Longitudinal Assessment of Neurodevelopment in Patients With Nonsyndromic Single-Suture Craniosynostosis: A Retrospective Review of 66 Patients.

The neurodevelopmental consequences of nonsyndromic single-suture (NSS) craniosynostosis are the subject of continued debate. Although the predictive validity of the Bayley Scales of Infant and Toddler Development (Third Edition) (BSID-III) have been questioned, this neurodevelopmental testing battery continues to be widely utilized among multidisciplinary craniofacial teams. The purpose of this study is to evaluate the neurodevelopmental functioning of patients with NSS craniosynostosis before and after surgical correction and the impact of surgical correction on neurodevelopmental trajectory based on BSID-III testing. All patients with NSS craniosynostosis who underwent cranial vault remodeling between 2009 and 2020 were considered for inclusion. Patients who failed to complete BSID-III testing within 2 months of surgery preoperatively and 2 years of surgery postoperatively were excluded. A total of 66 patients met criteria for the study. On language testing, both the preoperative mean score ( P =0.007) and postoperative mean score ( P =0.003) were significantly lower than the population norm. Furthermore, on motor testing, both the preoperative mean score ( P =0.005) and postoperative mean score ( P =0.001) were significantly lower than the population norm. Bayley Scales of Infant and Toddler Development (Third Edition) testing revealed no significant change between preoperative and postoperative neurodevelopmental functioning. Overall, this study suggests that patients with NSS craniosynostosis experience modest delays in language and motor development, which are present before and after cranial vault remodeling. In addition, this study provides evidence that cranial vault remodeling does not significantly impact the neurodevelopmental trajectory. Multicenter st udies and refined neurodevelopmental testing methods are necessary to definitively establish the neurodevelopmental implications of NSS craniosynostosis.

Amifostine Prophylaxis in Irradiated Breast Reconstruction: A Study of Oncologic Safety In Vitro.

BACKGROUND: Indications for adjuvant radiation therapy (XRT) in breast cancer have expanded. Although highly effective, XRT damages surrounding tissues and vasculature, often resulting in delayed or compromised breast reconstruction. Thus, effective yet safe methods of radiation injury prophylaxis would be desirable. Amifostine is a Food and Drug Administration-approved radioprotectant; however, concerns about its potential to also protect cancer remain. The purpose of this study was to evaluate the oncologic safety of amifostine (AMF) in vitro and determine its effect on human breast cancer cells in the setting of XRT. METHODS: One ER+/PR+/Her2- (MCF-7) and two ER-/PR-Her2- (MDA-MB-231, MDA-MB-468) breast cancer cell lines were investigated. Female fibroblasts were used as controls. Cells were treated with WR-1065, the active metabolite of AMF, 20 minutes before 0Gy, 10Gy, or 20Gy XRT. Live and dead cells were quantified; percent cell death was calculated. RESULTS: WR-1065 treatment significantly preserved viability and reduced healthy female fibroblasts death after XRT compared with untreated controls. All three breast cancer cells lines exhibited radiosensitivity with substantial cell death. Cancer cells retained their radiosensitivity despite WR-1065 pretreatment, achieving the same degree of cell death as untreated controls. CONCLUSIONS: This study demonstrated the proficiency of AMF to selectively protect healthy cells from XRT while breast cancer cells remained radiosensitive. These results support the oncologic safety of AMF in breast cancer in vitro. Further investigation is now warranted in vivo to ascertain the translational potential of using AMF as a radioprotectant to improve breast reconstruction after radiation treatment.

Novel Formulation Strategy to Improve the Feasibility of Amifostine Administration.

PURPOSE: Amifostine (AMF), a radioprotectant, is FDA-approved for intravenous administration in cancer patients receiving radiation therapy (XRT). Unfortunately, it remains clinically underutilized due to adverse side effects. The purpose of this study is to define the pharmacokinetic profile of an oral AMF formulation potentially capable of reducing side effects and increasing clinical feasibility. METHODS: Calvarial osteoblasts were radiated under three conditions: no drug, AMF, and WR-1065 (active metabolite). Osteogenic potential of cells was measured using alkaline phosphatase staining. Next, rats were given AMF intravenously or directly into the jejunum, and pharmacokinetic profiles were evaluated. Finally, rats were given AMF orally or subcutaneously, and blood samples were analyzed for pharmacokinetics. RESULTS: WR-1065 preserved osteogenic potential of calvarial osteoblasts after XRT to a greater degree than AMF. Direct jejunal AMF administration incurred a systemic bioavailability of 61.5%. Subcutaneously administrated AMF yielded higher systemic levels, a more rapid peak exposure (0.438 vs. 0.875 h), and greater total systemic exposure of WR-1065 (116,756 vs. 16,874 ng*hr/ml) compared to orally administered AMF. CONCLUSIONS: Orally administered AMF achieves a similar systemic bioavailability and decreased peak plasma level of WR-1065 compared to intravenously administered AMF, suggesting oral AMF formulations maintain radioprotective efficacy without causing onerous side effects, and are clinically feasible.

