Postoperative drainage management and wound complications following resection of lower limb soft tissue tumors: a retrospective cohort study.

PURPOSE: Postoperative wound complications are common in patients undergoing resection of lower extremity soft tissue tumors. Postoperative drainage therapy ensures adequate wound healing but may delay or complicate it. The aim of this study is to evaluate the incidence of postoperative wound complications and delayed or prolonged drainage treatment and to propose a standardized definition and severity grading of complex postoperative courses. METHODS: A monocentric retrospective analysis of 80 patients who had undergone primary resection of lower extremity soft tissue tumors was performed. A new classification was developed, which takes into account postoperative drainage characteristics and wound complications. Based on this classification, risk factors and the prognostic value of daily drainage volumes were evaluated. RESULTS: According to this new definition, regular postoperative course grade 0 (no wound complication and timely drainage removal) occurred in 26 patients (32.5%), grade A (minor wound complications or delayed drainage removal) in 12 (15.0%), grade B (major wound complication or prolonged drainage therapy) in 31 (38.8%), and grade C (reoperation) in 11 (13.7%) patients. Tumor-specific characteristics, such as tumor size (p = 0.0004), proximal tumor location (p = 0.0484), and tumor depth (p = 0.0138) were identified as risk factors for complex postoperative courses (grades B and C). Drainage volume on postoperative day 4 was a suitable predictor for complex courses (cutoff of 70 ml/d). CONCLUSION: The proposed definition incorporates wound complications and drainage management while also being clinically relevant and easy to apply. It may serve as a standardized endpoint for assessing the postoperative course after resection of lower extremity soft tissue tumors.

RETROPERITONEAL PERIVASCULAR EPITHELIOID CELL NEOPLASM (PECOMA) RESPONSE TO MTOR KINASE INHIBITION. A CASE REPORT WITH LITERATURE REVIEW.

Perivascular epithelioid cell tumors (PEComas) are a very rare group of neoplasms and were first reported in 1996. These tumors represent a family of mesenchymal neoplasms, related through activation of the mammalian target of rapamycin (mTOR) inhibitor signaling pathway. The objective of this case report is to demonstrate significant regression of the tumor after neoadjuvant treatment with an oral mTOR inhibitor, following surgical removal of the mass to avoid a multiorgan resection. We present a case of a 27-year-old female with retroperitoneal PEComa and evaluated the tumor with MRI and integrated 18F-FDG-PET/CT scans at presentation and serially during treatment with everolimus. After 6 months of treatment with everolimus the tumor showed a substantial size reduction. Therefore, a multiorgan resection could be omitted. The patient has not demonstrated any disease recurrence after nearly 2 years of follow-up. PEComas are tumors with unpredictable behavior. Our report indicates that treatment of PEComas with everolimus may achieve a significant clinical response. As indicated by our case and past reports, mTOR inhibitors may be one of the best treatment options for this disease.

Final analysis of the randomized trial on imatinib as an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), and Spanish Group for Research on Sarcomas (GEIS)☆.

BACKGROUND: In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk gastrointestinal stromal tumors (GIST) patients. Interim analysis results were published in 2015 upon recommendation from an independent data review committee. We report the final outcome of the study. PATIENTS AND METHODS: This was a randomized, open-label, multicenter phase III trial carried out at 112 hospitals in 12 countries. Patients were randomized to 2 years of imatinib, 400 mg daily, or no further therapy after surgery. The primary endpoint was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary endpoints. Adjusting for the interim analyses, results on IFFS were assessed on a 4.3% significance level; for the other endpoints, 5% was used. RESULTS: Nine hundred and eight patients were randomized between January 2005 and October 2008: 454 to imatinib and 454 to observation; 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm [hazard ratio (HR) = 0.87, 95.7% confidence interval (CI) (0.65; 1.15), P = 0.31]; RFS was 70% versus 63% at 5 years and 63% versus 61% at 10 years, [HR = 0.71, 95% CI (0.57; 0.89), P = 0.002]; OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years [HR = 0.88, 95% CI (0.65; 1.21), P = 0.43]. Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43%, respectively. CONCLUSIONS: With 9.1 years of follow-up, a trend toward better long-term IFFS in imatinib-treated patients was observed in the high-risk subgroup. Although the difference was not statistically significant and the surrogacy value of such an endpoint is not validated, this may be seen as supporting the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high-risk GIST patients treated with 3 years of adjuvant imatinib.

Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network.

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.

