HER-2/neu (c-erbB-2) evaluation in primary breast carcinoma by fluorescent in situ hybridization and immunohistochemistry with special focus on intratumor heterogeneity and comparison of invasive and in situ components.

We have studied the intratumor HER-2/neu heterogeneity in 78 consecutive and population-based primary invasive breast carcinomas. Within the invasive component, heterogeneity was detected in only 1 of 78 tumors. In 48 tumors (62%), we found both in situ and invasive components in analyzed tissue sections. Twelve of these 48 tumors had a difference of at least 2 arbitrary units in the in situ compared with the invasive part of the tumor with regard to the HER-2/neu status analyzed by HercepTest (immunohistochemistry). Eight of these 12 tumors were reanalyzed with fluorescent in situ hybridization and immunohistochemistry with and without a new Automated Cellular Imaging System. In this limited material, immunohistochemistry in combination with the Automated Cellular Imaging System seemed to have a better correlation with fluorescent in situ hybridization than immunostaining analyzed manually. In conclusion, HER-2/neu expression is not seldom heterogeneous in invasive compared with in situ components within a tumor. This finding should be considered in the choice of evaluation method. To avoid heterogeneity as a confounding factor in HER-2/neu analyses, detection methods such as immunohistochemistry and fluorescent in situ hybridization, which can provide evaluation in a preserved tissue architecture, should be used. Perhaps the intratumor HER-2/neu heterogeneity can explain some of the unexpected failures of trastuzumab therapy.     

A clinical comparison of the Laryngeal Tube™ and the Laryngeal Mask™ in spontaneously breathing anesthetized patients

Abstract: Background: The laryngeal mask airway (LMA) can be used in general anaesthesia without neuromuscular block. The laryngeal tube (LT) is a new airway device with similar airway features as LMA. LT is provided with a distal cuff to prevent regurgitation. In this study we compared the LMA and LT concerning patient and user aspects. Methods: Sixty patients with ASA (American Society of Anestesiologists) score 1–2 scheduled for minor surgery were randomized to be ventilated either through LMA or LT. After insertion, the number of insertion attempts, and “positioning” and “airway-assessment” was evaluated. The patients reported on “sore throat” after 30 and 60 minutes and the day after anaesthesia. Results: Gender and mean age were equal in both groups. The first insertion attempt was successful in 25 of 28 patients randomised to LMA and in 23 of 27 patients randomised to LT. LMA was evaluated to be easier in “positioning” whereas no difference in “sore throat” was reported. Conclusion: We found no difference between the LMA and the LT in terms user and patient friendliness and safety.     

Dysphagia,an unrecognized handicap

The aim of this study was to examine whether esophageal dysphagia can be described as a handicap and to grade the severity of handicap as the discrepancy between the subject's own eating goals and his or her eating disability. The severity of the disability-goal-handicap (DGH) regarding dysphagia was expressed on a scale ranging from 0 to 48 points. Nineteen patients with dysphagia of differing causes were selected from a patient register at a laboratory for diagnostic procedures of the esophagus. The severity of handicap for the 19 patients was, on average, 33 points (range, 20–44). The DGH score correlated significantly with the patients' own evaluation of the severity of their dysphagia (p=0.008). The DGH scores did not differ markedly based on patient's sex, age, or cause of dysphagia. Patients who were operated upon because of dysphagia had significantly more points on the DGH scale prior to operation than patients who were not (p=0.001). Denial of dysphagia (N=18), concealment of dysphagia (N=18), and lack of confirmation by the patient's physician (N=15) were common but did not influence the severity of handicap as assessed by the DGH scale. It was shown that dysphagia affects all aspects of life as expressed by reduction in self-esteem (N=13), security (N=16), work capacity (N=8), exercise (N=7), and leisure time (N=6). Esophageal dysphagia may therefore be regarded as a handicap when assessed using the DGH code described in this study.     

Ethylene–Propylene Copolymerisations: Effect of Metallocene Structure on Termination Reactions and Polymer Microstructure

Summary: Ethylene–propylene (EP) copolymerisations were performed with two sterically different metallocenes activated by methylaluminoxane (MAO) in an attempt to better understand the effect of catalyst structure on termination reactions and polymer microstructure. The metallocene precursors under investigation were rac‐dimethylsilylbis(2‐methyl‐4‐phenyl‐1‐indenyl)zirconium dichloride ( 1 ) and a more sterically hindered counterpart rac‐dimethylsilylbis(2‐isopropyl‐4‐[3,5‐dimethylphenyl]indenyl) zirconium dichloride ( 2 ). For both catalyst systems, the most common termination mechanism was chain transfer to aluminium. In addition, for polymer samples polymerised with 1 /MAO, chain growth was terminated by chain transfer to Zr metal in propylene‐rich polymerisations and by chain transfer to ethylene monomer in ethylene‐rich polymerisations. The steric hindrance of 2 was able to suppress the chain transfer to the ethylene monomer, and chain transfer to Zr metal was also found in the ethylene‐rich polymerisations. The greater steric hindrance of 2 also affected the EP copolymer microstructure: regioregularity in the propylene‐rich copolymers was greater and isotacticity less with 2 /MAO than with 1 /MAO.

