Nonmetastatic Soft Tissue Sarcoma Research Articles

Neoadjuvant treatment with camrelizumab in combination with doxorubicin and ifosfamide: A phase II clinical study of high-risk soft tissue sarcoma.

e23548 Background: Surgery remains the cornerstone in the management of non-metastatic soft tissue sarcomas. However, high rate of recurrence and metastasis are not uncommon in patients(pts) with high-risk soft tissue sarcoma. Although doxorubicin plus ifosfamide resulted in better tumor shrinkage which facilitate surgical resection, approaches of reducing recurrence and metastasis are still needed. Chemotherapy combined with PD-1 antibodies showed promising activity in several tumors. To date, there is no study to evaluate the efficacy and safety of camrelizumab combined with chemotherapy for high-risk Soft Tissue Sarcoma. Methods: This is a phase II, open-label single-arm study (NCT04606108), aimed to include pts aged 14-65 with histopathologically confirmed high risk soft tissue sarcoma and ECOG 0-1, at least one measurable lesion. One course of treatment every three weeks (camrelizumab 200 mg on day 1, doxorubicin 37.5 mg/m2 or liposomal doxorubicin 25 mg/m2 on days 1-2, and ifosfamide 3 g/m2 on days 1-3). After completing the 2nd course of chemotherapy, the drug will be stopped for 14 days, and surgery or the next stage of treatment will be carried out according to the efficacy of the treatment. Six courses of preoperative chemotherapy will be administered 2 weeks ± 5 days after surgery based on the effectiveness, followed by radiotherapy (50 Gy in 25 fractions or 60 Gy in 30 fractions.) within 3 months after surgery. The primary objective is the Objective response rate (ORR). Using the Simon minimax 2 stage design, planned sample size is 62 pts with 80% power and alpha of 5% to detect an increase in ORR from 27% to 42%. Interim analysis requiring at least 9 confirmed responses in the first 30 pts to proceed to full accrual. Results: 35 pts completed neoadjuvant therapy and surgery, 30 pts received postoperative adjuvant therapy and 1 patient achieved partial response (PR). Median age was 36.4 years (14-61), 62.8% were females, and 57.1% were ECOG-PS 0. Surgery was performed in 35 pts including 16/35 Synovial Sarcoma (SS), 5/35 Liposarcoma (LPS), 2/35 Myxofibrosarcoma (MFS), 2/35 Undifferentiated pleomorphic sarcoma (UPS), 1/35 Leiomyosarcoma (LMS), 5/35 Malignant mesenchymal tumors and 4/35 other pathologic subtype. The 2-year PFS rate was 84.9%, the 2-year OS rate was 96.77%, and the 2-year RFS rate was 72.6%. The most common grade 3-4 adverse events included leukopenia (37.7%), Neutrophil count decreased (37.7%), Platelet count decreased (20.0%), Blennisthmia (3.1%), and Aspartate aminotransferase increased (0.8%). Conclusions: Camrelizumab combined with doxorubicin, liposomal doxorubicin, and ifosfamide in the perioperative treatment of soft tissue sarcoma pts were safe and tolerable. Survival follow-up is still ongoing to analyze the effect of perioperative immunotherapy combined with chemotherapy on long-term outcomes of pts with soft tissue sarcoma. Clinical trial information: NCT04606108 .

Outcomes for Patients With Head and Neck Sarcoma Treated Curatively With Radiation Therapy and Surgery

Soft tissue sarcomas (STSs) of the head and neck (H&N) are rare malignancies that are challenging to manage. We sought to describe the outcomes of patients treated with curative intent using combined surgery and radiation therapy (RT) for H&N STS. We performed a single-institution retrospective review of patients with nonmetastatic STS of the H&N who were treated from 1968 to 2020. The Kaplan-Meier method was used to estimate disease-specific survival (DSS) and local control (LC). Multivariable analyses (MVAs) were conducted using Cox proportional hazards model. One hundred ninety-two patients had a median follow-up of 82 months. Tumors arose in the neck (n = 50, 26%), paranasal sinuses (n = 36, 19%), or face (n = 23, 12%). Most patients were treated with postoperative RT (n = 134, 70%). Postoperative RT doses were higher (median, 60 Gy; preoperative dose, 50 Gy; P < .001). Treatment sequence was not associated with LC (preoperative RT, 78% [63%-88%]; postoperative RT, 75% [66%-82%]; P = .48). On MVA, positive/uncertain margin was the only variable associated with LC (hazard ratio [HR], 2.54; 95% CI, 1.34-4.82; P = .004). LC was significant on MVA (HR, 4.48; 95% CI, 2.62-7.67; P < .001) for DSS. Patients who received postoperative RT were less likely to experience a major wound complication (7.5% vs 22.4%; HR, 0.28; 95% CI, 0.11-0.68; P = .005). There was no difference in the rate of late toxicities between patients who received preoperative or postoperative RT. H&N STS continues to have relatively poorer LC than STS of the trunk or extremities. We found LC to be associated with DSS. Timing of RT did not impact oncologic or long-term toxicity outcomes; however, preoperative RT did increase the chance of developing a major wound complication.

