Platelet-Derived Growth Factor Receptor-α Regulates Proliferation of Gastrointestinal Stromal Tumor Cells With Mutations in KIT by Stabilizing ETV1.

BACKGROUND & AIMS: In gastrointestinal muscles, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) is predominantly expressed by interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor-α (PDGFRA) polypeptide is expressed by so-called fibroblast-like cells. KIT and PDGFRA have been reported to be coexpressed in ICC precursors and gastrointestinal stromal tumors (GISTs), which originate from the ICC lineage. PDGFRA signaling has been proposed to stimulate growth of GISTs that express mutant KIT, but the effects and mechanisms of selective blockade of PDGFRA are unclear. We investigated whether inhibiting PDGFRA could reduce proliferation of GIST cells with mutant KIT via effects on the KIT-dependent transcription factor ETV1. METHODS: We studied 53 gastric, small intestinal, rectal, or abdominal GISTs collected immediately after surgery or archived as fixed blocks at the Mayo Clinic and University of California, San Diego. In human GIST cells carrying imatinib-sensitive and imatinib-resistant mutations in KIT, PDGFRA was reduced by RNA interference (knockdown) or inhibited with crenolanib besylate (a selective inhibitor of PDGFRA and PDGFRB). Mouse ICC precursors were retrovirally transduced to overexpress wild-type Kit. Cell proliferation was analyzed by methyltetrazolium, 5-ethynyl-2'-deoxyuridine incorporation, and Ki-67 immunofluorescence assays; we also analyzed growth of xenograft tumors in mice. Gastric ICC and ICC precursors, and their PDGFRA(+) subsets, were analyzed by flow cytometry and immunohistochemistry in wild-type, Kit(+/copGFP), Pdgfra(+/eGFP), and NOD/ShiLtJ mice. Immunoblots were used to quantify protein expression and phosphorylation. RESULTS: KIT and PDGFRA were coexpressed in 3%-5% of mouse ICC, 35%-44% of ICC precursors, and most human GIST samples and cell lines. PDGFRA knockdown or inhibition with crenolanib efficiently reduced proliferation of imatinib-sensitive and imatinib-resistant KIT(+)ETV1(+)PDGFRA(+) GIST cells (50% maximal inhibitory concentration = 5-32 nM), but not of cells lacking KIT, ETV1, or PDGFRA (50% maximal inhibitory concentration >230 nM). Crenolanib inhibited phosphorylation of PDGFRA and PDGFRB, but not KIT. However, Kit overexpression sensitized mouse ICC precursors to crenolanib. ETV1 knockdown reduced KIT expression and GIST proliferation. Crenolanib down-regulated ETV1 by inhibiting extracellular-signal-regulated kinase (ERK)-dependent stabilization of ETV1 protein and also reduced expression of KIT and PDGFRA. CONCLUSIONS: In KIT-mutant GIST, inhibition of PDGFRA disrupts a KIT-ERK-ETV1-KIT signaling loop by inhibiting ERK activation. The PDGFRA inhibitor crenolanib might be used to treat patients with imatinib-resistant, KIT-mutant GIST.

Improving inpatient warfarin therapy safety using a pharmacist-managed protocol.

INTRODUCTION: Safe management of warfarin in the inpatient setting can be challenging. At the Mayo Clinic hospitals in Rochester, Minnesota, we set out to improve the safety of warfarin management among surgical and non-surgical inpatients. METHODS: A multidisciplinary team designed a pharmacist-managed warfarin protocol (PMWP) which designated warfarin dosing to inpatient pharmacists with guidance from computerised dosing algorithms. Ordering this protocol was ultimately designed as an 'opt out' practice. The primary improvement measure was frequency of international normalised ratio (INR) greater than 5; secondary measures included adoption rate of the protocol, a counterbalance INR metric (INR <1.7 three days after first inpatient warfarin dose), and complication rates, including bleeding and thrombosis events. An interrupted time series analysis was conducted to compare outcomes. RESULTS: Among over 50 000 inpatient warfarin recipients, the PMWP was adopted for the majority of both surgical and non-surgical inpatients during the study period (1 January 2005 to 31 December 2011). The primary improvement measure decreased from 5.6% to 3.4% for medical patients and from 5.2% to 2.4% for surgical patients during the preimplementation and postimplementation periods, respectively. The INR counterbalance measure did not change. Postoperative bleeding decreased from 13.5% to 11.1% among surgical patients, but bleeding was unchanged among medical patients. CONCLUSION: Our PMWP led to achievement of improved INR control for inpatient warfarin recipients and to less near-term bleeding among higher risk, surgical patients.

Risk of Surgical Site Infection (SSI) following Colorectal Resection Is Higher in Patients With Disseminated Cancer: An NCCN Member Cohort Study.

