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Background: Marginally resectable and unresectable soft tissue sarcomas (STS) remain a therapy challenge due to the lack of highly active treatment. The aim of the study was to identify a biomarker to predict the pathological response (PR) to preplanned treatment of these STSs. Methods: In the phase II clinical trial (NCT03651375), locally advanced STS patients received preoperative treatment with a combination of doxorubicin-ifosfamide chemotherapy and 5 × 5 Gy radiotherapy. PR to the treatment was classified using the European Organization for Research and Treatment of Cancer–Soft Tissue and Bone Sarcoma Group recommendations. We have chosen HIF-1α, CD163, CD68, CD34, CD105, and γH2AFX proteins, rendering different biological phenomena, for biomarker study. Results: Nineteen patients were enrolled and in four cases a good PR was reported. The high expression of HIF-1α before surgery showed a negative correlation with PR, which means a poor response to therapy. Furthermore, the samples after surgery had decreased expression of HIF-1α, which confirmed the correlation with PR. However, high expression of γH2AFX positively correlated with PR, which provides better PR. The high number of positive-staining TAMs and the high IMVD did not correlate with PR. Conclusions: HIF1α and γH2AFX could be potential biomarkers for PR prediction after neoadjuvant treatment in STS.

Undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS) are genomically complex tumors commonly diagnosed in the extremities or trunk of elderly patients. They likely represent a spectrum of disease differentiated by myxoid stroma and curvilinear vessels observed in MFS but not in UPS. Limb-sparing surgery is the standard of care although the infiltrative nature of MFS mandates wider resection margins than are necessary for UPS. UPS are conversely associated with high risks of distal recurrence, often prompting recommendations for adjuvant chemotherapy. In both histologies, anthracycline-based therapies or gemcitabine and docetaxel are used to manage advanced disease; immunotherapy may be of benefit in a subset of patients.

The introduction of immunotherapy with checkpoint inhibitors into clinical practice has radically changed the treatment and prognosis of patients with cancer. This treatment is also extensively studied in patients diagnosed with advanced sarcomas, where the number of effective therapies is limited. The following review presents the latest reports on the use of immunotherapy in the treatment of patients with sarcomas.

Introduction Malignant peripheral nerve sheath tumor (MPNST) accounts for about 5% of soft tissue sarcomas. It can occur as sporadic diseases or can be associated with type 1 neurofibromatosis. MPNST is usually associated with poor prognosis, mostly due to their aggressive behavior, high metastatic potential, and resistance to chemotherapy. Our study aimed to determine treatment outcomes and associated prognostic factors in a large cohort of patients with MPNSTs treated at the reference sarcoma center. Methods 239 consecutive patients (114 women and 125 men) diagnosed with MPNST between March 1998 and March 2018 who were treated with surgery with curative intent in the reference sarcoma center were included in the retrospective analysis. Results The mean age at diagnosis was 51 years (range 15–86). 28 (11.7%) patients had neurofibromatosis type 1 associated tumors (NF1 positive). Median OS was 126.5 months and 5-year survival rate was 61.9% in the group treated with curative intent. Median DFS, LRFS and DMFS were 91.6, 126.5 and 126.5 months, respectively. We identified tumor size, high tumor grade and positive surgical margins as independent negative predictors of DFS, LRFS, DMFS and OS. Conclusions High-quality surgery remains a gold standard of MPNST treatment. High grade, size and quality of surgery are significant independent prognostic factors for overall survival. There is an unmet need for improvement, especially regarding the perioperative treatment and treatment of metastatic disease. Future studies on the biology of MPNST would lead to the development of novel treatment options and improvement of treatment outcomes.

Assessment of BRAF mutation status is mandatory in advanced, treatment-naïve melanoma patients. Liquid biopsy can be an alternative in cases with inadequate or unavailable tumor tissue. The aim of our study was to evaluate the clinical utility of plasma circulating tumor DNA analysis for BRAF mutation testing and to assess outcomes of therapy with BRAF/MEK inhibitors initiated based on the liquid biopsy results. This was a retrospective single-center analysis of 46 patients (21 female, 25 male) with advanced melanoma who underwent circulating tumor DNA (ctDNA) BRAF mutation testing. A BRAF mutation was found in 45.7% (21/46) of liquid biopsies and 44.8% (13/29) of tissue samples. In patients with both ctDNA and tissue samples (n = 29), the concordance between the results of both tests was 82.8%. A BRAF mutation was detected in 7/17 (41.2%) patients with only ctDNA analysis. In 18 patients, therapy with BRAF/MEK inhibitors was initiated on the basis of the result of liquid biopsy. The objective response rate was 77.8 %, and the median PFS was 6.0 months. Our study confirms the clinical utility of BRAF mutation detection in plasma ctDNA. This study provides initial real-world data showing that treatment with BRAF/MEK inhibitors could be commenced based on liquid biopsy results.

The data about treatment results of Ewing sarcoma in adult patients are limited. The aim of our study was to analyze prognostic factors and outcomes of therapy in this group of patients. Between 2000 and 2018, 180 patients at the age of > 18 years old diagnosed with Ewing sarcoma were treated in referral center according to multimodal protocols. In 50 patients (28%) treatment was initiated outside our hospital, and 23 of them had started recommended therapy after 3 months since the date of biopsy/unscheduled operation. We analyzed clinical prognostic factors and overall survival (OS). The median age was 28 years (18–67 years), primary tumor was localized axially in 114 patients (63%), metastases at presentation were detected in 51 pts (28%). 5-year OS rate was 65% for patients with localized disease, in metastatic disease it was 15%; the presence and the number of metastases was a prognostic factor. 5-year PFS was significantly better in patients treated at referral center (or when the patients were admitted to referral center within 3 months from the date of biopsy, which was performed outside referral center), comparing to patients treated initially outside referral center; 5-year PFS rates in total population were 28 and 13%, respectively. In terms of OS, unfavorable prognostic factor showing a statistical trend (p = 0.098) was lower dose density of neoadjuvant chemotherapy due to toxicity. Approximately two-third of adult patients with localized Ewing sarcoma survive 5 years. In order to improve survival of this patients the multidisciplinary treatment in referral center is mandatory.

