Bone marrow-derived cells in ocular neovascularization: contribution and mechanisms

Ocular neovascularization often leads to severe vision loss. The role of bone marrow-derived cells (BMCs) in the development of ocular neovascularization, and its significance, is increasingly being recognized. In this review, we discuss their contribution and the potential mechanisms that mediate the effect of BMCs on the progression of ocular neovascularization. The sequence of events by which BMCs participate in ocular neovascularization can be roughly divided into four phases, i.e., mobilization, migration, adhesion and differentiation. This process is delicately regulated and liable to be affected by multiple factors. Cytokines such as vascular endothelial growth factor, granulocyte colony-stimulating factor and erythropoietin are involved in the mobilization of BMCs. Studies have also demonstrated a key role of cytokines such as stromal cell-derived factor-1, tumor necrosis factor-α, as well as vascular endothelial growth factor, in regulating the migration of BMCs. The adhesion of BMCs is mainly regulated by vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and vascular endothelial cadherin. However, the mechanisms regulating the differentiation of BMCs are largely unknown at present. In addition, BMCs secrete cytokines that interact with the microenvironment of ocular neovascularization; their contribution to ocular neovascularization, especially choroidal neovascularization, can be aggravated by several risk factors. An extensive regulatory network is thought to modulate the role of BMCs in the development of ocular neovascularization. A comprehensive understanding of the involved mechanisms will help in the development of novel therapeutic strategies related to BMCs. In this review, we have limited the discussion to the recent progress in this field, especially the research conducted at our laboratory

375O - Final efficacy results from IMpower132: First-line atezolizumab + chemotherapy in patients with stage IV non-squamous NSCLC

Background The Phase III IMpower132 study, evaluating first line pemetrexed plus carboplatin/cisplatin with or without atezolizumab in Stage IV non-squamous NSCLC without EGFR or ALK driver mutations, has met its PFS endpoint with an HR of 0.60 (95% CI: 0.49, 0.72; P \u3c 0.0001; Papadimitrakopoulou, WCLC 2018). Here we present the final OS and safety results. Methods Patients were randomised 1:1 to 4 or 6 cycles of carboplatin AUC 6 mg/mL/min or cisplatin 75 mg/m2 + pemetrexed 500 mg/m2 Q3W alone (arm PP) or with atezolizumab 1200 mg Q3W (arm APP), followed by pemetrexed (PP) or atezolizumab + pemetrexed (APP) maintenance. Investigator-assessed PFS and OS were co-primary endpoints. Efficacy by PD-L1 status was an exploratory endpoint. Results At data cutoff (18 July 2019), 292 patients in arm APP and 286 patients in arm PP had a median follow-up of 28.4 mo. Updated median PFS was 7.7 months (APP) vs 5.2 months (PP); HR, 0.56 (95% CI: 0.47, 0.67). Final OS data are in the table. 38.7% (APP) vs 57.3% (PP) of patients received subsequent anti-cancer therapy, including immunotherapy in 5.5% vs 45.8%. Grade ≥ 3 treatment-related adverse events (AEs) occurred in 58.4% (APP) vs 43.1% (PP) of patients, including immune-mediated AEs in 6.9% (APP) vs 4.7% (PP) of patients. Table: 375O APP PP ITT n = 292 n = 286 mOS (95% CI), mo 17.5 (13.2, 19.6) 13.6 (11.0, 15.7) HRa (95% CI; P value) 0.86 (0.71, 1.06; P = 0.155) 12-Month OS 59.7% 55.0% 24-Month OS 39.1% 34.0% PD-L1–highb n = 25 n = 20 mOS (95% CI), mo NE (22.4, NE) 26.9 (4.7, NE) HR (95% CI) 0.73 (0.31, 1.73) PD-L1–lowb n = 63 n = 73 mOS (95% CI), mo 12.7 (8.7, 18.2) 16.2 (9.6, 22.6) HR (95% CI) 1.18 (0.80, 1.76) PD-L1–negativeb n = 88 n = 75 mOS (95% CI), mo 15.9 (11.6, 22.6) 10.5 (8.1, 13.5) HR (95% CI) 0.67 (0.46, 0.96) NE, not estimable. a Stratified. b PD-L1 status available in 60% of pts. PD-L1–high: ≥ 50% TC or ≥ 10% IC; PD-L1–low: ≥ 1% and \u3c 50% TC or ≥ 1% and \u3c 10% IC; PD-L1–negative: \u3c 1% TC and \u3c 1% IC. . Conclusions IMpower132 had met its co-primary PFS endpoint at the primary analysis but did not meet its co-primary OS endpoint in this final analysis. Atezolizumab + carboplatin/cisplatin + pemetrexed was well tolerated, and no new safety signals were identified. Clinical trial identification NCT02657434

Prediction of local and metastatic recurrence in solitary fibrous tumor: construction of a risk calculator in a multicenter cohort from the French Sarcoma Group (FSG) database.

