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Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28–61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3–4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. Although the combination of sorafenib and everolimus showed activity as a further-line treatment for patients with advanced or unresectable osteosarcoma, it did not attain the prespecified target of 6 month PFS of 50% or greater. Italian Sarcoma Group.

Background Dedifferentiated liposarcoma (DDLPS), a tumor that lacks effective treatment strategies and is associated with poor outcomes, expresses amplified MDM2 in the presence of wild-type p53. MDM2 ubiquitination of p53 facilitates its XPO1-mediated nuclear export, thus limiting p53 tumor suppressor functions. Consequently, nuclear export is a rational target in DDLPS. We directly compared the antitumor activity of the first-in class XPO1 inhibitor selinexor and doxorubicin, the standard front-line therapy in sarcomas, in DDLPS patient-derived xenografts (PDXs) and primary cell lines. Methods Drug activity was assessed in three PDXs (and two corresponding cell lines) established from the dedifferentiated component of primary untreated retroperitoneal DDLPS with myogenic ( N  = 2) and rhabdomyoblastic ( N  = 1) differentiation from patients who underwent surgery. These models were marked by amplification of MDM2 , CDK4 and HMGA2 genes. Results Selinexor was moderately active in the three PDXs but achieved greater tumor response compared to doxorubicin (maximum tumor volume inhibition: 46–80 % vs. 37–60 %). The PDX harboring rhabdomyoblastic dedifferentiation showed the highest sensitivity to both agents. PDX response to selinexor and doxorubicin was not associated with the extent of MDM2 and CDK4 gene amplification. Interestingly, the most chemosensitive PDX model showed the lowest extent of HMGA2 amplification. Selinexor was also more efficient than doxorubicinin in inducing an apoptotic response in PDXs and cell lines. Consistently, an increased nuclear accumulation of p53 was seen in all selinexor-treated models. In addition, a time-dependent decrease of survivin expression, with an almost complete abrogation of the cytoplasmic anti-apoptotic pool of this protein, was observed as a consequence of the decreased acetylation/activation of STAT3 and the increased ubiquitination of nuclear survivin. Conclusions Selinexor showed a moderate antitumor activity in three DDLPS PDXs, which was, however, consistently higher than doxorubicin across all different models regardless the extent of MDM2 amplification and the histological differentiation. The depletion of survivin protein seems to significantly contribute to the induction of apoptosis through which selinexor exerts its antitumor activity.

Background Chordoma is a rare tumor, and its natural history is still not well known. Materials and Methods All patients affected by localized chordoma surgically treated at Istituto Ortopedico Rizzoli, Bologna, and Istituto Nazionale Tumori, Milan, Italy, between 1980 and 2008 were reviewed. Local recurrence, distant metastasis, and overall survival (OS) were analyzed both from time of diagnosis and from time of local recurrence/distant metastasis. A multivariable analysis to identify independent prognostic factors was carried out. Results A total of 138 consecutive patients were identified (sacrum 78%, lumbar spine 15%, cervical-dorsal spine 7%). Of these, 130 underwent surgical resection. Median follow-up was 142 months. The 5- and 10-year OS, local relapse-free survival (LRFS), and distant relapse-free survival (DRFS) were, respectively, 78% and 54%, 52% and 33%, and 86% and 72%. Size was an independent prognostic factor for OS ( P value < .001), LRFS ( P value: .038), and DRFS ( P value: .004), while surgical margins independently predicted LRFS ( P value: .003) with a trend for OS. The 5- and 10-year OS, LRFS, and DRFS after the first local relapse were 50% and 26%, 47% and 31%, and 64% and 61%. The size of the recurrence and quality of surgical margins did not influence postrelapse OS. The 5-year OS after the second local relapse was 19%. 22% of patients developed distant metastases with a 5-year post-metastases OS of 33%. Conclusions Tumor size and surgical margins affected outcome only on initial presentation. However, wide surgery was feasible in a minority of cases. Most patients died of local–regional disease even when metastases occurred. Indeed, long-term prognosis was such that disease-free survival at 10 years was only 26%.

