Traumatic brain injury (TBI) survivors suffer from a range of morbidities, including post-traumatic endocrinopathies that can cause physical and mental changes in patients, greatly compromising quality of life. This study tested the hypothesis that mild and moderate diffuse TBI leads to chronic deficiencies in corticosterone (CORT) regulation following repeated exposure to restraint stress over time. Young adult male rats ( n = 9–11/group) were subjected to mild or moderate TBI induced by midline fluid percussion injury (mFPI) or control sham surgery. At 6 and 24 h post-injury, both mild and moderate TBI resulted in elevated resting plasma CORT levels compared with uninjured shams. Independent of TBI severity, all rats had lower resting plasma CORT levels at 7, 14, 28, and 54 days post-injury compared with pre-surgery baseline CORT. Circulating levels of CORT were also evaluated under restraint stress and in response to dexamethasone (DEX), a synthetic glucocorticoid. Independent of TBI severity, restraint stress elevated CORT at 30, 60, and 90 min post-stressor initiation at all post-injury time-points. A blunted CORT response to restraint stress was observed with lower CORT levels after restraint at 28 and 54 days compared with 7 days post-injury (DPI), indicative of habituation to the stressor. A high dose of DEX lowered CORT levels at 90 min post-restraint stress initiation compared with low-dose DEX, independent of TBI severity. These results support TBI-induced CORT dysregulation at acute time-points, but additional studies that investigate the onset and progression of endocrinopathies, controlling for habituation to repeated restraint stress, are needed to inform the diagnosis and treatment of such morbidities in TBI survivors.

PURPOSE: Hepatocellular carcinoma (HCC) has high relapse rates after standard-of-care (SOC) resection or liver transplantation (LT). We evaluated the utility of circulating tumor DNA (ctDNA) to predict relapse/progression risk in patients with HCC. Materials and Methods: This retrospective analysis examined real-world data from ctDNA testing on 125 patients with HCC (721 plasma samples) undergoing curative-intent treatments and SOC management. Patients were divided into four subcohorts: cohort A (n = 64) and B (n = 52) comprised patients under recurrence monitoring after LT or resection, respectively. Cohort C (n = 4) and D (n = 5) comprised patients under treatment response monitoring with known recurrence or inoperable disease, respectively. A personalized, tumor-informed 16-plex polymerase chain reaction next-generation sequencing assay (Signatera, Natera, Inc, Austin, TX) was used for ctDNA testing. The molecular residual disease (MRD) window was defined as 2-12 weeks post-LT/resection (cohorts A/B), before starting adjuvant therapy (AT). Surveillance window was defined as post-MRD window or 2 weeks post-AT (cohort B) or during ongoing treatment (cohorts C/D). RESULTS: The median follow-up was 40 (1.5-60) months. In cohort A, 97.2% (35/36) of patients with ctDNA negativity in the MRD window remained negative during surveillance. In cohort B, ctDNA was detected in 29.4% (10/34) of patients within the MRD window, all of whom experienced clinical recurrence (hazard ratio [HR], 7.2 [95% CI, 2.6 to 20]; P < .0001). In the surveillance window (cohort B), the ctDNA detection rate was 32.3% (10/31), and all experienced recurrence (HR, 18.0 [95% CI, 3.9 to 85]; P < .0001). In cohorts C/D, on-treatment ctDNA dynamics were concordant with treatment response as measured by imaging. Compared with alpha-fetoprotein, ctDNA had higher sensitivity and a significantly longer lead time (7.9 v 2.2 months) for recurrence detection. CONCLUSION: Serial ctDNA testing effectively identified HCC recurrence early, postresection and post-LT. ctDNA was also useful for treatment response monitoring and could help resolve ambiguous imaging results.

Over half of fatal pediatric traumatic brain injuries are estimated to be the result of physical abuse, i.e., abusive head trauma (AHT). Although intimate partner violence (IPV) is a well-established risk for child maltreatment, little is known about IPV as an associated risk factor specifically for AHT. We performed a single-institution, retrospective review of all patients (0–17 years) diagnosed at a Level 1 pediatric trauma center with head trauma who had been referred to an in-hospital child protection team for suspicion of AHT between 2010 and 2016. Data on patient demographics, hospitalization, injury, family characteristics, sociobehavioral characteristics, physical examination, laboratory findings, imaging, discharge, and forensic determination of AHT were extracted from the institution’s forensic registry. Descriptive statistics (mean, median), chi-square and Mann–Whitney U tests were used to compare patients with fatal head injuries to patients with nonfatal head injuries by clinical characteristics, family characteristics, and forensic determination. Multiple logistic regression was used to estimate adjusted odds ratios for the presence of IPV as an associated risk of AHT while controlling for other clinical and family factors. Of 804 patients with suspicion for AHT in the forensic registry, there were 240 patients with a forensic determination of AHT; 42 injuries were fatal. There were 101 families with a reported history of IPV; 64.4% of patients in families with reported IPV were <12 months of age. IPV was associated with a twofold increase in the risk of AHT (Exp( β ) = 2.3 [ p = .02]). This study confirmed IPV was an associated risk factor for AHT in a single institution cohort of pediatric patients with both fatal and nonfatal injuries. Identifying IPV along with other family factors may improve detection and surveillance of AHT in medical settings and help reduce injury, disability, and death.

