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The current American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system does not have sufficient details to encompass the variety of soft-tissue sarcomas, and available prognostic methods need refinement. We aimed to develop and externally validate two prediction nomograms for overall survival and distant metastases in patients with soft-tissue sarcoma in their extremities. Consecutive patients who had had an operation at the Istituto Nazionale Tumori (Milan, Italy), from Jan 1, 1994, to Dec 31, 2013, formed the development cohort. Three cohorts of patient data from the Institut Gustave Roussy (Villejuif, France; from Jan 1, 1996, to May 15, 2012), Mount Sinai Hospital (Toronto, ON, Canada; from Jan 1, 1994, to Dec 31, 2013), and the Royal Marsden Hospital (London, UK; from Jan 1, 2006, to Dec 31, 2013) formed the external validation cohorts. We developed the nomogram for overall survival using a Cox multivariable model, and a Fine and Gray multivariable model for the distant metastases nomogram. We applied a backward procedure for variables selection for both nomograms. We assessed nomogram model performance by examining overall accuracy (Brier score), calibration (calibration plots and Hosmer–Lemeshow calibration test), and discrimination (Harrell C index). We plotted decision curves to evaluate the clinical usefulness of the two nomograms. 1452 patients were included in the development cohort, with 420 patients included in the French validation cohort, 1436 patients in the Canadian validation cohort, and 444 patients in the UK validation cohort. In the development cohort, 10-year overall survival was 72·9% (95% CI 70·2–75·7) and 10-year crude cumulative incidence of distant metastases was 25·0% (95% CI 22·7–27·5). For the overall survival nomogram, the variables selected applying a backward procedure in the multivariable Cox model (patient's age, tumour size, Fédération Française des Centres de Lutte Contre le Cancer [FNCLCC] grade, and histological subtype) had a significant effect on overall survival. The same variables, except for patient age, were selected for the distant metastases nomogram. In the development cohort, the Harrell C index for overall survival was 0·767 (95% CI 0·743–0·789) and for distant metastases was 0·759 (0·736–0·781). In the validation cohorts, the Harrell C index for overall survival and distant metastases were 0·698 (0·638–0·754) and 0·652 (0·605–0·699; French), 0·775 (0·754–0·796) and 0·744 (0·720–0·768; Canadian), and 0·762 (0·720–0·806) and 0·749 (0·707–0·791; UK). The two nomograms both performed well in terms of discrimination (ability to distinguish between patients who have had an event from those who have not) and calibration (accuracy of nomogram prediction) when applied to the validation cohorts. Our nomograms are reliable prognostic methods that can be used to predict overall survival and distant metastases in patients after surgical resection of soft-tissue sarcoma of the extremities. These nomograms can be offered to clinicians to improve their abilities to assess patient prognosis, strengthen the prognosis-based decision making, enhance patient stratification, and inform patients in the clinic. None.

Purpose To explore patterns of failure and postrelapse outcome of patients with retroperitoneal sarcoma primarily treated by extended resection. Methods All consecutive patients with primary retroperitoneal sarcoma, treated between January 2002 and December 2011 at two European sarcoma centers were included. Five-year overall survival (OS) and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastases (DM) were calculated. Multivariate analyses for OS and CCI of LR and DM were performed. Postrelapse OS was investigated. Results A total of 377 patients were identified. Median follow-up from the time of primary surgery was 44 months [interquartile range (IQR) 27–82]. Five-year OS was 64 % [95 % confidence interval (CI) 0.588, 0710]. CCI of LR and DM were 23.6 % (95 % CI 18.9, 29.4) and 21.9 % (95 % CI 17.6, 27.3), respectively. OS, CCI of LR and DM were 87, 18 % and 0 for well-differentiated liposarcoma; 54, 44 and 9 % for grade II dedifferentiated liposarcoma; 41,33, and 44 % for grade III dedifferentiated liposarcoma; 58, 5, and 55 % for leiomyosarcoma; and 85, 4, and 17 % for solitary fibrous tumor, respectively. Seventy-six patients developed LR. Median postrelapse follow-up was 27 months (IQR 10–58). Twenty-one patients (27 %) underwent a second surgical resection (complete in 18), while 55 (73 %) did not (22 multifocal, 17 inoperable, 16 other causes). Median postrelapse OS was 17 months (IQR 7–31). Well-differentiated liposarcoma histology and disease-free interval predicted postrelapse OS, while surgical resection did not. Conclusions When primary extended surgery limits LR, histologic subtype and grade determine the outcome. At recurrence, a second surgery is of limited benefit.