Outcomes for Patients with Head and Neck Sarcoma Treated Curatively with Radiation Therapy and Surgery

Soft tissue sarcomas (STS) of the head and neck are rare and diverse entities that are challenging to manage. Definitive treatment requires surgery, often with radiation therapy (RT). We sought to describe the outcomes of patients treated curatively with surgery and RT for head and neck STS. We performed a retrospective review of patients treated at a tertiary cancer center for non-metastatic STS of the head and neck between 1968 and 2020; over half were treated in the modern era defined as 2005 or after. Patients with rhabdomyosarcomas or cutaneous angiosarcoma were excluded. The Kaplan-Meier method was used to estimate actuarial overall survival (OS), disease-specific survival (DSS) and local control (LC). Multivariable analyses (MVA) were conducted using Cox proportional hazards model. Median follow-up was 82 months. Of the 192 patients, the majority were male (n = 111, 58%), White (n = 158, 82%), and median age was 49.5 [IQR 32.5-64]. The highest proportion of tumors were in the neck (n = 50, 26%), paranasal sinuses (n = 36, 19%), or face (n = 23, 12%). The most common histology was sarcoma, not otherwise specified (n = 44, 23%), followed by undifferentiated pleomorphic sarcoma (n = 32, 17%), and neurogenic sarcoma (n = 15, 8%). Most patients were treated with postoperative RT (n = 134, 70%). Patients treated with preoperative RT were older (median 56.5 yrs vs post-op 44 yrs, p = 0.009). Post-op RT doses were higher (median 60 Gy, pre-op 50 Gy, p<0.001), and margins were more likely to be negative in those treated with pre-op RT (n = 39, 67%, post-op 69, 51%, p = 0.02). 5-year LC, DSS, and OS for the entire cohort was 76% (95% CI 69-82), 74% (67-80), and 71% (64-77), respectively. LC was not affected by treatment sequence (pre-op RT 78% (63-88), post-op RT 75% (66-82), p = 0.48). Patients with negative margins had improved 5-yr LC (86% (77-92), positive/uncertain 65% (53-74), p = 0.003). On MVA, positive/uncertain margin was the only variable associated with LC (HR 2.54 (1.34-4.82), p = 0.004). Poorer 5-yr DSS was associated with higher grade (grade 3 75% (63-84), grade 1-2 89% (75-94), p = 0.02), and treatment era (pre-2005 68% (57-76), on/after 2005 80% (70-87), p = 0.04). These both remained significant on MVA (grade 3 HR 2.39 (1.07-5.36), p = 0.034; pre-2005 HR 2.31 (1.03-5.21), p = 0.043). Sixteen patients (8%) developed a late RT toxicity, including fibrosis (n = 4, 2%), necrosis (osteoradionecrosis n = 2, brain necrosis n = 1, soft tissue necrosis n = 1), and eye dryness (n = 2, 1%). Neither the timing of RT nor dose was found to be associated with developing a late RT toxicity. Head and neck STS continues to have relatively poorer local control than STS of the trunk or extremities. Timing of RT did not impact oncologic or long-term RT-related toxicity outcomes. However, more data are needed to ascertain whether preoperative RT may impact acute surgical toxicities. These data contribute to multidisciplinary care planning for patients with STS in these challenging anatomic locations.

Elevated preoperative serum interleukin-6 level is predictive for worse postoperative outcome after soft tissue sarcoma surgery

BackgroundThe pro-inflammatory cytokine interleukin-6 (IL-6) plays a role in cancer development and progression, but research into the predictive value of IL-6 on postoperative outcome in soft tissue sarcoma (STS) is scarce. The purpose of this study is to investigate the predictive value of serum IL-6 level for the achievement of assumed (post)operative outcome after STS surgery, the so-called textbook outcome. MethodsPreoperative IL-6 serum levels were collected in all patients with a STS at first presentation between February 2020 and November 2021. Textbook outcome was defined as a R0 resection, no complications, no blood transfusions, no reoperation within the postoperative period, no prolonged hospital stay, no hospital readmission within 90-days, and no mortality within 90-days. Factors associated with textbook outcome were determined by multivariable analysis. ResultsAmong 118 patients with primary, non-metastatic STS, 35.6% achieved a textbook outcome. Univariate analysis showed that smaller tumor size (p = 0.026), lower tumor grade (p = 0.006), normal hemoglobin (Hb, p = 0.044), normal white blood cell (WBC) count (p = 0.018), normal C-reactive protein (CRP) serum level (p = 0.002) and normal IL-6 serum level (p = 1.5 × 10−5) were associated with achieving textbook outcome after surgery. Multivariable analysis showed that elevated IL-6 serum level (p = 0.012) was significantly associated with not achieving a textbook outcome. ConclusionsIncreased IL-6 serum level is predictive for not achieving a textbook outcome after surgery for primary, non-metastatic STS.

