Non-invasive monitoring of renal transplant recipients: Urinary excretion of soluble adhesion molecules and of the complement-split product C4d

Background: The number of inducible adhesion molecules known to be involved in cell-mediated allograft rejection is still increasing. In addition, recent data describe complement activation during acute humoral allograft rejection. The aim of this study was to assess whether specific molecules from either pathway are excreted into urine and whether they can provide useful diagnostic tools for the monitoring of renal transplant recipients. Methods: Urinary concentrations of soluble adhesion molecules (sICAM-1, sVCAM-1) and of the complement degradation product C4d were determined by standardized ELISA technique in 75 recipients of renal allografts and 29 healthy controls. Patient samples were assigned to four categories according to clinical criteria: group 1: acute steroid-sensitive rejection (ASSR, n=14), group 2: acute steroid-resistant rejection (ASRR, n=12), group 3: chronic allograft dysfunction (CAD, n=20) and group 4: stable graft function (SGF, n=29). Results: All patients with rejection episodes (groups 1-3) had significantly higher values of urinary sC4d compared with healthy controls and patients with stable graft function (p<0.05). The urinary levels of sVCAM-1 were significantly higher in group 2 (ASRR) compared with all other groups (p<0.001). Uniformly low amounts of s-VCAM-1 and complement-split product C4d were excreted by healthy controls (group 0). In contrast, urinary sICAM-1 concentration in healthy controls was almost as high as in group 2 (ASRR) whereas patients with a stable functioning graft (group 4) excreted significantly less sICAM-1 (p<0.05). Conclusion: The evaluation of sVCAM-1 and sC4d excretion in urine can provide a valuable tool with regard to the severity and type of allograft rejection. With respect to long-term allograft survival, serial measurements of these markers should have the potential to detect rejection episodes and prompt immediate treatment. Copyright (C) 2003 S. Karger AG, Basel

Malpractice Claims for Endoscopy

AIM: To summarize the magnitude and time trends of endoscopy-related claims and to compare total malpractice indemnity according to specialty and procedure. METHODS: We obtained data from a comprehensive database of closed claims from a trade association of professional liability insurance carriers, representing over 60% of practicing United States physicians. Total payments by procedure and year were calculated, and were adjusted for inflation (using the Consumer Price Index) to 2008 dollars. Time series analysis was performed to assess changes in the total value of claims for each type of procedure over time. RESULTS: There were 1901 endoscopy-related closed claims against all providers from 1985 to 2008. The specialties include: internal medicine (n = 766), gastroenterology (n = 562), general surgery (n = 231), general and family practice (n = 101), colorectal surgery (n = 87), other specialties (n = 132), and unknown (n = 22). Colonoscopy represented the highest frequencies of closed claims (n = 788) and the highest total indemnities ($54 093 000). In terms of mean claims payment, endoscopic retrograde cholangiopancreatography (ERCP) ranked the highest ($374  794) per claim. Internists had the highest number of total claims (n = 766) and total claim payment ($70  730  101). Only total claim payments for colonoscopy and ERCP seem to have increased over time. Indeed, there was an average increase of 15.5% per year for colonoscopy and 21.9% per year for ERCP after adjusting for inflation. CONCLUSION: There appear to be differences in malpractice coverage costs among specialties and the type of endoscopic procedure. There is also evidence for secular trend in total claim payments, with colonoscopy and ERCP costs rising yearly even after adjusting for inflation

Einfluss der CXCR4-Expression auf das Migrationsverhalten beim Rhabdomyosarkom und die CXCR4-Inhibition als mögliche Therapieoption in vitro