Solitary fibrous tumors (SFT) are rare unusual ubiquitous soft tissue tumors that are presumed to be of fibroblastic differentiation. At present, the challenge is to establish accurate prognostic factors. A total of 214 consecutive patients with SFT diagnosed in 24 participating cancer centers were entered into the European database (www.conticabase.org) to perform univariate and multivariate analysis for overall survival (OS), local recurrence incidence (LRI) and metastatic recurrence incidence (MRI) by taking competing risks into account. A prognostic model was constructed for LRI and MRI. Internal and external validations of the prognostic models were carried out. An individual risk calculator was carried out to quantify the risk of both local and metastatic recurrence. We restricted our analysis to 162 patients with local disease. Twenty patients (12.3%) were deceased at the time of analysis and the median OS was not reached. The LRI rates at 10 and 20 years were 19.2% and 38.6%, respectively. The MRI rates at 10 and 20 years were 31.4% and 49.8%, respectively. Multivariate analysis retained age and mitotic count tended to significance for predicting OS. The factors influencing LRI were viscera localization, radiotherapy and age. Mitotic count, tumor localization other than limb and age had independent values for MRI. Three prognostic groups for OS were defined based on the number of unfavorable prognostic factors and calculations were carried out to predict the risk of local and metastatic recurrence for individual patients. LRI and MRI rates increased between 10 and 20 years so relapses were delayed, suggesting that long-term monitoring is useful. This study also shows that different prognostic SFT sub-groups could benefit from different therapeutic strategies and that use of a survival calculator could become standard practice in SFTs to individualize treatment based on the clinical situation

Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: A Sarculator-based risk stratification analysis of the ISG-STS 1001 randomized trial