Background First described in 1977, myxofibrosarcoma is one of the most common sarcoma subtypes of the elderly. Until some years ago, myxofibrosarcoma was diagnosed as “myxoid malignant fibrous histiocytoma.” The aim of this retrospective case series analysis was to investigate prognostic factors and the clinical outcome of a cohort of patients with myxofibrosarcoma treated at a single institution. Methods We reviewed 158 patients with localized myxofibrosarcoma who underwent surgery at the Istituto Nazionale Tumori of Milan, Italy, over 15 years. Local recurrence, distant metastases, and survival were analyzed. Results One hundred twenty patients had primary tumors, while 38 patients had locally recurrent tumors. Five-year overall survival was 77%. Tumor size, grade, and margins were statistically significant predictors of survival. Five-year local recurrence and distant metastases rate were 18% and 15%, respectively. Surgical margins were the only statistically significant prognosticator of local relapses. Patients treated with radiotherapy had the same prognosis as nontreated patients, but likely they had worse local presentations. The histological grade correlated with distant recurrences but not with local relapses. The value of adjuvant chemotherapy could not be determined. Conclusions Patients with myxofibrosarcoma have a better disease-specific survival than other sarcoma subtypes, but also a higher local relapse rate. This is likely related to the peculiar local growth pattern of these tumors. Adequate surgery should be pursued, while the role of adjuvant therapies need to be investigated.

Purpose Surgery is still the standard treatment for desmoid-type fibromatosis (DF). Recently, the Institut Gustave Roussy (IGR), Villejuif, France, reported a series of patients treated with a front-line conservative approach (no surgery and no radiotherapy). The disease remained stable in more than half of patients. This study was designed to evaluate this approach on the natural history of the disease in a larger series of patients. Methods A total of 142 patients presenting to the IGR or Istituto Nazionale Tumori (INT), Milan, Italy, were initially treated using a front-line deliberately conservative policy. Their progression-free survival (PFS) was observed and a multivariate analysis was performed for major clinical variables. Results Seventy-four patients presented with primary tumor, 68 with recurrence. Eighty-three patients received a “wait & see” policy (W&S), whereas 59 were initially offered medical therapy (MT), mainly hormonal therapy and chemotherapy. A family history of sporadic colorectal cancer was present in 8% of patients. The 5-year PFS was 49.9% for the W&S group and 58.6% for the medically treated patients ( P  = 0.3196). Similar results emerged for primary and recurrent DF. Multivariate analysis identified no clinical variables as independent predictors of PFS. In the event of progression, all patients were subsequently managed safely. Conclusions A conservative policy could be a safe approach to primary and recurrent DF, which could avoid unnecessary morbidity from surgery and/or radiation therapy. Half of patients had medium-term stable disease after W&S or MT. A multidisciplinary, stepwise approach should be prospectively tested in DF.

Background Preoperative imatinib therapy of locally advanced GIST may facilitate resection and decrease morbidity of the procedure. Methods We have pooled databases from 10 EORTC STBSG sarcoma centers and analyzed disease-free survival (DFS) and disease-specific survival (DSS) in 161 patients with locally advanced, nonmetastatic GISTs who received neoadjuvant imatinib. OS was calculated from start of imatinib therapy for locally advanced disease until death or last follow-up (FU) after resection of the GIST. DFS was calculated from date of resection to date of disease recurrence or last FU. Median FU time was 46 months. Results The primary tumor was located in the stomach (55 %), followed by rectum (20 %), duodenum (10 %), ileum/jejunum/other (11 %), and esophagus (3 %). The tumor resection after preoperative imatinib (median time on therapy, 40 weeks) was R0 in 83 %. Only two patients have demonstrated disease progression during neoadjuvant therapy. Five-year DSS/DFS rates were 95/65 %, respectively, median OS was 104 months, and median DFS was not reached. There were 56 % of patients who continued imatinib after resection. Thirty-seven GIST recurrences were diagnosed (only 5 local relapses). The most common mutations affected exon 11 KIT (65 %). Poorer DFS was related to primary tumor location in small bowel and lack of postoperative therapy with imatinib. Conclusions Our analysis comprising the largest group of GIST patients treated with neoadjuvant imatinib in routine practice indicates excellent long-term results of combined therapy in locally advanced GISTs.