Bei fortgeschrittenen Stadien des Rhabdomyosarkom (RMS) im Kindesalter konnte in den letzten Jahren keine weitere relevante Verbesserung der Prognose mehr erreicht werden. Die gängigen Therapieoptionen sind ausgeschöpft, deren Weiterentwicklung sowie die Implementierung neuer therapeutischer Verfahren dringend erforderlich. Bei vielen Tumorentitäten wurde die große Bedeutung des CXC-Motiv Chemokinrezeptor 4 (CXCR4) bei der Metastasierung, Adhäsion und Angiogenese in vitro und in vivo Modellen bereits mehrfach beschrieben. Auch ein pro-metastatischer Einfluss von Zytostatika und Bestrahlung durch die Induktion von Chemokinen und Chemokinrezeptoren konnte bereits gezeigt werden. In der vorliegenden Arbeit wurde daher bei RMS-Zellen untersucht, inwieweit Zytostatika Einfluss auf die Expression von CXCR4 haben. Aufbauend darauf, ob eine Kombination von CXCR4-Inhibition und Chemotherapie eine neue/erweiterte Therapiestrategie bei der Behandlung des RMS darstellen kann. Dabei konnte erstmals bei den RMS-Zelllinien RH30 (alveoläres Rhabdomyosarkom) sowie der RD-Zelllinie (embryonales Rhabdomyosarkom) gezeigt werden, dass Chemotherapeutika einen modulatorischen Einfluss auf die Expression von CXCR4 haben. Dieser war abhängig von der Zelllinie, der Behandlungszeit sowie der Pharmakodynamik des Zytostatikums. In der Kombinationsanwendung von Zytostatika mit dem CXCR4-Antagonisten AMD3100 konnte, durch die reversible Bindung an CXCR4, eine Reduktion von CXCR4 positiven Zellen gegenüber der Monotherapie festgestellt werden. In daran anschließenden funktionellen Untersuchungen hatte das Expressionslevel von CXCR4 maßgeblichen Einfluss auf das Migrationsverhalten von RMS-Zellen. Dieses Verhalten konnte bereits in anderen Tumorentitäten gezeigt werden. Darüber hinaus reduzierte die Kombination von Zytostatika mit AMD3100 die Migration von RMS-Zellen gegenüber der Kontrolle ohne Behandlung, vereinzelt auch gegenüber der Monotherapie. Präklinische Untersuchungen zeigen, dass durch die Gabe von CXCR4 Inhibitoren die therapeutische Wirkung von Chemotherapeutika verbessert werden kann, indem sie die Interaktion mit dem Stroma Gewebe über CXCL12 unterbrechen. In Anlehnung daran lassen die Ergebnisse vermuten, dass die Modulation der CXCR4-Expression einen möglichen Mechanismus der Chemoresistenz beim RMS darstellen könnte. Des Weiteren konnte ein modulatorischer Einfluss von Zytostatika auf die Serum- und Glukokortikoid-induzierbare Kinase 3 (SGK3) nachgewiesen werden. Außerdem konnte bei Doxorubicin und Vincristin eine mögliche Verbindung zum Expressionsverhalten von CXCR4 hergestellt werden. Die beteiligten Signalmechanismen hierbei sind jedoch noch unklar. In Übereinstimmung mit der Literatur scheinen die im Rahmen dieser Dissertation erhobenen Daten vielversprechend. Insbesondere hinsichtlich ihrer Bedeutung für fortgeschrittene Stadien des RMS in Bezug auf die Metastasierung und Chemoresistenz. Allerdings legen die vorliegenden Ergebnisse auch nahe, dass eine Chemotherapie-induzierte Modulation von CXCR4 durch eine Vielzahl von Faktoren bestimmt wird. Im Vorfeld translationaler Überlegungen, sind somit zunächst weitere Untersuchungen im Mausmodell sowie Analysen an Tumorproben in Korrelation zur Vorbehandlung dringend erforderlich

National complicated acute diverticulitis (CADS) study: a protocol for a prospective observational scoping study for acute diverticulitis

Background Diverticular disease is a widely prevalent disease in western society, and acute diverticulitis is a common acute surgical presentation. However, there is a lack of level 1 evidence addressing the multifaceted presentations associated with acute diverticulitis. There is also a lack of robust epidemiological data that could be used to meaningfully inform randomised controlled trials. The National CADS project aims to generate baseline data for a cohort of patients managed for clinically suspected acute diverticulitis and evaluate the impact of variability in the management approach on patient outcomes in the short (3 months) and long (2 years) term. Method A Unit policy questionnaire will be completed by the principal investigator from all participating centres prior to study initiation. All patients aged above 18 years admitted with clinical suspicion of acute diverticulitis will be included from UK hospitals providing acute surgical care. Demographic, clinical, inpatient stay and outpatient follow-up data will be collected for index admissions between July and September 2014, 3 months follow-up and finally a 2-year follow-up. Results The study attracted participation from 108 centres nationally and has so far generated data on 2500 patients admitted between 1 July 2014 and 30 September 2014. Short-term follow-up data have been obtained for this cohort. Conclusions The National CADS study is currently ongoing with the long-term outcomes data anticipated to be submitted in autumn of 2016

