Roelof J. Bennink

Inflammatory bowel disease diagnosed with US, MR, scintigraphy, and CT: meta-analysis of prospective studies.

PURPOSE To compare, by performing a meta-analysis, the accuracies of ultrasonography (US), magnetic resonance (MR) imaging, scintigraphy, computed tomography (CT), and positron emission tomography (PET) in the diagnosis of inflammatory bowel disease (IBD). MATERIALS AND METHODS MEDLINE, EMBASE, CINAHL, and Cochrane databases were searched for studies on the accuracy of US, MR imaging, scintigraphy, CT, and PET, as compared with a predefined reference standard, in the diagnosis of IBD. Sensitivity and specificity estimates were calculated on per-patient and per-bowel-segment bases by using a bivariate random-effects model. RESULTS Thirty-three studies, from a search that yielded 1406 articles, were included in the final analysis. Mean sensitivity estimates for the diagnosis of IBD on a per-patient basis were high and not significantly different among the imaging modalities (89.7%, 93.0%, 87.8%, and 84.3% for US, MR imaging, scintigraphy, and CT, respectively). Mean per-patient specificity estimates were 95.6% for US, 92.8% for MR imaging, 84.5% for scintigraphy, and 95.1% for CT; the only significant difference in values was that between scintigraphy and US (P = .009). Mean per-bowel-segment sensitivity estimates were lower: 73.5% for US, 70.4% for MR imaging, 77.3% for scintigraphy, and 67.4% for CT. Mean per-bowel-segment specificity estimates were 92.9% for US, 94.0% for MR imaging, 90.3% for scintigraphy, and 90.2% for CT. CT proved to be significantly less sensitive and specific compared with scintigraphy (P = .006) and MR imaging (P = .037) CONCLUSION No significant differences in diagnostic accuracy among the imaging techniques were observed. Because patients with IBD often need frequent reevaluation of disease status, use of a diagnostic modality that does not involve the use of ionizing radiation is preferable.

Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn’s disease

Background: The human anti-tumour necrosis factor (TNF) antibody infliximab binds to the membrane TNF and subsequently induces apoptosis of activated lamina propria T lymphocytes in patients with Crohn’s disease in vitro. Aim: To test whether the ability of rapid anti-TNF-induced apoptosis in the gut predicts the efficacy of anti-TNF treatment in inflammatory bowel disease. Methods:99mTechnetium–annexin V single-photon emission computer tomography (SPECT) was performed in 2 models of murine experimental colitis and in 14 patients with active Crohn’s disease as assessed by the Crohńs Disease Activity Index (CDAI) to study the effect of anti-TNF treatment on apoptosis in the intestine during active colitis. Disease activity was evaluated 2 weeks after infliximab infusion using the CDAI (definition response: drop of >100 points). Results: Colonic uptake of 99mTc-annexin V significantly increased in 2,4,6-trinitrobenzene sulphonate-induced colitis as well as in transfer colitis on administration of anti-TNF antibodies compared with a control antibody as determined with dedicated animal pinhole SPECT. In addition, uptake of 99mTc–annexin V significantly increased in patients with active Crohn’s disease responding to infliximab treatment. Colonic 99mTc–annexin V uptake ratio (mean (SEM)) increased from 0.24 (0.03) to 0.41(0.07) (p<0.01), 24 h after infliximab infusion (5 mg/kg). A mean increase of 98.7% in colonic uptake of 99mTc–annexin V could be detected in 10 of the 14 responding patients (CDAI >100 points at week 2) compared with 15.2% in non-responding patients (p = 0.03). Analysis of the mucosal biopsy specimens identified lamina propria T cells as target cells undergoing apoptosis. Conclusions: These in vivo observations support the notion that colonic uptake of 99mTc–annexin V correlates with clinical benefit of anti-TNF treatment and might be predictive of therapeutic success.