Venous Thromboembolic Event Following Soft Tissue Sarcoma Diagnosis is Associated with the Development of Pulmonary Metastasis.

This study aimed to investigate whether venous thromboembolic events (VTEs) are clinically relevant predictors of pulmonary metastatic disease in patients with soft tissue sarcomas (STSs). In this retrospective cohort analysis, we included patients with STS surgically treated for sarcoma between January 2002 and January 2020. The primary outcome of interest was development of pulmonary metastasis after non-metastatic STS diagnosis. Tumor depth, stage, type of surgical intervention, chemotherapy, radiation therapy, body mass index, and smoking status were collected. Episodes of VTEs following STS diagnosis, including deep vein thrombosis, pulmonary embolism, and other thromboembolic events, were also obtained. Univariate analyses and multivariable logistic regression were used to identify potential predictors for pulmonary metastasis. We included 319 patients with mean age of 54.9±16 years. Thirty-seven patients (11.6%) had VTE after STS diagnosis, and 54 (16.9%) developed pulmonary metastasis. Univariate screening revealed pulmonary metastasis, pre- and postoperative chemotherapy, smoking history, and VTE after surgery as potential predictors of pulmonary metastasis. Multivariable logistic regression revealed smoking history [odds ratio (OR) 2.0, confidence interval (CI) 1.1-3.9, P=0.04] and VTE (OR 6.3, CI 2.9-13.6, P<0.001) as independent risk factors for predicting pulmonary metastasis in patients with STS, after adjusting for the factors in the univariate screening as well as age, sex, stage of the tumor, and neurovascular invasion. Patients with VTE after STS diagnosis have an odds ratio of 6.3 for developing metastatic pulmonary disease compared with patients without venous thromboembolic events. Smoking history was also associated with future pulmonary metastases.

Human soft tissue sarcomas harbor an intratumoral viral microbiome which is linked with natural killer cell infiltrate and prognosis

BackgroundGroundbreaking studies have linked the gut microbiome with immune homeostasis and antitumor immune responses. Mounting evidence has also demonstrated an intratumoral microbiome, including in soft tissue sarcomas (STS), although detailed...

Is Lymphocyte C-Reactive Protein Ratio Useful for Predicting Survival in Patients with Non-Metastatic Soft Tissue Sarcoma?

Recently, the lymphocyte-to-CRP ratio (LCR) was found to have a prognostic role in many cancers. However, the clinical significance of LCR in patients with soft tissue sarcoma (STS) has not yet been established. This study aimed to determine whether LCR can predict disease-specific survival (DSS) and event-free survival (EFS) in patients with STS. In this study, 132 patients were enrolled. The mean follow-up periods were 76.5 months. Blood examinations were performed prior to treatment for all patients. The 5-year DSS in patients with higher and lower LCR was 86.5% and 52.8%, respectively (p &lt; 0.001). Patients with lower LCR had worse survival than those with higher LCR. The 5-year EFS in patients with higher and lower LCR was 66.2% and 31.2%, respectively (p &lt; 0.001). On Receiver operating characteristic analysis, however, there was no significant difference in the area under curve (AUC) between CRP level (AUC = 0.72) and LCR (AUC = 0.711). LCR may be a prognostic factor for predicting oncological events in multivariate analysis, although ROC analysis could not show the superiority of LCR to CRP for predicting oncological outcomes in patients with STS.