[Principles of sarcoma surgery]. / Prinzipien der Sarkomchirurgie.

Soft-tissue sarcomas are rare malignant tumors. Surgery remains the most important treatment modality. Neoadjuvant and/or adjuvant chemo- and radiotherapy may be administered to improve the local and systemic outcome. Advances in oncological and reconstructive surgery, combined with the use of multimodal therapies, have made mutilating surgery rare events in extremity sarcomas. In retroperitoneal sarcomas, local recurrences are life-threatening events and multivisceral resection has become the standard surgical procedure. The subjects of this review are diagnostics, multimodal therapy, and resection strategy from a surgical point of view.

An update on the management of sporadic desmoid-type fibromatosis: a European Consensus Initiative between Sarcoma PAtients EuroNet (SPAEN) and European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG).

Desmoid-type fibromatosis is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Currently, there is no established or evidence-based treatment approach available for this disease. Therefore, in 2015 the European Desmoid Working Group published a position paper giving recommendations on the treatment of this intriguing disease. Here, we present an update of this consensus approach based on professionals' AND patients' expertise following a round table meeting bringing together sarcoma experts from the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group with patients and patient advocates from Sarcoma PAtients EuroNet. In this paper, we focus on new findings regarding the prognostic value of mutational analysis in desmoid-type fibromatosis patients and new systemic treatment options.

A phase II study of a human anti-PDGFRα monoclonal antibody (olaratumab, IMC-3G3) in previously treated patients with metastatic gastrointestinal stromal tumors.

Background: This study evaluated tumor response to olaratumab (an anti-PDGFRα monoclonal antibody) in previously treated patients with metastatic gastrointestinal stromal tumor (GIST) with or without PDGFRα mutations (cohorts 1 and 2, respectively). Patients and methods: Patients received olaratumab 20 mg/kg intravenously every 14 days until disease progression, death, or intolerable toxicity occurred. Outcome measures were 12-week tumor response, progression-free survival (PFS), overall survival (OS), and safety. Results: Of 30 patients enrolled, 21 patients received ≥1 dose of olaratumab. In the evaluable population (cohort 1, n = 6; cohort 2, n = 14), no complete response (CR) or partial response (PR) was observed. Stable disease (SD) was observed in 3 patients (50.0%) in cohort 1 and 2 patients (14.3%) in cohort 2. Progressive disease (PD) was observed in 3 patients (50.0%) in cohort 1 and 12 patients (85.7%) in cohort 2. The 12-week clinical benefit rate (CR + PR + SD) (90% CI) was 50.0% (15.3-84.7%) in cohort 1 and 14.3% (2.6-38.5%) in cohort 2. SD lasted beyond 12 weeks in 5 patients (cohort 1, n = 3; cohort 2, n = 2). Median PFS (90% CI) was 32.1 (5.0-35.9) weeks in cohort 1 and 6.1 (5.7-6.3) weeks in cohort 2. Median OS was not reached in cohort 1 and was 24.9 (14.4-49.1) weeks in cohort 2. All patients in cohort 1 and 9 (64.3%) in cohort 2 experienced an olaratumab-related adverse event (AE), most commonly fatigue (38.1%), nausea (19.0%), and peripheral edema (14.3%). Two grade ≥3 olaratumab-related events were reported (cohort 1, syncope; cohort 2, hypertension). Conclusions: Olaratumab had an acceptable AE profile in patients with GIST. While there was no apparent effect on PFS in patients without PDGFRα mutations, patients with PDGFRα-mutant GIST (all with D842V mutations) treated with olaratumab had longer disease control compared with historical data for this genotype. ClinicalTrials.gov Identifier: NCT01316263.

Best practices for the management of local-regional recurrent chordoma: a position paper by the Chordoma Global Consensus Group.

Chordomas are rare, malignant bone tumors of the skull-base and axial skeleton. Until recently, there was no consensus among experts regarding appropriate clinical management of chordoma, resulting in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation, the global chordoma patient advocacy group, convened a multi-disciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published, covering the management of primary and metastatic chordomas. Additional evidence and further discussion were needed to develop recommendations about the management of local-regional failures. Thus, ESMO and CF convened a second consensus group meeting in November 2015 to address the treatment of locally relapsed chordoma. This meeting involved over 60 specialists from Europe, the United States and Japan with expertise in treatment of patients with chordoma. The consensus achieved during that meeting is the subject of the present publication and complements the recommendations of the first position paper.