Physiological and biochemical basis of clinical liver function tests: a review

Objective:To review the literature on the most clinically relevant and novel liver function tests used for the assessment of hepatic function before liver surgery. Background:Postoperative liver failure is the major cause of mortality and morbidity after partial liver resection and develops as a result of insufficient remnant liver function. Therefore, accurate preoperative assessment of the future remnant liver function is mandatory in the selection of candidates for safe partial liver resection. Methods:A MEDLINE search was performed using the key words “liver function tests,” “functional studies in the liver,” “compromised liver,” “physiological basis,” and “mechanistic background,” with and without Boolean operators. Results:Passive liver function tests, including biochemical parameters and clinical grading systems, are not accurate enough in predicting outcome after liver surgery. Dynamic quantitative liver function tests, such as the indocyanine green test and galactose elimination capacity, are more accurate as they measure the elimination process of a substance that is cleared and/or metabolized almost exclusively by the liver. However, these tests only measure global liver function. Nuclear imaging techniques (99mTc-galactosyl serum albumin scintigraphy and 99mTc-mebrofenin hepatobiliary scintigraphy) can measure both total and future remnant liver function and potentially identify patients at risk for postresectional liver failure. Conclusions:Because of the complexity of liver function, one single test does not represent overall liver function. In addition to computed tomography volumetry, quantitative liver function tests should be used to determine whether a safe resection can be performed. Presently, 99mTc-mebrofenin hepatobiliary scintigraphy seems to be the most valuable quantitative liver function test, as it can measure multiple aspects of liver function in, specifically, the future remnant liver.

The position of the acid pocket as a major risk factor for acidic reflux in healthy subjects and patients with GORD

Introduction Gastro-oesophageal reflux occurs twice as much during transient lower oesophageal sphincter relaxations (TLOSRs) in patients with gastro-oesophageal reflux disease (GORD) compared to healthy volunteers (HVs). Our aim was to assess whether the localisation of the postprandial acid pocket and its interaction with a hiatal hernia (HH) play a role in the occurrence of acidic reflux during TLOSRs. Methods Ten HVs and 22 patients with GORD (12 with HH<3 cm (s-HH), 10 with HH≥3 cm (l-HH)) were studied. The squamocolumnar junction and diaphragmatic impression were marked with a radioactively labelled clip. To visualise the acid pocket, 99mTc-pertechnetate was injected intravenously and images were acquired up to 2 h postprandial. Concurrently, combined manometry/impedance and four-channel pH-metry were performed, with pH pull-through at multiple time-points. Results The rate of TLOSRs and the per cent associated with reflux was comparable between all groups. However, acidic reflux was significantly increased in patients, especially in patients with l-HH. Acid pocket length was significantly enlarged in patients. Moreover, immediately before a TLOSR, the acid pocket was more frequently located within the hiatus or above the diaphragm in patients with GORD (s-HH, 54%; l-HH, 77%) compared to HVs (22% of TLOSRs). Acidic reflux was significantly increased when the acid pocket was located above the diaphragm in all groups compared to a sub-diaphragmatic localisation. Conclusion The position of the acid pocket is largely determined by the presence of a HH. Entrapment of the pocket above the diaphragm, especially in patients with l-HH, is a major risk factor underlying the increased occurrence of acidic reflux during a TLOSR in patients with GORD.

Transporters involved in the hepatic uptake of 99mTc-mebrofenin and indocyanine green

BACKGROUND & AIMS (99m)Tc-mebrofenin hepatobiliary scintigraphy (HBS) and the indocyanine green (ICG) clearance test are used for the assessment of hepatic function before and after liver surgery. The hepatic uptake of (99m)Tc-mebrofenin and ICG is considered similar to the uptake of organic anions such as bilirubin and bile acids. Little is known about hepatic uptake mechanisms of both compounds and recent evidence suggests that the hepatic transporters for ICG and (99m)Tc-mebrofenin are distinct. The aim of this study was to identify the specific human hepatic transporters of (99m)Tc-mebrofenin and ICG. METHODS The uptake of (99m)Tc-mebrofenin was investigated in cRNA-injected Xenopus laevis oocytes expressing human OATP1B1, OATP1B3, OATP2B1, or NTCP. Chinese hamster ovary (CHO) cells stably expressing OATP1B1, OATP1B3, OATP2B1, or NTCP were used as a mammalian expression system. ICG transport into CHO cells was additionally imaged with confocal microscopy. RESULTS We demonstrated that OATP1B1 and OATP1B3 are involved in the transport of (99m)Tc-mebrofenin. OATP1B1 showed an approximately 1.5-fold higher affinity for (99m)Tc-mebrofenin compared to OATP1B3. ICG is transported by OATP1B3 and NTCP. CONCLUSIONS The transporter specificity of (99m)Tc-mebrofenin and ICG partially overlaps as both compounds are transported by OATP1B3. (99m)Tc-mebrofenin is also taken up by OATP1B1, whereas ICG is additionally transported by NTCP.