Introduction. Combined inhibition of BRAF and MEK improved progression-free survival and overall survival in patients with BRAFV600-mutation-positive metastatic melanoma. We conducted a retrospective study on real-life patients with BRAF-mutant melanoma treated with BRAF/MEK inhibitors. Patients and methods. Patients with untreated, unresectable stage IIIC/IV melanoma positive for the BRAFV600 mutation were treated with dabrafenib/trametinib or vemurafenib/cobimetinib. All patients received BRAF/MEK inhibitors as first-line therapy according to Polish National Drug Reimbursement Program Guidelines. Median follow-up time was 41 months. For the survival analysis, the Kaplan-Meier estimator was used with log-rank tests for univariate comparisons. Results. A total of 95 patients were included (48 women and 47 men; median age: 55 years). 80 patients received dabrafenib/trametinib and 15 received vemurafenib/cobimetinib. Overall, 12 patients continued therapy after the cutoff date. The objective response rate was 71%, including six patients (6%) with a complete response and 62 patients (65%) with a partial response. Median progression-free survival was 10 months and median overall survival was 15 months. High LDH level, ECOG > 0, stage M1c–M1d and three or more metastatic organ sites negatively impacted PFS and OS. Higher adverse event rate was reported in patients receiving vemurafenib/cobimetinib (87%) as compared to patients treated with dabrafenib/trametinib (64%). Overall, grade 3–4 toxicity was reported in 20% of patients. The most frequent adverse events in the dabrafenib/trametinib group were pyrexia, fatigue, nausea and arthralgia. In the vemurafenib/cobimetinib group, the most frequent adverse events were skin toxicity (rash, photosensitivity), arthralgia, myalgia and diarrhea. Conclusions. Despite the high response rate to BRAF and MEK inhibitor therapy, the overall survival is lower in clinical practice than observed in clinical trials. This difference may be explained by a more heterogeneous patient population seen in routine clinical practice, with more advanced disease and comorbidities.

The results of local-regional advanced melanoma (stage III) management are still not satisfactory. Particularly, there is no personalized treatment in stage III melanoma patients due to the lack of useful classical pathological markers for prognostication of indolent or aggressive course of the disease. The aim of this study was to explore melanoma genomic landscape by means of the mutational profiling of 50 genes influencing carcinogenesis pathways in the randomly selected 93 kinase inhibitor-naïve (KI-naïve) stage III patients. The genomic alterations were found in 27 out of 50 tested genes and at least one pathogenic variant was detected in 77 out of 93 cases (82.7%). Survival rate was negatively affected by the presence of the somatic mutations in AKT1, ATM, CDH1 and SMARCB1, while the BRAF+ status in KI-naïve stage III population correlated with the longer median overall survival. Genomic alterations in WNT pathway correlated with extranodal adipocyte tissue involvement (P = 0.027) and higher number of metastatic lymph nodes (P = 0.045). In terms of survival, the Cox model confirmed the worse prognosis in patients with mutation in the WNT pathway [hazard ratio (HR) = 2.9, P = 0.017], and better prognosis in cases with mutations in BRAF pathway (HR = 0.5, P = 0.004). WNT/β-catenin pathway alteration was associated with more advanced/aggressive disease. From this perspective, the concept of blocking the activity of the WNT pathway in selected cases appears promising and complementary to the BRAF inhibition therapeutic option for the future.

Objective: We assessed the status of the BRAF V600E mutation in cell-free circulating tumor DNA (cfDNA) isolated from the plasma of patients with metastatic melanoma treated with the BRAF inhibitor vemurafenib, collected at different time points during therapy to evaluate the sensitivity and specificity of quantitative polymerase chain reaction and droplet digital polymerase chain reaction (ddPCR) and the correlation between the level of plasma cfDNA p.V600E and the long-term clinical outcome. Methods: cfDNA in patients with BRAF-mutated melanoma ( n = 62) was analyzed at baseline and at 4−8 weeks from the start of vemurafenib therapy. BRAF mutations were assessed using tumor tissue-derived DNA and circulating cfDNA from plasma samples. Quantification of BRAF V600E was performed in cfDNA using ddPCR. Results: cfDNA V600E was detected in the plasma of 48/62 (77%) patients at baseline and in 18/62 (29%) patients after 4–8 weeks of treatment. Patients positive for BRAF mutations in cfDNA at baseline had shorter progression-free survival (PFS) and overall survival (OS) compared with patients with undetectable cfDNA BRAF mutations. Undetectable cfDNA p.V600E at baseline and after 4–8 weeks of therapy was associated with the best prognosis. When treated as a continuous variable, the log-transformed concentration of baseline cfDNA p.V600E was significantly associated with both PFS and OS. This effect was retained in the multivariate OS Cox model adjusted for Eastern Cooperative Oncology Group performance status, the presence of brain metastases, patient age, and previous systemic treatment. Conclusions: Monitoring of plasma BRAF p.V600E cfDNA concentrations in patients with metastatic melanoma on targeted therapy may have prognostic value. Undetectable cfDNA p.V600E before and during treatment was associated with a favorable prognosis.