Background Clinical Ethics Support Services (CESS) have been established to support healthcare professionals in addressing ethically sensitive issues in clinical practice and, in many countries, they are under development. In the context of growing CESS, exploring how healthcare professionals experience and address clinical ethics issues in their daily practice represents a fundamental step to understand their potential needs. This is even more relevant in the context of extremely sensitive diseases, such as cancer. On this basis, we carried out a qualitative study conducting in-depth semi-structured interviews with stakeholders of a major comprehensive cancer centre in Italy, with the twofold aim of investigating what ethical issues arise in the context of clinical oncology and how they are addressed, as well as stakeholders’ expectations about a potential CESS to be implemented within the Institution. Methods The study was conducted within the theoretical framework of Grounded Theory. Participants were healthcare professionals and other key stakeholders working within the cancer centre. The semi-structured interview aimed at exploring common ethical aspects of oncology, investigating stakeholders’ professional experience in dealing with clinical ethics issues, their expectations and requests regarding ethics support services. Transcripts of the interviews were coded and analysed according to the principles of Grounded Theory. Results Twenty-one stakeholders were interviewed. Our analysis showed a wide consensus on the identification of ethically relevant issues, above all those concerning communication, end-of-life, and resource allocation. The absence of institutional tools or strategies to address and manage ethical issues at the patient bedside emerged, and this is reflected in the widespread request for their development in the future. The ideal support service should be fast and flexible in order to adapt to different needs and clinical cases. Conclusions The interviewees showed a limited degree of ‘ethical awareness’: despite having reported many issues in clinical practice, they could hardly identify and describe the ethical aspects, while  complaining about a lack of ethical resources in their management. To build a truly effective support service, it therefore seems appropriate to take such context into consideration and address the emerged needs. Ethical sensitivity seems to be key and it becomes even more relevant in critical clinical areas, such as the therapeutic pathways of terminally ill patients.

Background The aim of this study was to report on sirolimus activity in a series of patients with hemangioendothelioma (HE) treated at the National Cancer Institute, Milan (Istituto Nazionale Tumori; INT) and within the Italian Rare Cancer Network (“Rete Tumori Rari”; RTR). Methods We retrospectively reviewed patients with advanced and progressing epithelioid hemangioendothelioma (EHE) treated with sirolimus at the INT and/or within the RTR. Pathologic review and molecular analysis for WWTR1 rearrangement were performed. Sirolimus was administered until unacceptable toxicity or progression, with the dose being adjusted to reach target plasma levels of 15–20 ng/dL. Responses were assessed using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Results Since 2005, 18 patients (17 EHE, 1 retiform HE; 1 locally advanced, 17 metastatic; WWTR1 rearrangement: 16) have been identified, with 17/18 patients being evaluable for response. Mean sirolimus daily dose was 4.5 mg. According to RECIST, best responses in EHE were 1 partial response (PR), 12 stable disease (SD), and 3 progressive disease (PD); the patient with retiform HE also achieved a PR, lasting >2 years. Four patients with a reversed interval progression on interruption were observed. Median overall survival was 16 months, and median progression-free survival was 12 months (range 1–45), with four patients progression-free at 24 months. The clinical benefit (complete response [CR] + PR + SD  > 6 months) was 56 %. Seven patients receiving sirolimus experienced an increase in pleural/peritoneal effusion plus worsening of tumor-related symptoms; six of these patients died within 1–8 months from evidence of effusion progression, while a RECIST PD was assessed in two of seven patients. Conclusions A clinical benefit was achieved in 56 % of patients receiving sirolimus, which lasted >24 months in four patients. Most patients with pleural effusion did not benefit from sirolimus and had a poor outcome.