Comparison between preoperative chemoradiation versus neoadjuvant chemotherapy with postoperative radiation for extremity soft-tissues sarcomas.

e23527 Background: Extremity soft-tissues sarcomas are a rare entity that represent 1% of solid tumors in adults. Surgery is the main treatment and limb sparing resection with adjuvant radiotherapy (RT) is associated with good local control. However, high rates of distant relapses motivated the evaluation of adjuvant systemic treatment protocols. We aim to compare survival rates between two cohorts of patients treated with two different preoperative protocols. Methods: An observational comparative cohort study were carried out. Two cohorts of patients with high grade, larger then 5.0 cm, and non-metastatic soft tissue sarcomas of extremities, treated with two distinct preoperative institutional protocols, in two different periods of time, were compared. Group 1 included patients treated in the period from January, 1995 to December, 2004, when patients with high risk extremities soft tissue sarcomas were submitted to preoperative radiation therapy (a total dose of 30 Gy) concomitant with doxorubicin (60 mg/m2); this protocol included adjuvant chemotherapy with doxorubicin and ifosfamide. Group 2 included patients treated in the period from April, 2005 to July, 2012, when our group changed the preoperative protocol to neoadjuvant chemotherapy without radiation, with four cycles doxorubicin (60 mg/m2 per cycle) and ifosfamide (9.000 mg/m2 per cycle), followed by surgery, and postoperative radiation. Data from the group 1 were retrospectively collected, and data from group 2 were from our prospective database. Results: Eighty-eight patients were included (37 in group 1 and 51 in group 2). There were no statistical differences between the groups with regards to age, gender, location and tumor size. Predominant histological subtypes were synovial sarcoma (27.3%), pleomorphic sarcoma (15.9%), leiomyosarcoma (11.4%) and liposarcoma (8%). Relapses occurred in 60.5% of patients, most in the lungs (48.1%). Amputation rates were 14.3% in the group 1 and 4.5% in the group 2. Five-year local recurrence free survival was 81.7% for the group 1 and 91.7% for the group 2. There was no difference in median overall survival when comparing group 1 and 2 (47 versus 78 months, respectively; IC 95 3.967 – 132.033; p = 0.49), but our data showed higher recurrence free survival in group 2 (19 versus 132 months; IC 95 5.9 – 60.09; p = 0.025, respectively). Among patients from the group 2, whom presented less than 10% of viable tumor cells in the surgical specimens (good responders), no local or distant recurrences have occurred. Conclusions: In our retrospective analysis, neoadjuvant chemotherapy was associated with greater recurrence free survival in patients with high-grade extremity soft tissue sarcomas as compared to neoadjuvant chemoradiation. For patients with high risk of distant relapse, neoadjuvant chemotherapy should be considered after a multidisciplinary discussion.

The added value of chest imaging after neoadjuvant radiotherapy for soft tissue sarcoma of the extremities and trunk wall: A retrospective cohort study

IntroductionThere is no clear evidence regarding the benefit of restaging for distant metastases after neoadjuvant radiotherapy (RTX) in patients with soft tissue sarcoma (STS) of the extremities and trunk wall. This study aimed to determine how often restaging of the chest identified metastatic disease that altered management in these patients. MethodsWe performed a single-centre retrospective study from 2010 to 2020. All patients with non-metastatic STS of the extremities and trunk wall who were treated with neoadjuvant RTX and received a staging and restaging chest CT scan or X-ray for distant metastasis were included. The outcome of interest was change in treatment strategy due to restaging after neoadjuvant RTX. ResultsWithin the 144 patients who were staged and treated with neoadjuvant RTX, a restaging chest CT or X-ray was performed in 134 patients (93%). A change in treatment strategy due to new findings at restaging after RTX was observed in 26 out of 134 patients (19%). In 24 patients the scheduled resection of the primary STS was cancelled at restaging (24/134, 18%), given the findings at restaging. The other two patients did receive the intended local resection, but either with palliative intent, or as a part of a previously unplanned multimodality treatment. ConclusionIn approximately one in five patients restaging results in a change in treatment strategy. This underlines the added value of routine restaging for distant metastases with chest CT or X-ray after neoadjuvant RTX in patients with STS.

Intra-Tumoral Pharmacokinetics of Pazopanib in Combination with Radiotherapy in Patients with Non-Metastatic Soft-Tissue Sarcoma.

Simple SummaryPazopanib plasma levels have been associated with treatment efficacy. Since pazopanib targets receptors present on cells in the vicinity of the tumor and on tumor cells themselves, measurement of pazopanib concentrations in tumor tissue might be an even better prognostic biomarker than plasma levels. The aim of our study was to quantify pazopanib concentrations in tumor tissue, correlate this with plasma concentrations, and assess whether this is a better biomarker for efficacy. A modest correlation was found between pazopanib tumor concentrations and plasma concentrations. Additionally, no correlation was found between pazopanib tumor concentrations and efficacy. We provide recommendations for future studies in which pazopanib concentrations are measured.There is a lack of understanding whether plasma levels of anticancer drugs (such as pazopanib) correlate with intra-tumoral levels and whether the plasma compartment is the best surrogate for pharmacokinetic and pharmacodynamic evaluation. Therefore, we aimed to quantify pazopanib concentrations in tumor tissue, to assess the correlation between tumor concentrations and plasma concentrations and between tumor concentrations and efficacy. In this clinical trial, non-metastatic STS patients were treated with neo-adjuvant concurrent radiotherapy and pazopanib. Plasma samples and tumor biopsies were collected, and pazopanib concentrations were measured using liquid chromatography-tandem mass spectrometry. Twenty-four evaluable patients were included. The median pazopanib tumor concentration was 19.2 µg/g (range 0.149–200 µg/g). A modest correlation was found between tumor concentrations and plasma levels of pazopanib (ρ = 0.41, p = 0.049). No correlation was found between tumor concentrations and percentage of viable tumor cells (p > 0.05); however, a trend towards less viable tumor cells in patients with high pazopanib concentrations in tumor tissue was observed in a categorical analysis. Possible explanations for the lack of correlation might be heterogeneity of the tumors and timing of the biopsy procedure.