Background: Sarcomas are rare malignant tumors of mesenchymal origin. The discovery of circulating biomarkers with high diagnostic value could supplement diagnosis of this heterogenous group of tumors. The aim of this study was to identify the profiles of circulating miRNA (c-miRNAs) in four groups of common bone and soft tissue sarcomas. Methods: At the time of diagnosis, blood samples were collected from 86 patients: 36 with locally advanced/unresectable/metastatic gastrointestinal stromal tumor (GIST) who received first-line treatment with imatinib; 16 with locally advanced osteosarcoma (OS); 26 with locally advanced synovial sarcoma (SS); and eight with locally advanced Ewing sarcoma (ES). In addition, samples were collected from 30 healthy controls. C-miRNAs were isolated using a miRCURY RNA Isolation Kit, followed by preparation of cDNA libraries and sequencing on the Ion Proton platform. Results: Pair-wise comparisons identified 156 unique c-miRNAs (adjusted P-value < 0.05) showing significant dysregulation between controls and patients; of these, 24, 36, 42, and 99 differentiated controls from pretherapeutic OS, SS, ES, and GIST, respectively. Ten c-miRNAs were commonly altered in at least three sarcoma types. Receiver operating characteristic curves and area under the curve (ROC-AUC) analyses revealed that a four-miRNA diagnostic classifier was able to differentiate controls from ES, GIST, OS, and SS, with AUC-ROC values of 1, 0.97, 0.95, and 0.94, respectively. Conclusions: Aberrant miRNA expression signatures were identified in serum from patients with four different sarcoma subtypes. Differences in miRNA expression profiles between sarcoma patients and healthy volunteers suggest that miRNAs may play a role in sarcoma development.

Simple Summary Neoadjuvant therapy for locally advanced disease or potentially resectable metastatic melanoma is expected to improve operability and clinical outcomes over upfront surgery. 46 patients were treated with BRAFi/MEKi or BRAFi before surgery with 78% R0 resection. In patients with a major pathological response with no, or less than 10%, viable cells in the tumor, median DFS and PFS were significantly longer than in patients with a minor pathological response. Abstract Neoadjuvant therapy for locally advanced disease or potentially resectable metastatic melanoma is expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment as it is for sarcoma, breast, rectal, esophageal, or gastric cancers. Patients with locoregional recurrence after initial surgery and those with advanced regional lymphatic metastases are at a high risk of relapse and melanoma-related death. There is an unmet clinical need to improve the outcomes for such patients. Patients with resectable bulky stage III or resectable stage IV histologically confirmed melanoma were enrolled and received standard-dose BRAFi/MEKi for at least 12 weeks before feasible resection of the pre-therapy target and then received at least for the next 40 weeks further BRAFi/MEKi. Of these patients, 37 were treated with dabrafenib and trametinib, three were treated with vemurafenib and cobimetinib, five with vemurafenib, and one with dabrafenib alone. All patients underwent surgery with 78% microscopically margin-negative resection (R0) resection. Ten patients achieved a complete pathological response. In patients with a major pathological response with no, or less than 10%, viable cells in the tumor, median disease free survival and progression free survival were significantly longer than in patients with a minor pathological response. No patient discontinued neoadjuvant BRAFi/MEKi due to toxicity. BRAFi/MEKi pre-treatment did not result in any new specific complications of surgery. Fourteen patients experienced disease recurrence or progression during post-operative treatment. We confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of melanoma. Pathological response to neoadjuvant treatment may be considered as a surrogate biomarker of disease recurrence.

Assessment of

Ewing sarcoma (ES) is a rare and aggressive disease that requires multidisciplinary treatment with the use of chemotherapy, radiotherapy, and surgery. Our retrospective study aimed to analyze the prognostic factors and treatment results in different age groups of patients. Between 1998 and 2018, 569 patients with ES were treated in two referral centers. The patients were divided into four age groups (≤10 years, 11–18 years, 19–25, and &gt, 25). The treatment results and prognostic factors were assessed for each group. For statistical analyses, we used the Chi2 test, the Kaplan–Meier estimator with a log-rank test, and the multivariate Cox model. Five-year overall survival (OS) rate was 56%. In the age subgroups: ≤10 years, 11–18 years, 19–25 years, and &gt, 25 years, the 5-year OS rates were 75%, 58%, 41%, and 52%, respectively. Favorable prognostic factors: female gender (p = 0.024), non-axial localization (p = 0.005), VIDE regimen (p &lt, 0.001), and surgery as a local treatment (p &lt, 0.001) dominated in the group ≤10 years. In multivariate analysis, male (HR = 1.53), axial localization (HR = 1.46), M1 status at presentation (HR = 2.64), and age &gt, 10 years (HR = 2.29) were associated with shorter OS. The treatment results in ES are significantly better in children aged ≤10 years, the challenge is to provide therapy for adolescents and young adults. The diagnostics and treatment of ES patients must be provided in referral centers.

Melanoma is a malignant neoplasm with a very high rate of growth in the number of cases. In Poland, in the years 1980–2010, the number of cases of melanoma increased threefold. Although the incidence rates of melanoma are rising, the mortality rate due to melanoma is falling. In recent years, the treatment of patients with melanoma has changed to a great extent. Thanks to the development of molecular research, the presence of specific mutations in melanoma cells was discovered. The progress in understanding the molecular mechanisms occurring in this neoplastic cells and the interaction between the immune system cells and melanoma cells contributed to the development of new classes of drugs: immunotherapy and targeted therapy. With the use of checkpoint inhibitors, long-term remission of the disease can be achieved, which has been confirmed in many clinical trials that have shown improvements in overall survival (OS) and progression free survival (PSF). However, the predominant problem is the low response rate to checkpoint inhibitors and the time between the initiation of therapy and the response to treatment. This is not the case with targeted therapies, where the response rate is high and the response time is very short. Therefore, a promising treatment strategy can be a combination of these two classes of drugs, so that one can try to achieve a quick and long-term response to the treatment. The paper discusses the current treatment options for melanoma patients in the spreading phase of the disease and analyzes the benefits of combined and sequential treatment.