Corrigendum: The Influence of Task-Irrelevant Flankers Depends on the Composition of Emotion Categories

Face recognition usually takes place in a social context, where faces are surrounded by other stimuli. These can act as distracting flankers which impair recognition. Previous work has suggested that flankers expressing negative emotions distract more than positive ones. However, the various negative emotions differ in their relative impact and it is unclear whether all negative emotions are equally distracting. We investigated the impact of three negative (angry, fearful, sad) and one positive (happy) facial flanker conditions on target recognition in an emotion discrimination task. We examined the effect of the receiver’s gender, and the impact of two different temporal delays between flanker and target onset, as stimulus onset asynchrony is assumed to affect distractor strength. Participants identified and rated the emotional intensity of target faces surrounded by either face (emotional and neutral) or non-face flankers. Target faces were presented either simultaneously with the flankers, or delayed by 300 ms. Contrary to our hypothesis, negative flankers did not exert stronger distraction effects than positive or neutral flankers. However, happy flankers reduced recognition performance. Results of a follow-up experiment with a balanced number of emotion categories (one positive, one negative and one neutral flanker condition) suggest that the distraction effect of emotional flankers depends on the composition of the emotion categories. Additionally, congruency effects were found to be valence-specific and overruled by threat stimuli. Females responded more quickly and rated targets in happy flankers as less intense. This indicates a gender difference in emotion processing, with greater sensitivity to facial flankers in women. Targets were rated as more intense when they were presented without a temporal delay, possibly due to a stronger flanker contrast. These three experiments show that an exceptional processing of threat-related flanker stimuli depends on emotion category composition, which should be considered a mediating factor when examining emotional context effects

Clinical and pathological outcomes of induction chemotherapy before neoadjuvant radiotherapy in locally‐advanced rectal cancer

Background and ObjectivesIn North America, preoperative combination chemoradiation is the most commonly recommended and utilized approach to locally advanced rectal cancer. There is increasing interest in the use of induction chemotherapy (IC) before radiation and surgery in locally advanced rectal cancer. How widely IC is being used and whether it improves pathologic and oncologic outcomes is unknown.MethodsWe evaluated clinical stage 2 or 3 rectal cancer patients in the National Cancer Database between 2006 and 2015. We identified predictors of use of IC with multivariable logistic regression and compared survival between groups using Cox proportional hazards regression.ResultsAmong 36 268 patients, IC use increased significantly over time from 5.5% in 2006 to 15.9% in 2015 (P < 0.001). Treatment at a hospital with a high IC rate was an independent predictor of receipt of IC. IC and traditional therapy yielded similar pathologic complete response rates (32.2% vs 30.5%, P = 0.2) and similar 5‐year survival (82.4% vs 81.4%, 0.71).ConclusionsUse of IC for locally advanced rectal cancer has increased significantly. The choice of IC seems to be driven more by institutional and regional practice patterns than clinical characteristics and is not associated with improved pathologic or oncologic outcomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150518/1/jso25474.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150518/2/jso25474_am.pd

Review of Ongoing Clinical Trials in Non–Small-Cell Lung Cancer: A Status Report for 2012 from the ClinicalTrials.gov Web Site