Background The Complexity INdex in SARComas (CINSARC) is a transcriptional signature derived from the expression of 67 genes involved in mitosis control and chromosome integrity. This study aims to assess CINSARC value of in an independent series of high‐risk patients with localized soft tissue sarcoma (STS) treated with preoperative chemotherapy within a prospective, randomized, phase III study (ISG‐STS 1001). Patients and Methods Patients with available pre‐treatment samples, treated with 3 cycles of either standard (ST) preoperative or histotype‐tailored (HT) chemotherapy, were scored according to CINSARC (low‐risk, C1; high‐risk, C2). The 10‐year overall survival probability (pr‐OS) according to SARCULATOR was calculated, and patients were classified accordingly (low‐risk, Sarc‐LR, 10‐year pr‐OS>60%; high‐risk, Sarc‐HR, 10‐year pr‐OS<60%). Survival functions were estimated using the Kaplan–Meier method and compared using log‐rank test. Results Eighty‐six patients were included, 30 C1 and 56 C2, 49 Sarc‐LR and 37 Sarc‐HR. A low level of agreement between CINSARC and SARCULATOR was observed (Cohen's Kappa = 0.174). The 5‐year relapse‐free survival in C1 and C2 were 0.57 and 0.55 (p = 0.481); 5‐year metastases‐free survival 0.63 and 0.64 (p = 0.740); 5‐year OS 0.80 and 0.72 (p = 0.460). The 5‐year OS in C1 treated with ST and HT chemotherapy was 0.84 and 0.76 (p = 0.251) respectively; in C2 treated it was 0.72 and 0.70 (p = 0.349). The 5‐year OS in Sarc‐LR treated with S and HT chemotherapy was 0.80 and 0.82 (p = 0.502) respectively; in Sarc‐HR it was 0.70 and 0.61 (p = 0.233). Conclusions Our results, although constrained by the small size of the series, suggest that CINSARC has weak prognostic power in high‐risk, localized STS treated with neoadjuvant chemotherapy. This study aims to assess the value of CINSARC, a transcriptional signature derived from the expression of 67 genes involved in mitosis control and chromosome integrity, in an independent series of high‐risk patients with localized soft tissue sarcoma (STS) treated with preoperative chemotherapy within a prospective, randomized, phase III study (ISG‐STS 1001). As it can be seen in the figure, which shows Kaplan Meier curves for relapse‐free survival, metastases‐free survival, and overall survival in CINSARC low‐risk (C1) and high‐risk (C2) patients, our results, although constrained by the small size of the series, suggest that CINSARC has a weak prognostic power in this population.

Chordoma is an exceedingly rare tumor, marked by a slow growth rate. Surgery is the treatment of choice, but the most frequent sites of origin (spine and skull base) make treatment of primary disease challenging. Local relapses affect more than 50% of cases, with a minority of patients being cured by further surgery. Furthermore, metastases occur in at least 20% of patients. For residual or recurrent disease, high-dose radiation therapy may be indicated. Radiation therapy is currently the preferred local treatment when surgery is problematic, exploiting most recent techniques, including proton beams and carbon ions. However, systemic therapy is needed in patients non-amenable to surgery and/or radiation therapy. We reviewed systemic treatments currently available, and targets possibly druggable in the future in this orphan disease.

Objective Percutaneous cryoablation (PC) has been incorporated among first-line treatment options for desmoid-type fibromatosis (DF). Loco-regional therapies, including PC, induce tissue changes that may precede measurable tumor shrinkage, thereby limiting the reliability of purely dimensional response criteria. To address this limitation, we compared response evaluation criteria in solid tumors (RECIST) 1.1 and magnetic resonance imaging (MRI)-adapted (M-)RECIST in patients with DF treated with PC. Materials and methods We retrospectively identified all consecutive patients with progressing extra-abdominal DF treated with PC. Responses were assessed with RECIST 1.1 and M-RECIST, the latter relying on T2- and diffusion-weighted imaging, as well as unenhanced and contrast-enhanced T1-weighted imaging, to define residual viable tumor. Non-progression (NPR) and overall response rates (ORR) were defined as the percentage of patients without radiological progression and partial/complete responses, respectively. Results Thirty-four patients (females/males, 26/8) and 37 procedures were identified. RECIST 1.1 and M-RECIST were applicable in 35 and 34 procedures, respectively. At a median follow-up of 15.7 months (interquartile range [IQR] 19.5), RECIST 1.1. Responses were: 10/35 (28.6%) partial response (PR), 22/35 (62.9%) stable disease (SD), and 3/35 (8.6%) progressive disease (PD), with ORR 28.6% and NPR 91.4%. At a median follow-up of 16.0 months (IQR 20.5), M-RECIST responses were: 15/34 (44.1%) complete response (CR), 12/34 (35.3%) PR, 4/34 (11.8%) SD, and 3/34 (8.8%) PD, with ORR 79.4% and NPR 91.2%. Overall concordance was negligible. Conclusion M-RECIST yielded higher NPR/ORR than RECIST 1.1. These findings pave the way for studies addressing whether this shift in response categorization associates with improved outcomes prediction. Relevance statement This work provides supporting evidence for the implementation of residual viable disease assessment in evaluating DF responses to PC. Key Points In patients with DF, responses to cryoablation can be characterized using purely dimensional and viability-based criteria. RECIST 1.1 and M-RECIST yielded complete agreement for PD. M-RECIST may refine response categorization below the progression threshold. Graphical Abstract

Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline- and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90%) was caused by gemcitabine, EPZ-011989, and the doxorubicin–ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin–ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.

Pazopanib was assessed prospectively in the GEIS-32 phase II study (NCT02066285) on advanced solitary fibrous tumour (SFT), resulting in a longer progression-free survival (PFS) and overall survival (OS) compared with historical controls treated with chemotherapy. A retrospective analysis of peripheral inflammatory indexes in patients enrolled into GEIS-32 was performed to evaluate their prognostic and predictive value. Patients received pazopanib 800 mg/day as the first antiangiogenic line. The impacts of baseline neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and red cell distribution width (RDW) on PFS, OS, and Choi response were evaluated by univariate and multivariate analysis. Metastasis-free interval (MFI), mitotic count, and ECOG were also included as potential prognostic factors. Sixty-seven SFT patients, enrolled in this study, showed a median age of 63 years and a female/male distribution of 57/43. The median follow-up from treatment initiation was 16.8 months. High baseline NLR, PLR, and standardised RDW were significantly associated with worse PFS and OS. NLR, RDW, MFI, and mitotic count were independent variables for PFS, while RDW and ECOG were independent for OS. Further, NLR and mitotic count were independent factors for Choi response. High baseline NLR and RDW values were independent prognostic biomarkers for worse outcome in advanced SFT patients treated with pazopanib.

Background We aimed to investigate changes in volume and MRI T2‐weighted intensity in desmoid‐type fibromatosis (DF) receiving methotrexate plus vinca‐alkaloids (MTX‐VA) at Istituto Nazionale dei Tumori, Milan. Methods All cases of sporadic DF treated with MTX‐VA from 1999 to 2019 were reviewed. MRIs at baseline, 6 and 12 months of chemotherapy and at treatment withdrawal were retrospectively reviewed, contouring the tumor lesion and measuring diameters, volume, and mean T2‐signal intensity (normalized to muscle) changes. These parameters were also evaluated according to clinical variables. Results Thirty‐two DF patients were identified. Best RECIST response was: 25% partial response, 69% stable disease, 6% progression. A ≥65% tumor volume reduction was observed in 38%, <65% reduction in 53%, an increase in 9%. 22% had RECIST stable disease with a ≥65% tumor volume reduction. T2‐signal intensity decreased by ≥50% in 47%, <50% in 41% and increased in 12%. In patients with symptomatic improvement while on therapy and in patients maintaining symptomatic improvement during follow‐up, median T2‐signal intensity showed a reduction along the time points (3.0, 1.9, 1.2, 1.1; 2.9, 2.0, 1.2, 1.2, respectively); in patients without symptomatic improvement and in those clinically progressing during follow‐up, a reduction was not observed. High T2‐signal intensity at baseline was observed in patients showing RECIST progression during follow‐up. Conclusions In this series, RECIST detected a lower proportion of responses as compared to volumetric and T2‐signal changes. T2‐signal reduction seemed to better reflect symptomatic improvement. High T2‐signal intensity at baseline was related to a higher proportion of further progression. In this series of patients with sporadic desmoid‐type fibromatosis treated with low‐dose chemotherapy and evaluated with MRI, T2 signal reduction was detected in more patients as compared to RECIST responses and volume reductions, and seemed to better reflect symptomatic improvement and worsening. RECIST may have underestimated treatment responses as compared to volumetric and T2 signal intensity changes. A high T2 signal intensity at baseline seemed to be related to a higher risk of RECIST progression after the end of chemotherapy. ​