Lack of durable response to cytotoxic chemotherapy is a major contributor to the dismal outcomes seen in pancreatic ductal adenocarcinoma (PDAC). Extensive tumor desmoplasia and poor vascular supply are two predominant characteristics which hinder the delivery of chemotherapeutic drugs into PDAC tumors and mediate resistance to therapy. Previously, we have shown that STAT3 is a key biomarker of therapeutic resistance to gemcitabine treatment in PDAC, which can be overcome by combined inhibition of the Src and EGFR pathways. Although it is well-established that concurrent EGFR and Src inhibition exert these antineoplastic properties through direct inhibition of mitogenic pathways in tumor cells, the influence of this combined therapy on stromal constituents in PDAC tumors remains unknown. In this study, we demonstrate in both orthotopic tumor xenograft and Ptf1a cre/þ ; LSL-Kras G12D/þ ;Tgfbr2 flox/flox (PKT) mouse models that concurrent EGFR and Src inhibition abrogates STAT3 activation, increases microvessel density, and prevents tissue fibrosis in vivo. Furthermore, the stromal changes induced by parallel EGFR and Src pathway inhibition resulted in improved overall survival in PKT mice when combined with gemcitabine. As a phase I clinical trial utilizing concurrent EGFR and Src inhibition with gemcitabine has recently concluded, these data provide timely translational insight into the novel mechanism of action of this regimen and expand our understanding into the phenomenon of stromal-mediated therapeutic resistance.Implications: These findings demonstrate that Src/EGFR inhibition targets STAT3, remodels the tumor stroma, and results in enhanced delivery of gemcitabine to improve overall survival in a mouse model of PDAC.

a b s t r a c tPurpose: Child abuse is a national, often hidden, epidemic. The study objective was to determine at-risk populations that have been previously hospitalized prior to their admission for child abuse. Methods: The Nationwide Readmissions Database (NRD) was queried for all children hospitalized for abuse. Outcomes were previous admissions and diagnoses. χ 2 analysis was used; significance equals p b 0.05. Results: 31,153 children were hospitalized for abuse (half owing to physical abuse) during the study period. 11% (n = 3487) of these children had previous admissions (one in three to a different hospital), while 3% (n = 1069) had multiple hospitalizations. 60% of prior admissions had chronic conditions, and 12% had traumatic injuries. Children with chronic conditions were more likely to have sexual abuse (89% vs. 57%, p b 0. 001) and emotional abuse (75% vs. 60%, p b 0. 01). 25% of chronic diagnoses were psychiatric, who were also more likely to have sexual and emotional abuse (47% vs. 5.5% and 10% vs. 1%, all p b 0. 001). Conclusion: This study uncovers a hidden population of children with past admissions for chronic conditions, especially psychiatric diagnoses that are significantly associated with certain types of abuse. Improved measures to accurately identify at-risk children must be developed to prevent future childhood abuse and trauma. Level of evidence: Level III. Type of study: Retrospective comparative study.

Gastrointestinal stromal tumors are exceedingly rare tumors in the pediatric population, as a result many clinicians either may never see this diagnosis or will encounter it only a few times throughout their careers. It is imperative in the pediatric population to follow appropriate steps to ensure a swift diagnosis and referral to specialized centers that are equipped with the multidisciplinary teams accustomed to treating rare diseases. This review aims to discuss the most recent data available on the diagnostic modalities utilized in cases of suspected Pediatric GIST.

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