Introduction. Vismodegib is a small-molecule inhibitor of the sonic hedgehog pathway, registered for the treat- ment of patients with metastatic or locally advanced basal cell carcinoma, who were disqualified from surgical excision or radiotherapy. The full treatment refund from the National Health Fund has been available in Poland since 1st January 2018. The aim of the study was to analyse the frequency of occurrence of adverse events based on CTCAE and the treatment results based on the RECIST 1.1 criteria, in a group of patients treated for six or 12 months with vismodegib. Material and methods. The patient database was gathered from three sites and consisted of 42 patients, who represented 53.8% of the patients treated with vismodegib in Poland. The duration of the treatment ranged between three weeks and 68 months. The median of the treatment period was 8.25 months (0.75–68); the median of the observation of patients treated for less than 12 months was eight months (6–11), and for those treated for more than 12 months it was 14 months (12–68). Results. The summary of the treatment results after six and 12 months was performed on 29/42 and 17/42 patients accordingly. Complete response was achieved in 3/29 (10.3%) and 3/16 (17.6%) patients after six and 12 months of treatment, respectively, partial response in 13/29 (44.8%) and 5/16 (29.4%) patients, respectively, and stable disease in 13/29 (44.8%) and 8/16 (50.0%) patients, respectively. Progression of the disease was experienced by 7/42 (16.6%) patients within the period of 3–28 months of treatment. One patient with brain metastases died due to the progression of the disease. Adverse events were reported in 31/42 (73.8%) patients, more than one adverse event in a single patient was reported in 22/42 (52.3%) patients. No serious adverse events were observed.

Liposarcomas are the most common soft tissue sarcomas in adults. Diagnosis and treatment of liposarcoma should always be planned and conducted in centres experienced in the treatment of these heterogeneous malignancies with different prognosis and sensitivity to the treatment used. In the following paper, we present a summary of current knowledge about liposarcomas considering the differences between subtypes and new directions in treatment.

Introduction The use of immunotherapy in older patients remains challenging due to very few data on the efficacy and safety of treatment in this group. Aim To analyse the efficacy and safety of immunotherapy with checkpoint inhibitors in older patients (≥ 70 years) with metastatic melanoma. Material and methods In the Maria Skłodowska-Curie Institute – Oncology Centre, between 2011 and 2017, 318 non-resectable or metastatic melanoma patients were treated with immune checkpoint inhibitors: anti-CTLA-4 or/and anti-PD-1. Eighty-two patients were ≥ 70 years (median age: 76 years; range: 70–90 years). Among this group 10% of patients had brain metastases, 24% of patients had BRAF mutant melanoma, and co-morbidities were present in 86% of patients (mainly hypertension, cardiovascular diseases and/or diabetes). Results Median PFS and OS were similar in patients < 70 years and ≥ 70 years. In the group of patients ≥ 70 years old, the 2-year OS rate (from the start of immunotherapy) was 27%, and in patients aged < 70 it was 28% (p = NS). Two-year progression-free survival was 13.7% in the group of patients ≥ 70 years old and in patients aged < 70 it was 13% (p = NS). Patients ≥ 70 years of age were significantly less likely to have a BRAF mutation (p = 0.020). The presence of co-morbidities was not associated with an increased risk of immunotherapy (p = 0.790). Conclusions The survival and toxicity profile in the older patients treated with immune checkpoint inhibitors are similar to younger patients. Therefore, the age as a clinical factor should not exclude this population from the most effective therapy used nowadays in melanoma treatment.

Purpose/objective(s) Soft tissue sarcomas (STS) is a large group of rare cancers which present high intratumoral heterogeneity. Thus, the assessment of response to the neoadjuvant treatment applied for locally advanced STS remains a challenge. We hypothesized that the pathological response (PR) could be predicted using biomarkers of the tumor microenvironment, hypoxia, and DNA damage. Materials/methods We analyzed prospectively collected core biopsy tissue samples from patients who received preoperative 5 × 5 Gy with doxorubicin-ifosfamide for marginally resectable high-grade STS in a phase II clinical trial. We have chosen tumor-infiltrating macrophages (TAMs) and intratumoral microvascular density (IMVD) as biomarkers for the tumor microenvironment. Hypoxia-inducible factor 1-alpha (HIF1A) expression was selected as a biomarker of intratumoral hypoxia. Double-strand DNA breaks were evaluated by expression of the phosphorylated form of H2A histone family member X (gH2AFX). Immunohistochemical analysis (CD163, CD68, CD105, CD34, HIF1A, gH2AFX) was evaluated by experienced sarcoma pathologists blinded to sample identification with a semi-quantitative method. We scored TAMs by counting the number of positive-staining macrophages per mm2: 0-none, 1-low, and 2-high. IMVD were counted in five randomly selected fields at 200x magnification (∼6.9 mm2), and a total number of microvessels included scoring scale: 1 (1-25), 2 (26-50), 3 (51-100), and 5 (> 500). HIF1A and gH2AFX were assessed in H-score scale, including intensity: 0-none, 1-weak, 2-moderate, 3-strong, and percentage of stained cells in each category (range: 0-300). All markers were studied preoperatively, while HIF1A was additionally assessed in postoperative tissues to define hypoxic microenvironment shift after therapy. PR to the treatment was classified using the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group recommendations; grades A, B, C indicated good PR, whereas D and E suggested poor PR. Spearman rank correlation was used to measure the degree of association between biomarkers and PR. Results Nineteen patients were eligible for the analysis. We identified a good treatment PR in four cases (grades A = 1, B = 2, C = 1, D = 11, E = 4). High tumor infiltration with TAMs and high IMVD did not correlate with PR. High initial expression of HIF1A correlated with poor PR, whereas high expression of gH2AFX correlated with better PR (Tab. 1). We also confirmed decreased HIF1A expression after therapy between biomarkers and PR. Conclusion HIF1A (hypoxia degree) and gH2AFX (DNA damage extent) are candidate biomarkers for PR's prediction after neoadjuvant treatment in STS. Further evaluation in prospective studies is warranted.

Soft tissue sarcomas (STS) are rare malignant tumours derived from connective tissue. They constitute about 1% of malignancies occurring in adults. We distinguish over 60 subtypes of soft tissue sarcoma, each with a unique clinical course and a diversified response to systemic treatment. The prognosis for patients with locally advanced, unresectable or metastatic disease remains poor. For years, doxorubicin — used alone or in combination with ifosfamide — has been the basis of treatment for these patients. Trabectedin is a relatively new molecule registered in the treatment of patients diagnosed with STS. The drug was originally obtained from marine tunicates ( Ecteinascidia turbinata ), currently it is obtained semi-synthetically. So far, a number of potential mechanisms of trabectedin have been descri­bed, including DNA-binding, disruption of DNA repair mechanisms and cell cycle, as well as effects on transcription factors and the tumour microenvironment. The aim of the following review is to summarize the current knowledge on the efficacy and safety of trabectedin in the treatment of patients diagnosed with STS.