The Epidermal Growth Factor-Seven Transmembrane (EGF-TM7) Receptor CD97 Is Required for Neutrophil Migration and Host Defense

The epidermal growth factor-seven transmembrane (EGF-TM7) family is a group of seven-span transmembrane receptors predominantly expressed by cells of the immune system. Family members CD97, EGF module-containing mucin-like receptor (EMR) 1, EMR2, EMR3, EMR4, and EGF-TM7-latrophilin-related protein are characterized by an extended extracellular region with a variable number of N-terminal EGF-like domains. EGF-TM7 receptors bind cellular ligands as demonstrated by the interaction of CD97 with decay accelerating factor (CD55) and dermatan sulfate. Investigating the effect of newly generated mAb on the migration of neutrophilic granulocytes, we here report for the first time in vivo data on the function of CD97. In dextran sulfate sodium-induced experimental colitis, we show that homing of adoptively transferred neutrophils to the colon was significantly delayed when cells were preincubated with CD97 mAb. The consequences of this defect in neutrophil migration for host defense are demonstrated in a murine model of Streptococcus pneumoniae-induced pneumonia. Mice treated with CD97 mAb to EGF domain 1 (1B2) and EGF domain 3 (1C5) displayed a reduced granulocytic inflammatory infiltrate at 20 h after inoculation. This was associated with a significantly enhanced outgrowth of bacteria in the lungs at 44 h and a strongly diminished survival. Together, these findings indicate an essential role for CD97 in the migration of neutrophils.

Assessment of Future Remnant Liver Function Using Hepatobiliary Scintigraphy in Patients Undergoing Major Liver Resection

Background99mTc-mebrofenin hepatobiliary scintigraphy (HBS) was used as a quantitative method to evaluate liver function. The aim of this study was to compare future remnant liver function assessed by 99mTc-mebrofenin hepatobiliary scintigraphy with future remnant liver volume in the prediction of liver failure after major liver resection.MethodsComputed tomography (CT) volumetry and 99mTc-mebrofenin hepatobiliary scintigraphy were performed prior to major resection in 55 high-risk patients, including 30 patients with parenchymal liver disease. Liver volume was expressed as percentage of total liver volume or as standardized future remnant liver volume. Receiver operating characteristic (ROC) curve analysis was performed to identify a cutoff value for future remnant liver function in predicting postoperative liver failure.ResultsPostoperative liver failure occurred in nine patients. A liver function cutoff value of 2.69%/min/m2 was calculated by ROC curve analysis. 99mTc-mebrofenin hepatobiliary scintigraphy demonstrated better sensitivity, specificity, and positive and negative predictive value compared to future remnant liver volume. Using 99mTc-mebrofenin hepatobiliary scintigraphy, one cutoff value suffices in both compromised and noncompromised patients.ConclusionPreoperative 99mTc-mebrofenin hepatobiliary scintigraphy is a valuable technique to estimate the risk of postoperative liver failure. Especially in patients with uncertain quality of the liver parenchyma, 99mTc-mebrofenin HBS proved of more value than CT volumetry.

