Empiric antifungals do not decrease the risk for organ space infection in patients with perforated peptic ulcer.

INTRODUCTION: Infection control in patients with perforated peptic ulcers (PPU) commonly includes empiric antifungals (AF). We investigated the variation in the use of empiric AF and explored the association between their use and the subsequent development of organ space infection (OSI). METHODS: This was a secondary analysis of a multicenter, case-control study of patients treated for PPU at nine institutions between 2011 and 2018. Microbiology and utilization of empiric AF, defined as AF administered within 24 hours from the index surgery, were recorded. Patients who received empiric AF were compared with those who did not. The primary outcome was OSI and secondary outcome was OSI with growth of Candida spp. A logistic regression was used to adjust for differences between the two cohorts. RESULTS: A total of 554 patients underwent a surgical procedure for PPU and had available timing of AF administration. The median age was 57 years and 61% were male. Laparoscopy was used in 24% and omental patch was the most common procedure performed (78%). Overall, 239 (43%) received empiric AF. There was a large variation in the use of empiric AF among participating centers, ranging from 25% to 68%. The overall incidence of OSI was 14% (77/554) and was similar for patients who did or did not receive empiric AF. The adjusted OR for development of OSI for patients who received empiric AF was 1.04 (95% CI 0.64 to 1.70), adjusted p=0.86. The overall incidence of OSI with growth of Candida spp was 5% and was similar for both groups (adjusted OR 1.29, 95% CI 0.59 to 2.84, adjusted p=0.53). CONCLUSION: For patients undergoing surgery for PPU, the use of empiric AF did not yield any significant clinical advantage in preventing OSI, even those due to Candida spp. Use of empiric AF in this setting is unnecessary. STUDY TYPE: Original article, case series. LEVEL OF EVIDENCE: III.

Laparoscopic omental patch for perforated peptic ulcer disease reduces length of stay and complications, compared to open surgery: A SWSC multicenter study.

RCTs showed benefits in Lap repair of perforated peptic ulcer (PPU). The SWSC Multi-Center Trials Group sought to evaluate whether Lap omental patch repairs compared to Open improved outcomes in PPU in general practice. Data was collected from 9 SWSC Trial Group centers. Demographics, operative time, 30-day complications, length of stay and mortality were included. 461 PATIENTS: Open in 311(67%) patients, Lap in 132(28%) with 20(5%) patients converted from Lap to Open. Groups were similar at baseline. Significant variability was found between centers in their utilization of Lap (0-67%). Complications at 30 days were lower in Lap (18.5% vs. 27.5%, p < 0.05) as was unplanned re-operation (4.7% vs 14%, p < 0.05). Lap reduced LOS (6 vs 8 days, p < 0.001). Ileus was more in Lap (42% vs 18 p < 0.001) operative time was 14 min higher in Lap(p < 0.01) and admission to OR time was 4 h higher in Lap(<0.05). No significant difference readmission or mortality. Our results suggest Lap should be considered a first-line option in suitable PPU patients requiring omental patch repair in centers that have the capacity and resources 24/7.

Hes4: A potential prognostic biomarker for newly diagnosed patients with high-grade osteosarcoma.

BACKGROUND: Prognostic biomarkers for osteosarcoma (OS) at the time of diagnosis are lacking. Necrotic response of OS to preoperative chemotherapy correlates with survival and is determined 3-4 months after diagnosis. The purpose of this study is to identify biomarkers that will stratify patients into good or poor responders to chemotherapy at diagnosis and determine the role of potential biomarkers in OS pathogenesis. PROCEDURE: Because OS may be caused by disruptions of osteogenic differentiation, and the Notch pathway is one regulator of bone development, we examined the link between Notch effectors, OS differentiation, and OS outcome. We probed the R2: Genomics Analysis and Visualization Platform for RNA expression levels of Notch targets in mixed high-grade OS pretreatment biopsies. We used human OS cell lines in vitro and in mice to determine the role of the Notch target hairy/enhancer of split 4 (Hes4) in OS. RESULTS: We found that in OS patients, high expression of Hes4 is correlated with decreased metastasis-free and overall survival. Human OS cells that overexpress Hes4 are more immature and have an increased invasive capacity in vitro. This was not universal to all Notch effectors, as Hes1 overexpression induced opposing effects. When injected into NSG mice, Hes4-overexpressing OS cells produced significantly larger, more lytic tumors and significantly more metastases than did control cells. CONCLUSIONS: Hes4 overexpression promotes a more aggressive tumor phenotype by preventing osteoblastic differentiation of OS cells. Hes4 expression may allow for the stratification of patients into good or poor responders to chemotherapy at diagnosis.

Developmental pathways hijacked by osteosarcoma.

Cancer of any type often can be described by an arrest, alteration or disruption in the normal development of a tissue or organ, and understanding of the normal counterpart's development can aid in understanding the malignant state. This is certainly true for osteosarcoma and the normal developmental pathways that guide osteoblast development that are changed in the genesis of osteogenic sarcoma. A carefully regulated crescendo-decrescendo expression of RUNX2 accompanies the transition from mesenchymal stem cell to immature osteoblast to mature osteoblast. This pivotal role is controlled by several pathways, including bone morphogenic protein (BMP), Wnt/ß-catenin, fibroblast growth factor (FGF), and protein kinase C (PKC). The HIPPO pathway and its downstream target YAP help to regulate proliferation of immature osteoblasts and their maturation into non-proliferating mature osteoblasts. This pathway also helps regulate expression of the mature osteoblast protein osteocalcin. YAP also regulates expression of MT1-MMP, a membrane-bound matrix metalloprotease responsible for remodeling the extracellular matrix surrounding the osteoblasts. YAP, in turn, can be regulated by the ERBB family protein Her-4. Osteosarcoma may be thought of as a cell held at the immature osteoblast stage, retaining some of the characteristics of that developmental stage. Disruptions of several of these pathways have been described in osteosarcoma, including BMP, Wnt/b-catenin, RUNX2, HIPPO/YAP, and Her-4. Further, PKC can be activated by several receptor tyrosine kinases implicated in osteosarcoma, including the ERBB family (EGFR, Her-2 and Her-4 in osteosarcoma), IGF1R, FGF, and others. Understanding these functions may aid in the understanding the mechanisms underpinning clinical observations in osteosarcoma, including both the lytic and blastic phenotypes of tumors, the invasiveness of the disease, and the tendency for treated tumors to ossify rather than shrink. Through a better understanding of the relationship between normal osteoblast development and osteosarcoma, we may gain insights into novel therapeutic avenues and improved outcomes.