BACKGROUNDSurgical site infections (SSIs) following colorectal surgery (CRS) are among the most common healthcare-associated infections (HAIs). Reduction in colorectal SSI rates is an important goal for surgical quality improvement.OBJECTIVETo examine rates of SSI in patients with and without cancer and to identify potential predictors of SSI risk following CRSDESIGNAmerican College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) data files for 2011-2013 from a sample of 12 National Comprehensive Cancer Network (NCCN) member institutions were combined. Pooled SSI rates for colorectal procedures were calculated and risk was evaluated. The independent importance of potential risk factors was assessed using logistic regression.SETTINGMulticenter studyPARTICIPANTSOf 22 invited NCCN centers, 11 participated (50%). Colorectal procedures were selected by principal procedure current procedural technology (CPT) code. Cancer was defined by International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes.MAIN OUTCOMEThe primary outcome of interest was 30-day SSI rate.RESULTSA total of 652 SSIs (11.06%) were reported among 5,893 CRSs. Risk of SSI was similar for patients with and without cancer. Among CRS patients with underlying cancer, disseminated cancer (SSI rate, 17.5%; odds ratio [OR], 1.66; 95% confidence interval [CI], 1.23-2.26; P=.001), ASA score ≥3 (OR, 1.41; 95% CI, 1.09-1.83; P=.001), chronic obstructive pulmonary disease (COPD; OR, 1.6; 95% CI, 1.06-2.53; P=.02), and longer duration of procedure were associated with development of SSI.CONCLUSIONSPatients with disseminated cancer are at a higher risk for developing SSI. ASA score >3, COPD, and longer duration of surgery predict SSI risk. Disseminated cancer should be further evaluated by the Centers for Disease Control and Prevention (CDC) in generating risk-adjusted outcomes.Infect Control Hosp Epidemiol 2018;39:555-562.

Influence of Social Media on the Dissemination of a Traditional Surgical Research Article.

OBJECTIVE: Many institutions use social media to share research with the general public. However, the influence of social media on the dissemination of a surgical research article itself is unknown. Our objective was to determine whether a blog post highlighting the findings of a surgical research article would lead to increased dissemination of the article itself. DESIGN: We prospectively followed the online page views of an article that was published online in Surgery in May 2015 and published in print in August 2015. The authors subsequently released a blog post in October 2015 to promote the research. The number of article page views from the journal's website was obtained before and after the blog post, along with the page views from the blog post itself. Social media influence data were collected, including social activity in the form of mentions on social media sites, scholarly activity in online libraries, and scholarly commentary. RESULTS: The article's online activity peaked in the first month after online publication (475 page views). Online activity plateaued by 4 months after publication, with 118 monthly page views, and a blog post was subsequently published. The blog post was viewed by 1566 readers, and readers spent a mean of 2.5 minutes on the page. When compared to the projected trend, the page views increased by 33% in the month after the blog post. The blog post resulted in a 9% increase in the social media influence score and a 5% absolute increase in total article page views. CONCLUSIONS: Social media is an important tool for sharing surgical research. Our data suggest that social media can increase distribution of an article's message and also potentially increase dissemination of the article itself. We believe that authors should consider using social media to increase the dissemination of traditionally published articles.

Intraoperative parathyroid hormone assay: an accurate predictor of symptomatic hypocalcemia following thyroidectomy.

HYPOTHESIS: Intraoperative parathyroid hormone (IOPTH) assay is useful for predicting symptomatic hypocalcemia following total thyroidectomy. DESIGN: A prospective study of 30 patients undergoing total thyroidectomy with IOPTH levels obtained following skin closure and ionized calcium (Ca2+) levels obtained 6 hours postoperatively and on postoperative day 1. All patients were evaluated for symptoms of hypocalcemia. SETTING: University teaching hospital. MAIN OUTCOME MEASURES: Patients who developed symptomatic hypocalcemia were compared with asymptomatic patients in regard to age, diagnosis, thyroid weight, thyrotropin level, Ca2+ level, parathyroid status, and IOPTH level. RESULTS: The onset of symptomatic hypocalcemia ranged from 8 to 48 hours postoperatively (n = 10). One patient required readmission. Of 10 patients with symptoms, 5 developed tetany. There were no significant differences in age, diagnosis, thyroid weight, thyrotropin level, or the number of parathyroid glands preserved in patients with or without symptomatic hypocalcemia. All patients with an IOPTH level of less than 10 pg/mL (1.1 pmol/L) had symptoms (n = 8). The mean +/- SD IOPTH level (7.6 +/- 12.0 pg/mL [0.8 +/- 1.3 pmol/L]) in patients who developed symptomatic hypocalcemia was significantly lower than the mean IOPTH level (55.7 +/- 31.8 pg/mL [5.9 +/- 3.3 pmol/L]) in patients without symptoms (P =.001). The 6-hour and postoperative day 1 Ca2+ levels were significantly lower in patients with symptomatic hypocalcemia (P =.19 and P =.13, respectively). An IOPTH level of less than 10 pg/mL is 80% sensitive and 100% specific for the development of symptomatic hypocalcemia. CONCLUSION: The incorporation of the IOPTH assay in the management of thyroid disease is recommended to prevent and prospectively treat symptomatic hypocalcemia, thereby reducing readmissions following thyroidectomy.

Reasons for conversion from laparoscopic to open cholecystectomy: a 10-year review.

Laparoscopic cholecystectomy is now considered the "gold standard" operation for patients with gallstone disease. A number of patients require conversion to an open cholecystectomy for the safe completion of the procedure. This study investigates how the etiology and incidence of conversion from laparoscopic to open cholecystectomy has changed over time. All 5884 patients undergoing laparoscopic cholecystectomy between March 1991 and June 2001 were prospectively collected in a database. A total of 310 patients (5.2%) had had their cholecystectomies converted to an open procedure. The mortality rate for these patients was 0.7%. Causes for conversion were inability to correctly identify anatomy (50%), "other" indications (16%), bleeding (14%), suspected choledocholithiasis (11%), and suspected bile duct injury (8%). After an initial learning curve in thin patients with symptomatic cholelithiasis, inclusion of patients with acute cholecystitis, morbid obesity, or a prior celiotomy resulted in a peak conversion rate of 11% by 1994. From 1994 to the first half of 2001, the conversion rate has declined significantly for all patients (10% to 1%), as well as for patients with acute cholecystitis (26% to 1%). Although unclear anatomy secondary to inflammation remains the most common reason for conversion, the impact of acute cholecystitis on the operative outcome has decreased with time.