Intestinal handling-induced mast cell activation and inflammation in human postoperative ileus

Background: Murine postoperative ileus results from intestinal inflammation triggered by manipulation-induced mast cell activation. As its extent depends on the degree of handling and subsequent inflammation, it is hypothesised that the faster recovery after minimal invasive surgery results from decreased mast cell activation and impaired intestinal inflammation. Objective: To quantify mast cell activation and inflammation in patients undergoing conventional and minimal invasive surgery. Methods: (1) Mast cell activation (ie, tryptase release) and pro-inflammatory mediator release were determined in peritoneal lavage fluid obtained at consecutive time points during open, laparoscopic and transvaginal gynaecological surgery. (2) Lymphocyte function-associated antigen-1 (LFA-1), intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) mRNA as well as leucocyte influx were quantified in non-handled and handled jejunal muscle specimens collected during biliary reconstructive surgery. (3) Intestinal leucocyte influx was assessed by 99mTc-labelled leucocyte single photon emission computed tomography (SPECT) – computed tomography (CT) scanning before and after abdominal or vaginal hysterectomy. Results: (1) Intestinal handling during abdominal hysterectomy resulted in an immediate release of tryptase followed by enhanced interleukin 6 (IL6) and IL8 levels. None of the mediators increased during minimal invasive surgery except for a slight increase in IL8 during laparoscopic surgery. (2) Jejunal ICAM-1 and iNOS mRNA transcription as well as leucocyte recruitment were increased after intestinal handling. (3) Leucocyte scanning 24 h after surgery revealed increased intestinal activity after abdominal but not after vaginal hysterectomy. Conclusions: This study demonstrates that intestinal handling triggers mast cell activation and inflammation associated with prolonged postoperative ileus. These results may partly explain the faster recovery after minimal invasive surgery and encourage future clinical trials targeting mast cells to shorten postoperative ileus.

Increase in future remnant liver function after preoperative portal vein embolization

Preoperative portal vein embolization (PVE) is performed in patients with insufficient future remnant liver (FRL) to allow safe resection. Although many studies have demonstrated an increase in FRL volume after PVE, little is known about the increase in FRL function. This study evaluated the increase in FRL function after PVE using 99mTc‐labelled mebrofenin hepatobiliary scintigraphy (HBS) with single photon emission computed tomography (SPECT) and compared this with the increase in FRL volume.

Risk Assessment of Posthepatectomy Liver Failure Using Hepatobiliary Scintigraphy and CT Volumetry

A major part of morbidity and mortality after liver resections is caused by inadequate remnant liver function leading to liver failure. It is therefore important to develop accurate diagnostic tools that can predict the risk of liver resection–related morbidity and mortality. In this study, preoperative hepatobiliary scintigraphy of the future remnant liver and CT volumetric measurement of the future remnant liver were performed on patients who were to undergo liver resection. The accuracy of risk assessment for postoperative morbidity, liver failure, and mortality was evaluated. Methods: Forty-six patients who were scheduled for liver resection because of hepatobiliary tumors, including 17 patients with parenchymal disease (37%) and 13 patients with hilar cholangiocarcinoma (28%), were assessed preoperatively. Hepatobiliary scintigraphy was performed by drawing regions of interest around the future remnant to calculate 99mTc-mebrofenin uptake in it. CT volumetry was used to measure the volume of the total liver, the tumors, and the future remnant. Receiver-operating-characteristic analysis was performed to assess cutoff values for risk assessment of morbidity, liver failure, and mortality. Furthermore, univariate and multivariate analyses were performed to determine factors related to morbidity and mortality. Results: Morbidity and mortality rates were 61% and 11%, respectively. Liver failure occurred in 6 patients (13%). Significantly decreased uptake in the future remnant was found in patients in whom liver failure and liver failure–related mortality developed (P = 0.003 and 0.02, respectively). The volume of the future remnant was not significantly associated with any of the outcome parameters. In receiver-operating-characteristic analysis, uptake cutoff values for liver failure and liver failure–related mortality were 2.5%/min/body surface area and 2.2%/min/body surface area, respectively. In multivariate analysis, uptake was the only significant factor associated with liver failure. Conclusion: Preoperative measurement of 99mTc-mebrofenin uptake in the future remnant liver on hepatobiliary scintigraphy proved more valuable than measurement of the volume of the future remnant on CT in assessing the risk of liver failure and liver failure–related mortality after partial liver resection.