Abdul H. Khan

ERCP with cholangiopancreatoscopy may be associated with higher rates of complications than ERCP alone: a single-center experience

BACKGROUND Comparative data regarding complications associated with ERCP alone or when performed with cholangiopancreatoscopy (CP) are lacking. OBJECTIVE To determine whether ERCP complications are more frequent when concomitant CP is performed. DESIGN A retrospective query of a prospectively maintained database of ERCP, CP, and complications. MAIN OUTCOME MEASUREMENTS Consensus criteria complications and additional adverse events (AEs), including unplanned medical evaluation, cardiopulmonary/sedation events, and others. SETTING Academic, tertiary referral center. RESULTS A total of 4214 ERCPs were performed (337 sphincter of Oddi manometry cases excluded) during the study period, of which 3475 ERCPs and 402 ERCPs with CP were analyzed. There were 28 of 402 AEs (7.0%) in the ERCP with CP group and 101 of 3475 (2.9%) in the ERCP-only group (odds ratio [OR], 2.50; 95% CI, 1.56-3.89). Subgroup analysis revealed a significantly higher rate of cholangitis in the CP group versus ERCP group (1.0% vs 0.2%; OR, 4.98; 95% CI, 1.06-19.67) and similar rates of pancreatitis (2.2% vs 1.3%; OR, 1.75; 95% CI, 0.74-3.65) and perforation (1.0% vs 0.3%; OR, 3.16; 95% CI, 0.73-10.75). LIMITATIONS Retrospective review of a complications database that relies on physician self-reporting. CONCLUSIONS AEs from CP may be more than double those of ERCP alone (when sphincter of Oddi manometry cases are excluded). CP appears to be associated with a significantly higher rate of cholangitis, possibly because of intermittent intraductal irrigation required during the procedure.

Efficacy and safety of self-expandable metal stents for biliary decompression in patients receiving neoadjuvant therapy for pancreatic cancer: a prospective study

BACKGROUND Increasing numbers of patients with resectable pancreatic cancer are receiving neoadjuvant therapy. Biliary drainage with plastic stents during this period can be associated with recurrent episodes of stent occlusion resulting in unplanned ERCPs and interruptions in therapy. OBJECTIVE To evaluate the efficacy and safety of self-expandable metal stents (SEMSs) during the neoadjuvant period for resectable pancreatic cancer. DESIGN Patients with proven pancreatic adenocarcinoma with biliary obstruction underwent placement of SEMSs, and data on stent patency and complication rates were collected prospectively. SETTING Tertiary-care referral center. PATIENTS This study involved 55 patients with resectable and borderline resectable pancreatic duct adenocarcinoma who were recruited between March 2009 and December 2010. INTERVENTION SEMSs were placed for biliary decompression. The shortest length of stent required to bridge the stricture was used so as to leave enough of the normal bile duct above the stent available for subsequent surgical anastomosis. Endoscopic reintervention was performed in those with stent malfunction. Stents were not removed before surgery. MAIN OUTCOME MEASUREMENTS Stent patency rate during the neoadjuvant period, stent malfunction rate, and complication rates. Information on stent-related difficulties, if any, during surgery. RESULTS Fifty-five patients were recruited (29 men, 26 women; age, mean [± SD] 65.9 ± 11 years; resectable 23, borderline resectable 32). Median time for neoadjuvant therapy and restaging before surgery was 104 days (range 70-260 days). At the median time of 104 days, 88% of SEMSs remained patent. By 260 days, stent malfunction occurred in 15% of patients. These included stent occlusion in 13% and stent migration in 2%. SEMS malfunction occurred in 3 of 27 patients (11%) who ultimately underwent pancreaticoduodenectomy and in 5 of 21 patients (24%) with disease progression (P = not significant). The presence of SEMSs did not interfere with pancreaticoduodenectomy in any patients who underwent surgery. LIMITATIONS Nonrandomized study. CONCLUSION SEMSs are effective and safe in achieving durable biliary drainage in patients with pancreatic cancer receiving neoadjuvant therapy. It is not necessary to remove SEMSs before surgery if the shortest length of stent required to bridge the stricture is used.