Introduction Desmoid fibromatosis (DF) is a locally aggressive, not metastasizing tumor associated with high local recurrence rates. Surgery was a standard-of-care for DF treatment; however, recently, conservative treatment and active surveillance are preferred. This study aimed to evaluate the real-life outcomes of DF treatment. Materials and methods All consecutive patients diagnosed with DF and treated between 01.1999 and 12.2018 at one sarcoma reference institution were included in this retrospective analysis. Kaplan-Meier estimator, long-rank test, Cox regression model, and Chi2 tests were used for statistical analyses. Results The analyses included 363 patients (254 female, 109 male). 195 patients (53.7%) underwent surgical resection, and 139 (38.3%) experienced a watch-and-wait approach with or without concomitant therapy with nonsteroid anti-inflammatory drugs (NSAIDs) in the first line. Disease recurrence/progression occurred in 43.2% of patients treated with surgery and 42.6% in the watch-and-wait group, resulting in 5-year event-free survival (EFS) rates of 60% and 55%, respectively. There was no difference in EFS between both groups (HR1.28, 95%CI 0.91–1.79). Surgery without prior biopsy and extra-abdominal wall location was associated with inferior outcomes. Conclusions Results of DF treatment in our center showed that watch-and-wait approach ± NSAIDs has similar efficacy to upfront surgery and allows to avoid unnecessary surgery in approximately half of the patients, primarily when tumors are located in unfavorable sites, like extremities.

The introduction of BRAF inhibitors dramatically improved the outcome of patients diagnosed with metastatic melanoma harboring BRAF mutation. The later addition of MEK inhibitors contributed to further improvement of treatment results without significant additional toxicity. The purpose of this chapter is to approximate knowledge about BRAF and MEK inhibitors—vemurafenib and cobimetinib, to present their mechanism of action, safety profile, and the results of clinical trials to date.

Malignant peripheral nerve sheath tumor (MPNST) is a rare type of soft tissue sarcomas. The localized disease is usually treated with surgery along with perioperative chemo- or radiotherapy. However, up to 70% of patients can develop distant metastases. The study aimed to evaluate the modes and outcomes of systemic treatment of patients with diagnosed MPNST treated in a reference center. In total, 115 patients (56 female and 59 male) diagnosed with MPNST and treated due to unresectable or metastatic disease during 2000&ndash, 2019 were included in the retrospective analysis. Schemes of systemic therapy and the outcomes&mdash, progression-free survival (PFS) and overall survival (OS)&mdash, were evaluated. The median PFS in the first line was 3.9 months (95% CI 2.5&ndash, 5.4). Doxorubicin-based regimens were the most commonly used in the first line (50.4% of patients). There were no significant differences in PFS between chemotherapy regimens most commonly used in the first line (p = 0.111). The median OS was 15.0 months (95% CI 11.0&ndash, 19.0) and the one-year OS rate was 63%. MPNST are resistant to the majority of systemic therapies, resulting in poor survival in advanced settings. Chemotherapy with doxorubicin and ifosfamide is associated with the best response and longest PFS. Future studies and the development of novel treatment options are necessary for the improvement of treatment outcomes.

Introduction: Myxoid liposarcoma (MLPS) has been reported to be more radiosensitive compared with other soft tissue sarcomas. The main objective of the study was to assess the efficacy of hypofractionated radiotherapy (RT) in the preoperative setting in patients with locally advanced primary MLPS. Methods: Single-arm prospective exploratory clinical trial enrolled MLPS patients for preoperative 5 &times, 5 Gy RT with delayed surgery. The endpoints of the study were the rate of early wound healing complications and 5-year local control rate. Results: 29 patients (pts) were included, all had tumors located on the lower limb. The median maximum size of the tumor was 13 cm (IQR 10&ndash, 15 cm). Early RT tolerance was good. Postoperative wound complications occurred in 11 pts (37.9%), late complications concerned 13.8% of patients. A total of 27 patients were included for the efficacy analyses. The pathological features of response to RT were detected in all analyzed surgical specimens. In 25 patients R0 margins were achieved, two patients had an R1 resection. None of the patients had local recurrence. Conclusion: Preoperative hypofractionated RT with a prolonged gap between RT and surgery is a feasible method of the management of MLPS, providing a good local control and low rates of treatment toxicity.

Purpose There is no standard treatment for marginally resectable soft tissue sarcomas (STSs) of the extremities and trunk wall, and current approaches produce unsatisfactory results. We hypothesized that the combination of doxorubicin-ifosfamide (AI) chemotherapy and 5 × 5 Gy hypofractionated radiotherapy can generate a higher ratio of limb-sparing or conservative surgeries with negative microscopic margins (R0) and acceptable treatment toxicity. Methods and Materials We conducted a single-arm prospective clinical trial. Treatment combined 1 cycle of AI with subsequent 5 × 5 Gy radiotherapy within 1 week, followed by 2 cycles of AI and surgery. The primary endpoint was to assess the number of patients in whom en bloc R0 resection was achieved. Results Forty-six patients met the eligibility criteria. Three patients had resectable lung metastases at baseline. Forty-two received the planned protocol treatment. In 2 patients, the treatment was prematurely stopped because of the toxicity of chemotherapy. One patient died of septic shock because of severe bone marrow suppression after the second AI cycle; a second death was not related to treatment for STS. Three patients underwent amputation. In 72% of patients in the intention-to-treat analysis, we achieved en bloc R0 resections. Grade 3+ Common Terminology Criteria for Adverse Events 4.03 chemotherapy toxicity requiring dose reduction or treatment interruption occurred in 15 patients. Wound complications occurred in 18 patients, but they were severe in only 6 patients. Conclusions Preoperative AI combined with 5 × 5 Gy radiotherapy is a promising method for the management of marginally resectable STS. This protocol enables a high ratio of R0 limb-sparing or conservative surgeries. Further evaluation of this strategy is warranted.

