George A. Makar

Liver transplantation in patients with cystic fibrosis: Analysis of united network for organ sharing data

The improved life expectancy of patients with cystic fibrosis (CF) has led to a change in the impact of liver disease on the prognosis of this population. Liver transplantation has emerged as the procedure of choice for patients with CF and features of hepatic decompensation and for intractable variceal bleeding as a major manifestation. We retrospectively reviewed the United Network for Organ Sharing database to analyze the outcomes of 55 adults and 148 children with CF who underwent liver transplantation, and we compared them to patients who underwent transplantation for other etiologies. We additionally compared the benefits of liver transplantation among patients who underwent transplantation for cystic fibrosis–related liver disease (CFLD) and those who remained on the waiting list. The 5‐year survival rates for children and adults undergoing liver transplantation were 85.8% and 72.7%, respectively (P = 0.016). A multivariate Cox regression analysis comparing pediatric and adult CF patients to patients who underwent transplantation for other etiologies noted lower 5‐year survival rates (P < 0.0001). However, compared to those remaining on the waiting list, pediatric transplant recipients with CF (hazard ratio = 0.33, 95% confidence interval = 0.16‐0.70, P = 0.004) and adult transplant recipients with CF (hazard ratio = 0.25, 95% confidence interval = 0.11‐0.57, P = 0.001) gained a significant survival benefit. In conclusion, long‐term outcomes in patients with CFLD are acceptable but are inferior in comparison with the outcomes of those undergoing transplantation for other etiologies. Despite such observations, a survival benefit was noted in transplant patients versus those who remained on the waiting list. Liver Transpl, 2011.

Angiotensin-Converting Enzyme Inhibitor Therapy and Colorectal Cancer Risk

BACKGROUNDnLaboratory data suggest a role of angiotensin II in the pathogenesis of colorectal cancer (CRC). Whether angiotensin converting enzyme inhibitor (ACE-I) and/or angiotensin receptor blocker (ARB) use reduces the risk of colorectal neoplasia remains unclear. Given their widespread use, we sought to determine whether exposure to these agents would have a secondary benefit on CRC incidence.nnnMETHODSnA nested case-control study was conducted using EPICs General Practice Research Database (1987-2002). The study cohort consisted of hypertensive patients. Case patients were those diagnosed with CRC after the diagnosis of hypertension. Each case patient was matched to up to 10 control subjects on age, sex, and both calendar year and duration of follow-up using incidence density sampling. The association between CRC and ACE-I/ARB exposure was assessed with conditional logistic regression. All statistical tests were two-sided.nnnRESULTSnTwo thousand eight-hundred forty-seven case patients were matched with 28239 control subjects. The adjusted odds ratios (ORs) of CRC were 0.84 (95% confidence interval [CI] = 0.72 to 0.98; P = .03) for or more years of ACE-I/ARB therapy and 0.75 (95% CI = 0.58 to 0.97; P = .03) for 5 or more years of exposure. The strength of this association increased with high-dose exposure (OR = 0.53; 95% CI = 0.35 to 0.79; P = .003 for ≥3 years of high-dose exposure). Among patients receiving antihypertensive medications, the association with long-term therapy was no longer statistically significant for ≥5 years), but the benefit of high-dose therapy remained (OR = 0.59; 95% CI = 0.39 to 0.89; P = .01 for ≥3 years of high-dose exposure).nnnCONCLUSIONSnLong-term/high dose exposure to ACE-Is/ARBs may be associated with a decreased incidence of CRC.

Lack of Standardization in Exception Points for Patients with Primary Sclerosing Cholangitis and Bacterial Cholangitis

For conditions that the Model for End‐Stage Liver Disease (MELD) score does not accurately predict waitlist mortality, transplant centers may apply to regional review boards for exception points. For patients with primary sclerosing cholangitis (PSC) suffering from bacterial cholangitis, consensus recommendations published in December 2006 are to grant exception points for recurrent cholangitis with ≥2 episodes of bacteremia or ≥1 episode septic complications. Using data provided by the United Network for Organ Sharing, we evaluated PSC patients who applied for exception points due to bacterial cholangitis from February 27, 2002 to March 14, 2011. Before publication of the recommendations, 66.0% of applications were accepted, compared with 80.1% after (p < 0.001). Focusing on applications after publication of the recommendations, 311 (74.6%) did not meet the recommended criteria, and 250 (80.4%) of these were approved. Of patients with approved applications, those not meeting consensus criteria were more likely to be transplanted, (77.4% vs. 62.8%, p = 0.043), whereas those with denied applications for approved indications were more liked to die/be removed (44.4% vs. 9.5%, p = 0.49). Although data are needed to properly identify those patients at highest risk for waitlist mortality, standardized criteria or a centralized review board should be adopted to ensure consistency in the granting of exception points.