Transcription Factor Foxq1 Controls Mucin Gene Expression and Granule Content in Mouse Stomach Surface Mucous Cells

BACKGROUND & AIMS The gastric mucosa provides a stringent epithelial barrier and produces acid and enzymes that initiate digestion. In this regenerating tissue, progenitors differentiate continually into 4 principal specialized cell types, yet underlying mechanisms of differentiation are poorly understood. We identified stomach-restricted expression of the forkhead transcription factor FOXQ1. METHODS We used a combination of genetic, histochemical, ultrastructural, and molecular analysis to study gastric cell lineages with respect to FOXQ1. RESULTS Within the developing and adult gastrointestinal tract, Foxq1 messenger RNA (mRNA) is restricted to the stomach and expressed predominantly in foveolar (pit) cells, the abundant mucin-producing cells that line the mucosal surface. Mice carrying Foxq1 coding mutations show virtual absence of mRNA and protein for the backbone of the major stomach mucin MUC5AC. These observations correspond to a paucity of foveolar cell secretory vesicles and notable loss of stomach but not intestinal mucus. Transcriptional profiling identified a surprisingly restricted set of genes with altered expression in Foxq1 mutant stomachs. MUC5AC is a highly tissue-restricted product that similarly depends on FOXQ1 in its other major site of expression, conjunctival goblet cells. CONCLUSIONS Taken together, these observations imply that promotion of gastric MUC5AC synthesis is a primary, cell-autonomous function of FOXQ1. This study is the first to implicate a transcription factor in terminal differentiation of foveolar cells and begins to define the requirements to assemble highly specialized organelles and cells in the gastric mucosa.

Transmission of carbapenem-resistant Enterobacteriaceae during ERCP: time to revisit the current reprocessing guidelines.

The emergence of antimicrobial-resistant organisms continues to be a serious concern both in the United States and globally. Carbapenem-resistant Enterobacteriaceae (CRE) such as Klebsiella pneumoniae and Escherichia coli have been increasingly recognized since the early 1990s. The high mortality associated with CRE infections, combined with the limited therapeutic options, makes this an issue of significant epidemiologic importance. A novel CRE subtype, New Delhi metallo-b-lactamase (NDM-1), producing K pneumoniae, was first described in 2009 in a Swedish patient who had undergone medical care in India where this strain is frequently recovered. NDM-1– producing CRE demonstrate broad antibiotic resistance that is typically susceptible only to tigecycline and colistin. Currently, NDM-1–producing CRE have been isolated and reported in 15 states in the United States. Previous reports describe the transmission of CRE during endoscopy. A systematic review from 2013 identified 6 separate outbreaks of K pneumoniae carbapenemase worldwide. To our knowledge, there are 3 reports of outbreaks of CRE in the United States associated with endoscopy, specifically ERCP. One series that was presented as an abstract described an epidemiological investigation into an observed increased prevalence of CRE in abdominal

Soluble epoxide hydrolase inhibition and peroxisome proliferator activated receptor γ agonist improve vascular function and decrease renal injury in hypertensive obese rats

Cardiometabolic syndrome occurs with obesity and consists of pathophysiological factors that increase the risk for cardiovascular events. Soluble epoxide hydrolase inhibition (sEHi) is a novel therapeutic approach that exerts renal and cardiovascular protection. Although sEHi as a therapeutic approach is promising, it could be more effective for the treatment of cardiometabolic syndrome when combined with peroxisome proliferator activated receptor γ (PPARγ) agonists. We hypothesized that the PPARγ agonist, rosiglitazone in combination with a sEHi (tAUCB) will provide synergistic actions to decrease blood pressure, improve vascular function, decrease inflammation, and prevent renal damage in spontaneously hypertensive obese rats (SHROB). SHROB were treated with rosiglitazone, tAUCB or the combination of tAUCB and rosiglitazone for four-weeks and compared with spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Blood pressure increased in SHROB (164±7 mmHg) and decreased 10 mmHg when treated with rosiglitazone, tAUCB, or tAUCB and rosiglitazone. Mesenteric artery dilation to the KATP channel opener pinacidil was attenuated in SHROB (EMax =77±7%), compared with WKY (EMax =115±19) and SHR (EMax = 93±12%). Vasodilation to pinacidil was improved by rosiglitazone (EMax = 92±14%) but not tAUCB. Renal macrophage infiltration increased in SHROB and significantly decreased with rosiglitazone or tAUCB and rosiglitazone treatment. Albuminuria was increased in SHROB (90±20 mg/d) and was significantly decreased by the combination of tAUCB and rosiglitazone (37±9 mg/d). Glomerular injury in SHROB was also significantly decreased by tAUCB and rosiglitazone. These results indicate that even though sEHi or PPARγ agonist have benefits when used individually, the combination is more beneficial for the multidisease features in cardiometabolic syndrome.