In-vivo quantification of the revascularization of a human acellular dermis seeded with EPCs and MSCs in co-culture with fibroblasts and pericytes in the dorsal chamber model in pre-irradiated tissue.

INTRODUCTION: Transplantation of a cell-seeded graft may improve wound healing after radiotherapy. However, the survival of the seeded cells depends on a rapid vascularization of the graft. Co-culturing of adult stem cells may be a promising strategy to accelerate the vessel formation inside the graft. Thus, we compared the in vivo angiogenic potency of mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC) using dorsal skinfold chambers and intravital microscopy. MATERIALS AND METHODS: Cells were isolated from rat bone marrow and adipose tissue and characterized by immunostaining and flow cytometry. Forty-eight rats received a dorsal skinfold chamber and were divided into 2 main groups, irradiated and non-irradiated. Each of these 2 groups were further subdivided into 4 groups: unseeded matrices, matrices + fibroblasts + pericytes, matrices + fibroblasts + pericytes + MSCs and matrices + fibroblasts + pericytes + EPCs. Vessel densities were quantified semi-automatically using FIJI. RESULTS: Fibroblasts + pericytes - seeded matrices showed a significantly higher vascular density in all groups with an exception of non-irradiated rats at day 12 compared to unseeded matrices. Co-seeding of MSCs increased vessel densities in both, irradiated and non-irradiated groups. Co-seeding with EPCs did not result in an increase of vascularization in none of the groups. DISCUSSION: We demonstrated that the pre-radiation treatment led to a significant decreased vascularization of the implanted grafts. The augmentation of the matrices with fibroblasts and pericytes in co-culture increased the vascularization compared to the non-seeded matrices. A further significant enhancement of vessel ingrowth into the matrices could be achieved by the co-seeding with MSCs in both, irradiated and non-irradiated groups.

Impact of chemotherapy in uterine sarcoma (UtS): review of 13 clinical trials from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) involving advanced/metastatic UtS compared to other soft tissue sarcoma (STS) patients treated with first line chemotherapy.

OBJECTIVE: UtS are a group of uncommon tumors representing 1% of malignant neoplasms of the female genital tract, and 7% of sarcomas. The objective of this study was to evaluate the factors associated with the clinical behavior UtS. METHODS: Information on 269 patients with advanced or metastatic first line UtS treated by chemotherapy was available in a database containing information on 3270 patients with advanced soft tissue sarcomas (STS) entered in EORTC-STBSG clinical trials between 1977 and 2010. The chemotherapy was aggregated in 4 categories: anthracyclines alone, ifosfamide alone, the combination of doxorubicin and ifosfamide, and CYVADIC. RESULTS: Among the 269 UtS pts, there were 231 deaths (median OS 10.4months, 95% CI: 9.1-11.9) and 257 progressions and/or deaths (median PFS 4.1months, 95% CI: 3.5-4.9). Multivariate analyses reported PS (p<0.001) only to be a statistically significant prognostic factor for OS in UtS; for PFS, LMS histology (p=0.025) is associated with a better outcome. There was no relationship between the 4 groups of chemotherapy regimens and impact on clinical outcomes. Histological subtype was significantly correlated with response to chemotherapy (RR: LMS 19% vs other 33%, p=0.026). Ifosfamide single agent yielded only 5% of RR. CONCLUSIONS: Clearly, UtS are very aggressive neoplasms with poor outcome when treated with chemotherapy consisting of anthracyclines with or without ifosfamide or cyclophosphamide. New strategies are urgently needed.

Guidelines for time-to-event end point definitions in sarcomas and gastrointestinal stromal tumors (GIST) trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: The use of potential surrogate end points for overall survival, such as disease-free survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCTs) in cancer. However, the definition of time-to-event (TTE) end points is rarely precise and lacks uniformity across trials. End point definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event End points in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for RCT in sarcomas and gastrointestinal stromal tumors (GIST). METHODS: We first carried out a literature review to identify TTE end points (primary or secondary) reported in publications of RCT. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points. Recommendations were developed through a validated consensus method formalizing the degree of agreement among experts. RESULTS: Recommended guidelines for the definition of TTE end points commonly used in RCT for sarcomas and GIST are provided for adjuvant and metastatic settings, including DFS, TTF, time to progression and others. CONCLUSION: Use of standardized definitions should facilitate comparison of trials' results, and improve the quality of trial design and reporting. These guidelines could be of particular interest to research scientists involved in the design, conduct, reporting or assessment of RCT such as investigators, statisticians, reviewers, editors or regulatory authorities.

