STAT6-targeting antisense oligonucleotides against solitary fibrous tumor.

Solitary fibrous tumor (SFT) is a rare, non-hereditary soft tissue sarcoma thought to originate from fibroblastic mesenchymal stem cells. The etiology of SFT is thought to be due to an environmental intrachromosomal gene fusion between NGFI-A-binding protein 2 (NAB2) and signal transducer and activator protein 6 (STAT6) genes on chromosome 12, wherein the activation domain of STAT6 is fused with the DNA-binding domain of NAB2 resulting in the oncogenesis of SFT. All NAB2-STAT6 fusion variations discovered in SFTs contain the C-terminal of STAT6 transcript, and thus can serve as target site for antisense oligonucleotides (ASOs)-based therapies. Indeed, our in vitro studies show the STAT6 3' untranslated region (UTR)-targeting ASO (ASO 993523) was able to reduce expression of NAB2-STAT6 fusion transcripts in multiple SFT cell models with high efficiency (half-maximal inhibitory concentration: 116-300 nM). Encouragingly, in vivo treatment of SFT patient-derived xenograft mouse models with ASO 993523 resulted in acceptable tolerability profiles, reduced expression of NAB2-STAT6 fusion transcripts in xenograft tissues (21.9%), and, importantly, reduced tumor growth (32.4% decrease in tumor volume compared with the untreated control). Taken together, our study established ASO 993523 as a potential agent for the treatment of SFTs.

Circulating TNF-RII, IP-10 and HGF are associated with severity of COVID-19 in oncologic patients.

The COVID-19 patients showed hyperinflammatory response depending on the severity of the disease but little have been reported about this response in oncologic patients that also were infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Sixty-five circulating cytokines/chemokines were quantified in 15 oncologic patients, just after SARS-CoV-2 infection and fourteen days later, and their levels were compared in patients who required hospitalisation by COVID-19 versus non-hospitalised patients. A higher median age of 72 years (range 61-83) in oncologic patients after SARS-CoV-2 infection was associated with hospitalisation requirement by COVID-19 versus a median age of 49 years (20-75) observed in the non-hospitalised oncologic patients (p = 0.008). Moreover, oncologic patients at metastatic stage or with lung cancer were significantly associated with hospitalisation by COVID-19 (p = 0.044). None of these hospitalised patients required ICU treatment. Higher basal levels of tumour necrosis factor receptor II (TNF-RII), interferon-γ (IFNγ)-induced protein 10 (IP-10) and hepatocyte growth factor (HGF) in plasma were significantly observed in oncologic patients who required hospitalisation by COVID-19. Higher TNF-RII, IP-10 and HGF levels after the SARS-CoV-2 infection in oncologic patients could be used as biomarkers of COVID-19 severity associated with hospitalisation requirements.

Delays in diagnosis and surgery of sarcoma patients during the COVID-19 outbreak in Spain.

Background and objectives: Social distancing and quarantine implanted during the COVID-19 outbreak could have delayed the accession of oncologic patients to hospitals and treatments. This study analysed the management of sarcoma patients during this period in five Spanish hospitals. Design and methods: Clinical data from adult sarcoma patients, soft tissue and bone sarcomas, managed during the COVID-19 outbreak, from 15 March to 14 September 2020 (Covid cohort), were retrospectively collected and time for diagnosis, surgery and active treatments were compared with sarcoma patients managed during the same pre-pandemic period in 2018 (Control cohort). Results: A total of 126 and 182 new sarcoma patients were enrolled in the Covid and Control cohorts, respectively, who were mainly diagnosed as soft tissue sarcomas (81.0% and 80.8%) and at localized stage (80.2% and 79.1%). A diagnostic delay was observed in the Covid cohort with a median time for the diagnosis of 102.5 days (range 6-355) versus 83 days (range 5-328) in the Control cohort (p = 0.034). Moreover, a delay in surgery was observed in cases with localized disease from the Covid cohort with a median time of 96.0 days (range 11-265) versus 54.5 days (range 2-331) in the Control cohort (p = 0.034). However, a lower delay for neoadjuvant radiotherapy was observed in the Covid cohort with a median time from the diagnosis to the neoadjuvant radiotherapy of 47 days (range 27-105) versus 91 days (range 27-294) in the Control cohort (p = 0.039). No significant differences for adjuvant radiotherapy, neoadjuvant/adjuvant chemotherapy and neoadjuvant/adjuvant palliative chemotherapy were observed between both cohorts. Neither progression-free survival (PFS) nor overall survival (OS) was significantly different. Conclusion: Delays in diagnosis and surgery were retrospectively observed in sarcoma patients during the COVID-19 outbreak in Spain, while the time for neoadjuvant radiotherapy was reduced. However, no impact on the PFS and OS was observed.

A phase II trial of weekly nab-paclitaxel for progressive and symptomatic desmoid tumors.

Desmoid fibromatosis (DF) are mesenchymal neoplasms, with potential aggressive course and relevant clinical impact. New systemic therapy modalities are needed in this symptomatic/progressive population. In this multicenter, phase II trial (NCT03275818), patients with symptomatic/progressing DF received three cycles of weekly nab-paclitaxel. Brief pain inventory short form (BPI-SF) was collected at baseline and in every visit. MRI was performed every 3 months. Primary composite endpoint was RECIST 1.1 overall response rate (ORR) and/or clinical response (improvement ≥ 2 points in BPI-SF). If 40% of patients achieved clinical/radiological response, further investigation would be warranted. Toxicity, progression-free survival (PFS), pattern of response and its correlation with clinical best response and BPI, variation of physical function, and analgesic consumption were secondary endpoints. The translational research reported was not a pre-specified secondary outcome. Forty eligible patients started therapy, being 35 radiologically and clinically evaluable. The study achieved its primary endpoint, as 7(20%) patients obtained RECIST partial response, whereas 31(89%) experienced pain reduction of ≥2 points in BPI-SF worst pain. Therapy was well tolerated. With a median follow-up of 30(14-44) months, median 12 and 24-months PFS rates were 91%(CI 95%, 82-100) and 84%(CI 95%, 71-97). For clinical progression, 12 and 24-months PFS rates were 85% (CI 95%, 73-97) and 74% (CI 95%, 58-90) respectively. Short course of nab-paclitaxel is active, safe and achieves quick and durable responses in progressing/symptomatic DF patients.