Background:Recent years have brought the dynamic development of a new method of cancer treatment: immunotherapy. Monoclonal antibodies blocking the programmed death receptor 1 (PD-1) are now widely used in the treatment of several malignancies: melanoma, lung, head and neck cancer, among others. The therapeutic benefit of immunotherapy in soft tissue sarcoma (STS) has not yet been proven. The exception is results obtained in the treatment of a rare STS subtype alveolar soft part sarcoma (ASPS).Case report:We describe a case of a man with a diagnosis of metastatic ASPS in whom the use of immunotherapy with nivolumab resulted in excellent long-term clinical benefit and a pathologically confirmed complete response.Conclusion:There are strong indications that immunotherapy may become the next important treatment method of ASPS.

Introduction The real-world data on adjuvant imatinib therapy in high-risk primary GIST are scarce. Methods We have analysed the data of 107 consecutive patients with gastrointestinal stromal tumour (GIST) after resection treated with adjuvant imatinib (for planned 3 years with initial dose 400 mg daily, started not later than 4 months after operation) in 6 oncological centres in 2013–2018. All patients were required to have high risk of recurrence (at least 50% according to NCCN/AFIP criteria), known mutational status to exclude PDGFRA D842V mutants and KIT/PDGFRA-wild type cases from therapy without any further selection. Median follow-up time was 27 months. Results The most common primary localization of GIST was small bowel (63 patients; 59%), followed by the stomach (40 patients; 37%). The majority of GIST cases harboured exon 11 KIT mutations (88 cases, 82%), 11 cases had exon 9 KIT mutations (10%), 8 had other KIT/PDGFRA mutations potentially sensitive to imatinib. Forty patients (37%) finished 3-year adjuvant imatinib therapy as planned, 48 (45%) still continue therapy, 5 (4.5%) patients had finished adjuvant therapy prematurely due to toxicity, 6 (6%) due to disease progression on treatment and 8 (7.5%) due to other reasons. The disease relapse was detected in 19 patients, of them in 5 cases in exon 9 KIT mutants (45%), and 14 cases in patients with exon 11 KIT mutations (11%) [p Conclusions The early results of adjuvant therapy with imatinib in routine practice outside clinical trials in high-risk mutation-driven GIST patients only confirm high efficacy of this therapy with better tolerability than in clinical trials. We found overrepresentation of exon 9 KIT mutants and ruptured tumors in a group of patients with disease relapse.

BACKGROUND: Liposarcomas can be divided into four subtypes and are most frequently located in the extremities. There are currently no studies comparing the clinical outcomes, such as local recurrence and distant metastasis, between the distinct subtypes of primary LPS of the extremity specifically.METHODS: Retrospective databases of two expertise centres (Rotterdam-R, Warsaw-W) of patients with liposarcoma located in the extremities from 1985 to 2015 were used to analyse 5-year local recurrence-free survival (5y-LRFS), 5-year distant metastasis-free survival (5y-DMFS) and 5-year overall survival (5y-OS).RESULTS: We identified 456 patients: 192 well-differentiated liposarcomas (WDLPS), 172 myxoid liposarcomas (MLPS), 54 pleomorphic liposarcomas (PLPS), 23 dedifferentiated liposarcomas (DDLPS) and 15 other subtypes. The frequency of (neo)adjuvant radiotherapy (R: 34.5% vs. W: 78.4%) and R0-resections (R: 41.0% vs. W: 84.1%) differed between the datasets. Local recurrences (LR) were observed most frequently in DDLPS (5y-LRFS 62.4%), followed by PLPS (71.4%), WDLPS (77.0%) and MLPS (84.5%, p = 0.054). Distant metastases (DM) were most commonly observed in PLPS (5y-DMFS 46.9%), followed by MLPS (74.0%), DDLPS (86.3%) and WDLPS (97.3%). 5y-OS was poorest in patients with PLPS (47.6%) and DDLPS (54.4%), followed by MLPS (79.7%) and WDLPS (92.4%, p < 0.001). Male gender significantly increased the risk of LR and DM. The subtypes MLPS and PLPS were significant prognostic factors for DM and OS. Additionally, DDLPS and age had significant impact on OS.CONCLUSION: In the largest cohort of extremity LPS patients reported to date, LPS subtypes show distinct patterns of LR, DM and OS, stressing that 'extremity LPS' is not a single entity.

e21541 Background: Immunotherapy (ITH) holds the possibility of tumor burden decrease after initial RECIST defined progression (PD). Clinical concept of treating of selected patients (pts) beyond PD is supported by this pseudoprogression phenomenon. The aim of this study was to evaluate real-life practice and outcomes related to treatment beyond progression (TBP) in melanoma patients. Methods: We evaluated advanced melanoma pts who started anti-PD1 treatment between 12/2015 and 12/2018 and identified pts who received TBP and had subsequent imaging to evaluate the tumor burden. Survival analyses were performed using the Kaplan-Meier method, Log-rank, chi-square and Fisher exact tests were used for comparison between groups. Data cut-off was 02/2021. Results: Of 399 subsequent melanoma pts treated, 57 (14%) patients received TBP. Anti-PD1 was 1st line treatment in 61.4% and 2nd line - in 38.6% of patients. 71.9% patients were diagnosed with skin, 7.0% - mucosal and 21.1% with FPI melanoma and 47.4% were BRAF mutated, 56.1% were male and 12.3% had 3 or more metastatic sites at treatment initiation. In this cohort median time to 1st PD (TTFP) was 4.43 months(m), while to 2nd PD (TTSP) – 8.01 m. On TBP 26.3% pts achieved objective response (OR), and next 42.1% - SD. 1st PD was reported most often as increase in 3 or more targets or one new lesion – both 22.8%; and in 24.6% cases involved central nervous system. In 56.8% second PD was observed in the same targets as 1st PD. 61.4% patients received multimodal treatment of ITH combined with radiation therapy – in 49.1%, surgery - 5.3% and both - 7.0%. There was no correlation of TTSP with gender, ECOG, initial disease stage or TNM, BRAF mutation, number of metastatic sites or pattern of progression. Multimodal treatment resulted in 13.6 m TTSP, while ITH alone - 8.0 m (p = 0.056). 1st line OR correlated with DCR on TBP while TTFP > 6 m correlated with TTSP (HR = 0.53, 95%CI 0.28-0.99). Patients with 1st line CR – had median TTSP 16.4 m, with PR – 23.5 m, while those with PD – 5.1 m. Median OS after 1st PD was 26 months and correlated with OR on TBP. Conclusions: Selected clinically fit melanoma patients despite evidence of first radiographic progression may benefit from continued treatment with PD-1 inhibitors. Multidisciplinary treatment should be offered to these patients including radiosurgery or stereotactic radiotherapy of progressing loci. Molecular biomarkers of TTSP should be analyzed in prospective studies.

