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MiRNA expression in Malignant (N=21) versus Benign (N=21) IPMN cases, sorted by P value

miR-145-5p expression differentiates between cases and non-diseased controls. A) Box plot reveals miR-145-5p expression is higher in cases versus controls. B) ROC analysis reveals that miR-145-5p expression can differentiate between groups with an AUC=79.3 (95% CI: 68.3-90.3). Estimates of sensitivity, specificity, positive predictive value, and negative predictive value are 81%, 62.5%, 79%, and 65%, respectively.

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal cancers worldwide, partly because methods are lacking to detect disease at an early, operable stage. Noninvasive PDAC precursors called intraductal papillary mucinous neoplasms (IPMN) exist, and strategies are needed to aid in their proper diagnosis and management. Data support the importance of miRNAs in the progression of IPMNs to malignancy, and we hypothesized that miRNAs may be shed from IPMN tissues and detected in blood. Our primary goals were to measure the abundance of miRNAs in archived preoperative plasma from individuals with pathologically confirmed IPMNs and healthy controls and discover plasma miRNAs that distinguish between IPMN patients and controls and between “malignant” and “benign” IPMNs. Using novel nCounter technology to evaluate 800 miRNAs, we showed that a 30-miRNA signature distinguished 42 IPMN cases from 24 controls [area underneath the curve (AUC) = 74.4; 95% confidence interval (CI), 62.3–86.5, P = 0.002]. The signature contained novel miRNAs and miRNAs previously implicated in pancreatic carcinogenesis that had 2- to 4-fold higher expression in cases than controls. We also generated a 5-miRNA signature that discriminated between 21 malignant (high-grade dysplasia and invasive carcinoma) and 21 benign (low- and moderate-grade dysplasia) IPMNs (AUC = 73.2; 95% CI, 57.6–88.9, P = 0.005), and showed that paired plasma and tissue samples from patients with IPMNs can have distinct miRNA expression profiles. This study suggests feasibility of using new cost-effective technology to develop a miRNA-based blood test to aid in the preoperative identification of malignant IPMNs that warrant resection while sparing individuals with benign IPMNs the morbidity associated with overtreatment. Cancer Prev Res; 8(9); 826–34. ©2015 AACR.

Purpose Trauma is the leading cause of death before the age of 45 in the United States. Precision medicine (PM) is the most advanced scientific form of medical practice and seeks to gather data from the genome, environmental interactions, and lifestyles. Relating to trauma, PM promises to significantly advance our understanding of the factors that contribute to the physiologic response to injury. Methods We review the status of PM-driven trauma care. Semantic-based methods were used to gather data on genetic/epigenetic variability previously linked to the principal causes of trauma-related outcomes. Data were curated to include human investigations involving genomics/epigenomics with clinical relevance identifiable early after injury. Results Most studies relevant to genomic/epigenomic differences in trauma are specific to traumatic brain injury and injury-related sepsis. Genomic/epigenomic differences rarely encompass other relevant factors, such as coagulability and pharmacogenomics. Few studies describe clinical use of genomics/epigenomics for therapeutic intervention in trauma care, and even fewer attempt to incorporate real-time genomic/epigenomic information to precisely guide clinical decision-making. Conclusion Considering that genomics/epigenomics, environmental exposures, and lifestyles are most likely to be of significant medical relevance in advancing the field of trauma, the lack of application of concepts and methodologies from PM to trauma education, research, practice, and community wellness is underwhelming. We suggest that significant effort be given to incorporate the tools of what is becoming the “new medicine”.

In recent years, there has been an increased focus on developing and validating venous thromboprophylaxis guidelines in the pediatric trauma population. We review the current literature regarding the incidence of and risk factors for venous thromboembolism (VTE) and the use of prophylaxis in the pediatric trauma population. Risk factors such as age, injury severity, central venous catheters, mental status, injury type, surgery, and comorbidities can lead to a higher incidence of VTE. Risk stratification tools have been developed to determine whether mechanical and/or pharmacologic prophylaxis should be implemented depending on the degree of VTE risk. When VTE risk is high, pharmacologic prophylaxis, such as with low molecular weight heparin, is often initiated. However, the timing and duration of VTE prophylaxis is dependent on patient factors including ambulatory status and contraindications such as bleeding. In addition, the utility of screening ultrasound for VTE surveillance has been evaluated and though they are not widely recommended, no formal guidelines exist. While more research has been done in recent years to assess the most appropriate type, timing, and duration of VTE prophylaxis, further studies are warranted to create optimal guidelines for decreasing the risk of VTE after pediatric trauma.

