Readmission after colorectal surgery is related to preoperative clinical conditions and major complications.

BACKGROUND: Hospital readmission is increasingly perceived as a marker of quality and is poorly investigated in patients receiving colorectal surgery. OBJECTIVE: The objective of this study was to describe patterns and etiology of readmission, to determine the rate of readmission, and to identify risk factors for readmission after colorectal surgery. DESIGN: This study is a retrospective medical chart review. Significant (p < 0.1) preoperative and perioperative factors associated with readmission on univariate analysis were examined in a multivariable model. SETTING: The investigation was conducted in a tertiary care hospital. PATIENTS: Patients included adults undergoing major colorectal operations by colorectal surgeons at the University of Minnesota in 2008-2009. MAIN OUTCOME MEASURES: The primary outcome measure was hospital readmission at 60 days. RESULTS: The study included 220 patients. Common surgical indications were inflammatory bowel disease (21%), colorectal cancer (39%), and diverticular disease (13%), and 11% were emergencies. Readmissions at 60 days occurred in 25% (n = 54), mostly because of major complications (57%), nonspecific nausea, vomiting and/or pain (18%), dehydration (11%), and wound infections (11%). Predictors of readmission in multivariable analysis were major complications (OR, 13.0), female sex (OR, 5.9), prednisone use (OR, 4.3), BMI ≥30 (OR, 2.6), and preoperative weight loss (OR, 3.4). Age and comorbidity (Charlson score) were not predictors. LIMITATIONS: This was a retrospective study at a single institution, with a small sample size. CONCLUSIONS: Predictors of readmission were major complications and immediate preoperative condition of the patients. Comorbidity profiling does not capture readmission risk. Because most readmissions relate to complications, further efforts to prevent these will improve readmission rates.

Antitumor activity of SNX-2112, a synthetic heat shock protein-90 inhibitor, in MET-amplified tumor cells with or without resistance to selective MET Inhibition.

PURPOSE: Heat shock protein-90 (HSP-90), a molecular chaperone required by numerous oncogenic kinases [e.g., HER-2, epidermal growth factor receptor (EGFR), Raf-1, v-Src, and AKT] for conformational stability, has attracted wide interest as a novel target for cancer therapy. HSP-90 inhibition induces degradation of HSP-90 client proteins, leading to a combinatorial inhibition of multiple oncogenic signaling pathways with consecutive growth arrest and apoptosis. MET, a tyrosine kinase that is constitutively active in tumor cells with MET oncogene amplification, has recently been identified as another HSP-90 client. EXPERIMENTAL DESIGN: The aim of our study was to assess the efficacy of SNX-2112, a synthetic HSP-90 inhibitor, in 3 different MET-amplified tumor cell lines (GTL-16, MKN-45, and EBC-1) as well as PR-GTL-16 cells, a GTL-16 subline selected for resistance to the highly selective MET kinase inhibitor PHA-665752. RESULTS: In all cell lines, SNX-2112 led to degradation of MET, HER-2, EGFR, and AKT, as well as abrogation of Ras/Raf/MEK/MAPK and PI3K/AKT signaling, followed by complete cell cycle arrest. SNX-5542, an orally bioavailable prodrug of SNX-2112, displayed significant antitumor efficacy in vivo in nude mice bearing MET-amplified tumor xenografts. Importantly, HSP-90 inhibition maintained its antitumor efficacy in PR-GTL-16 cells both in vitro and in vivo, suggesting that HSP-90 inhibition could be a particularly valuable strategy in MET-amplified tumors that have acquired resistance to MET kinase inhibition. CONCLUSIONS: Our study provides evidence for the efficacy of HSP-90 inhibition in MET-amplified cancer cells, particularly when MET kinase inhibitor resistance has emerged.

HER kinase activation confers resistance to MET tyrosine kinase inhibition in MET oncogene-addicted gastric cancer cells.

Tumor cells with genomic amplification of MET display constitutive activation of the MET tyrosine kinase, which renders them highly sensitive to MET inhibition. Several MET inhibitors have recently entered clinical trials; however, as with other molecularly targeted agents, resistance is likely to develop. Therefore, elucidating possible mechanisms of resistance is of clinical interest. We hypothesized that collateral growth factor receptor pathway activation can overcome the effects of MET inhibition in MET-amplified cancer cells by reactivating key survival pathways. Treatment of MET-amplified GTL-16 and MKN-45 gastric cancer cells with the highly selective MET inhibitor PHA-665752 abrogated MEK/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling, resulting in cyclin D1 loss and G(1) arrest. PHA-665752 also inhibited baseline phosphorylation of epidermal growth factor receptor (EGFR) and HER-3, which are transactivated via MET-driven receptor cross-talk in these cells. However, MET-independent HER kinase activation using EGF (which binds to and activates EGFR) or heregulin-beta1 (which binds to and activates HER-3) was able to overcome the growth-inhibitory effects of MET inhibition by restimulating MEK/MAPK and/or PI3K/AKT signaling, suggesting a possible escape mechanism. Importantly, dual inhibition of MET and HER kinase signaling using PHA-665752 in combination with the EGFR inhibitor gefitinib or in combination with inhibitors of MEK and AKT prevented the above rescue effects. Our results illustrate that highly targeted MET tyrosine kinase inhibition leaves MET oncogene-"addicted" cancer cells vulnerable to HER kinase-mediated reactivation of the MEK/MAPK and PI3K/AKT pathways, providing a rationale for combined inhibition of MET and HER kinase signaling in MET-amplified tumors that coexpress EGFR and/or HER-3.

