Citations

Introduction Proton dose driven continuous scanning (DDCS) is a form of proton pencil beam scanning (PBS) in which the beam may remain on during transitions between successive spots. Mayo Clinic Florida (MCF) is preparing to commission a synchrotron-based proton therapy system designed for DDCS, incorporating novel irradiation control features. Given the novelty and complexity of this system, a systematic risk-based analysis was performed to inform upcoming commissioning strategies. Methods A prospective risk analysis was conducted using the American Association of Physicists in Medicine (AAPM) Task Group 100 (TG 100) framework. A comprehensive process map of the DDCS irradiation control workflow was developed. Failure modes and effects analysis (FMEA) was performed to identify potential delivery system failure modes and to score each failure mode based on occurrence, severity, and lack of detectability. Targeted mitigation and commissioning strategies were then developed to address the highest-risk items. Results Twenty-nine delivery system failure modes were identified. The highest-risk failure modes were specific to DDCS operation. Targeted commissioning strategies were defined, including scan path measurement and modeling, validation of move and flap dose, dose monitor collection efficiency testing, spot position monitor performance evaluation, and verification of control system intervention behavior. Incorporation of these strategies into the commissioning plan reduced the mean RPN by more than 50%. Discussion This work provides a detailed description of the MCF proton DDCS irradiation control system and uses a TG 100 based approach for identifying system-specific risks. As new systems incorporate technologies for which limited guidance exists, institutions must perform their own risk analyses to determine appropriate quality management strategies.

Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) and lacks effective treatment options. Polyphyllin B (PB), a saponin extracted from Paris formosana Hayata, has shown potential in cancer therapy. However, its anti-TNBC effects and mechanisms are not well studied. This study investigated the effects and underlying mechanisms of PB in TNBC. Methods CCK8 assay, Wound healing assay, Transwell migration experiments, and clonogenic assay were performed to assess the effects of PB in three TNBC cells lines. Iron level, lipid ROS, and MDA levels were assessed as ferroptosis markers. Mechanistic studies were conducted using molecular docking, Western blot, immunofluorescence, RT-qPCR, Nrf2 overexpression assays and establishment of a TNBC mouse model. Results PB treatment resulted in significant cell death and inhibited the migration of TNBC cells. Accumulation of iron and MDA suggested that PB induces ferroptosis. In vitro and in vivo , PB downregulated the expression of nuclear factor E2-related factor 2 (NRF2) and sequestosome-1 (P62) and upregulated the expression of Kelch-like ECH-associated protein 1 (KEAP1). Furthermore, it modulated the expression of key ferroptosis regulators, including acyl-CoA synthetase long-chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4). In a TNBC mouse model, PB suppressed tumor growth and increased malondialdehyde accumulation. Conclusion PB inhibits cell proliferation and migration and induces ferroptosis in TNBC through the inactivation of NRF2. PB is a promising candidate for TNBC treatment that warrants further investigation.

Introduction Studies have revealed circadian rhythms affect many organ systems and time of injury can impact healing, lung function, and inflammation. We hypothesized operative time may impact post-operative risk. Accordingly, the aim of this study was to compare post-operative complications in patients whose surgery started and finished before 12pm (Group 1); after 12pm (Group 2); and started before 12pm and finished after 12pm (Group 3). Methods Patients from two previous prospective studies were included in this post-hoc analysis. Inclusion criteria were indication for lung resection surgery (confirmed or highly suspicious tumor), age ≥18 and ability to undergo cardiopulmonary exercise testing (CPET). Exclusion criterion was inability to perform surgery (either low predicted postoperative oxygen consumption or inoperability). All patients underwent pre-operative CPET and spirometry. Post-operative pulmonary (PPC) and cardiovascular complications (PCC) were prospectively assessed from the hospital stay up to 30 days. Results Data from 497 patients were analyzed. On comparison of groups, there were differences in BMI (highest in Group 3), surgery duration (lowest in Group 1) and frequency of lobectomies (lowest in Group 1). Incidence of PPC was lowest in Group 1 (n=17; 9%) compared to n=17 (21%) in Group 2 and n=37 (17%) in Group 3 (p=0.01). Incidence of PCC was lowest in Group 1 n=25 (13%) compared to n=19 (23%) in Group 2 and n=46 (21%) in Group 3 (p=0.05). Multivariate logistic regression adjusted for confounders (BMI, surgery duration and lobectomy) showed time of surgery after 12pm was independently associated with PPC with OR = 2.17 (95% CI 1.07-4.41); p=0.03. Conclusion Time of surgery may impact the incidence of PPC in lung resection surgery patients with highest risk in patients undergoing the surgery after 12pm.