Low Prevalence of Clinically Significant Hyponatremia following Cranial Vault Reconstruction for Single-Suture Craniosynostosis.

BACKGROUND: Patients are commonly monitored for hyponatremia after intracranial procedures, yet the prevalence of hyponatremia after cranial vault reconstruction (CVR) remains unclear. The purpose of this study is to define the prevalence, risk factors, and complications of hyponatremia after CVR to optimize postoperative sodium surveillance protocols. METHODS: Patients with nonsyndromic, single-suture craniosynostosis who underwent primary CVR between 2009 and 2020 at Michigan Medicine were included (n = 231). Demographic, intraoperative, and postoperative characteristics were compared by postoperative hyponatremia status at P < 0.05 significance. Hyponatremia was defined as mild (<135 mEq/L), moderate (<130 mEq/L), or severe (<125 mEq/L) based on the lowest postoperative laboratory draw. RESULTS: Twenty-three patients (10.0%) developed mild postoperative hyponatremia. No patient developed moderate or severe postoperative hyponatremia. On multivariable regression, decreased preoperative sodium level (P = 0.03) and decreased preoperative weight (P = 0.02) were significantly associated with mild postoperative hyponatremia. No patient developed complications or required hospital readmission because of hyponatremia. CONCLUSIONS: This large retrospective cohort study of patients with nonsyndromic single-suture craniosynostosis demonstrated a 10% prevalence of mild, clinically inconsequential hyponatremia and 0% prevalence of moderate or severe, clinically significant hyponatremia after primary CVR. Patients with low preoperative sodium level or weight were at increased risk for developing mild postoperative hyponatremia. The results suggest that patients with preoperative sodium greater than 140 mEq/L or preoperative weight greater than 10 kg may be candidates for limited postoperative sodium surveillance; however, future prospective studies are warranted before implementation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Surgical Timing and Neurocognitive Development among Patients with Craniosynostosis: Analysis of Confounders.

BACKGROUND: In 1988, Renier and Marchac asserted that children with craniosynostosis who undergo cranial vault remodeling (CVR) after 12 months of age experience delayed neurocognitive development compared to children who undergo CVR before 12 months of age. The purpose of this study was to identify factors potentially confounding this cause-and-effect relationship. The authors hypothesize that children with socioeconomic disadvantages or comorbid conditions are more likely to undergo CVR after 12 months and may represent a selection bias toward delayed neurocognitive development. METHODS: Patients with nonsyndromic single-suture craniosynostosis who underwent CVR between 2009 and 2020 at Michigan Medicine were included ( n = 227). Sociodemographic and clinical variables were documented. The sample was dichotomized to compare patients who underwent CVR before (early) and after (late) 12 months of age. Statistical analysis was performed at P < 0.05 significance. RESULTS: The early and late groups contained 157 patients and 70 patients, respectively. Compared to the early group, the late group contained a larger proportion of patients who identified as non-White ( P = 0.03), qualified for need-based financial assistance ( P = 0.03), were born preterm ( P < 0.01), or had a comorbid condition ( P < 0.01). Based on preoperative testing, the late group contained a larger proportion of patients with baseline cognitive ( P < 0.001) and language ( P = 0.008) delays relative to the early group. CONCLUSIONS: This study demonstrates that socioeconomic disadvantages and comorbid conditions are prevalent among patients who undergo delayed CVR and may represent a selection bias toward delayed neurocognitive development. Future studies evaluating the relationship between surgical timing and neurocognitive development must control for these factors. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Overcoming Nuclear Winter: The Cutting-edge Science of Bone Healing and Regeneration in Irradiated Fields.

BACKGROUND: The incidence of cancer worldwide is expected to be more than 22 million annually by 2030. Approximately half of these patients will likely require radiation therapy. Although radiotherapy has been shown to improve disease control and increase survivorship, it also results in damage to adjacent healthy tissues, including the bone, which can lead to devastating skeletal complications, such as nonunion, pathologic fractures, and osteoradionecrosis. Pathologic fractures and osteoradionecrosis are ominous complications that can result in large bone and soft tissue defects requiring complex reconstruction. Current clinical management strategies for these conditions are suboptimal and dubious at best. The gold standard in treatment of severe radiation injury is free tissue transfer; however, this requires a large operation that is limited to select candidates. METHODS: With the goal to expand current treatment options and to assuage the devastating sequelae of radiation injury on surrounding normal tissue, our laboratory has performed years of translational studies aimed at remediating bone healing and regeneration in irradiated fields. Three therapeutics (amifostine, deferoxamine, and adipose-derived stem cells) have demonstrated great promise in promoting healing and regeneration of irradiated bone. RESULTS: Amifostine confers prophylactic protection, whereas deferoxamine and adipose-derived stem cells function to remediate postradiation associated injury. CONCLUSIONS: These prospective therapeutics exploit a mechanism attributed to increasing angiogenesis and ultimately function to protect or restore cellularity, normal cellular function, osteogenesis, and bone healing to nonirradiated metrics. These discoveries may offer innovative treatment alternatives to free tissue transfer with the added benefit of potentially preventing and treating osteoradionecrosis and pathologic fractures.