Thyroid carcinoma incidence rates in western societies are among the fastest rising, compared to all malignant tumors over the past two decades. While risk factors such as age and exposure to ionizing radiation are known, early-state carcinogenic processes or pre-lesions are poorly understood or unknown. This study aims at the identification and characterization of early-state radiation-associated neoplastic processes by histologic and transcriptomic analyses of thyroid tissues derived from a mouse model. Comprehensive histological examination of 246 thyroids (164 exposed, 82 non-exposed) was carried out. Proliferative and normal tissues from exposed cases and normal tissue from non-exposed cases were collected by laser-capture microdissection, followed by RNAseq transcriptomic profiling using a low input 3`-library preparation protocol, differential gene expression analysis and functional association by Gene Set Enrichment Analysis. Nine exposed samples exhibited proliferative lesions, while none of the non-exposed samples showed histological abnormalities, indicating an association of ionizing radiation exposure with histological abnormalities. Activated immune response signaling and deregulated metabolic processes were observed in irradiated tissue with normal histology compared to normal tissue from non-exposed samples. Proliferative lesions compared to corresponding normal tissues showed enrichment for mainly proliferation-associated gene sets. Consistently, proliferative lesion samples from exposed mice showed elevated proliferation-associated signaling and deregulated metabolic processes compared to normal samples from non-exposed mice. Our findings suggest that a molecular deregulation may be detectable in histologically normal thyroid tissues and in early proliferative lesions in the frame of multi-step progression from irradiated normal tissue to tumorous lesions.
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) using T-cell-replete grafts and post-transplantation cyclophosphamide (PTCY) provides a popular curative approach for older patients (pts) with high-risk (HR) MDS/AML. The sequential therapeutic concept herein, is used to optimize disease control and gain time, especially in patients suffering from active disease at time of haplo-HSCT. Yet, sequential conditioning regimens prior to haplo-HSCT are often associated with a considerable risk of severe adverse events especially in older comorbid patients. Previous studies in the HLA-matched setting have demonstrated feasibility and safety of treosulfan-based reduced intensity conditioning (RIC) by stable engraftment and low non-relapse mortality (NRM). However, data for treosulfan-based conditioning in the unmanipulated HLA-haplo-HSCT setting in HR AML/MDS pts are rare, especially in the context of sequential conditioning. Here we report on a matched-pair analysis of 26 patients treated with either a treosulfan- or melphalan-based sequential conditioning for haplo-HSCT using PTCY as GvHD prophylaxis in HR MDS/AML. We retrospectively analyzed the outcome and toxicity profile of 26 patients undergoing sequential haplo-HSCT at our center between January 2009 and June 2019. Thirteen patients with HR AML/MDS and >54 years old who underwent sequential haplo-HSCT using treosulfan (3x10g/m2) for RIC were considered for potential matching with recipients (n=30) of a sequential melphalan-based RIC regimen. Matching criteria comprised (1) disease activity (blast yes or no), (2) disease status (relapse, refractory, high-risk cytogenetics), (3) HCT-CI and (4) age (+/- 5 years). Post-grafting immunosuppression consisted of cyclophosphamide, tacrolimus and MMF. Thirteen patients undergoing treosulfan-haplo-HSCT were successfully pair-matched with thirteen recipients of melphalan-based haplo-HSCT, respectively ((1) p=1.0; (2) p=1.0; (3) p=1.0; (4) p=0,76). Median age of the entire cohort was 63 years (54-71). Each group consisted of two MDS patients and eleven AML patients. All recipients treated with treosulfan showed neutrophil engraftment with a median of 20 days while only 69% of the melphalan treated patients engrafted (median=19 days, p= 0.9). In the melphalan group one graft rejection occurred, three patients died in early aplasia. Acute GvHD °II-IV occurred in 23% and 44% of the patients treated with treosulfan or melphalan, respectively. Severe (°III-IV) non-hematologic regimen-related toxicities were seen in 2/13 pts of the treosulfan and 7/13 pts of the melphalan group, predominately affecting the GI-tract in both. NRM at day +100 was 0% and 31% (p=0.06) for the treosulfan and melphalan group, respectively. Thereby, infections made up for most NRM events. Conversely, CI of relapse at one year was 23% vs 0 % (p=0.004) for treosulfan vs melphalan. OS at 1-year (treosulfan group: 69% vs melphalan gropup: 62%) and PFS at 1-year (treosulfan group: 69% vs melphalan group: 62%) did not differ significantly between the groups (p=0.72) Sequential haplo-HSCT using treosulfan and PTCY in older advanced MDS/AML patients is safe, resulting in lower NRM at the expense of higher relapse incidence compared to the melphalan-based sequential conditioning approach. Treosulfan-based RIC in haplo-HSCT though might be an alternative in older pts with low leukemic burden. However for disease control its intensity should be reconsidered and all available post-grafting mantainance strategies applied. Disclosures Fraccaroli: Medac: Other: Travel Grant. Buecklein:Celgene: Research Funding; Amgen: Consultancy; Pfizer: Consultancy; Gilead: Consultancy, Research Funding; Novartis: Research Funding.
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