Accumulation of small hyaluronan oligosaccharides in tumour interstitial fluid correlates with lymphatic invasion and lymph node metastasis.

BACKGROUND: Association studies have implicated the glycosaminoglycan hyaluronan (hyaluronic acid, HA) and its degrading enzymes the hyaluronidases in tumour progression and metastasis. Oligosaccharides of degraded HA have been ascribed a number of biological functions that are not exerted by high-molecular-weight HA (HMW-HA). However, whether these small HA oligosaccharides (sHA) have a role in tumour progression currently remains uncertain due to an inability to analyse their concentration in tumours. METHODS: We report a novel method to determine the concentration of sHA ranging from 6 to 25 disaccharides in tumour interstitial fluid (TIF). Levels of sHA were measured in TIF from experimental rat tumours and human colorectal tumours. RESULTS: While the majority of HA in TIF is HMW-HA, concentrations of sHA up to 6 µg ml(-1) were detected in a subset of tumours, but not in interstitial fluid from healthy tissues. In a cohort of 72 colorectal cancer patients we found that increased sHA concentrations in TIF are associated with lymphatic vessel invasion by tumour cells and the formation of lymph node metastasis. CONCLUSIONS: These data document for the first time the pathophysiological concentration of sHA in tumours, and provide evidence of a role for sHA in tumour progression.

Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma: pooled analysis of two STBSG-EORTC phase III clinical trials.

BACKGROUND: The EORTC-STBSG coordinated two large trials of adjuvant chemotherapy (CT) in localized high-grade soft tissue sarcoma (STS). Both studies failed to demonstrate any benefit on overall survival (OS). The aim of the analysis of these two trials was to identify subgroups of patients who may benefit from adjuvant CT. PATIENTS AND METHODS: Individual patient data from two EORTC trials comparing doxorubicin-based CT to observation only in completely resected STS (large resection, R0/marginal resection, R1) were pooled. Prognostic factors were assessed by univariate and multivariate analyses. Patient outcomes were subsequently compared between the two groups of patients according to each analyzed factor. RESULTS: A total of 819 patients had been enrolled with a median follow-up of 8.2 years. Tumor size, high histological grade and R1 resection emerged as independent adverse prognostic factors for relapse-free survival (RFS) and OS. Adjuvant CT is an independent favorable prognostic factor for RFS but not for OS. A significant interaction between benefit of adjuvant CT and age, gender and R1 resection was observed for RFS and OS. Males and patients >40 years had a significantly better RFS in the treatment arms, while adjuvant CT was associated with a marginally worse OS in females and patients <40 years. Patients with R1 resection had a significantly better RFS and OS favoring adjuvant CT arms. CONCLUSION: Adjuvant CT is not associated with a better OS in young patients or in any pathology subgroup. Poor quality of initial surgery is the most important prognostic and predictive factor for utility of adjuvant CT in STS. Based on these data, we conclude that adjuvant CT for STS remains an investigational procedure and is not a routine standard of care.

[Principles of surgery for retroperitoneal sarcoma]. / Chirurgische Therapieprinzipien bei retroperitonealen Sarkomen.

The successful treatment of retroperitoneal soft tissue sarcomas requires an experienced team consisting of not only surgeons but also pathologists and radiologists with a high case load in these tumours. The decisive step in the preoperative work-up of these, often late detected, tumours is their reliable grading as well as, if necessary, recognition of the sarcoma subtype as a basis for determining the direction of treatment. Imaging methods provide essential information with regard to the detection of infiltration of neighbouring structures and organs. Magnetic resonance imaging (MRI) is the most suitable method for this purpose. Punch needle biopsy is to be preferred over fine-needle biopsy in all cases for histological confirmation. The surgical standard procedure for the majority of the patients comprises multivisceral resection as principle, with additional colon resection, nephrectomy, and resection of abdominal wall musculature or, respectively, the psoas muscle in order to achieve an R0 resection of the retroperitoneal compartment. If only small margins of clearance are to be expected, a preoperative (neoadjuvant) treatment with radiation and/or chemotherapy even in combination with deep wave hyperthermia for high grade sarcomas should be strongly considered. Adjuvant postoperative radiation therapy often cannot be adequately applied due to the occupation of the former tumour bed by abdominal organs that were displaced by the mass effect, especially the radiation-sensitive small bowel. The optimal treatment strategy for these patients must be discussed in a multidisciplinary tumour board prior to any diagnostic or therapeutic procedure.