Erythroferrone (ERFE) is an erythroblast‐secreted regulator of iron metabolism. The production of ERFE increases during stress erythropoiesis, leading to decreased hepcidin expression and mobilization of iron. Pregnancy requires a substantial increase in iron availability to sustain maternal erythropoietic expansion and fetal development and is commonly affected by iron deficiency. To define the role of ERFE during iron‐replete or iron‐deficient pregnancy, we utilized mouse models expressing a range of ERFE levels: transgenic (TG) mice overexpressing ERFE, wild‐type (WT), and ERFE knockout (KO) mice. We altered maternal iron status using diets with low or standard iron content and performed the analysis at E18.5. Iron deficiency increased maternal ERFE in WT pregnancy. Comparing different maternal genotypes, ERFE TG dams had lower hepcidin relative to their liver iron load but similar hematological parameters to WT dams on either diet. In ERFE KO dams, most hematologic and iron parameters were comparable to WT, but mean corpuscular volume (MCV) was decreased under both iron conditions. Similar to dams, TG embryos had lower hepcidin on both diets, but their hematologic parameters did not differ from those of WT embryos. ERFE KO embryos had lower MCV than WT embryos on both diets. The effect was exacerbated under iron‐deficient conditions where ERFE KO embryos had higher hepcidin, lower Hb and Hct, and lower brain iron concentration compared to WT embryos, indicative of iron restriction. Thus, under iron‐deficient conditions, maternal and embryo ERFE facilitate iron mobilization for embryonic erythropoiesis.
Purpose/Objective(s): Organ-at-risk (OAR) sparing is a critical challenge for many cancers, but is particularly important for head and neck cancer patients, who experience significant acute and late toxicity. Prescription to the CTV with robust optimization against setup and range uncertainty has replaced planning target volume (PTV) optimization for proton therapy at our institution. We hypothesized that optimizing head and neck IMRT plans to the CTV, but ensuring robustness of target coverage against setup uncertainty, would allow for clinically significant reductions in OAR doses compared to traditional PTV-based optimization. Materials/Methods: We identified 10 head and neck cancer patients who completed radiotherapy: 4 with squamous cell carcinoma (SCC) of the right oropharynx, 3 with SCC of the supraglottic larynx, and 3 with SCC of the nasopharynx. For the control arm, we first optimized to the PTV (typically a 3 mm uniform expansion from CTV), with target goals of 95% PTV receiving 100% prescription (Rx) dose and 99% PTV receiving 93% Rx dose. For the experimental arm, we optimized to the CTV to achieve equivalent target goals (95%-100% and 99%-93%) for the second-to-worst case scenario under 3 mm isocenter shift uncertainty analysis. The worstcase scenario was rejected as an outlier; this is current practice for proton robust multi-field optimization (rMFO) planning. Differences in OAR doses were compared with 2-tailed paired Student's t-tests. Results: Across all patients, substantial dose reductions were seen. Parotid gland dose was reduced by a mean of 293 cGy (range-96-813, p<0.01), submandibular glands by 210 cGy (-192-654, p<0.01), constrictors by 410 cGy (102-624, p<0.01), esophagus by 223 cGy (-48-463, p<0.01), oral cavity-less-PTV by 296 cGy (-33-466, p<0.01), and mandible-less-PTV by 263 cGy (-109-680, p<0.01). In specific cases, major reductions in maximum OAR dose were achieved: brainstem by 1005 cGy in a nasopharynx cancer patient, optic nerve by 1257 cGy in a nasopharynx cancer patient, and cochlea by 1012-2076 cGy in 3 patients (2 oropharynx and 1 nasopharynx); mean cochlea dose was reduced by 821-1207 cGy in 3 patients. Conclusion: IMRT plan optimization to the CTV that achieves robust target coverage against setup uncertainty may yield clinically significant improvements in OAR sparing for head and neck patients, as compared to standard PTV-based planning.
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