Center variation in the use of nonstandardized model for end‐stage liver disease exception points

The Model for End‐Stage Liver Disease (MELD) score is an imperfect prognosticator of waitlist dropout, so transplant centers may apply for exception points to increase a waitlist candidates priority on the waitlist. Exception applications are categorized as recognized exceptional diagnoses (REDs; eg, hepatocellular carcinoma) and non‐REDs (eg, cholangitis). Although prior work has demonstrated regional variation in the use of exceptions, no work has examined the between‐center variability. We analyzed all new waitlist candidates from February 27, 2002 to June 3, 2011 to explore variations in the use of non‐REDs, for which no strict exception criteria exist. There were 58,641 new waitlist candidates, and 4356 (7.4%) applied for a non‐RED exception. The number of applications increased steadily over time, as did the approval rates for such applications: from <50% in 2002 to nearly 75% in 2010. When we adjusted for patient factors, there was significant variability (Pu2009<u20090.001) in the use of non‐RED exceptions in 8 of 11 United Network for Organ Sharing (UNOS) regions and in the approval of these exceptions in 6 of 11 UNOS regions. The variability in the use and approval of non‐REDs was clinically significant: waitlist candidates with approved exceptions were significantly more likely to undergo transplantation (68.3% versus 53.4%, Pu2009<u20090.001) and were less likely to be removed for death or clinical deterioration (10.4% versus 16.2%, Pu2009<u20090.001). Increased median MELD score at transplantation within a donor service area was the only center factor associated with increased odds of applying for exceptions, while no center factors were associated with having non‐RED exceptions approved. Further work is needed to identify other sources of variation to ensure the appropriate and equitable use of non‐RED exceptions. Liver Transpl 19:1330–1342, 2013.

Lack of a discriminatory function for endoscopy skills on a computer-based simulator

BackgroundComputer-based endoscopy simulators have been developed to enable trainees to learn and gain technical endoscopic skills before operating on patients. However, these simulators have not been validated as models of patient-based endoscopy. This study aimed to determine whether a computer-based simulator can accurately represent an actual esophagogastroduodenoscopy (EGD) and colonoscopy and to evaluate its ability to discriminate between varying levels of expertise in performing endoscopic procedures based on objective parameters.MethodsIn a prospective, observational trial, five first-year gastroenterology fellows and six gastroenterology attendings from a single academic center completed six endoscopy cases on the Simbionix GI Mentor II endoscopy simulator. The cases were selected to represent common clinical scenarios. The performance parameters were collected by the simulator. The 13 performance parameters measured by the endoscopy simulator were compared between the two study groups. After the simulator cases, the participants completed a survey evaluating the realism of the simulator.ResultsNovices and experts were able to complete the tasks in the simulated cases with no significant overall differences between the two groups. The computer-based simulator was able to discriminate levels of expertise only for parameters related to the time spent on the procedure (total time, time to reach the second duodenum, time to reach the cecum, and efficiency of screening). No statistically significant differences were found for the other nine performance parameters measured by the simulator. Based on the survey data, expert opinion concluded that the simulator does not offer a realistic simulation of human endoscopy.ConclusionsThe computer-based endoscopy simulator displays a lack of ability to discriminate between novices and experts in terms of endoscopic skills based on measured objective performance parameters. The findings of this study suggest that the computer-based simulator lacks fidelity and that upgrades are necessary to increase the simulator’s ability to reproduce human endoscopy more accurately.

Poor discriminatory function for endoscopic skills on a computer-based simulator

BACKGROUNDnComputer-based endoscopy simulators may enable trainees to learn and develop technical skills before performing on patients. Simulators require validation as adequate models of live endoscopy before being used for training or assessment purposes.nnnOBJECTIVEnTo evaluate content and criterion validity of the CAE EndoscopyVR Simulator colonoscopy and EGD modules as predictors of clinical endoscopic skills.nnnDESIGNnProspective, observational, non-randomized, parallel cohort study.nnnSETTINGnSingle academic center with accredited gastroenterology training program.nnnPARTICIPANTSnFive novice first-year gastroenterology fellows and 6 expert gastroenterology attending physicians.nnnINTERVENTIONnParticipants performed 18 simulated colonoscopies and 6 simulated EGDs. The simulator recorded objective performance parameters. Participants then completed feedback surveys.nnnMAIN OUTCOME MEASUREMENTSnThe 57 objective performance parameters measured by the endoscopy simulator were compared between the two study groups. Novice and expert survey responses were analyzed.nnnRESULTSnSignificant differences between novice and expert performance were detected in only 19 of 57 (33%) performance metrics. Eight of these 19 (42%) were time-related metrics, such as total procedure time, time to anatomic landmarks, and time spent in contact with GI mucosa. Of 49 non-time related measures, the few additional statistically significant differences between novices and experts involved air insufflation, sedation management, endoscope force, and patient comfort. These findings are of uncertain clinical significance. Survey data found multiple aspects of the simulation to be unrealistic compared with human endoscopy.nnnLIMITATIONSnSmall sample size.nnnCONCLUSIONnThe CAE EndoscopyVR Simulator displays poor content and criterion validity and is thereby incapable of predicting skill during in vivo endoscopy.