A unique case of classic pleomorphic sarcoma restricted to the toes

Over 50% of soft tissue sarcomas occurring in older adults are histologically pleomorphic and high grade. Most have traditionally been classified as malignant fibrous histiocytoma (MFH). MFH was originally defined as a malignant pleomorphic spindle cell neoplasm showing fibroblastic and histiocytic differentiation. More recently, pathologists have accepted that this morphology may be shared by a wide range of malignant neoplasms. Many sarcomas that were previously classified as pleomorphic MFH, on careful immunohistochemical and histopathologic analyses, revealed a specific line of differentiation and could be reclassified as myxofibrosarcoma (30%), myogenic sarcoma (30%), liposarcoma (4%), malignant peripheral nerve sheath tumor (2%), or soft tissue osteosarcoma (3%), whereas about 30% had no specific line of differentiation or were myofibroblastic. The term undifferentiated pleomorphic sarcoma (UPS) is now reserved for pleomorphic sarcomas that show no definable line of differentiation by current technology. The majority of extremity sarcomas occur in the lower extremity (74 vs. 26% in the upper limb). According to one of the studies conducted on 315 patients, non-metastatic soft tissue sarcoma of the lower extremity who were treated at one institution over a ten-year period. Sixty-six percent of the lesions were above the knee, and 60% were high grade. This case had a 3x3 cm ulcer at the 3rd toe in a 30-year-old male patient who subsequently underwent midfoot ampuatation.

Complete pathological response to neoadjuvant treatment is associated with better survival outcomes in patients with soft tissue sarcoma: Results of a retrospective multicenter study

BackgroundLocally advanced soft tissue sarcoma (STS) management may include neoadjuvant or adjuvant treatment by radiotherapy (RT), chemotherapy (CT) or chemoradiotherapy (CRT) followed by wide surgical excision. While pathological complete response (pCR) to preoperative treatment is prognostic for survival in osteosarcomas, its significance for STS is unclear. We aimed to evaluate the prognostic significance of pCR to pre-operative treatment on 3-year disease-free survival (3y-DFS) in STS patients. MethodsThis is an observational, retrospective, international, study of adult patients with primary non-metastatic STS of the extremities and trunk wall, any grade, diagnosed between 2008 and 2012, treated with at least neoadjuvant treatment and surgical resection and observed for a minimum of 3 years after diagnosis. The primary objective was to evaluate the effect of pCR. (≤5% viable tumor cells or ≥95% necrosis/fibrosis) on 3y-DFS. Effect on local recurrence-free survival (LRFS), distant recurrence-free survival (MFS) overall survival (OS) at 3 years was also analyzed. Statistical univariate analysis utilized chi-square independence test and odds ratio confidence interval (CI) estimate, multivariate analysis was performed using LASSO. ResultsA total of 330 patients (median age 56 years old, range:19–95) treated by preoperative RT (67%), CT (15%) or CRT (18%) followed by surgery were included. pCR was achieved in 74/330 (22%) of patients, of which 56/74 (76%) had received RT. 3-yr DFS was observed in 76% of patients with pCR vs 61% without pCR (p < 0.001). Multivariate analysis showed that pCR is statistically associated with better MFS (95% CI, 1.054–3.417; p = 0.033), LRFS (95% CI, 1.226–5.916; p = 0.014), DFS (95% CI, 1.165–4.040; p = 0.015) and OS at 3 years (95% CI, 1.072–5.210; p = 0.033). ConclusionsIn a wide, heterogeneous STS population we showed that pCR to preoperative treatment is prognostic for survival.