e21521 Background: Merkel cell carcinoma (MCC) is an uncommon, aggressive neuroendocrine skin cancer. The prognosis in the unresectable and metastatic setting is very poor. Distant metastases develop in more than 30%. Chemotherapy (CHT), the previous mainstay of treatment, is associated with the high response rates (RR) of limited duration. The main cytotoxic drugs have been platinum derivatives, taxoids, anthracyclines, and etoposide. The standard systemic treatment for this disease has changed in the last few years. Immunotherapy (IO) is currently the basis of systemic therapy in the metastatic setting. This study aimed to analyze outcomes for unresectable and metastatic MCC pts treated in routine clinical practice, mostly before the era of IO availability. Methods: We conducted the retrospective analysis of data from 36 MCC pts in unresectable (n= 23) and metastatic (n=13) settings treated in three oncological centers, diagnosed between 01/2010 and 12/2019, with data cut-off on 31/12/2020. The data collected included epidemiological and clinical information. Survival analyses were performed using the Kaplan-Meier method and log-rank test. Results: The median patient age at diagnosis was 72 years (57-88); 58.3% were male. The most common primary tumor (PT) locations were lower limbs (41.7%), head and neck (30.6%), and upper limbs (16.7%). In 63.9% the PT was located in the sun-exposed skin. The most common location of distant metastases were nonregional lymph nodes (n=9) and lungs (n=3). Thirty-six pts received 1st line CHT with the median progression-free survival (mPFS) of 5.3 months (95%CI 2.88-7.7) and objective response of 61.1%, with 13.9% complete responses (CR). The most commonly used regimens were platinum-based and anthracycline-based regimens (n=26). Disease progression (PD) was observed in 91.7% of pts treated with 1st line CHT. Twenty-one pts received 2nd line therapy, IO (n=14), or CHT (n=7), with PD in 19 pts (90.6%), mPFS 2.83 months (95% CI 0.59-5.06) and RR of 33.3% (0% CR). 13 pts were treated with avelumab (AVE), all in the 2nd line, with RR of 38.5% (0% CR). The mPFS in the 2nd line was 5 months (95%CI 0-11.46) on AVE compared to 2.82 (95%CI 0.46-5.19) on CHT (HR 0.65, 95%CI 0.25-1.70, p=0.378). During 1st line systemic therapy, 16 pts underwent palliative surgery (n=7, 19.4%) or received radiation therapy (RT) (n=9, 25%), and during 2nd line, one patient was treated with surgery, and five pts received RT. The median overall survival was 10.38 months (95% CI 2.90-17.87). Local treatment did not improve the treatment outcomes in the 1st (p=0.119) nor 2nd line (p=0.821). Conclusions: Our results confirm the poor prognosis of pts with unresectable and metastatic MCC. The response rates and median PFS for CHT in the 1st and 2nd line setting are consistent with historical data. The treatment with AVE in the 2nd line allows achieving better results, similar to the results reported in the clinical trials.

e21566 Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with a high risk of recurrence and poor prognosis. The treatment of locally advanced disease includes surgery (SUR) and radiotherapy (RTH) to achieve high locoregional control rates. The sentinel lymph node biopsy (SLNB) is recommended procedure in cases without clinical nodal involvement. In selected cases, chemotherapy (CHT) may also be considered, but its role is not confirmed. This study aimed to analyze outcomes for locally advanced MCC pts treated in routine clinical practice. Methods: We conducted the retrospective analysis of data from 156 MCC pts treated with curative surgery in four oncological centers, diagnosed between 01/2010 and 12/2019, with data cut-off on 31/12/2020. The data collected included epidemiological and clinical information. Survival analyses were performed using the Kaplan-Meier method, log-rank test and multivariate Cox regression. Results: The median patient age at diagnosis was 72 years (30-94); 50.6% were male. The primary tumor (PT) locations were lower limbs (33.3%), upper limbs (30.1%), and head and neck (28.2%). MCC with no PT was diagnosed in 3.9%. In 62.0% the PT was located in the sun-exposed skin. The median tumor size was 25 mm (4-170). Lymph node (LN) involvement (clinical or positive SLNB or LND) at diagnosis was found in 26.9% (n = 42). The scar excision was done in 50.0% (positive in 16.6%), SLNB in 36.5% (positive in 10.5 %), 51.9% of pts received perioperative treatment, including RTH- 86.4%, CHT- 21%. The relapse rate was 38.3% (35.8% local-regional, 11.1% distant). With the median follow-up of 2.2-years, the median disease-free survival (DFS), local relapse-free survival (LRFS), and distant metastases-free survival (DMFS) were not reached. The 1-year DFS, LRFS and DMFS rates were 65%, 68%, and 90%. The negative independent risk factors for DFS were male gender (HR 1.42, 95%CI 1.06-3.01), metastases in LN at diagnosis (HR 5.41, 95%CI 2.39-12.26), no SLNB in pts with no clinical metastases in LN (HR 5.45, 95%CI 2.41-12.3), and no perioperative RTH (HR 2.19, 95%CI 1.29-3.76). The median overall survival (OS) was 6.9 years (95%CI 4.64-9.15). The negative independent risk factors for OS were male gender (HR 1.95, 95%CI 1.16-3.27), age above 70 (HR 2.0, 95%CI 1.15-3.48), metastases in LN at diagnosis (HR 3.15, 95%CI 1.49-6.68), and no SLNB in pts with no clinical metastases in LN (HR 2.30, 95%CI 1.10-4.82). PT location, UV-exposure, and perioperative CHT or RTH were not independent risk factors for OS. Conclusions: Our results confirm that the MCC treatment should be done in an experienced multidisciplinary team. Male gender, nodal involvement at diagnosis, and no SLNB in pts without clinical metastases in LN are associated with poor prognosis in DFS and OS. The perioperative RTH improves the treatment outcomes and reduces disease progression risk but does not impact OS. Perioperative CHT does not affect pts survival.

