Introduction: The utility of pancreaticoduodenectomy (PD) for high-grade traumatic injuries remains unclear and data surrounding its use are limited. We hypothesized that PD does not result in improved outcomes when compared with non-PD surgical management of grade IV–V pancreaticoduodenal injuries. Methods: This is a retrospective, multicenter analysis from 35 level 1 trauma centers from January 2010 to December 2020. Included patients were ≥15 years of age with the American Association for the Surgery of Trauma grade IV–V duodenal and/or pancreatic injuries. The study compared operative repair strategy: PD versus non-PD. Results: The sample (n=95) was young (26 years), male (82%), with predominantly penetrating injuries (76%). There was no difference in demographics, hemodynamics, or blood product requirement on presentation between PD (n=32) vs non-PD (n=63). Anatomically, PD patients had more grade V duodenal, grade V pancreatic, ampullary, and pancreatic ductal injuries compared with non-PD patients (all p<0.05). 43% of all grade V duodenal injuries and 40% of all grade V pancreatic injuries were still managed with non-PD. One-third of non-PD duodenal injuries were managed with primary repair alone. PD patients had more gastrointestinal (GI)-related complications, longer intensive care unit length of stay (LOS), and longer hospital LOS compared with non-PD (all p<0.05). There was no difference in mortality or readmission. Multivariable logistic regression analysis determined PD to be associated with a 3.8-fold greater odds of GI complication (p=0.010) compared with non-PD. In a subanalysis of patients without ampullary injuries (n=60), PD patients had more anastomotic leaks compared with the non-PD group (3 (30%) vs 2 (4%), p=0.028). Conclusion: While PD patients did not have worse hemodynamics or blood product requirements on admission, they sustained more complex anatomic injuries and had more GI complications and longer LOS than non-PD patients. We suggest that the role of PD should be limited to cases of massive destruction of the pancreatic head and ampullary complex, given the likely procedure-related morbidity and adverse outcomes when compared with non-PD management. Level of evidence: IV, Multicenter retrospective comparative study.

Background: Nasopharyngeal carcinoma (NPC) is a rare head and neck cancer arising from the mucosal lining of the nasopharynx, for which systemic therapeutic options remain scarce, reflecting the limited characterization of its genomic profile. This study utilized a large patient-level genomic repository to characterize genetic alterations, identify potential therapeutic targets, and improve disease modeling in NPC. Methods: A retrospective analysis of NPC samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set at p < 0.05. Results: Frequent mutations were identified in KMT2D (20%), TP53 (16%), CYLD (9.6%), NFKBIA (6.4%), and PIK3CA (5.6%), implicating the p53, NF-κB, and PI3K pathways in NPC development. Notably, significantly distinct mutational profiles were observed based on both sex and race, with female patients exhibiting higher frequencies of PIK3C2G, ETV6, and CDKN1B mutations and non-Asian patients showing enrichment in KDM5A, CCND2, and TP53 mutations. Conclusions: This study presents a detailed genomic profile of NPC, identifying key mutations within established cancer-associated pathways. The identification of frequently mutated pathways (p53, NF-κB, and PI3K) suggests potential targets for novel therapies. Furthermore, distinct mutational landscapes in female and Asian NPC patients offer possibilities for precision therapeutic interventions.

Objective(s): To delineate the somatic mutational landscape of follicular thyroid carcinoma (FTC) from a large, real-world cohort to identify molecular subtypes and actionable targets for personalized therapeutic interventions. Methods: Genomic and clinical data for 168 FTC samples were retrieved from the AACR Project GENIE^® registry via cBioPortal. This study assessed mutation frequencies, copy number alterations, and subgroup differences (primary vs. metastatic; adult vs. pediatric) using statistical tests. Results: NRAS was the most common mutation (33.9%), followed by TERT (22.6%), DICER1 (15.5%), HRAS (11.9%), and PTEN (10.7%). DICER1 mutations were significantly enriched in pediatric cases (44.4% vs. 4.6% in adults, p < 0.001), while TERT mutations were exclusive to adults (42%). NRAS mutations were more frequent in metastatic tumors (42.4%) than primary tumors (29.2%). Conclusions: FTC tumorigenesis is driven by distinct molecular pathways, with significant heterogeneity between pediatric and adult patients as well as primary and metastatic disease. These findings underscore the necessity of molecular profiling for patient stratification and provide a strong rationale for developing personalized treatment strategies to improve clinical outcomes.