Captopril attenuates hypertension and renal injury induced by the vascular endothelial growth factor inhibitor sorafenib.

Vascular endothelial growth factor inhibitors (VEGFi) are known to cause hypertension and renal injury that severely limits their use as an anticancer therapy. We hypothesized that the angiotensin‐converting enzyme inhibitor captopril not only prevents hypertension, but also decreases renal injury caused by the VEGFi sorafenib. Rats were administered sorafenib (20 mg/kg per day) alone or in combination with captopril (40 mg/kg per day) for 4 weeks. Sorafenib administration increased blood pressure, which plateaued by day 10. Concurrent treatment with captopril for 4 weeks resulted in a 30 mmHg decrease in blood pressure compared with sorafenib alone (155 ± 5 vs 182 ± 6 mmHg, respectively; P < 0.05). Furthermore, concurrent captopril treatment reduced albuminuria by 50% compared with sorafenib alone (20 ± 8 vs 42 ± 9 mg/day, respectively; P < 0.05) and reduced nephrinuria by eightfold (280 ± 96 vs 2305 ± 665 μg/day, respectively; P < 0.05). Glomerular injury, thrombotic microangiopathy and tubular cast formation were also decreased in captopril‐treated rats administered sorafenib. Renal autoregulatory efficiency was determined by evaluating the afferent arteriolar constrictor response to ATP. Sorafenib administration attenuated the vasoconstriction to ATP, whereas concurrent captopril treatment improved ATP reactivity. In conclusion, captopril attenuated hypertension and renal injury and improved renal autoregulatory capacity in rats administered sorafenib. These findings indicate that captopril treatment, in addition to alleviating the detrimental side‐effect of hypertension, decreases the renal injury associated with anticancer VEGFi therapies such as sorafenib.

Multimodality therapy in patients with borderline resectable or locally advanced pancreatic cancer: Importance of locoregional therapies for a systemic disease

Historically, the clinical staging of pancreatic cancer has centered on the surgical management of the primary tumor, because few effective chemotherapeutic agents were available and long-term survival was only achieved in the context of surgical resection. Such a strategy of complete oncologic surgical care is reasonable when surgery is both the principal therapy and highly effective. However, complex surgery for pancreatic cancer-often performed in older patients after a lengthy period of induction therapy-can be associated with significant morbidity and mortality. The majority of patients with pancreatic cancer present either locally advanced or metastatic disease at the time of diagnosis. In this article, we will discuss the role of multimodality management of patients with borderline resectable and locally advanced pancreatic cancer. Considering that surgery has a modest impact on the natural history of pancreatic cancer in most patients, a neoadjuvant approach to treatment sequencing is favored for patients with borderline resectable pancreatic cancer, and this same rationale has been extended to select patients with locally advanced disease who demonstrate an exceptional response to induction therapy.

Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy.

Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by CYP epoxygenases, and EETs are kidney protective in multiple pathologies. We determined the ability of an EET analogue, EET-A, to mitigate experimental radiation nephropathy. The kidney expression of the EET producing enzyme CYP2C11 was lower in rats that received total body irradiation (TBI rat) compared with non-irradiated control. At 12 weeks after TBI, the rats had higher systolic blood pressure and impaired renal afferent arteriolar function compared with control, and EET-A or captopril mitigated these abnormalities. The TBI rats had 3-fold higher blood urea nitrogen (BUN) compared with control, and EET-A or captopril decreased BUN by 40-60%. The urine albumin/creatinine ratio was increased 94-fold in TBI rats, and EET-A or captopril attenuated that increase by 60-90%. In TBI rats, nephrinuria was elevated 30-fold and EET-A or captopril decreased it by 50-90%. Renal interstitial fibrosis, tubular and glomerular injury were present in the TBI rats, and each was decreased by EET-A or captopril. We further demonstrated elevated renal parenchymal apoptosis in TBI rats, which was mitigated by EET-A or captopril. Additional studies revealed that captopril or EET-A mitigated renal apoptosis by acting on the p53/Fas/FasL (Fas ligand) apoptotic pathway. The present study demonstrates a novel EET analogue-based strategy for mitigation of experimental radiation nephropathy by improving renal afferent arteriolar function and by decreasing renal apoptosis.

