Development and validation of a five-factor score for prediction of pathologic pneumatosis.

BACKGROUND: The significance of pneumatosis intestinalis (PI) remains challenging. While certain clinical scenarios are predictive of transmural ischemia, risk models to assess the presence of pathologic PI are needed. The aim of this study was to determine what patient factors at the time of radiographic diagnosis of PI predict the risk for pathologic PI. METHODS: We conducted a retrospective cohort study examining patients with PI from 2010 to 2016 at a multicenter hospital network. Multivariate logistic regression was used to develop a predictive model for pathologic PI in a derivation cohort. Using regression-coefficient-based methods, the final multivariate model was converted into a five-factor-based score. Calibration and discrimination of the score were then assessed in a validation cohort. RESULTS: Of 305 patients analyzed, 102 (33.4%) had pathologic PI. We identified five factors associated with pathologic PI at the time of radiographic diagnosis: small bowel PI, age 70 years or older, heart rate 110 bpm or greater, lactate of 2 mmol/L or greater, and neutrophil-lymphocyte ratio 10 or greater. Using this model, patients in the validation cohort were assigned risk scores ranging from 0 to 11. Low-risk patients were categorized when scores are 0 to 4; intermediate, score of 5 to 6; high, score of 7 to 8; and very high risk, 9+. In the validation cohort, very high-risk patients (n = 17; 18.1%) had predicted rates of pathologic pneumatosis of 88.9% and an observed rate of 82.4%. In contrast, patients labeled as low risk (n = 37; 39.4%) had expected rates of pathologic pneumatosis of 1.3% and an observed rate of 0%. The model showed excellent discrimination (area under the curve, 0.90) and good calibration (Hosmer-Lemeshow goodness-of-fit, p = 0.37). CONCLUSION: Our score accurately stratifies patient risk of pathologic pneumatosis. This score has the potential to target high-risk individuals for expedient operation and spare low-risk individuals invasive interventions. LEVEL OF EVIDENCE: Prognostic Study, Level III.

Neutrophil extracellular traps as a novel biomarker to predict recurrence-free and overall survival in patients with primary hepatic malignancies.

BACKGROUND: The incidence of primary hepatic malignancies including Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) is on the rise. (i) Surgery remains the mainstay of potential curative treatment, however the vast majority of patients will recur and not be amenable to curative therapy. (ii) Inflammation has been associated with poor prognosis, however there is no preoperative marker that can predict recurrence-free- or overall survival. Our aim is to correlate inflammation measured as neutrophil extracellular traps (NETs) with survival. METHODS: A retrospective analysis was performed using sera/tissue from patients with hepatic malignancies. NET levels were measured in the serum (MPO-DNA) or tumor (Cit-H3). Log rank analysis for RFS/OS was performed. RESULTS: Cancer patients had higher pre-surgery MPO-DNA levels compared to healthy individuals (healthy vs cancer: 2.6 ± 1.0 ng/ml vs 34.7 ± 2.13 ng/ml; p < 0.0001). High pre-surgery serum NET levels were associated with shorter RFS/OS compared to those with low levels (RFS-HCC: HR: 2.91, 95% CI: 1.61-5.26, p < 0.0001, RFS-CC: HR: 3.22, 95% CI: 1.33-7.77 p < 0.0093). High Cit-H3 tumor levels similarly predicted shorter RFS/OS. CONCLUSION: The current study shows a correlation between pre-operative NET levels and survival. Studying NET formation as a biomarker pre-surgery can help identify patients that could benefit from closer follow-up due to higher risk for recurrence.

Systematic review of May-Thurner syndrome with emphasis on gender differences.