The dystrophin gene encodes multiple dystrophin isoforms with tissue-specific functions, including several shorter isoforms expressed in the central nervous system and retina. While Duchenne muscular dystrophy (DMD) has historically been charac-terized as a primary myopathy resulting from loss of the full-length dystrophin Dp427, increasing clinical evidence indicates that dysfunction of shorter dystrophin isoforms contributes to significant extramuscular pathology, including retinal disease. In par-ticular, loss of the Dp71 isoform has been implicated in retinal inflammation, blood–retinal barrier breakdown, and pathological angiogenesis. In this study, we investigated whether low-level residual expression of Dp71 is sufficient to mitigate retinal inflammation in the mdx3Cv mouse model, which displays reduced—but not absent—expression of multiple dystrophin isoforms. Western blot analysis revealed that mdx3Cv retinas express approximately 4% of wild-type Dp71 protein levels. Despite this marked reduction, mdx3Cv mice did not exhibit the in-flammatory phenotype previously observed in Dp71-null mice. Retinal VEGF protein levels and VEGF receptor (FLT-1 and KDR) mRNA expression were preserved, while VEGF mRNA levels were modestly reduced. Furthermore, expression of inflammatory markers ICAM-1 and ALOX5AP, leukocyte adhesion to retinal vasculature, Aqua-porin-4 expression, and BRB permeability to albumin were all comparable to wild-type littermates. Together, these findings demonstrate that minimal residual expression of Dp71 is sufficient to preserve retinal vascular homeostasis and prevent inflammatory and permeability defects in the mdx3Cv retina. These results further suggest that partial dystrophin restoration—at levels achievable with current exon-skipping or gene-based therapies—may be adequate to prevent or attenuate retinal pathology in DMD, providing a realistic and clinically relevant therapeutic target.

The dystrophin gene encodes multiple dystrophin isoforms with tissue-specific functions, including several shorter isoforms expressed in the central nervous system and retina. While Duchenne muscular dystrophy (DMD) has historically been characterized as a primary myopathy resulting from loss of the full-length dystrophin Dp427, increasing clinical evidence indicates that dysfunction of shorter dystrophin isoforms contributes to significant extramuscular pathology, including retinal disease. In particular, loss of the Dp71 isoform has been implicated in retinal inflammation, blood–retinal barrier breakdown, and pathological angiogenesis. In this study, we investigated whether low-level residual expression of Dp71 is sufficient to mitigate retinal inflammation in the mdx3Cv mouse model, which displays reduced—but not absent—expression of multiple dystrophin isoforms. Western blot analysis revealed that mdx3Cv retinas express approximately 4% of wild-type Dp71 protein levels. Despite this marked reduction, mdx3Cv mice did not exhibit the inflammatory phenotype previously observed in Dp71-null mice. Retinal VEGF protein levels and VEGF receptor (FLT-1 and KDR) mRNA expression were preserved, while VEGF mRNA levels were modestly reduced. Furthermore, expression of inflammatory markers ICAM-1 and ALOX5AP, leukocyte adhesion to retinal vasculature, Aquaporin-4 expression, and BRB permeability to albumin were all comparable to wild-type littermates. Together, these findings demonstrate that minimal residual expression of Dp71 is sufficient to preserve retinal vascular homeostasis and prevent inflammatory and permeability defects in the mdx3Cv retina. These results further suggest that partial dystrophin restoration—at levels achievable with current exon-skipping or gene-based therapies—may be adequate to prevent or attenuate retinal pathology in DMD, providing a realistic and clinically relevant therapeutic target.

The mdx52 mouse model exhibits a common mutation profile associated with brain involvement in Duchenne muscular dystrophy (DMD), characterized by heightened anxiety, fearfulness, and impaired associative fear learning. Deletion of exon 52 disrupts the expression of two dystrophins found in the brain (Dp427 and Dp140), and is eligible for therapeutic exon-skipping strategies. We previously demonstrated that a single intracerebroventricular administration of an antisense oligonucleotide (ASO) targeting exon 51 of the Dmd gene could restore 5% to 15% of Dp427 expression. This treatment reduced anxiety and unconditioned fear in mdx52 mice, improved fear conditioning acquisition, and partially improved fear memory tested 24 hours later. To improve the restoration of Dp427 and induce a long-lasting therapeutic effect, we employed a vectorized approach using an AAV-U7snRNA vector to deliver antisense sequences to the brains of mdx52 mice. We evaluated two AAV serotypes known for their brain transduction efficiency (AAV9 and RH10) and two delivery routes, intracisterna magna and intracerebroventricular (ICV) injections, to maximize brain targeting. Based on GFP expression data, we selected the AAV9 capsid and a bilateral ICV delivery route. Using this approach, we demonstrated that ICV administration of AAV9-U7-Ex51M induced exon 51 skipping and restored Dp427 expression in the brains of adult mdx52 mice, though with significant variability among individuals. While a few mice showed high Dp427 expression levels, the average restoration was limited to approximately 6% to 12%. In conclusion, inducing exon skipping in the brains of adult mdx52 mice using the vectorized AAV9-U7 approach was less effective than synthetic ASO treatment and did not improve the emotional behavior of mdx52 mice.