of rhabdomyosarcoma.

Greater travel distance to specialized facilities is associated with higher survival for patients with soft-tissue sarcoma: US nationwide patterns.

PURPOSE: The survival impact of geographic access to specialized care remains unknown in patients with soft-tissue sarcomas (STS). This study aimed to clarify the association between the patient travel distance and survival outcome and investigate the factors lying behind it. METHODS: A total of 34 528 patients with STS registered in the National Cancer Data Base, diagnosed from 2004-2016, were investigated. RESULTS: Tumor stage correlated with travel distance: patients with metastatic disease stayed closer to home. However, the type of facility showed greatest variation: 37.0%, 51.0%, 73.5%, and 75.9% of patients with ≤10 miles, 10.1-50 miles, 50.1-100 miles, and >100 miles, respectively (P<0.001), had a sarcoma care at academic/research centers. On a multivariable analysis, reduced mortality risk was associated with longer (versus short) travel distance (>100 miles: HR = 0.877; P = 0.001) and management at academic/research (versus non-academic/research) centers (HR = 0.857; P<0.001). The greatest divergence was seen in patients traveling very long distance (>100 miles) to an academic/research center, with a 26.9% survival benefit (HR = 0.731; P<0.001), compared with those traveling short distance (≤10 miles; 95.4% living in metropolitan area) to a non-academic/research center. There was no significant correlation between travel distance and survival in patients who had care at academic/research centers, whereas a survival benefit of management at academic/research centers was observed in every group of travel distance, regardless of tumor stage. CONCLUSIONS: This national study demonstrated that increased travel distance was associated with superior survival, attributable to a higher proportion of patients receiving sarcoma care at distant academic/research centers. These data support centralized care for STS. Overcoming referral and travel barriers may enable more patients to be treated at specialized centers and may further improve survival rates for patients with STS, even when it imposes an increased travel burden.

Clinical and immunological characteristics of sarcomas patients with clonogenic tumors.

Tumorigenesis is related to the generation of heterogeneous tumor cell population, which is the result of genetic and epigenetic alterations followed by clonal selections and subsequent expansion. In basic studies genetic, histological and morphological diversity of different clones within a patient's neoplasm and specifics of their interrelation with patient's immune system are investigated mostly on the models of tumors of epithelial origin. Mesenchymal tumors such as soft tissue and bone-derived sarcomas (STBS) have been poorly studied in this regard. The molecular genetic methods used to examine intratumoral heterogeneity do not currently provide insight into which portion of the identified subclones are able to grow autonomously. Limiting dilution cloning demonstrates the existence of self-regulating tumor cells in the population and can serve as an independent prognostic predictor of poor prognosis. Intratumoral heterogeneity results not only in differences in growth dynamics, gene expression, and phenotypic markers, but also in the resistance to treatment, especially immunotherapy, thus causing tumor eluding immune escape. The changes that accompany this process can be affected by the cellular immune system, resulting in an imbalance between populations. The variations in the population composition of immune system cells are now widely debated as a predictor of response to immunotherapy, which is of obvious interest for sarcomas, where the effectiveness of chemotherapy is low and the prognosis is unfavorable, especially in case of metastatic disease development. The search for new predictive markers of disease prognosis and treatment efficacy is an important task, to which this study is focused. Our results demonstrate that clonogenic tumor characteristics such as clonogenic potential is independent predictor of unfavorable prognosis in cases of cancer and correlate with the clinical characteristics of the tumor such as overall survival (OS) and progression free survival (PFS). It was found that patients with clonogenic sarcomas had a lower content of activated cytotoxic T-lymphocytes (CTL) with the CD3+CD8+HLA-DR+ phenotype and an increased number of natural NK killers (p < 0.05) compared to nonclonogenic tumors. In addition, according to our data, a high neutrophil to lymphocyte ratio (NLR), a low value of major T-lymphocyte populations, and a higher number of natural killer cells (NK) in the blood can be negative prognostic factors for the immunotherapy of this disease.

Management Strategies for Patients With Epithelioid Hemangioendothelioma: Charting an Indolent Disease Course.

BACKGROUND: Epithelioid hemangioendothelioma (EHE) is a malignant vascular neoplasm representing ∼1% of sarcomas. Due to its rarity, its clinical course is not well characterized and optimal treatment remains unknown. MATERIALS AND METHODS: This was a retrospective review of patients with EHE treated at Stanford University between 1998 and 2020. Demographic characteristics, pathology results, treatment modalities, and clinical outcomes were collected from the electronic medical records. RESULTS: A total of 58 patients had a mean age of 50.6 years and a slight female predominance (52%). Primary disease sites were liver (33%), soft tissue (29%), lung (14%), bone (9%), and mediastinum (9%). A majority (55%) had advanced or metastatic disease. Median overall survival (OS) was 16.9 years, with OS 89% at 1 year, 68% at 5 years, and 64% at 10 years. The longest median OS was associated with soft tissue sites and shortest with lung and mediastinal disease (P=0.03). The localized disease had improved median OS compared with metastatic disease (P=0.02). There was no OS difference between tumors >3 cm and those equal or smaller (P=0.85). Surgery was a common treatment (71%), while radiation and ablation were sometimes used (28% and 9%, respectively). The median time to initiating therapy of any kind was 68 days. The median time to systemic therapy was 114 days. CONCLUSIONS: We report on the clinical characteristics and outcomes of patients with EHE at a large academic center. Treatment options included surgical excision, liver transplant, ablation, radiation, and systemic therapy. A subset of patients had indolent disease not requiring treatment upfront.