Early post-transplant survival: Interaction of MELD score and hospitalization status

BACKGROUND & AIMSnUrgency-based allocation that relies on the MELD score prioritizes patients at the highest risk of waitlist mortality. However, identifying patients at greatest risk for short-term post-transplant mortality is needed in order to optimize the potential gains in overall survival obtained through improved long-term management of transplant recipients. There are limited data on the predictive ability of MELD score for early post-transplant mortality, and no data assessing the interaction between MELD score and hospitalization status.nnnMETHODSnWe analyzed UNOS data from 2002 to 2013 on 50,838 non-status 1 single-organ liver transplant recipients and fit multivariable logistic models to evaluate the association and interaction between MELD score and pre-transplant hospitalization status on short-term post-transplant mortality.nnnRESULTSnThere was a significant interaction (p<0.01) between laboratory MELD score and hospitalization status on three-, six-, and 12-month post-transplant mortality in multivariable logistic models. This interaction was most pronounced in patients with a laboratory MELD score <25 transplanted from an ICU, whose adjusted predicted three-, six-, and 12-month post-transplant mortality approximated those of patients with a MELD score ⩾30. Compared to hospitalized patients with a MELD score of 30-34, those with a MELD score ⩾35 in an ICU had significantly increased risk of three-month (OR: 1.54, 95% CI: 1.21-1.97), 6-month (OR: 1.35, 95% CI: 1.09-1.67), and 12-month (OR: 1.25, 95% CI: 1.03-1.52) post-transplant mortality.nnnDISCUSSIONnPre-transplant ICU status modifies the risk of early post-transplant mortality, independent of MELD score. This should be considered when determining candidacy for transplantation in order to optimize efficient use of a scarce resource.

Exception point applications for 15 points: An unintended consequence of the Share 15 policy†

In 2005, the United Network for Organ Sharing (UNOS) adopted the Share 15 policy to improve organ allocation by facilitating transplantation for local and regional patients with Model for End‐Stage Liver Disease (MELD) scores of 15 or higher. There has been concern that the lack of standardization in the use of exception points is potentially diminishing the benefits of this policy. We reviewed all applications for 15 exception points submitted through UNOS from January 1, 2005 through March 14, 2011 (notably, there were only 5 applications for 15 MELD exception points submitted before the initiation of the Share 15 policy). Four hundred fifty‐two applications were submitted for 301 patients. There was significant regional variability, with regions 3 and 10 submitting 72.1% of all applications. More than one‐quarter of the applications (32.7%) specifically requested exception points to make a patient eligible for a local, regional, or higher risk organ. All applications were accepted for 74.1% of the patients, and 72.2% of these patients ultimately underwent transplantation; however, when all applications were denied, only 54.0% underwent transplantation (P = 0.006). Overall, 197 applicants (65.4%) underwent transplantation with a deceased donor organ, and 80.2% of these patients had a native MELD score at transplantation less than 15. In conclusion, these analyses demonstrate several important changes in practice that have occurred as a result of the implementation of the Share 15 policy. Since 2005, there has been a marked increase in the number of applications for 15 exception points, with significant regional variability in their use and a lack of standardization in their approval. Liver Transpl, 2012.

Safety of short-term administration of celecoxib in decompensated cirrhosis.

spect to other published series gives a solid estimation of a possible greater risk of HCC in the transjugular intrahepatic portosystemic shunt (TIPS) cohort. Regarding the interesting information provided by Libbrecht et al., it is important to emphasize the long follow-up period after TIPS insertion (median 30 months [range 7.8-110.8]) in our study. This length allows the detection of the potential influence of TIPS in the development of HCC. In the Libbrecht et al. series, the maximum follow-up period was only 21 months. Timing is very important, because the 1-year probability of developing HCC in our study was quite similar in both groups. Therefore, the time between TIPS insertion and histological analysis in the Libbrecht et al. cohort may be too short for detecting the possible influence of TIPS on HCC. Another interesting point is that the Libbrecht et al. study was designed to evaluate the incidence of HCC and dysplastic nodules in explanted organs as well as the accuracy of imaging techniques for early detection of these focal lesions in the pretransplantation time. We believe the design of their study makes it difficult to draw conclusions about the risk of HCC associated with TIPS, because it does not represent the whole population at risk (i.e., patients who received TIPS irrespective of the indication of liver transplantation).2 Therefore, we believe the information provided by Libbrecht et al. does not clarify whether TIPS insertion increases the risk of HCC development. We agree with Libbrecht et al. regarding the benefits of TIPS when adequately indicated according to recently published guidelines.3 However, we completely disagree with the suggestion that a 1.5-fold increase of risk of developing HCC is not meaningful. While adequate prospective studies confirm our results, the increase of risk of HCC after TIPS insertion described in our study should be taken into account when planning the follow-up of these patients.