Cholesterol induces renal vasoconstriction and anti-natriuresis by inhibiting nitric oxide production in anesthetized rats

Although hypercholesterolemia is implicated in the pathophysiology of many renal disorders as well as hypertension, its direct actions in the kidney are not yet clearly understood. In the present study, we evaluated renal responses to administration of cholesterol (8 microg x min(-1).100 g body wt(-1); bound by polyethylene glycol) into the renal artery of anesthetized male Sprague-Dawley rats. Total renal blood flow (RBF) was measured by a Transonic flow probe, and glomerular filtration rate (GFR) was determined by Inulin clearance. In control rats (n = 8), cholesterol induced reductions of 10 +/- 2% in RBF [baseline (b) 7.6 +/- 0.3 microg x min(-1).100 g(-1)], 17 +/- 3% in urine flow (b, 10.6 +/- 0.9 microg x min(-1).100 g(-1)), 29 +/- 3% in sodium excretion (b, 0.96 +/- 0.05 mumol.min(-1).100 g(-1)) and 24 +/- 2% in nitrite/nitrate excretion (b, 0.22 +/- 0.01 nmol.min(-1).100 g(-1)) without an appreciable change in GFR (b, 0.87 +/- 0.03 ml.min(-1).100 g(-1)). These renal vasoconstrictor and anti-natriuretic responses to cholesterol were absent in rats pretreated with nitric oxide (NO) synthase inhibitor, nitro-l-arginine methylester (0.5 microg x min(-1).100 g(-1); n = 6). In rats pretreated with superoxide (O(2)(-)) scavenger tempol (50 microg x min(-1).100 g(-1); n = 6), the cholesterol-induced renal responses remained mostly unchanged, although there was a slight attenuation in anti-natriuretic response. This anti-natriuretic response to cholesterol was abolished in furosemide-pretreated rats (0.3 microg x min(-1).100 g(-1); n = 6) but remained unchanged in amiloride-pretreated rats (0.2 microg x min(-1).100 g(-1); n = 5), indicating that Na(+)/K(+)/2Cl(-) cotransport is the dominant mediator of this effect. These data demonstrate that cholesterol-induced acute renal vasoconstrictor and antinatriuretic responses are mediated by a decrease in NO production. These data also indicate that tubular effect of cholesterol on sodium reabsorption is mediated by the furosemide sensitive Na(+)/K(+)/2Cl(-) cotransporter.

A Novel Protocol Obviates Endoscope Sampling for Carbapenem-Resistant Enterobacteriaceae: Experience of a Center with a Prior Outbreak

BackgroundNumerous published outbreaks, including one from our institution, have described endoscope-associated transmission of multidrug-resistant organisms (MDROs). Individual centers have adopted their own protocols to address this issue, including endoscope culture and sequestration. Endoscope culturing has drawbacks and may allow residual bacteria, including MDROs, to go undetected after high-level disinfection.AimTo report the outcome of our novel protocol, which does not utilize endoscope culturing, to address our outbreak.MethodsAll patients undergoing procedures with elevator-containing endoscopes were asked to permit performance of a rectal swab. All endoscopes underwent high-level disinfection according to updated manufacturer’s guidance. Additionally, ethylene oxide (EtO) sterilization was done in the high-risk settings of (1) positive response to a pre-procedure risk stratification questionnaire, (2) positive or indeterminate CRE polymerase chain reaction (PCR) from rectal swab, (3) refusal to consent for PCR or questionnaire, (4) purulent cholangitis or infected pancreatic fluid collections. Two endoscopes per weekend were sterilized on a rotational basis.ResultsFrom September 1, 2015 to April 30, 2016, 556 endoscopy sessions were performed using elevator-containing endoscopes. Prompted EtO sterilization was done on 46 (8.3%) instances, 3 from positive/indeterminate PCR tests out of 530 samples (0.6%). No CRE transmission was observed during the study period. Damage or altered performance of endoscopes related to EtO was not observed.ConclusionIn this pilot study, prompted EtO sterilization in high-risk patients has thus far eliminated endoscope-associated MDRO transmission, although no CRE infections were noted throughout the institution during the study period. Further studies and a larger patient sample will be required to validate these findings.