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One of the most important steps forward in the management of cancer was the discovery of immunotherapy. It has become an essential pillar in the treatment paradigm of cancer patients. Unfortunately, despite the various options presented with immune checkpoint inhibitors (ICIs), the benefit is still limited to select patients and the vast majority of these patients gain either minimal benefit or eventually progress, leaving an unmet need for the development of novel therapeutic agents and strategies. Lymphocyte activation gene-3 (LAG-3), an immune checkpoint receptor protein, is a molecule found on the surface of activated T-cells. It plays a major role in negatively regulating T-cell function thereby providing tumors with an immune escape in the tumor microenvironment (TME). Given its importance in regulating the immune system, LAG-3 has been considered as a promising target in oncology and precision medicine. To date, two LAG-3-directed agents (eftilagimod alpha and relatlimab) have been approved in combination with programmed death-1 (PD-1) inhibitors in the setting of advanced solid tumors. In this review, we discuss the structure of LAG-3, its mechanism of action, and its interaction with its ligands. We also shed light on the emerging treatments targeting LAG-3 for the treatment of solid tumors. [ABSTRACT FROM AUTHOR]

Gemcitabine has shown clinical activity against angiosarcoma in small series, alone, or combined with taxanes. We aimed to evaluate its activity as a single‐agent in a larger series of patients with advanced angiosarcoma. We retrospectively reviewed the electronic medical records of consecutive adult patients with advanced angiosarcoma treated with single‐agent gemcitabine at our institutions from January 2010 to January 2021. Response was evaluated according to RECIST 1.1, and toxicity was graded according to NCI‐CTC v5.0. 42 patients were identified. 38 patients (90%) had received prior anthracyclines and weekly paclitaxel, and 9 (21%) had received pazopanib. The best tumor response was partial response (PR) in 16 patients (38%), or stable disease (10 patients, 24%). All 8 patients with cardiac angiosarcoma experienced a PR. Median PFS was 5.4 months (95%CI: 3.1–6.5), and median OS was 9.9 months (95%CI: 6.6–13.4). Single‐agent gemcitabine has clinically meaningful activity in advanced, heavily pre‐treated angiosarcoma. [ABSTRACT FROM AUTHOR]

Successful pregnancy in women with metastatic cancer is rare in the published literature. We report here on four women with sarcoma who started and conducted their first pregnancies while in metastatic disease. All four pregnancies were first pregnancies, and all four women are long‐term survivors from 20 to 248 months after pregnancy. One patient had three pregnancies. All four women stopped systemic cancer treatment during their pregnancies, and two had RECIST progression during treatment interruption. Three patients still have unresectable metastatic disease, whereas one is in complete remission. In selected metastatic sarcomas with indolent courses, successful pregnancies are possible with no or minor impact on cancer progression and with prolonged life duration after pregnancy. As metastatic cancer becomes more often a chronic disease, this possibility opens important practical and ethical questions on how to best to advise women of childbearing age with metastatic cancers who are long‐term survivors. This case series reports four women with sarcoma who successfully conceived and managed their first pregnancies while in metastatic disease. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal stromal tumors (GISTs) are rare, but represent the most common mesenchymal neoplasms of the gastrointestinal tract. EPIdemiology GIST, is an observational multicenter longitudinal follow-up cohort study reporting the prescribing patterns of imatinib in patients with GIST and the impact of the treatment in a real-world (standard clinical) setting. Methods: Eligible patients had a confirmed diagnosis of unresectable or metastatic KIT-positive GIST and started treatment with imatinib for the first time between May 24, 2002, and June 30, 2010. During routine visits, annual collection of clinical characteristics was requested, i.e., age, GIST stage at diagnosis, history, imatinib treatment duration and dosage, adherence, and concomitant medications. Survival outcomes were estimated using the Kaplan-Meier method. Other data were analyzed using descriptive statistics. Results: Of 151 patients enrolled, imatinib was initiated for 126 patients before enrollment and for 25 patients on the day of enrollment or soon after. The patient characteristics were similar to those in published prospective trials. The estimated 1-, 2-, 3-, and 4-year overall survival rates were 90.4% (95% confidence interval [CI; 84.8%-94.0%]), 84.7% (95% CI [78.1%-89.4%]), 73.0% (95% CI [65.0%-79.4%]), and 60.7% (95% CI [51.4%-68.8%]), respectively. The most common adverse events (AEs) were diarrhea (39%), asthenia (39%), eyelid or periorbital edema (32%), abdominal pain (23%), and anemia (21%). Eight of 126 serious AEs were possibly related to the treatment as assessed by investigators. Conclusions: Study results showed that patients in real-life populations are generally treated in accordance with national and international clinical recommendations and have outcomes comparable to those of patients in clinical trials. [ABSTRACT FROM AUTHOR]

