The tyrosine kinase inhibitor (TKI) imatinib has radically changed the natural history of KIT-driven gastrointestinal stromal tumours (GISTs). Approved second-line and thirdline medical therapies are represented by the TKIs sunitinib and regorafenib, respectively. While imatinib remains the cardinal drug for patients with GISTs, novel therapies are being developed and clinically tested to overcome the mechanisms of resistance after treatments with the approved TKI, or to treat subsets of GISTs driven by rarer molecular events. Here, we review the therapy of GISTs, with a particular focus on the newest drugs in advanced phases of clinical testing that might soon change the current therapeutic algorithm.

The desmoid tumor is a locally aggressive proliferative disease within the family of soft-tissue sarcomas. Despite its relatively good prognosis, the clinical management of desmoid tumors requires constant multidisciplinary evaluation due to its highly variable clinical behavior. Recently, active surveillance has being regarded as the appropriate strategy at diagnosis, as indolent persistence or spontaneous regressions are not uncommon. Here, we review the most recent advances in desmoid tumor therapy, including low-dose chemotherapy and treatment with tyrosine kinase inhibitors. We also explore the recent improvements in our knowledge of the molecular biology of this disease, which are leading to clinical trials with targeted agents.

Background Despite its proven activity as third-line treatment in gastrointestinal stromal tumors (GIST), regorafenib can present a poor tolerability profile which often leads to treatment modifications and transient or permanent discontinuation; thus, in clinical practice physicians usually adopt various dosing and interval schedules to counteract regorafenib-related adverse events and avoid treatment interruption. The aim of this real-world study was to investigate the efficacy and safety of personalized schedules of regorafenib in patients with metastatic GIST, in comparison with the standard schedule (160 mg daily, 3-weeks-on, 1-week-off). Patients and methods Institutional registries across seven Italian reference centers were retrospectively reviewed and data of interest retrieved to identify patients with GIST who had received regorafenib from February 2013 to January 2021. The Kaplan–Meier method was used to estimate survival and the log-rank test to make comparisons. Results Of a total of 152 patients with GIST, 49 were treated with standard dose, while 103 received personalized schedules. At a median follow-up of 36.5 months, median progression-free survival was 5.6 months [95% confidence interval (CI) 3.73-11.0 months] versus 9.7 months (95% CI 7.9-14.5 months) in the standard-dose and the personalized schedule groups, respectively [hazard ratio (HR) 0.51; 95% CI 0.34-0.75; P = 0.00052]. Median overall survival was 16.6 months (95% CI 14.1-21.8 months) versus 20.5 months (95% CI 15.0-25.4 months), respectively (HR 0.75; 95% CI 0.49-1.22; P = 0.16). Conclusions Regorafenib-personalized schedules are commonly adopted in daily clinical practice of high-volume GIST expert centers and correlate with significant improvement of therapeutic outcomes. Therefore, regorafenib treatment optimization in patients with GIST may represent the best strategy to maximize long-term therapy.

Background: Dexrazoxane (DEX) is indicated as a cardioprotective agent for breast cancer patients receiving the anthracycline doxorubicin. Two meta-analyses in metastatic breast cancer reported an apparent increase in the severity of myelosuppression when DEX was used. So far, no data in soft-tissue sarcoma (STS) patients are available. Methods: We retrospectively analyzed hematological toxicity data from 133 consecutive STS patients who received a chemotherapy regimen containing an anthracycline and ifosfamide (AI) in the perioperative or metastatic settings between January 2006 and December 2017. Of these, 46 received off-label DEX concurrently with the AI treatment. The differences between incidence of any of the explored outcomes were assessed according to the Fisher exact test. Results: Compared with the non-DEX group, DEX treatment was associated with significantly higher rates of grade 3/4 hematological toxicities: leukopenia (56.5 vs. 28.7%; p = 0.0014), neutropenia (69.6 vs. 24.1%; p = 0.0001), febrile neutropenia (52.2 vs. 20.7%; p = 0.0004), anemia (41.3 vs. 28.7%; p = 0.1758), and thrombocytopenia (54.3 vs. 32.1%; p = 0.0159). Similarly, in the DEX group dose reductions were more frequent compared to the non-DEX group (39.1 vs. 19.5%; p = 0.0221). Conclusion: Adding DEX to AI in STS patients leads to higher rates of bone marrow suppression in all blood components, as well as to more frequent events of febrile neutropenia and dose reductions.

Purpose The prognostic significance of lactate dehydrogenase (LDH) in patients with metastatic seminoma is not defined. We investigated the prognostic impact of LDH levels prior to first-line systemic treatment and other clinical characteristics in this subset of patients. Methods Files from two registry studies and one single-institution database were analyzed retrospectively. Uni- and multivariate analyses were conducted to identify patient characteristics associated with recurrence free survival (RFS), overall survival (OS), and complete response rate (CRR). Results The dataset included 351 metastatic seminoma patients with a median follow-up of 5.36 years. Five-year RFS, OS and CRR were 82%, 89% and 52%, respectively. Explorative analysis revealed a cut-off LDH level of < 2.5 upper limit of normal (ULN) (n = 228) vs. ≥ 2.5 ULN (n = 123) to be associated with a significant difference concerning OS associated with 5-years OS rates of 93% vs. 83% (p = 0.001) which was confirmed in multivariate analysis (HR 2.87; p = 0.004). Furthermore, the cut-off LDH < 2.5 ULN vs. ≥ 2.5 ULN correlated with RFS and CRR associated with a 5-years RFS rate and CRR of 76% vs. 86% (p = 0.012) and 32% vs. 59% (p  ≤  0.001), respectively. Conclusions LDH levels correlate with treatment response and survival in metastatic seminoma patients and should be considered for their prognostic stratification.