Background Alveolar soft part sarcoma (ASPS) is a rare, highly vascularized soft tissue sarcoma characterized by a high frequency of metastatic disease and resistance to classical chemotherapy. The purpose of our analysis was to assess long-term sunitinib activity in the treatment of metastatic ASPS. Patients and Methods Between 2009 and 2015, 15 patients were diagnosed with metastatic ASPS and received therapy with sunitinib at initial continuous daily dosing of 37.5 mg. Median age was 32 years. The primary tumor sites were lower extremities ( 8 ), trunk-retroperitoneum/pelvis ( 2 ), upper extremity ( 3 ) and other ( 2 ). All patients had unresectable disease (primary or relapse in the form of metastases to the lungs ± bones). Five patients received systemic therapy before initiating sunitinib. Median follow-up from start of sunitinib was 38 months (range 5-69 months). Results At the time of analysis 4 patients continue therapy and 9 are still alive. Six patients had RECIST partial remission as best response, 8 had stable disease, and 1 had disease progression. The median progression-free survival was 19 months, with 86% of patients being free of progression at 6 months. Median overall survival was 56 months; the 5-year overall survival rate was 49%. Five patients were treated with sunitinib longer than 2 years. All patients experienced some side effects: 8 patients (53%) had CTCAE grade 3/4 toxicity, 7 patients required dose reduction. The most common toxicities were neutropenia, thrombocytopenia, hypothyroidism, arterial hypertension, and hand-foot syndrome. Conclusions Our analysis confirms the long-term efficacy of sunitinib in patients with advanced ASPS.

BACKGROUND: Patients with well-differentiated liposarcoma (WDLPS) of the extremity are mostly treated surgically, thereby possibly inducing severe morbidities. Despite the excellent prognosis, the natural history is barely studied. The aim of this study was to evaluate the natural history of extremity WDLPS by evaluating the outcome of patients treated with active surveillance (AS), who thereby exhibited the natural history of extremity WDLPS, and of patients treated surgically.METHODS: A large retrospective database of patients with extremity WDLPS was assessed to evaluate treatment, dedifferentiation and disease-specific survival. Lastly, our experience with patients treated with AS was explored.RESULTS: Distant metastases (5/191 patients, 2.6%) were mainly seen after a dedifferentiated local recurrence. Death of disease occurred in 4/191 patients (2.1%); two patients died from metastatic disease (although not pathologically proven), two patients died of treatment-related complications. In our center, 24 patients are treated with AS. Time of AS varied from 0.1 to 8.9 years (median 1.8). Four patients eventually underwent surgery after a period of AS (range 14-52 months) because of symptoms and/or tumor growth. No areas of dedifferentiation were found in these resection specimens. The other patients are still under active surveillance.CONCLUSION: Since surgical treatment might induce morbidity and even mortality, there might be overtreatment of these patients. Evaluation of the natural history of extremity WDLPS showed that AS could be a reasonable option for selected patients. Prospective studies in patients with extremity WDLPS are needed to assess the safety of AS as a treatment option.

Introduction. Melanoma is a heterogeneous group of tumours with poor prognosis if the disease is metastatic. More than half of patients with melanoma of the skin have detectable mutations in the BRAF gene. Vemurafenib is the BRAF kinase inhibitor used in the treatment of patients with advanced melanoma with the BRAF mutation. This improves time to progression-free survival and overall survival in patients with this diagnosis. The aim of the study was to analyse the results of treatment and safety of vemurafenib in patients treated during the Polish drug programme. Materials and methods .Between October 2013 and April 2015 a total of 189 patients were treated, 90 women and 99 men, who had previously been diagnosed with unresectable/metastatic melanoma with BRAF V600 mutation. Patients received vemurafenib in 960 mg dose twice per day. The estimated progression-free survival, overall survival and adverse events were assessed. For the survival analysis the Kaplan-Meier method and log-rank test (log-rank) for multi-factor analysis were used. Results. In the first evaluation of the effectiveness of treatment, 8 patients (4.3%) had a complete response, 75 patients (39.7%) partial response, 62 patients (32.8%) had stable disease, and 44 patients (23.2%) had progression of the disease. The disease was controlled in 76.7% of patients. After progression during the therapy with vemurafenib 27% of the patients received subsequent lines of systemic therapy. Twenty-eight patients received chemotherapy and 22 patients immunotherapy with ipilimumab. During the last analysis dated 5 September 2015, the median observation time for still living patients was 8 months (range 3–26). Median progression-free survival was 6.7 months. The median overall survival was 12 months. 146 patients (77%) had adverse events, mostly in the form of dermal toxicity of Grades 1 and 2. Thirty-two patients (17%) presented with side effects of the 3rd and 4th grades of toxicity. Two patients had to stop the treatment due to the toxicity. There were no deaths reported due to the toxicity of treatment. Conclusions. The multicentre analysis confirmed the efficacy and safety of vemurafenib in routine clinical practice in a heterogeneous group of advanced melanomas with BRAF mutation. We confirmed the importance of the known prognostic factors for overall survival in this group of patients, such as lactate dehydogenaze activity (LDH) and ECOG performance status. The current survival of patients with the metastatic melanomas with BRAF mutations are longer than those observed in historical groups.