Is no additional excision after unplanned excision with positive margins justified in patients with small (≤5 cm) high-grade soft-tissue sarcoma?: Analysis from the Bone and Soft Tissue Tumor registry in Japan

BackgroundThis study aimed to elucidate the clinical outcomes of patients with small (≤5 cm) high-grade soft tissue sarcoma, who underwent unplanned excision with positive surgical margin, using data from the Bone and Soft Tissue Tumor registry in Japan. MethodsWe examined 174 patients (101 males and 73 females; mean age, 59 years) with primary non-metastatic soft tissue sarcoma. The tumor size was ≤5 cm, and tumor histological grade was high in all patients. The mean follow-up duration was 50 months. ResultsUnplanned excision with R1 and R2 margins was reported in 115 (66%) and 59 patients (34%), respectively. After unplanned excision, immediate additional excision was performed in 154 patients, whereas no additional excision was performed in the remaining 20. Of the 154 patients who underwent additional excision, wide surgical margin resection was achieved in 140 patients, while marginal and intralesional resections were achieved in 10 and 3 patients, respectively. Additionally, 93 patients (60%) underwent reconstruction after additional excision. During the last follow-up, 8 patients died of the disease, 22 developed distant metastasis, and 14 reported local recurrence. The 5-year disease-specific survival rate and 5-year metastasis-free survival rate was 93.5% and 85%, respectively. Tumor depth and additional excision after unplanned excision showed statistical significance in the multivariate analysis. The 5-year metastasis-free survival rate was 89.1% in patients with additional excision and 39.2% in those without. Univariate analysis showed an association between additional excision and local control. The 5-year local recurrence-free survival was significantly worse in patients without additional excision after unplanned excision (52.6%) than in those with additional excision (92.8%). ConclusionIf unplanned excision is performed in patients with small high-grade soft tissue sarcoma, additional excision is recommended for preventing metastasis, along with necessary preparations for reconstruction.

Diabetes mellitus is independently associated with adverse clinical outcome in soft tissue sarcoma patients

Diabetes mellitus (DM) and hyperglycemia are known predictors of adverse outcome in different tumor entities. The present study investigated the effect of DM and pre-surgery blood glucose levels on cancer specific survival (CSS), overall survival (OS), and disease-free survival (DFS) in non-metastatic soft tissue sarcoma (STS) patients. A total of 475 STS patients who underwent curative resection were included in this retrospective study. CSS, DFS, and OS were assessed using Kaplan–Meier curves. The association between pre-existing DM as well as mean pre-surgery blood glucose levels and all 3 survival endpoints was analyzed using Cox-hazard proportional (for OS and DFS) and competing risk regression models (for CSS). In unadjusted analysis, DM was significantly associated with adverse CSS (sub-hazard ratio [SHR]: 2.14, 95% confidence interval [CI] 1.18–3.90, p = 0.013) and OS (hazard ratio [HR]: 2.05, 95% CI 1.28–3.28) and remained significant after adjusting for established prognostic factors (CSS: adjusted SHR 2.33, 95% CI 1.21–4.49, p = 0.012; OS: adjusted HR 1.96, 95% CI 1.17–3.28, p = 0.010), respectively. There was no significant association of DM with DFS (p = 0.149). The mean pre-surgery glucose levels were not significantly associated with inferior outcome (CSS: p = 0.510, OS: p = 0.382 and DFS: p = 0.786). This study shows, that DM represents a negative prognostic factor for clinical outcome in STS patients after curative resection.

The Circulating Nucleic Acid Characteristics of Non-Metastatic Soft Tissue Sarcoma Patients.

Soft tissue sarcomas (STS) are rare, malignant tumours with a generally poor prognosis. Our aim was to explore the potential of cell free DNA (cfDNA) and circulating tumour DNA (ctDNA) analysis to track non-metastatic STS patients undergoing attempted curative treatment. The analysed cohort (n = 29) contained multiple STS subtypes including myxofibrosarcomas, undifferentiated pleomorphic sarcomas, leiomyosarcomas, and dedifferentiated liposarcomas amongst others. Perioperative cfDNA levels trended towards being elevated in patients (p = 0.07), although did not correlate with tumour size, grade, recurrence or subtype, suggesting a limited diagnostic or prognostic role. To characterise ctDNA, an amplicon panel covering three genes commonly mutated in STSs was first trialled on serial plasma collected from nine patients throughout follow-up. This approach only identified ctDNA in 2.5% (one in 40) of the analysed samples. Next custom-designed droplet digital PCR assays and Ion AmpliSeq™ panels were developed to track single nucleotide variants identified in patients’ STSs by whole exome sequencing (1–6 per patient). These approaches identified ctDNA in 17% of patients. Although ctDNA was identified before radiologically detectable recurrence in two cases, the absence of demonstrable ctDNA in 83% of cases highlights the need for much work before circulating nucleic acids can become a useful means to track STS patients.