none79Background: The value of neoadjuvant chemotherapy in soft tissue sarcoma (STS) is not completely understood. This study investigated the benefit of neoadjuvant chemotherapy according to prognostic stratification based on the Sarculator nomogram for STS. Methods: This study analyzed data from ISG-STS 1001, a randomized study that tested 3 cycles of neoadjuvant anthracycline plus ifosfamide (AI) or histology-tailored (HT) chemotherapy in adult patients with STS. The 10-year predicted overall survival (pr-OS) was estimated with the Sarculator and was stratified into higher (10-year pr-OS .99). In lower risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.85 and 0.80, respectively, and 0.89 and 0.82, respectively, in the AI arm (P =.507); the corresponding figures in the HT arm were 0.87 and 0.81, respectively, and 0.86 and 0.74, respectively (P =.105). Conclusions: High-risk patients treated with AI performed better than predicted, and this adds to the evidence for the efficacy of neoadjuvant AI in STS. Lay Summary: People affected by soft tissue sarcomas of the extremities and trunk wall are at some risk of developing metastasis after surgery. Preoperative or postoperative chemotherapy has been tested in clinical trials to reduce the chances of distant metastasis. However, study findings have not been conclusive. This study stratified the risk of metastasis for people affected by sarcomas who were included in a clinical trial testing neoadjuvant chemotherapy. Exploiting the prognostic nomogram Sarculator, it found a benefit for chemotherapy when the predicted risk, based on patient and tumor characteristics, was high.nonePasquali S.; Palmerini E.; Quagliuolo V.; Martin-Broto J.; Lopez-Pousa A.; Grignani G.; Brunello A.; Blay J.-Y.; Tendero O.; Diaz-Beveridge R.; Ferraresi V.; Lugowska I.; Infante G.; Braglia L.; Merlo D.F.; Fontana V.; Marchesi E.; Donati D.M.; Palassini E.; Bianchi G.; Marrari A.; Morosi C.; Stacchiotti S.; Bague S.; Coindre J.M.; Dei Tos A.P.; Picci P.; Bruzzi P.; Miceli R.; Casali P.G.; Gronchi A.; Dani C.; Villa C.; Messina A.; Rusi L.; Nuzzo A.M.; Nuzzo C.; De Paoli A.; Buonadonna A.; Comandone A.; Boglione A.; Livi L.; Greto D.; Riva N.; Monti M.; Pennacchioli E.; De Pas T.; Ippolito V.; Ledesma P.; Redondo A.; Valverde C.; Bratos R.; Cruz J.; Martinez Trufero J.; Cubedo R.; Sevilla I.; Luna P.; Lopez R.; Sancho P.; Bally O.; Brahmi M.; Ray-Coquard I.; Cassier P.; Marques N.; Tassy L.; Boudou-Rouquette P.; Tlemsani C.; Alexandre J.; Goldwasser F.; Bompas E.; Rolland F.; Perrin C.; Talarmin M.; Italiano A.; Toulmonde M.; Laramas M.; Bay J.-O.; Dubray-Longeras P.; Rutkowski P.Pasquali, S.; Palmerini, E.; Quagliuolo, V.; Martin-Broto, J.; Lopez-Pousa, A.; Grignani, G.; Brunello, A.; Blay, J. -Y.; Tendero, O.; Diaz-Beveridge, R.; Ferraresi, V.; Lugowska, I.; Infante, G.; Braglia, L.; Merlo, D. F.; Fontana, V.; Marchesi, E.; Donati, D. M.; Palassini, E.; Bianchi, G.; Marrari, A.; Morosi, C.; Stacchiotti, S.; Bague, S.; Coindre, J. M.; Dei Tos, A. P.; Picci, P.; Bruzzi, P.; Miceli, R.; Casali, P. G.; Gronchi, A.; Dani, C.; Villa, C.; Messina, A.; Rusi, L.; Nuzzo, A. M.; Nuzzo, C.; De Paoli, A.; Buonadonna, A.; Comandone, A.; Boglione, A.; Livi, L.; Greto, D.; Riva, N.; Monti, M.; Pennacchioli, E.; De Pas, T.; Ippolito, V.; Ledesma, P.; Redondo, A.; Valverde, C.; Bratos, R.; Cruz, J.; Martinez Trufero, J.; Cubedo, R.; Sevilla, I.; Luna, P.; Lopez, R.; Sancho, P.; Bally, O.; Brahmi, M.; Ray-Coquard, I.; Cassier, P.; Marques, N.; Tassy, L.; Boudou-Rouquette, P.; Tlemsani, C.; Alexandre, J.; Goldwasser, F.; Bompas, E.; Rolland, F.; Perrin, C.; Talarmin, M.; Italiano, A.; Toulmonde, M.; Laramas, M.; Bay, J. -O.; Dubray-Longeras, P.; Rutkowski, P

Management and outcomes of adolescent and young adult sarcoma patients: results from the French nationwide database NETSARC.

International audienceBackgroundThe initial management of patients with sarcoma is a critical issue. We used the nationwide French National Cancer Institute-funded prospective sarcoma database NETSARC to report the management and oncologic outcomes in adolescents and young adults (AYAs) patients with sarcoma at the national level.Patients and methodsNETSARC database gathers regularly monitored and updated data from patients with sarcoma. NETSARC was queried for patients (15–30 years) with sarcoma diagnosed from 2010 to 2017 for whom tumor resection had been performed. We reported management, locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in AYA treated in French reference sarcoma centers (RSC) and outside RSC (non-RSC) and conducted multivariable survival analyses adjusted for classical prognostic factors.ResultsAmong 3,227 patients aged 15–30 years with sarcoma diagnosed between 2010 and 2017, the study included 2,227 patients with surgery data available, among whom 1,290 AYAs had been operated in RSC, and 937 AYAs in non-RSC. Significant differences in compliance to guidelines were observed including pre-treatment biopsy (RSC: 85.9%; non-RSC 48.1%), pre-treatment imaging (RSC: 86.8%; non-RSC: 56.5%) and R0 margins (RSC 57.6%; non-RSC: 20.2%) (p < 0.001). 3y-OS rates were 81.1% (95%CI 78.3–83.6) in AYA in RSC and 82.7% (95%CI 79.4–85.5) in AYA in non-RSC, respectively. Whereas no significant differences in OS was observed in AYAs treated in RSC and in non-RSC, LRFS and PFS were improved in AYAs treated in RSC compared to AYAs treated in non-RSC (Hazard Ratios (HR): 0.58 and 0.83, respectively).ConclusionsThis study highlights the importance for AYA patients with sarcoma to be managed in national sarcoma reference centers involving multidisciplinary medical teams with paediatric and adult oncologists