Gastrointestinal stromal tumours: a regular origin in the muscularis propria, but an extremely diverse gross presentation

Background Gastrointestinal stromal tumours (GISTs) are thought to arise from the interstitial cells of Cajal (ICCs). ICCs form a network surrounding the myenteric plexus and between-muscle fibres of the muscularis propria of the tubular GI tract. The cell of origin of so-called extra-gastrointestinal stromal tumours (EGISTs) is not known.Aim and methods To study the diversity of gross presentation of GISTs and to critically assess the incidence of EGISTs and their relationship to mural GISTs, a total of 200 neoplasms with typical morphologic and immunohistochemical features of GISTs were reviewed, looking for any degree of association with the muscularis propria of the gut wall.Results There were 130 gastric (65%), 9 duodenal (4.5%), 48 small intestinal (24%), 9 colorectal (4.5%), 1 appendiceal (0.5%) and 3 unclassifiable GISTs (1.5%). Fourteen cases (7%) were initially submitted as EGISTs (four mesenteric, four omental, one pararectal/prostatic, one pelvic/Douglas, one perivesical, one located between root of mesentery and tail of pancreas, one involving the mesentery, omentum and abdominal wall extensively and one located between liver and stomach). After critical re-evaluation of surgical reports and remote clinical history and a careful search for residual muscular tissue from the gut wall in the tumour pseudocapsule (in some cases supported by desmin immunoreactivity), it was possible to reclassify most of these cases (11/14) as either GISTs with extensive extramural growth resulting in loss of contact to the external muscle coat of the gut (8/14) or as metastases from an inoperable GIST (2/14) or from a previously resected deceptively benign tumour (1/14).Conclusion EGISTs are probably rarer than previously reported (1.5% or less in this study). We concluded that most so-called EGISTs represent apparent EGISTs that should have arisen from the outermost muscle coat, but have lost their contact to the point of origin due to extensive extramural growth pattern. From a surgical point of view, it is crucial to document and mark any focal attachment or adhesions to the gut wall noticed during surgery for an apparent EGIST. In contrast to most other neoplasms, GISTs should be defined by virtue of any degree of association with the muscularis propria (no matter how minimal), but not by localisation of the bulk of the tumour.     

The Well-being Model: A New Drug Interaction Model for Positive and Negative Effects

Background: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account.

Methods: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs.

Results: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed.     

Heart Rate Variability Predicts Severe Hypotension after Spinal Anesthesia

Background: Hypotension due to vasodilatation after spinal anesthesia (SA) may be harmful. Heart rate variability, an indirect measure of autonomic control, may predict hypotension.

Methods: One hundred patients were studied. Retrospectively, heart rate variability was analyzed in 30 patients, classified depending on the lowest systolic blood pressure (SBP) after SA. Seventy patients were studied prospectively, assigned to one of two groups by their low to high frequency ratio (LF/HF) before SA. Sensitivity and specificity of LF/HF for prediction of decrease of SBP greater 20% of baseline were tested.

Results: Retrospective analysis showed differences of LF/HF depending on the degree of hypotension after SA. Prospective analysis demonstrated significant differences of SBP after SA depending on baseline LF/HF (mean +/- SD): low LF/HF (1.3 +/- 0.7) = > SBP: 91 +/- 8% of baseline versus high LF/HF (5.5 +/- 2.4) = > SBP: 66 +/- 10% of baseline (P < 0.05). Baseline LF/HF as well as high frequency and proportional decrease of SBP after SA correlated significantly, in contrast to baseline hemodynamic parameters heart rate and SBP. A receiver operator curve characteristic analysis showed a sensitivity and specificity of LF/HF > 2.5 of 85% to predict SBP decrease of greater than 20% of baseline after SA.     

Does monthly native arteriovenous fistula blood-flow surveillance detect significant stenosis--a randomized controlled trial.

BACKGROUND: Clinical practice guidelines recommend that the preferred method of surveillance for arteriovenous fistula (AVF) is the measurement of AVF blood flow (Qa). As these recommendations are based on observational studies, we conducted a randomized, prospective, double-blind, controlled trial to assess whether Qa surveillance results in an increased detection of AVF stenosis. METHODS: A total of 137 patients were randomly assigned to receive either continuing AVF surveillance using current clinical criteria (control, usual treatment) or usual treatment plus AVF blood-flow surveillance by ultrasound dilution (Qa surveillance group). The primary outcome measure was the detection of a significant (>50%) AVF stenosis. RESULTS: There were 67 and 68 patients assigned to the control and Qa surveillance groups, respectively. Patients in the Qa surveillance group were twice as likely to have a stenosis detected compared with the control hazard ratio (HR) confidence interval (CI) group (2.27, 95% 0.85-5.98, P = 0.09), with a trend for a significant stenosis to be detected earlier in the Qa surveillance group (P = 0.09, log rank test). However, using the Qa results alone prior to angiography, the area under the receiver operating characteristic curve demonstrated, at best, a moderate prediction of (>50%) AVF stenosis (0.78, 95% CI 0.63-0.94, P = 0.006). CONCLUSION: This study demonstrates that the addition of AVF Qa monitoring to clinical screening for AVF stenosis resulted in a non-significant doubling in the detection of angiographically significant AVF stenosis. Further, large multi-centre randomized trials are feasible and will be necessary to confirm whether Qa surveillance and the correction of detected AVF stenosis will lead to a reduction in AVF thrombosis and increased AVF survival.     