ABSTRACT Age‐related changes in human hematopoietic stem cells (HSCs) often form the basis for clonal hematopoiesis (CH), which presages the development of overt myeloid neoplasm with variable risk. CH can also arise after exposure to chemotherapy, radiotherapy, or immune interventions. In this study, we performed clinico‐genomic profiling of therapy‐related CH (t‐CH) ( n = 67) versus de novo CH ( n = 123) from a multidisciplinary CHIP Clinic. The most enriched mutations in t‐CH were TET2 (26.2%), DNMT3A (22.4%), and TP53 (8.4%). Median latency period from the time of initial exposure to the diagnosis of t‐CH was 6.96 ± 1.10 years. Patients with t‐CH had inferior event‐free survival compared to de novo CH (median 29.9 months versus 122.1 months, p = 0.0045). Overall survival was also shorter in t‐CH versus de novo CH (median 55.3 months vs. 129.2 months, p = 0.043). Genes that imparted significantly increased risk for progression from t‐CH to overt therapy‐related myeloid neoplasm (t‐MN) included JAK2 (relative risk (RR) 9.42, p = 0.0001), RUNX1 (RR 7.11, p = 0.001), EZH2 (RR 7.11, p = 0.001), and TET2 (RR 13.4, p = 0.01). Clonal dynamic modeling of patients with t‐CH who progressed to overt t‐MN showed an increase in the relative clonal fraction and new clonal outgrowth. In the t‐CH cohort, higher mean variant allele frequency was observed in progressors versus non‐progressors (77.1% vs. 30.6%, p = 0.017). This study sheds light onto outcomes for CH based on differing clinical ontogeny and has implications for previvorship for secondary malignancies.

Abstract Functional magnetic resonance imaging (fMRI) data are inherently complex, characterized by high dimensionality, intricate inter-regional dependencies, and substantial individual variability across experimental paradigms. Traditional linear mixed models (LMMs) provide a principled framework that models population-level fixed effects while estimating variance components arising from subject-level random effects; however, they often fail to adequately capture nonlinear relationships inherent in neuroimaging data. To address these limitations, we introduce the nonlinear mixed model (NMM) approach, an innovative extension of the LMM framework that integrates neural networks to flexibly model complex fixed-effect relationships while preserving the random-effects structure to account for individual differences. NMM advances fMRI analysis by: (1) identifying robust functional connectivity (FC) patterns consistently observed across multiple paradigms; (2) leveraging SHapley Additive exPlanations (SHAP) analysis to provide post-hoc interpretability of the nonlinear fixed effects, quantifying how age, sex, and paradigm contribute to predicted FC and how these effects are distributed across large-scale brain networks; and (3) using subject-specific random effects as neural fingerprints that not only show systematic variability across attention and default mode systems but also predict standardized cognitive scores, demonstrating biological relevance. Applied to the Philadelphia Neurodevelopmental Cohort (PNC) across emotion, n-back, and resting-state paradigms, NMM achieved superior model fit relative to classical LMMs, as evidenced by lower mean squared error (MSE) in predicting FC. This framework offers a statistically rigorous and practically explainable approach for modeling large-scale FC from modest covariates while explicitly separating population-level effects from stable individual variability in functional brain organization.