The catalyst precursors used: rac‐dimethylsilylbis(2‐methyl‐4‐phenyl‐1‐indenyl)zirconium dichloride ( 1 ) and rac‐dimethylsilylbis(2‐isopropyl‐4‐[3,5‐dimethylphenyl]indenyl) zirconium dichloride ( 2 ).     

Susceptibility to beta-lactam antibiotics and production of beta-lactamase inBacteroides fragilis

Using the agar dilution technique, 231 strains of Bacteroides fragilis, isolated during a 2-year period from human infections, were identified at subspecies level and were tested for susceptibility to 13 beta-lactam antibiotics. The penicillins were benzylpenicillin, ampicillin, carbenicillin, cloxacillin, and the recently described penicillin derivatives cyclacillin, ticarcillin, and PC-904. The following cephalosporin derivatives were tested: cephaloridine, cephalothin, cephalexin, cefamandole and cefuroxime. The cephamycin C derivative cefoxitin was also included in the study. Cefoxitin was the most effective drug tested since more than 80% of the strains were inhibited by 8 microgram/ml or less, and no strain had a minimal inhibitory concentration (MIC) of more than 64 microgram/ml. There was no marked difference in sensitivity among the subspecies with exception of subspecies vulgatus, which was slightly more sensitive to all antibiotics tested. The size of the inoculum was an important factor for obtaining reproducible results in the sensitivity tests. Increased inocula resulted in markedly higher MICs for cephaloridine and cefuroxime. Production of beta-lactamase was performed on all isolates by a chromogenic cephalosporin substrate and about 90% of the strains were found to be beta-lactamase producers.     

High frequency of Coxsackie-B-virus-specific IgM in children developing type I diabetes during a period of high diabetes morbidity

Twenty-four consecutive children with newly diagnosed insulin-dependent (type I) diabetes mellitus (IDDM) were investigated for a history of infectious disease. Thirteen of the 24 (54%) patients reported symptoms of acute infection within two months before diabetes was diagnosed. The mean age was 8.5 years and 15 (63%) of the patients were girls. No clear seasonal variation in onset was seen. Coxsackie B (CB)-virus-specific IgM responses were detected by reverse radioimmunoassay (RIA) in 16 of the 24 (67%) patients on the day of diagnosis of IDDM. The highest titre was usually recorded at that time, but with some the highest titre was found with a second serum obtained three to seven weeks after diagnosis. Thereafter the titres declined, and after six months IgM was detected only in a few patients. Thirteen patients displayed monotypic IgM responses, whereas three patients showed ditypic responses. Among the former, IgM was recorded against Coxsackie B4 (CB4) in four, B5 (CB5) in three, B1 (CB1) in two, B2 (CB2) in two, and B3 (CB3) in two patients. The ditypic responses were against CB2 and CB3, CB3 and CB4, and CB5. No CB-virus-specific IgM was detected in sera, found during the same period, from age-matched nondiabetic children without evidence of infection. In neutralisation (NT) tests, antibodies to the homotypic virus were found in 12 of the 16 diabetic patients showing CB-virus-specific at the time of diagnosis. A significant rise in NT titre was demonstrated in three of these patients. No significant clinical difference was noted between IgM positive and IgM negative patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy.