The prognostic role of the preoperative systemic immune-inflammation index and high-sensitivity modified Glasgow prognostic score in patients after radical operation for soft tissue sarcoma

IntroductionThe prognostic values of nutritional and immune-inflammatory indicators in non-metastatic soft tissue sarcoma (STS) patients are not clear. We investigated the utility of systemic immune-inflammation index (SII) and the high-sensitivity modified Glasgow prognostic score (Hs-mGPS) in the prediction of STS patient's prognosis. Materials and methodsPatients admitted between January 2000 and December 2016, who underwent R0 resection for STS at SYSUCC were carefully retrospectively reviewed, and 454 patients were enrolled. The laboratory data and clinical data were collected from the patient's record. ROC analysis is used to determine the optimal cutoff value. Survival curves were analysed by Kaplan-Meier method. Cox proportional hazard model was used to find out prognostic variables. ResultsIncreased SII and Hs-mGPS values were significantly related to larger tumour size, deep tumour location, higher tumour grade and more advanced American Joint Committee on Cancer (AJCC) stage. Patients with an elevated SII had a shorter median survival time and a lower 5-year OS rate than those with a low SII. And patients with low Hs-mGPS had longer median OS and DFS. Multivariate analysis revealed that both the SII and the Hs-mGPS were independent predictive indicators for OS. And a joint model containing both the Hsm-GPS and the SII appeared to have the strongest predictive ability. ConclusionOur findings indicated that malnutrition and systemic inflammation are risk factors for the survival of STS patients after operation, and early recognition and intervention of malnutrition and systemic inflammation may help to improve the survival of the patients.

Plasma YKL-40 as a biomarker in patients with nonmetastatic bone and soft tissue sarcomas: a prospective exploratory clinical study

Purpose: YKL-40 is a glycoprotein with a role in inflammation, tissue remodeling, tumor angiogenesis, and protection against apoptosis. We hypothesized that high preoperative plasma YKL-40 in patients with nonmetastatic bone and soft tissue sarcoma (STS) is associated with short overall survival (OS), and that plasma YKL-40 is an independent predictor for OS. Materials and methods: Plasma was collected preoperatively from 65 patients with nonmetastatic bone (n=14) or STS (n=51) in the lower extremities (n=43), the upper extremities (n=16) or the trunk wall/spine (n=6). All patients underwent surgical cancer treatment. Twenty patients developed metastases during the follow-up period (minimum 5 y). The plasma concentration of YKL-40 was determined by enzyme-linked immunosorbent assay. Results: Twenty-seven patients died [mean: 3.2 (range: 0.2–7.3) y postoperatively] and 38 patients were still alive after a follow-up of mean 6.9 (5.8–8.2) years postoperatively. Plasma YKL-40 was higher in patients who died during follow-up (P=0.008), in males (P=0.007) and in patients 61 years of age and above (P=0.001). The 5-year OS was 68% and OS was lower in patients with high (≥95% percentile age-corrected) plasma YKL-40 (P=0.021), age 61 years and above (P=0.013), high histologic malignancy grade (P=0.047) and male sex (P=0.051). Multivariable analysis showed that only plasma YKL-40 (age-corrected (hazard ratio=2.80, 95% confidence interval: 1.13–6.91, P=0.026) and malignancy grade (hazard ratio=9.9×107, 95% confidence interval: 0–∞, P=0.007) remained independent prognostic factors for OS. Conclusions: High preoperative plasma YKL-40 was related to short OS in patients with nonmetastatic bone and STS and plasma YKL-40 (age-corrected) was an independent prognostic risk factor for OS.

Hypofractionated radiotherapy for non-metastatic bone and soft tissue sarcomas

PurposeTo evaluate the efficacy and toxicity of hypofractionated radiotherapy in non-metastatic soft tissue and bone sarcomas. Patients and methodsThirty patients underwent hypofractionated radiotherapy between 2007 and 2015. Overall, 17 patients underwent primary hypofractionated radiotherapy, nine underwent hypofractionated radiotherapy for reirradiation, and four received a boost dose via hypofractionated radiotherapy after external beam radiotherapy. Most common disease sites were head and neck and retroperitoneum. Hypofractionated radiotherapy was administered with a definitive, adjuvant, or neoadjuvant intent. ResultsMedian age was 37 years (range: 11–82 years). Median hypofractionated radiotherapy dose was 35Gy (range: 20–50Gy) in three to five fractions. Median follow-up was 21 months (range: 1–108 months). One- and 2-year overall survival rate was 75% and 52%, respectively. One- and 2-year local recurrence-free survival rate was 59% and 48%, with local recurrence rates of 16% and 33% in 1 and 2 years, respectively. Univariate analysis revealed tumour size (P=0.04), hypofractionated radiotherapy intent (P=0.016) and reirradiation (P=0.001) as prognostic factors for local recurrence-free survival. Severe late toxicity was observed in one patient as grade 3 trismus. ConclusionHypofractionated radiotherapy as the primary treatment or for reirradiation has been shown to be safe in the treatment of bone and soft tissue sarcomas. It can provide relatively good local control and survival rates.