Patients with traumatic brachial plexus injuries (TBPI) undergo clinical examination and electromyography (EMG) to characterize injury severity and localization. However, precise localization with EMG alone can be difficult when multiple injury sites are possible. Brachial plexus ultrasound (BPUS) allows direct visualization of the brachial plexus, a needed adjunct to EMG to reveal multiple sites of injury in TBPI. We summarize three cases of EMG-confirmed upper trunk TBPI which were clarified using BPUS to additionally involve electrically hidden injuries to the extraforaminal C5 and C6 nerve roots. BPUS demonstrated extensive scarring and focal enlargement of the upper trunk in each patient (all cross-sectional area [CSA] ≥24 mm 2 ). However, all patients also had C5 and C6 extraforaminal nerve root enlargement (all CSA ≥9 mm 2 and 12 mm 2 , respectively), revealing further neural involvement proximal to the upper trunk into the EMG “gray zone”– postganglionic, extraforaminal cervical nerve root injury which is clinically and electrodiagnostically indistinguishable from the plexus but anatomically and radiographically distinguishable on BPUS. Some EMG-identified upper trunk TBPI may have more proximal involvement of the contributing extraforaminal C5-6 nerve roots, an area electrically indistinguishable from an upper trunk TBPI without the assistance of advanced imaging.

Sacral stress fractures are rare in athletes, present as nonspecific gluteal and/or back pain, and are often missed on radiographs. Standard treatment includes activity modification, physical therapy, and pain medications. However, prolonged recovery and recurrence remain concerns in athletes. There is evidence for the use of extracorporeal shockwave therapy (ESWT) in the treatment of stress fractures, and platelet-rich plasma (PRP) has also shown promise in accelerating bony healing. This case report describes a 48-year-old male triathlete with a recurrent sacral stress fracture unresponsive to conservative management. Following MRI diagnosis, he underwent sequential ESWT and PRP injection, resulting in successful return to competitive training levels at 8-weeks post-treatment. Although an MRI at 3-months post-treatment showed persistent bony edema, his PROMIS-Pain Interference (PI) and Global Pain Scale (GPS) scores improved from 54 to 40 and 62/100 to 4/100, respectively. There is currently no published literature on the sequential use of ESWT and PRP for the treatment of sacral stress fractures. To our knowledge, this is the first documented case of this novel treatment, suggesting a potential role for combination therapy in such injuries. Further research is warranted to validate the efficacy and long-term outcomes of this emerging therapeutic approach in athletic populations.

BACKGROUND: Compared to standard labor epidurals, placement of a dural puncture epidural (DPE) has been shown to improve labor analgesia efficacy, speed onset of analgesia, and decrease failure rates. However, there is a concern of increased post-dural puncture headache (PDPH) risk. A 25-gauge or larger spinal needle is typically needed for a DPE to have improved efficacy over a standard epidural. A prior meta-analysis comparing combined spinal-epidurals (CSEs) with epidurals did not identify a difference in PDPH rates, but many of the included randomized controlled trials (RCTs) used smaller diameter (27–29 gauge) spinal needles. This systematic review and meta-analysis of RCTs evaluates headache frequency following CSE or DPE labor analgesia techniques with 24- or 25-gauge spinal needles. METHODS: Medline, EMBASE, Scopus, Database of Abstracts of Reviews of Effects, Web of Science Core Collection, and Cochrane databases were searched on May 7, 2024, for RCTs comparing either DPE or CSE techniques using 24- or 25-gauge spinal needles with epidural labor analgesia. The primary outcome was headache. The risk-of-bias 2 tool was used to assess bias. The odds ratio (OR) was the chosen effect size using binomial family Bayesian estimation. The reference category for estimation was the conventional epidural technique group. RESULTS: Encompassing 3278 patients, 1765 (53.8%) received labor epidurals, 971 (29.6%) received DPEs, and 542 (16.5%) received CSEs. The rate of headaches in both groups was low, with headache rates of CSE/DPE and epidural groups (0.59% vs 0.34%), respectively. Headache was a secondary outcome in all the RCTs. In 10 of the 16 RCTs (62.5%), no patients of 1428 (0%; 95% credible interval [CI], 0.00–0.25) reported a headache. A total of nine (0.6%) headaches were reported in the DPE/CSE patients (denominator 1513) and six (0.3%) headaches were reported in the traditional epidural patients (denominator 1765). The posterior distribution of the treatment effect ( θ ) showed that the log OR of 0.35 favored the control group as having fewer events, but the number of events was rare, and the 95% CI was wide (−0.49 to 1.22). CONCLUSIONS: Headache was a rare event in both groups. Although these results are reassuring that either technique is clinically safe, they should be interpreted cautiously. A large RCT examining PDPH as the primary outcome with long-term follow-up is needed to more precisely determine if placement of a DPE or CSE with a 24- or 25-gauge spinal needle increases the risk of PDPH.