Validation of a simplified technique for using the POPQ pelvic organ prolapse classification system

Our objective was to determine the inter-examiner agreement of a simplified pelvic organ prolapse quantification (POPQ) exam and to assess its correlation with the standard POPQ exam. This study consists of two parts; both were preformed in a prospective, randomized, blinded fashion on women presenting with complaints attributed to pelvic organ support defects. The first study was done to determine the inter-examiner reliability of a simplified POPQ exam. The simplified POPQ exam is based on the POPQ with similar ordinal staging but with only four points measured instead of nine. Forty-eight women underwent exams by five different investigators. The order of exams was randomized and the examiners were blinded to the results of each other’s findings. The results of these two exams were compared using weighted kappa statistics. The second part of the study was done to determine the inter-system agreement between the simplified vs standard POPQ exam. A group of 49 women were examined by four different investigators: one using the simplified and the other using standard POPQ exams. The order of the exams was randomized and the examiners were blinded to the results of each other’s exam. Kendall’s tau-b statistics were used to determine the inter-system agreement. For the inter-examiner reliability of the POPQ exam, the average age was 60±13 years. The weighted kappa statistics for the inter-examiner reliability of the simplified prolapse classification system were 0.86 for the overall stage, 0.89 and 0.86 for the anterior and posterior vaginal walls, respectively, 0.82 for the apex/cuff, and 0.72 for the cervix. All demonstrate significant agreement. For the inter-system association between the simplified POPQ and standard POPQ, the average age was 61±15 year. The Kendall’s tau-b value for overall stage was 0.90, 0.83, and 0.87 for the anterior and posterior walls respectively, and 0.78 for the cuff/apex and 0.98 for the cervix. There is good inter-examiner agreement of a simplified POPQ classification system and it appears to have good inter-system association with the POPQ.IUGA Standardization of Terminology Committee members: Robert Freeman MD (chairman), Steven Swift, Eckhard Petri MD, Richard J. Scotti MD, and Peter Dwyer MD.     

Intrathecal Ziconotide in the Treatment of Chronic Nonmalignant Pain: A Randomized,Double‐Blind,Placebo‐Controlled Clinical Trial

Objective. The safety and efficacy of intrathecal (IT) ziconotide was studied in a randomized, double‐blind, placebo‐controlled trial. Materials and Methods. Patients (169 ziconotide, 86 placebo) with severe chronic nonmalignant pain unresponsive to conventional therapy and a visual analog scale of pain intensity (VASPI score) ≥ 50 mm were treated over a 6‐day period in an inpatient hospital setting. Initial starting dose was 0.4 µg/hour and was titrated to analgesia or intolerance (maximum dose 7.0 µg/hour). The starting and maximum doses were reduced to 0.1 µg/hour and 2.4 µg/hour, respectively, due to adverse events (AEs). Results. The mean percent reduction in VASPI score from baseline was 31.2% and 6.0% for ziconotide‐ and placebo‐treated patients, respectively (p ≤ 0.001). During the initial titration phase, a significantly greater percentage of patients in the ziconotide group compared to the placebo group reported AEs, including abnormal gait, amblyopia, dizziness, nausea, nystagmus, pain, urinary retention, and vomiting. Conclusion. Ziconotide provided significant analgesia in patients for whom conventional therapy failed. However, there was a considerable incidence of ziconotide‐associated AEs due to the rapid titration and high doses administered.     

Predictive value and limitations of animal models for human transplantation: do we need more models for facial transplantation?

Animal models have traditionally provided the basis for preliminary investigation of new techniques prior to trials taking place in human subjects. The timing of when to proceed with human trials is difficult, as the accuracy of preclinical models can only be determined with hindsight. This review outlines the progression from transplantation in animal models to man. Now that many transplant procedures are well established, it is possible to assess the predictive value and limitations of animal models. These results are of great importance in the current debate about composite tissue allotransplantation (CTA) and in particular facial transplantation. This progression of CTA from animal models to man is outlined and compared with early renal, cardiac, and liver transplants. There is some evidence to suggest that animal models may have been misleading in CTA and that this has effectively delayed the transition to humans. The role for animal models in facial transplantation, which is currently making the step to clinical trials, is discussed.     

Digestive properties of the venom of the Australian Coastal Taipan, Oxyuranus scutellatus (Peters, 1867).

The digestive properties of Australian elapid snake venoms have not been studied to any great extent. To address this, the in vitro digestive properties of Oxyuranus scutellatus (Australian Coastal Taipan) venom were investigated in a simulation of the in vivo conditions using the parameters reported for the stomach of snakes and representative prey for this species. The amount of soluble protein released was measured over time using a bicinchoninic acid (BCA) assay. Dismembered mouse hindlegs were injected intramuscularly with 0.1 ml O. scutellatus venom (concentration 10 mg/ml) and maintained in a micro-anaerobic, acidic environment (pH approximately 1.2-1.7) at 25 degrees C. The bathing liquid was sampled every 24 h for 7 days, and assayed for soluble protein. Statistical analysis revealed that O. scutellatus venom increased the rate at which proteins were released when compared to a negative control suggesting the potential importance of envenomation in the digestion of whole prey.     

Human hepatocellular carcinoma tumor xenografts

Castrated or sham-operated male athymic mice were inoculated with cells from the human hepatocellular carcinoma cell line PLC/PRF/5. There were no significant differences between the two groups with respect to the number of animals developing tumors, the time to tumor development, or the subsequent rate of increase in either tumor base area or mouse serum alpha-fetoprotein concentration. Androgen receptors were assayed in nuclei obtained from three separate liver cancer cell lines and from normal adult human liver. Similar concentrations, ranging from 235 to 550 fmol/mg DNA, of nuclear androgen receptors were detected in all tissues. Low percentages of androgen receptors were retained on DNA-cellulose. Although the presence of receptors implies the potential for metabolic effects of androgens in normal and malignant liver, our in vivostudies suggest that castration does not alter significantly the growth of liver cancer xenografts in athymic mice.