Assessment of health-related quality of life (HRQoL) is essential for holistic care. Greater efforts are required to incorporate HRQoL measures into clinical trials and daily practice. Considerable HRQoL data are available for localized soft tissue sarcomas (STS), particularly in the orthopedic setting. In future, HRQoL is expected to become increasingly important in the evaluation of palliative therapy in advanced STS. A patient-centric approach is advocated for STS management. Greater awareness of STS by nonspecialist clinicians, and timely referral to specialized sarcoma reference centers, is crucial for patient welfare. The patient is central to shared decision-making during consultations and during case review in tumor boards. The management approach to STS should be collaborative, involving a multidisciplinary team, multiple centers and patient advocacy groups. [ABSTRACT FROM AUTHOR]

Background: Leiomyosarcoma (LMS) are 15% of adult sarcomas and remain seldom curable in metastatic phase. The TAM receptors and their ligands are overexpressed or activated in multiple malignancies, including LMS.Methods: The TAM receptor and ligand expression was evaluated in LMS cell lines and 358 sarcoma samples by either gene expression or immunohistochemistry. TYRO3 and AXL were knocked down. Crizotinib and foretinib were investigated in vitro.Results: High expression of TYRO3 and AXL was detected in LMS cell lines. TYRO3 or AXL gene knockdown reduced cell proliferation/colony formation. Crizotinib and foretinib decreased TYRO3 and AXL phosphorylation, apoptosis, G2/arrest and reduced colony formation. Immunohistochemistry performed in 107 sarcomas showed higher expression of TYRO3 and GAS6 in LMS vs other sarcomas and nuclear TYRO3 only in LMS. Microarray gene expression performed in 251 sarcomas revealed significantly higher expression of TYRO3 and GAS6 in LMS than other sarcomas. Leiomyosarcoma patients with high expression of GAS6 or PROS1 present a significantly worse PFS.Conclusions: Leiomyosarcoma patients, especially those whom develop metastasis, express higher levels of TYRO3 and GAS6. Crizotinib and foretinib showed effective antitumour activity in LMS through TYRO3 and AXL deactivation indicating that clinical trials using TYRO3 and AXL inhibitors are warranted in advanced LMS. [ABSTRACT FROM AUTHOR]

Background: Desmoplastic small round cell tumor (DSRCT) is a very rare mesenchymal tumor that mainly affects teenagers and young adults with a mean age at diagnosis around 20-25 years. Although initial management still needs standardization, many centers will use multimodal treatment including intensive chemotherapy, extensive surgical resection followed by radiotherapy. Despite this, prognosis remains very poor and the median overall survival is 25 months. Recurrent disease is mainly treated by chemotherapy. Recently, due to the unmet medical need for recurrent disease, targeted therapies were explored for DSRCT. Methods: In this study, we assessed the response rate and progression free survival in nine cases of progressive DSRCT included in the OUTC's registry and treated with antiangiogenics targeted agents (sunitinib, sorafenib and bevacizumab). OUTC's, a French national registry, collects data about the use of off-label targeted therapy in sarcoma. Results: Eight males and one woman were included, with median age at diagnosis of 27.3 years (range from 9 to 48 years). They received a mean 3 lines (2-5) of treatment before antiangiogenic agent initiation. Six patients received sunitinib, two received sorafenib and one bevacizumab. Median progression free survival was 3.1 months (range 2-5.5 months) and best response observed was 5.5 months stable disease. Most patients had manageable low-grade toxicities, mainly fatigue, abdominal pain and skin toxicity. Conclusions: Despite very limited activity of antiangiogenics in our study, prospective collection of cases of these rare tumors together with molecular data should guide therapeutic decision and enhance outcome. [ABSTRACT FROM AUTHOR]

Aims: We aimed to evaluate the effect of prior chemotherapies on the outcomes of patients with liposarcoma and leiomyosarcoma treated with trabectedin as a 24-h infusion every 3 weeks.Patients& Methods: Data from 129 patients who received trabectedin as second-line treatment following failure with an anthracycline/ifosfamide and those who had received at least two lines of prior chemotherapy were analyzed.Results: Forty seven patients received one prior regimen (group A) and 82 patients received at least two lines of chemotherapy (group B). A favorable trend in median time to progression (4.4 vs 3.0 months), progression-free survival (4.4 vs 2.6 months) and overall survival (17.4 vs 13.3 months) was found in group A. A trend toward higher overall response rate (6.4 vs 4.9%) and disease control rate (34.0 vs 26.8%) also favored group A. Both groups had equivalent safety profiles.Conclusion: All efficacy outcomes were better in patients who received trabectedin as second-line treatment compared with patients with more extensive prior therapy. [ABSTRACT FROM AUTHOR]