IntroductionClinical research in non–small-cell lung cancer (NSCLC) is a rapidly evolving field. In an effort to identify the current trends in lung cancer clinical research, we reviewed ongoing clinical trials in NSCLC listed in the ClinicalTrials.gov registry in 2012, and we also compared this data to a similar survey conducted by us in 2009.MethodsThe Web site's advanced search function was used to search for the term “non-small cell lung cancer.” The search was further refined by using the following options from the search page drop-down menu, “open studies” and “interventional.” Studies with non-NSCLC tumor histologies and pediatric studies were excluded.ResultsOf the 477 trials included in the analysis, 105 (22.0%) were phase I, 223 phase II (46.8%), and 63 phase III trials (13.2%). When compared with data from 2009, university-sponsored trials decreased in number (45.4%–34.2%; p < 0.001) whereas industry-sponsored trials remained almost the same. There was a significant increase in trials conducted exclusively outside of the United States (35.9%–48.8%; p = 0.001). The number of studies with locations in China (61, 12.8%) was second only to that in the United States (244, 51.2%). Studies reporting biomarker analysis increased significantly from 37.5% to 49.1% in 2012 (p < 0.001). Biomarker-based patient selection also increased significantly from 7.9% to 25.8% (p < 0.001). Targeted therapies were evaluated in 70.6% of phase I/II and II trials, and the most common class of targeted agent studied was epidermal growth factor receptor tyrosine kinase inhibitors (38.0%). Prespecified accrual times were observed to increase when compared with data reported in 2009, especially among industry-sponsored studies.ConclusionsOur survey identified major changes in lung cancer clinical research since 2009. Almost half of all studies registered at the ClinicalTrials.gov Web site are being conducted outside the United States, and several novel molecularly targeted agents are being evaluated in the treatment of patients with NSCLC. More importantly, we identified a threefold increase in the number of studies that perform biomarker testing to determine patient selection over the last 3 years

Digital analysis of cDNA abundance; expression profiling by means of restriction fragment fingerprinting

BACKGROUND: Gene expression profiling among different tissues is of paramount interest in various areas of biomedical research. We have developed a novel method (DADA, Digital Analysis of cDNA Abundance), that calculates the relative abundance of genes in cDNA libraries. RESULTS: DADA is based upon multiple restriction fragment length analysis of pools of clones from cDNA libraries and the identification of gene-specific restriction fingerprints in the resulting complex fragment mixtures. A specific cDNA cloning vector had to be constructed that governed missing or incomplete cDNA inserts which would generate misleading fingerprints in standard cloning vectors. Double stranded cDNA was synthesized using an anchored oligo dT primer, uni-directionally inserted into the DADA vector and cDNA libraries were constructed in E. coli. The cDNA fingerprints were generated in a PCR-free procedure that allows for parallel plasmid preparation, labeling, restriction digest and fragment separation of pools of 96 colonies each. This multiplexing significantly enhanced the throughput in comparison to sequence-based methods (e.g. EST approach). The data of the fragment mixtures were integrated into a relational database system and queried with fingerprints experimentally produced by analyzing single colonies. Due to limited predictability of the position of DNA fragments on the polyacrylamid gels of a given size, fingerprints derived solely from cDNA sequences were not accurate enough to be used for the analysis. We applied DADA to the analysis of gene expression profiles in a model for impaired wound healing (treatment of mice with dexamethasone). CONCLUSIONS: The method proved to be capable of identifying pharmacologically relevant target genes that had not been identified by other standard methods routinely used to find differentially expressed genes. Due to the above mentioned limited predictability of the fingerprints, the method was yet tested only with a limited number of experimentally determined fingerprints and was able to detect differences in gene expression of transcripts representing 0.05% of the total mRNA population (e.g. medium abundant gene transcripts)

Robotic proctectomy for rectal cancer: analysis of 71 patients from a single institution

BackgroundDespite increasing use of robotic surgery for rectal cancer, few series have been published from the practice of generalizable US surgeons.MethodsA retrospective chart review was performed for 71 consecutive patients who underwent robotic low anterior resection (LAR) or abdominoperineal resection (APR) for rectal adenocarcinoma between 2010 and 2014.Results46 LARs (65%) and 25 APRs (35%) were identified. Median procedure time was 219 minutes (IQR 184–275) and mean blood loss 164.9 cc (SD 155.9 cc). Radial margin was negative in 70/71 (99%) patients. Total mesorectal excision integrity was complete/near complete in 38/39 (97%) of graded specimens. A mean of 16.8 (SD+/− 8.9) lymph nodes were retrieved. At median follow‐up of 21.9 months, there were no local recurrences.ConclusionsRobotic proctectomy for rectal cancer was introduced into typical colorectal surgery practice by a single surgeon, with a low conversion rate, low complication rate, and satisfactory oncologic outcomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139933/1/rcs1841_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139933/2/rcs1841.pd