Purpose: Circulating tumor DNA (ctDNA) has emerged as an important biomarker for early recurrence detection and disease status monitoring during treatment in patients with cancer, including melanoma. We evaluate the prognostic value and impact of postoperative ctDNA detection in patients with stage I to IIIB melanoma using a clinically validated ctDNA assay. Experimental Design: We conducted a retrospective analysis of real-world data of patients with stage I to IIIB melanoma, including ctDNA results using a personalized, tumor-informed, 16-plex multiplex PCR–next-generation sequencing assay. Adjuvant treatment decisions and postsurgical plasma sample collection timepoints were at the physician’s discretion. ctDNA results were correlated with clinical outcomes. Results: Across 190 patients and a total of 1,578 samples, a median of 7 ctDNA tests (range: 1–33) per patient were performed over a median period of 24.6 months (range: 3.7–74.7). ctDNA positivity at any postoperative timepoint was significantly associated with shorter recurrence-free survival [RFS; hazard ratio (HR): 40.63; 95% confidence interval (CI), 19.9–82.96; P < 0.0001). This finding was also observed in patients specifically with regional or distant recurrence (HR: 39.55; 95% CI, 18.08–86.51; P < 0.0001). In multivariate analysis, ctDNA positivity was the most significant prognostic factor associated with RFS when compared with other clinicopathologic factors, including stage, sex, and mitotic rate (HR: 25.36; 95% CI, 9.16–70.3; P < 0.001). Conclusions: Our findings highlight the prognostic value of postsurgical, personalized ctDNA detection of recurrence and longitudinal disease surveillance in stage I to IIIB melanoma. The impact of ctDNA on real-world clinical decision-making highlights the need to assess outcomes when cancer management is influenced by ctDNA dynamics.

Intimate partner violence (IPV) increases risk of traumatic brain injury (TBI). Physical assaults increase in frequency and intensity during pregnancy. The consequences of TBI during pregnancy (gravida TBI; gTBI) on offspring development is unknown, for which stress and inflammation during pregnancy worsen fetal developmental outcomes. We hypothesized that gTBI would lead to increased anxiety- and depression-related behavior, altered inflammatory responses and gut pathology, and distorted brain circuitry in mixed-sex offspring compared to mice born to control mothers. Pregnant dams received either diffuse TBI or sham injury (control) 12 days post-coitum. We found that male gTBI offspring were principal drivers of the gTBI effects on health, physiology, and behavior. For example, male, but not female, gTBI offspring weighed significantly less at weaning compared to male control offspring. At post-natal day (PND) 28, gTBI offspring had significantly weaker intralaminar connectivity onto layer 5 pre-frontal pyramidal neurons compared to control offspring. Neurological performance on anxiety-like behaviors was decreased, with only marginal differences in depressive-like behaviors, for gTBI offspring compared to control offspring. At PND42 and PND58, circulating neutrophil and monocyte populations were significantly smaller in gTBI male offspring than control male offspring. In response to a subsequent inflammatory challenge at PND75, gTBI offspring had significantly smaller circulating neutrophil populations than control offspring. Anxiety-like behaviors persisted during the immune challenge in gTBI offspring. However, spleen immune response and gut histology showed no significant differences between groups. The results compel further studies to determine the full extent of gTBI on fetal and maternal outcomes.

Background: Circulating tumor DNA (ctDNA) is a valuable biomarker for assessing treatment response and molecular residual disease. In advanced esophageal and gastric cancer (gastroesophageal cancer [EGC]), ctDNA dynamics remain poorly understood. The authors investigated ctDNA in patients with advanced EGC to evaluate its clinical utility. Methods: This was a multi‐institutional, retrospective analysis of 200 patients with recurrent/metastatic EGCs who underwent commercial ctDNA testing using a personalized, tumor‐informed assay (Signatera; Natera, Inc.). Patients were divided into cohort A ( N = 36; stage I–III with recurrence) or cohort B ( N = 164; metastatic at diagnosis). Longitudinal ctDNA dynamics were correlated with clinical and radiographic findings. Results: In cohort A, 31 of 36 patients (86.1%) had ctDNA collected ≤90 days before recurrence; of these, 25 of 31 patients (80.65%) were ctDNA‐positive before recurrence. In cohort B, baseline ctDNA was available for 29 of 164 patients (17.68%), and all 29 were ctDNA‐positive. Among 52 patients who had on‐treatment ctDNA assessments, 62 treatment lines were analyzed ( N = 6 in cohort A; N = 46 in cohort B). All who remained ctDNA‐negative throughout treatment (Neg‐Neg) showed treatment benefit ( n = 6 of 6). Those who converted to ctDNA‐positive (Neg‐Pos) progressed ( n = 2 of 2). Among ctDNA‐positive patients (Pos‐Pos), 27 of 40 (67.5%) showed treatment benefit, whereas 13 of 40 (32.5%) progressed. Patients who cleared ctDNA (Pos‐Neg) had favorable outcomes (12 of 14 patients; 85.7%). A decrease >90% in ctDNA levels among Pos‐Pos patients was linked to superior progression‐fee survival. Grouping treatment lines into favorable (Neg‐Neg, Pos‐Neg, and Pos‐Pos with >90% decrease) versus unfavorable (Neg‐Pos and Pos‐Pos with a <90% decrease or an increase) had significantly improved progression‐free survival in the favorable group ( p < .0001). Conclusions: ctDNA dynamics predicted progression and may guide treatment or imaging. ctDNA offers a minimally invasive, cost‐effective adjunct to radiographic surveillance.