OBJECTIVE: May-Thurner syndrome (MTS) is increasingly recognized as a frequent source of leg swelling and a precipitating factor for venous thromboembolism. This paper is a systematic review of the English literature on MTS with an analysis focusing on gender differences in presentation and treatment. METHODS: A systematic review of the English literature between April 1967 and December 2014 was performed using the following terms: "May-Thurner syndrome," "Cockett syndrome," and "iliac vein compression syndrome." After review, there were 174 articles in the analysis. We first analyzed all presented cases, followed by a gender comparison if case reports and case series had detailed description. Asymptomatic patients with just anatomic compression without symptoms were excluded. Statistical differences between data sets were assessed using χ2 test and Student t-test. RESULTS: There were 1569 patients with MTS after exclusion of articles based on our criteria. The female to male ratio was 2:1 (976 [67.1%] vs 480 [32.9%]). Women presented at a younger age compared with men (38.7 ± 14.0 years vs 46.2 ± 16.9 years; P = .02). Gender comparison at presentation, which was available for 254 patients, showed that men had significantly more reported leg swelling (92.7% vs 80.8%; P = .037) and more leg pain (88% vs 74.3%; P = .045) compared with women. There was no difference in the reported proportion of patients presenting with deep venous thrombosis between the two groups (88.9% vs 81.7%; P = .14). However, women were significantly more likely to have a pulmonary embolus on presentation compared with men (9.9% vs 1.6%; P = .035). Treatment modalities included endovascular interventions without thrombolysis (53%) or with thrombolysis (33.2%), open surgery (6.8%), and medical management (7%). Endovascular treatment was more common than surgical or medical treatment (P < .001). Because of lack of granularity in the data, it was not possible to distinguish treatment methods between female and male patients. There was no statistically significant difference in complication rate between men and women based on the articles that provided that information (P = .34). However, open procedures had significantly higher complications compared with endovascular interventions (P = .021). CONCLUSIONS: Based on the reported literature, MTS is more common in women and is at least twice as frequent in women as in men. Men tend to have more pain and swelling in the legs, whereas women tend to be younger and more likely to have a pulmonary embolus on presentation. MTS and iliac vein compression are sometimes used interchangeably in an inaccurate manner.

A Tumor Cell-Selective Inhibitor of Mitogen-Activated Protein Kinase Phosphatases Sensitizes Breast Cancer Cells to Lymphokine-Activated Killer Cell Activity.

Dual specificity mitogen-activated protein kinase (MAPK) phosphatases [dual specificity phosphatase/MAP kinase phosphatase (DUSP-MKP)] have been hypothesized to maintain cancer cell survival by buffering excessive MAPK signaling caused by upstream activating oncogenic products. A large and diverse body of literature suggests that genetic depletion of DUSP-MKPs can reduce tumorigenicity, suggesting that hyperactivating MAPK signaling by DUSP-MKP inhibitors could be a novel strategy to selectively affect the transformed phenotype. Through in vivo structure-activity relationship studies in transgenic zebrafish we recently identified a hyperactivator of fibroblast growth factor signaling [(E)-2-benzylidene-5-bromo-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI-215)] that is devoid of developmental toxicity and restores defective MAPK activity caused by overexpression of DUSP1 and DUSP6 in mammalian cells. Here, we hypothesized that BCI-215 could selectively affect survival of transformed cells. In MDA-MB-231 human breast cancer cells, BCI-215 inhibited cell motility, caused apoptosis but not primary necrosis, and sensitized cells to lymphokine-activated killer cell activity. Mechanistically, BCI-215 induced rapid and sustained phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) in the absence of reactive oxygen species, and its toxicity was partially rescued by inhibition of p38 but not JNK or ERK. BCI-215 also hyperactivated MKK4/SEK1, suggesting activation of stress responses. Kinase phosphorylation profiling documented BCI-215 selectively activated MAPKs and their downstream substrates, but not receptor tyrosine kinases, SRC family kinases, AKT, mTOR, or DNA damage pathways. Our findings support the hypothesis that BCI-215 causes selective cancer cell cytotoxicity in part through non-redox-mediated activation of MAPK signaling, and the findings also identify an intersection with immune cell killing that is worthy of further exploration.