Background The marine drug trabectedin has shown unusual effectiveness in the treatment of myxoid liposarcoma (MLPS), a liposarcoma characterized by the expression of the FUS-DDIT3 chimera. Trabectedin elicits a significant transcriptional response in MLPS resulting in cellular depletion and reactivation of adipogenesis. However, the role of the chimeric protein in the mechanism of action of the drug is not entirely understood. Methods FUS-DDIT3-specific binding sites were assessed through Chromatin Immunoprecipitation Sequencing (ChIP-Seq). Trabectedin-induced effects were studied on pre-established patient-derived xenograft models of MLPS, one sensitive to (ML017) and one resistant against (ML017ET) trabectedin at different time points (24 and 72 h, 15 days). Data were integrated with RNA-Seq from the same models. Results Through ChIP-Seq, here we demonstrate that trabectedin inhibits the binding of FUS-DDIT3 to its target genes, restoring adipocyte differentiation in a patient-derived xenograft model of MLPS sensitive to trabectedin. In addition, complementary RNA-Seq data on the same model demonstrates a two-phase effect of trabectedin, characterized by an initial FUS-DDIT3-independent cytotoxicity, followed by a transcriptionally active pro-differentiation phase due to the long-lasting detachment of the chimera from the DNA. Interestingly, in a trabectedin-resistant MLPS model, the effect of trabectedin on FUS-DDIT3 rapidly decreased over time, and prolonged treatment was no longer able to induce any transcription or post-transcriptional modifications. Conclusions These findings explain the unusual mechanism underlying trabectedin's effectiveness against MLPS by pinpointing the chimera's role in inducing the differentiation block responsible for MLPS pathogenesis. Additionally, the findings hint at a potential mechanism of resistance acquired in vivo. Graphical Abstract

Background This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra‐rare sarcoma, marked by WWTR1‐CAMTA1 or YAP1‐TFE3 fusions. Methods Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan‐Meier method. Results Overall, 73 patients were included; 21 had more than one treatment. Thirty‐three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m‐) PFS and m‐OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m‐PFS and m‐OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m‐PFS and m‐OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF‐α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m‐PFS and m‐OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported. Conclusion Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed. Anthracycline‐based regimens, the standard first line treatment in advanced soft tissue sarcomas, paclitaxel and pazopanib have a very limited activity in advanced, progressive epithelioid haemangioendothelioma. In the absence of available, potentially active medical therapies, epithelioid haemangioendothelioma remains today an unmet clinical need.

Background Alveolar soft part sarcoma (ASPS) is a rare soft tissue tumor that usually affects young patients. A comprehensive retrospective review was performed of clinical presentation, treatment, outcome, and patterns of failure in a consecutive series of patients with localized or metastatic ASPS between 1975 and 2008. Methods Demographics, tumor sizes, sites and extent of disease, treatments provided, progression-free survival, and overall survival were evaluated. Results A total of 33 patients were identified. Preoperative imaging misdiagnosed a vascular malformation in three cases (9%), delaying treatment. The most common location of primary tumor was the thigh. The median diameter of the mass was 9 cm (range, 2–15 cm). The tumor was deeply located in most cases (78.7%). A R0 resection was obtained in 27 cases. Adjuvant radiotherapy was delivered in 12 cases, in 6 cases in association with chemotherapy; preoperative systemic chemotherapy was delivered in 4 cases, in the adjuvant setting in another 3 cases. Twenty-one (63.6%) of 33 patients exhibited metastases either at presentation (10 patients, 30.3%) or later. Metastatic sites included lymph nodes, lung, bone, and liver. Median overall follow-up was 72 months. Overall survival was 68.7% at 5 years and 53.4% at 10 years. Metastectomies were performed in 33% of metastatic cases (7 of 21 patients). Conclusions Prognosis of ASPS is basically related to the characteristics of the disease and the quality of surgery. Overall, the occurrence of distant metastases is quite common, with a typical indolent course. New agents are eagerly needed to complement surgery to eradicate this disease.