CONTEXT: Inflammatory activity is associated with high rates of long-term mortality in unstable coronary artery disease (CAD). Interleukin 6 (IL-6) induces C-reactive protein and fibrinogen, systemic markers of inflammation. OBJECTIVES: To determine whether plasma levels of IL-6 are predictive of mortality and to evaluate the interaction of IL-6 levels with the effects of invasive vs noninvasive treatment strategies in unstable CAD patients. DESIGN, SETTING, AND PATIENTS: The prospective, randomized Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease II trial, conducted among 3489 patients, 3269 of whom had plasma samples analyzed for IL-6 levels, with diagnosed unstable CAD (67% male; median age, 67 years) at 58 Scandinavian hospitals between June 1996 and August 1998. INTERVENTIONS: Patients were randomly assigned to receive either an early invasive (n = 1222) or a noninvasive treatment strategy (n = 1235). The latter group, as well as 666 patients with contraindications to invasive therapy, were further randomized to 90-day treatment with low-molecular-weight heparin (dalteparin, 5000-7500 IU twice per day; n = 1140) or placebo (n = 1127). MAIN OUTCOME MEASURE: Mortality at 6 and 12 months in the medically and interventionally randomized cohorts, respectively, in relation to IL-6 levels, measured at randomization. RESULTS: Plasma levels of IL-6 that were at least 5 ng/L compared with levels lower than 5 ng/L were associated with greatly increased mortality in the noninvasive group (7.9% vs 2.3%; relative risk [RR], 3.47; 95% confidence interval [CI], 1.94-6.21) and in the placebo-treated group (7.9% vs 2.5%; RR, 3.19; 95% CI, 1.77-5.74). The association remained significant after adjustment for most established risk indicators. An early invasive treatment strategy strongly reduced 12-month mortality among those with elevated IL-6 levels (5.1% absolute reduction; P =.004) whereas mortality was not reduced among patients without elevated IL-6 concentrations. Those taking dalteparin with elevated IL-6 levels experienced lower 6-month mortality than those who did not take dalteparin (3.5% absolute reduction; P =.08). CONCLUSIONS: Circulating IL-6 is a strong independent marker of increased mortality in unstable CAD and identifies patients who benefit most from a strategy of early invasive management.     

Extra- and Intracellular pH in the Brain During Ischaemia,Related to Tissue Lactate Content in Normo- and Hypercapnic rats

The objective of the present study was to assess the relationship between the amount of lactate accumulated during complete ischaemia and the ensuing changes in extra- and intracellular pH (pHe and pHi, respectively). The preischaemic plasma glucose concentration of anaesthetized rats was varied by administration of glucose or insulin, pHe was determined in neocortex with ion-sensitive microelectrodes, and tissue lactate and CO2 contents were measured, tissue CO2 tension being known from separate experiments. The experiments were carried out in both normocapnic [arterial CO2 tension (PaCO2) approximately 40 mm Hg] and hypercapnic (PaCO2 approximately 80 mm Hg) animals. Irrespective of the preischaemic CO2 tension, DeltapHe was linearly related to tissue lactate content. Depending on the preischaemic glucose concentration, DeltapHe varied from <0.4 to >1.4 units. The results thus fail to confirm previous results that the changes in pHe describe two plateau functions (DeltapHe approximately 0.5 and 1.1, respectively), with a transition zone at tissue lactate contents of 17 - 20 mmol kg-1. Changes in pHi given in this study are based on the assumption of a uniform intracellular space. The pHi changed from a normal value of approximately 7.0 to 6.5, 6.1 and 5.8 at tissue lactate contents of 10, 20 and 30 mmol kg-1. The intrinsic (non-bicarbonate) buffer capacity, derived from these figures, was 23 mmol kg-1 pH-1. Some differences in pH and in HCO3- concentration between extra- and intracellular fluids persisted in the ischaemic tissue. These differences were probably caused by a persisting membrane potential in the ischaemic cells.     

Method for Dissection of Mesenteric Metastases in Mid-gut Carcinoid Tumors

With adequate medical management the midgut carcinoid tumor generally is an indolent malignancy associated with substantial life expectancy and appreciable life quality, even in the presence of liver metastases and significant tumor burden. Abdominal complications may occur in this entity of carcinoids owing to entrapment of intestines and encasement of mesenteric vessels by mesenteric metastases and associated marked mesenteric fibrosis. This may be the cause of abdominal pain, disabling diarrhea, weight loss to the extent of malnutrition, and eventually the risk of death with acute or chronic intestinal obstruction or intestinal gangrene. Operative removal of the mesentericointestinal lesion is often indicated to prevent or treat these complications but may be technically difficult when mesenteric metastases extend in the vicinity of major vessels in the mesenteric root. At laparotomy 56 patients with advanced midgut carcinoids underwent removal of the mesenteric tumor with a method for preserving the mesenteric vessels. This was feasible by mobilizing and releasing the right colon and mesenteric root from posterior adhesions, identifying the mesenteric artery below the pancreas, and free-dissecting this artery on the tumor capsule in the mobilized mesentery. Dissection was successful even with tumors initially judged inoperable unless tumor growth completely surrounded the mesenteric vessels or extended retroperitoneally. One patient was subjected to distal intestinal artery bypass. Symptom relief was been substantial and often of long duration after mesenteric tumor removal in patients who prior to surgery often had threatening intestinal ischemia. Patients with advanced midgut carcinoids may benefit markedly from dissectional removal of mesenteric tumors, which (conceivably better than conventional wedge resection) preserves the length of the remaining intestine.