Radiation and Chemotherapy Improve Survival in Patients with High-Risk Soft Tissue Sarcomas of the Extremities: An Updated Analysis of the Surveillance, Epidemiology, and End Results (SEER) Database

The primary treatment modality for non-metastatic soft tissue sarcomas (STS) of the extremity is surgical resection. This can be accomplished with amputation, or limb sparing surgery (LSS) when feasible. Radiation therapy improved survival in patients with tumors that were high grade or undifferentiated and >5cm (high risk) in a prior SEER analysis. The role of chemotherapy remains controversial in STS. The SEER 18 registries database was queried to identify patients age 18 and older with pathologically confirmed STS of the extremity diagnosed in 2004 or later that underwent surgical resection. Patients with Kaposi’s sarcoma were excluded as well as those with metastatic disease, <3 months of follow up and if the type of surgery was not specified. The primary endpoint of this study was overall survival, which was determined using the Kaplan and Meier method. Survival curves were subsequently compared using log rank analysis. A total of 8,584 patients were identified that met inclusion criteria, Females comprised 3,862 patients and males 4,722 patients. The average age at diagnosis was 57 (range 18-98). Grade III or undifferentiated tumors were present in 3,860 patients while 4,915 patients had tumors >5cm. The 5 year OS for patients who underwent amputation was 53.4% compared to 77.0% with LSS, corresponding to a HR of 0.40 (p<0.001). Median OS was 68 months with amputation and not reached at 10 years with LSS. Of the 8,122 patients who underwent LSS, 4,369 patients were known to have received radiation therapy and 1,135 were known to have been treated with chemotherapy. Neither radiation therapy nor chemotherapy improved survival in the entire cohort of patients undergoing LSS. In a subset of 2,331 patients with high risk tumors, radiation improved 5 year OS from 51.1% to 59.6% while median OS improved from 71 to 97 months, corresponding to a HR of 0.78 (p=0.002). In the same subset of patients treated with radiation, 689 (37.2%) had neoadjuvant radiation with or without postoperative radiation (PORT) and 1,161 (62.8%) had PORT alone. 5 year OS was 58.5% with PORT and 61.5% with neoadjuvant radiation while median OS was 89 and 97 months respectively, corresponding to a HR of 0.97 (p=.671). For the 720 patients with high risk tumors who were known to have received chemotherapy, the 5 year OS and median OS were 61.7% and 117 months respectively versus 58.5% and 83 months respectively for patients not known to receive chemotherapy, corresponding to a HR of 0.83 (p=0.025). The findings of this analysis support continued use of LSS in surgically eligible patients with STS of the extremity. While neither radiation therapy nor chemotherapy improved survival in all comers treated with LSS, the subset of patients with high risk tumors (high grade/ undifferentiated and >5cm) showed a significant survival benefit from both modalities in addition to surgery. The timing of radiation therapy, neoadjuvant versus PORT did not impact survival in this subset of patients.

(Neo)adjuvant chemotherapy and interdigitated split-course hyperfractionated radiation in high risk soft tissue sarcoma \u2013 Results from a large single-institution series

A single-institution series using a (neo)adjuvant chemotherapy and interdigitated hyperfractionated split-course radiation therapy (CRT) treatment protocol for soft tissue sarcoma was reviewed. Our specific aims were to study recurrence rates and long-term toxicity. Between 1998 and 2016, 89 patients with non-metastatic soft tissue sarcoma were treated with surgery combined with six courses of doxorubicin and ifosfamide and hyperfractionated radiation therapy (42–60 Gy/1.5 Gy twice daily). Patients were considered being at high risk if tumour malignancy grade was high and the tumour fulfilled at least two of the following criteria: size >8 cm, presence of necrosis or vascular invasion. The mean age of the patients was 50.7 years. With a median follow-up of 5.4 years for survivors, the local control rate was 81.4%. Six (7%) patients progressed during neoadjuvant CRT. Seven (8%) patients discontinued the treatment due to toxicity. Eighty-six patients were operated and three (3%) of these developed a long-term complication. The estimated metastasis-free survival was 47.6% and overall survival 53.0% at five years. The limb-salvage rate was 93%. The limb-salvage rate, local control and complication rates were good in these patients with high risk soft tissue sarcoma. Metastases-free survival and overall survival rates were less satisfactory, reflecting the aggressive nature of these tumours.