Pediatric appendicitis is managed by general and pediatric surgeons at both children's hospitals and non-children's hospitals. A statewide assessment of surgeons and facilities providing appendicitis care was performed to identify factors associated with location of surgical care.Children aged18 years undergoing appendectomy for appendicitis in Wisconsin from 2018-2020 were identified through the International Classification of Diseases, 10th revision, and Current Procedural Terminology codes using Wisconsin Hospital Association data. Patient residence and hospital locations were used to determine travel distance, rurality, and neighborhood-level socioeconomic status.Among 3,604 children with appendicitis, 36.0% and 12.8% had an appendectomy at 2 major children's hospitals and 4 other children's hospitals, respectively, and 51.2% had an appendectomy at 99 non-children's hospitals. Pediatric surgeons performed 76.1% of appendectomies at children's hospitals and 2.9% at non-children's hospitals. Only 32.2% of patients received care at the hospital closest to their homes. Non-children's hospitals disproportionally cared for older, non-Hispanic White, and privately insured children, those with uncomplicated appendicitis, and those living in rural areas, in mid-socioeconomic status neighborhoods, and greater distances from children's hospitals (all P.001). After multivariable adjustment, receipt of care at children's hospitals was associated with younger age, minority race, complicated appendicitis, shorter distance to children's hospitals, and urban residence.Over half of surgical care for pediatric appendicitis occurred at non-children's hospitals, especially among older children and those living in rural areas far from children's hospitals. Future work is necessary to determine which children benefit most from care at children's hospitals and which can safely receive care at non-children's hospitals to avoid unnecessary time and resource utilization associated with travel to children's hospitals.

In recent years, there has been an increased focus on developing and validating venous thromboprophylaxis guidelines in the pediatric trauma population. We review the current literature regarding the incidence of and risk factors for venous thromboembolism (VTE) and the use of prophylaxis in the pediatric trauma population. Risk factors such as age, injury severity, central venous catheters, mental status, injury type, surgery, and comorbidities can lead to a higher incidence of VTE. Risk stratification tools have been developed to determine whether mechanical and/or pharmacologic prophylaxis should be implemented depending on the degree of VTE risk. When VTE risk is high, pharmacologic prophylaxis, such as with low molecular weight heparin, is often initiated. However, the timing and duration of VTE prophylaxis is dependent on patient factors including ambulatory status and contraindications such as bleeding. In addition, the utility of screening ultrasound for VTE surveillance has been evaluated and though they are not widely recommended, no formal guidelines exist. While more research has been done in recent years to assess the most appropriate type, timing, and duration of VTE prophylaxis, further studies are warranted to create optimal guidelines for decreasing the risk of VTE after pediatric trauma.

Vascular access is frequently a critical component of the diagnostic and therapeutic procedures required to manage childhood illnesses, including many emergent conditions and critical illnesses. Vascular access in the pediatric population presents unique challenges, and many clinical and technical factors must be considered to avoid complications that can occur with vascular access procedures. This article reviews various aspects of vascular access and associated iatrogenic trauma in children, including risk factors, management of complications, and preventive measures to avoid complications. It is only with a comprehensive understanding of the topic that vascular access in children can be performed safely, effectively, and efficiently.

