Characteristics and outcome of patients with low-/intermediate-risk acute promyelocytic leukemia treated with arsenic trioxide - an international collaborative study

The aim of this study was to characterize a large series of 154 patients with acute promyelocytic leukemia (APL; median age, 53 years; range, 18-90 years) and evaluate real-life outcome after up-front treatment with arsenic trioxide (ATO) and alltrans retinoic acid (ATRA). All patients were included in the prospective NAPOLEON registry (NCT02192619) between 2013 and 2019. APL was de novo in 91% (n=140) and therapy-related in 9% (n=14); 13% (n=20) were older than 70 years. At diagnosis bleeding/hemorrhage was present in 38% and thrombosis in 3%. Complete remission was achieved in 152 patients (99%), whereas two patients (1%) experienced induction death within 18 days after start of therapy. With a median follow-up of 1.99 years (95%-CI, 1.61-2.30 years) 1-year and 2-years overall survival (OS) rates were 97% (95%-CI, 94-100%) and 95% (95%-CI, 91-99%), respectively. Age above 70 years was associated with a significantly shorter OS (P<0.001) as compared to younger patients. So far no relapses were observed. Six patients (4%) died in CR after in median 0.95 years after diagnosis (range, 0.18-2.38 years). Our data confirm the efficiency and durability of ATO/ATRA in the primary management of adult low-/ intermediate-risk APL patients in the real life setting, irrespective of age

An advanced non-animal model for cultivation and pharmacological perturbation of human tumor tissue

Question: Tumors in patients are appropriately described as pathological organs. In their in vivo environment these tumor organs are entangled in a complex interplay of the genotypically and phenotypically heterogeneous tumor cells and healthy host cell. This tumor milieu plays a key role in tumor development, progression and response to therapy. To preserve the complex in vivo tumor environment in a preclinical model we developed a device to culture slices of tumor in a perfusion air culture (PAC) system. We analyzed PAC cultivation and pharmacological perturbation of tumor tissue slices from patients. Methods: To facilitate continuous supply with nutrients, oxygen and drugs, we developed a perfusion air culture (PAC) system to culture tumor slices. The precision-cut tumor slices (250 μm to 300 μm thickness) are kept in-between two organotypic supports and fixed in a special chamber. The chamber is settled vertically inside of an air-permeable tube and connected with a syringe pump via a silicon tube allowing continuous perfusion of medium and drugs. Regular culture conditions are achieved by placing the PAC system in a standard CO2-incubator. In vivo therapy is simulated by adding of Cisplatin to the supplied culture medium. To investigate the drug effects common biomarkers (Ki67, γH2AX, HIF1α, GMNN, cleaved caspase-3) were analyzed in IHC staining. Results: Primary tumor tissue from high grade serous ovarian carcinoma was cut in 280 μm slices and cultured in the PAC system. Using de-cellularised porcine intestine as organotypic supports in the PAC system, we can culture the primary ovarian tumor tissue slices more than 7 days with good morphology. For pharmacological perturbation experiments culture medium was supplemented with 13 μM Cisplatin and constantly delivered to slices for 72 h, mimicking the in vivo situation in patients. Biomarkers showed the expected response to Cisplatin. Interestingly, tumor cells derived from slices can be further cultured as tumoroids in Matrigel, passaged and cryopreserved. Conclusion: The PAC system facilitates the cultivation and pharmacological perturbation of tumor tissue slices in the context of the complex tumor microenvironment. Due to the flexibility and adjustability of all culture conditions (e.g. oxygen, scaffolds, flow rate and drug supply) the PAC system closely resembles the in vivo situation and is suitable for individual testing of drug efficacy