Novel xenograft model expressing human hepatocyte growth factor shows ligand-dependent growth of c-Met-expressing tumors.

c-Met, a receptor tyrosine kinase responsible for cellular migration, invasion, and proliferation, is overexpressed in human cancers. Although ligand-independent c-Met activation has been described, the majority of tumors are ligand dependent and rely on binding of hepatocyte growth factor (HGF) for receptor activation. Both receptor and ligand are attractive therapeutic targets; however, preclinical models are limited because murine HGF does not activate human c-Met. The goal of this study was to develop a xenograft model in which human HGF (hHGF) is produced in a controllable fashion in the mouse. Severe combined immunodeficient mice were treated with adenovirus encoding the hHGF transgene (Ad-hHGF) via tail vein injection, and transgene expression was determined by the presence of hHGF mRNA in mouse tissue and hHGF in serum. Ad-hHGF administration to severe combined immunodeficient mice resulted in hHGF production that was (a) dependent on quantity of virus delivered; (b) biologically active, resulting in liver hypertrophy; and (c) sustainable over 40 days. In this model, the ligand-dependent human tumor cell line SW1417 showed enhanced tumor growth, whereas the ligand-independent cell lines SW480 and GTL-16 showed no augmented tumor growth. This novel xenograft model is ideal for investigating c-Met/HGF-dependent human tumor progression and for evaluating c-Met targeted therapy.

Simple harmonic scalpel hemorrhoidectomy utilizing local anesthesia combined with intravenous sedation: a safe and rapid alternative to conventional hemorrhoidectomy.

BACKGROUND: Harmonic Scalpel(R) hemorrhoidectomy (HSH) is an established surgical therapy for the treatment of symptomatic grade III and IV hemorrhoids. Hemorrhoid surgery is still being performed as an inpatient procedure with general or regional anesthesia in many centers today. There was a trend toward performing hemorrhoid surgery as an ambulatory procedure using local anesthesia supplemented with intravenous sedation. The aim of the current study was to evaluate the safety and efficacy of HSH performed with combination local anesthesia and intravenous sedation in an ambulatory surgical center. MATERIALS AND METHODS: A retrospective review was performed on the clinical charts of all patients undergoing HSH in an ambulatory surgical center from 2001 to 2005. All hemorrhoidectomies were attempted under propofol/ketamine intravenous sedation and local anesthesia in the prone position. A simple, open technique without routine suture was used. RESULTS: During the study period, 180 patients (70 females) underwent HSM. Mean procedure and total operating room time were 12 and 28 min, respectively. One patient (0.6%) was converted to general endotracheal anesthesia. Ten patients (5.6%) required post anesthesia care unit (PACU) observation. All patients were discharged home after the procedure. Postoperative complications occurred in 19 patients (10.6%). There were no reoperations and the total readmission rate was 3.7%. CONCLUSION: HSH performed with a combination of intravenous sedation and local anesthesia is safe and effective in the ambulatory surgery setting. The combined technique was associated with a rate of complications comparable to published series utilizing conventional hemorrhoidectomy techniques. Added benefits include shorter hospital stay and a potential for cost savings.

Ischemic colitis.

Ischemic colitis is the most common form of gastrointestinal ischemia. Patients present with either occlusive or nonocclusive vascular disease, although the latter is more common. Many causes of nonocclusive disease have been identified, but the exact pathophysiology remains unclear. Most commonly, patients develop abdominal discomfort and bloody diarrhea. Diagnosis is confirmed with colonoscopy. Treatment is contingent on the severity of disease: mucosal/nongangrenous ischemia requires only supportive measures and medical management, whereas transmural/gangrenous ischemia may require prompt surgical intervention. Ischemic colitis can also become a chronic process with persistent segmental colitis or colonic stricturing. The patient's outcome depends on the severity of disease, prompt recognition, and appropriate treatment.

Combination propofol/ketamine is a safe and efficient anesthetic approach to anorectal surgery.

PURPOSE: Concerns persist regarding respiratory complications from combination deep intravenous sedation and local anesthesia for prone position anorectal surgery. We examined the safety and efficacy of this approach by using a propofol-based and ketamine-based technique. METHODS: A retrospective review was conducted on all patients undergoing anorectal surgery. Outcomes (perioperative times, specific complications) were compared with respect to operative position and anesthetic approach. Significance was determined using Student's t-test and chi-squared analysis. RESULTS: Surgery was performed on 448 patients during a three-year period. There was no significant difference in the two anesthetic groups with regard to age and gender. There were 19 anesthesia-related adverse events occurring in the study group (Monitored Anesthesia Care Group): nausea and vomiting (n = 8), airway obstruction necessitating conversion to general anesthesia (n = 2), excessive pain (n = 2), urinary retention (n = 5), and hospital readmission (n = 2). These occurred in <5 percent of those receiving the combination technique (19/407). Although there was no difference in total procedural time, there was a significant difference in total time spent in the operating room (P = 0.001) and in the hospital overall (P = 0.002). Of the patients receiving combination technique anesthesia, only 31 (7 percent) required the use of the postanesthesia care unit. All patients receiving general anesthesia (n = 23) required the postanesthesia care unit. CONCLUSIONS: Combination deep intravenous sedation with local anesthesia based on propofol and ketamine is a safe and effective technique for prone-position anorectal surgery. It results in decreased use of the postanesthesia care unit and earlier hospital discharge, reflecting a more efficient use of hospital resources.