Primary aortoduodenal fistula is a rare, life-threatening pathology that is difficult to diagnose and manage. We present the case of a 64-year-old male with a primary aortoduodenal fistula. Our patient initially underwent an endovascular aneurysm repair at an outside institution before being transferred to our tertiary care center, where he ultimately had definitive management with an extra-anatomic bypass, aortic ligation, duodenal resection with primary anastomosis, and gastrojejunostomy tube placement. His surgical cultures grew Candida albicans, and he was discharged with a 6-week course of intravenous antibiotics with subsequent antibiotic suppression for 1 year. He died 14 months postoperatively from tongue squamous cell carcinoma. We also review the current literature regarding epidemiology, pathology, diagnostics, management, and case reports from 2015 to present. Overall, timely diagnosis and treatment is imperative for reducing mortality from primary aortoduodenal fistula, and although formal consensus is lacking regarding most clinical aspects, an increasing number of case reports has helped describe options for management.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal cancers worldwide, partly because methods are lacking to detect disease at an early, operable stage. Noninvasive PDAC precursors called intraductal papillary mucinous neoplasms (IPMN) exist, and strategies are needed to aid in their proper diagnosis and management. Data support the importance of miRNAs in the progression of IPMNs to malignancy, and we hypothesized that miRNAs may be shed from IPMN tissues and detected in blood. Our primary goals were to measure the abundance of miRNAs in archived preoperative plasma from individuals with pathologically confirmed IPMNs and healthy controls and discover plasma miRNAs that distinguish between IPMN patients and controls and between “malignant” and “benign” IPMNs. Using novel nCounter technology to evaluate 800 miRNAs, we showed that a 30-miRNA signature distinguished 42 IPMN cases from 24 controls [area underneath the curve (AUC) = 74.4; 95% confidence interval (CI), 62.3–86.5, P = 0.002]. The signature contained novel miRNAs and miRNAs previously implicated in pancreatic carcinogenesis that had 2- to 4-fold higher expression in cases than controls. We also generated a 5-miRNA signature that discriminated between 21 malignant (high-grade dysplasia and invasive carcinoma) and 21 benign (low- and moderate-grade dysplasia) IPMNs (AUC = 73.2; 95% CI, 57.6–88.9, P = 0.005), and showed that paired plasma and tissue samples from patients with IPMNs can have distinct miRNA expression profiles. This study suggests feasibility of using new cost-effective technology to develop a miRNA-based blood test to aid in the preoperative identification of malignant IPMNs that warrant resection while sparing individuals with benign IPMNs the morbidity associated with overtreatment. Cancer Prev Res; 8(9); 826–34. ©2015 AACR.

Cancer stem cells (CSC) contribute to epithelial ovarian cancer (EOC) progression and therapeutic response. We hypothesized that germline single nucleotide polymorphisms (SNPs) in CSC-related genes may predict an initial therapeutic response for women newly diagnosed with EOC. A nested case-control design was used to study 361 women with advanced-stage serous EOC treated with surgery followed by first-line platinum-based combination therapy at Moffitt Cancer Center or as part of The Cancer Genome Atlas Study. "Cases" included 102 incomplete responders (IRs) and "controls" included 259 complete clinical responders (CRs) to therapy. Using Illumina genotyping arrays and imputation, DNA samples were evaluated for 5,509 SNPs in 24 ovarian CSC-related genes. We also evaluated the overall significance of each CSC gene using the admixture maximum likelihood (AML) test, and correlated genotype with EOC tumor tissue expression. The strongest SNP-level associations with an IR to therapy were identified for correlated (r(2) > 0.80) SNPs within signal transducer and activator of transcription 3 (STAT3) [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.32-3.78; p = 0.0027], after adjustment for age, population stratification, grade and residual disease. At the gene level, STAT3 was significantly associated with an IR to therapy (pAML = 0.006). rs1053004, a STAT3 SNP in a putative miRNA-binding site, was associated with STAT3 expression (p = 0.057). This is the first study to identify germline STAT3 variants as independent predictors of an unfavorable therapeutic response for EOC patients. Findings suggest that STAT3 genotype may identify high-risk women likely to respond more favorably to novel therapeutic combinations that include STAT3 inhibitors.

Background Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic ductal adenocarcinoma (PDAC) precursors. Differentiating between high-risk IPMNs that warrant surgical resection and low-risk IPMNs that can be monitored is a significant clinical problem, and we sought to discover a panel of mi(cro)RNAs that accurately classify IPMN risk status. Methodology/Principal Findings In a discovery phase, genome-wide miRNA expression profiling was performed on 28 surgically-resected, pathologically-confirmed IPMNs (19 high-risk, 9 low-risk) using Taqman MicroRNA Arrays. A validation phase was performed in 21 independent IPMNs (13 high-risk, 8 low-risk). We also explored associations between miRNA expression level and various clinical and pathological factors and examined genes and pathways regulated by the identified miRNAs by integrating data from bioinformatic analyses and microarray analysis of miRNA gene targets. Six miRNAs (miR-100, miR-99b, miR-99a, miR-342-3p, miR-126, miR-130a) were down-regulated in high-risk versus low-risk IPMNs and distinguished between groups (P