Background: The long term outcome of advanced sarcoma patients treated with trabectedin outside of clinical trials and the utility of maintenance treatment has not been reported. Methods: Between 2003 and 2008, patients with advanced sarcoma failing doxorubicin could be treated within a compassionate use program (ATU, Temporary Use Authorization) of trabectedin in France using the standard 3-weekly regimen. Data from 181 patients (55%) were collected from 11 centres and analyzed. Results: Trabectedin was given in first, second, third or fourth line in metastatic phase in 6%, 37%, 33% and 23% of patients respectively. With a median follow-up of 6 years, median PFS and OS were 3.6 months and 16.1 months respectively. The median number of cycles was 3 (range 1-19). Best response were partial response (PR, n = 18, 10%), stable disease (SD, n = 69, 39%) and progressive disease (PD, n = 83, 46%), non evaluable (NE, n = 9, 5%). Thirty patients (17%) had to be hospitalized for treatment- related side effects. Independent prognostic factors in multivariate analysis (Cox model) were myxoid LPS and line of trabectedin for PFS, and myxoid LPS and retroperitoneal sarcomas for OS. Patients in PR or SD after 6 cycles continuing treatment had a better PFS (median 5.3 vs 10.5 months, p = 0.001) and OS (median 13.9 vs 33.4 months, p = 0.009) as compared to patients who stopped after 6 cycles. Conclusions: In this compassionate use program, trabectedin yielded similar or better PFS and OS than in clinical trials. Maintenance treatment beyond 6 cycles was associated with an improved survival. [ABSTRACT FROM AUTHOR]

Purpose: Act.In.Sarc (NCT02379845) demonstrated that the first-in-class radioenhancer NBTXR3, activated by preoperative radiation therapy (RT), doubled the rate of pathologic complete response after resection compared with preoperative RT alone in adult patients with locally advanced soft tissue sarcoma of the extremity or trunk wall (16.1% vs 7.9%, P = .045), and more patients achieved R0 resections (77.0% vs 64.0%, P = .042). These are the toxicity and health-related quality of life (HRQoL) results.Methods and Materials: Act.In.Sarc randomized eligible patients 1:1 to either NBTXR3 (single intratumoral injection, volume equivalent to 10% of baseline tumor volume, at 53.3 g/L) activated by external-beam RT (arm A) or external-beam RT alone (arm B) (50 Gy in 25 fractions), followed by surgery in both arms. Here, we report the safety analyses in the all-treated population with a long-term follow-up of at least 2 years, and HRQoL in the intention-to-treat full analysis set.Results: During the on-treatment period, serious adverse events (SAEs) of all grades related to NBTXR3 occurred in 10.1% (9/89) of patients (arm A), and SAEs related to RT occurred in 5.6% (5/89) (arm A) versus 5.6% (5/90) (arm B); postsurgery hospitalization owing to SAEs occurred in 15.7% (14/89) (arm A) versus 24.4% (22/90) (arm B). During the follow-up period, posttreatment SAEs (regardless of relationship) occurred in 13.5% (12/89) (arm A) versus 24.4% (22/90) (arm B). NBTXR3 did not negatively affect HRQoL; during the follow-up period, there was an improvement in most mean Toronto extremity salvage, EuroQoL 5-dimension (EQ-5D), EQ5D02-EQ visual analog scale, reintegration to normal living index, and musculoskeletal tumor rating scale scores.Conclusions: NBTXR3 did not negatively affect safety or HRQoL. Long-term safety results reinforce the favorable benefit-risk ratio of NBTXR3 plus RT. [ABSTRACT FROM AUTHOR]

Background: The added value of tumoural genomic profiles to conventional clinico-biological factors to predict progression-free survival (PFS) and overall survival (OS) was prospectively investigated in patients with advanced gastrointestinal stromal tumours (GIST) treated in the BFR14 study. Methods: Of the 434 included patients, mutational analysis was performed in 322 patients. Survival analysis was performed in patients with validated mutational status. Results: Mutational status was validated in 228 patients. We identified 196 patients with tumours harbouring 200 KIT alterations (exon 11: 173 patients, exon 9: 22 patients, exon 17: 3 patients, exon 13: 2 patients; 4 patients had double KIT mutations), 6 patients with PDGFRA mutations and 26 patients with wild-type (WT) GIST genotype. On a median follow-up of 73 months, median PFS/OS were 12.3/54.9 months for WT GIST, 12.6/55 months for KIT exon 9, and 39.4 months/not reached (69.1% at 5 years) for KIT exon 11. Tumour size, female gender, KIT exon 11 mutations and CD34 positivity were independent prognostic factors for a higher PFS. A higher OS was predicted by performance status (PS) <2, low neutrophil and normal lymphocyte counts, KIT exon 11 mutations, non-advanced tumour and female gender. KIT exon 11 mutations at codons 557-558 showed better tumour response (p=0.028) but shorter PFS (p=0.0176). Conclusions: In GIST patients, presence of a KIT exon 11 mutation is an independent prognostic factor for PFS and OS, along with gender, PS, tumour size, lymphocyte and neutrophil counts. Subsets of exon 11 mutations are associated with significantly different response patterns and PFS. [ABSTRACT FROM AUTHOR]