Use of limited color-flow duplex for a carotid screening project.

BACKGROUND: Although the efficacy of carotid endarterectomy for asymptomatic carotid stenosis has been established, no cost-effective approach for identification of these patients has yet been devised. The purpose of this study was to develop a limited carotid duplex screening examination to be utilized for the detection of asymptomatic carotid stenoses. METHODS: Carotid screening examinations employed rapid identification of the carotid bifurcation using color-flow duplex imaging and an immediate Doppler-derived velocity of the segment of the internal carotid artery with the most turbulent flow. Complete examinations were then finished using well-established protocols in our accredited vascular laboratory. A total of 512 patients were referred for complete studies based upon standard indications. Criteria for at least a 50% internal carotid artery stenosis on the complete examination was defined as a peak systolic velocity (PSV) of at least 125 cm/sec. Receiver operator characteristic (ROC) curves were then constructed to identify the optimal screening velocity criteria as compared with the final results on the complete examination. RESULTS: Five screening examinations were technically limited yielding a total of 507 patients with 1,014 carotid arteries available for analysis. Comparison of screening examinations versus complete examinations for a PSV of 125 cm/sec yielded sensitivity 86%, specificity 98%, positive predictive value (PPV) 95%, and a negative predictive value (NPV) 93%. ROC analysis identified a "cut point" of 115 cm/sec on the screening examinations to achieve sensitivity 91%, specificity 95%, PPV 89%, and NPV 96%. Time to perform screening examinations averaged 3.2 minutes per patient. Three patients had common carotid lesions not identified on the limited internal carotid screening examinations. CONCLUSIONS: Screening carotid examinations are a rapid, reliable, and relatively inexpensive method for detection of patients with asymptomatic internal carotid artery stenosis. Limited screening examinations should be developed in each vascular laboratory and utilized in high-risk patients.     

Recombinant Human Erythropoietin and Hemoglobin Concentration at Operation and during the Postoperative Period: Reduced Need for Blood Transfusions in Patients Undergoing Colorectal Surgery—Prospective Double-blind Placebo-controlled Study

p < 0.05). On postoperative days 3 and 7 the values were 7.2 (5.3–8.2) and 7.5 (5.4–9.4) mmol/L, respectively, in the erythropoietin group compared to 6.7 (5.2–7.8) and 6.9 (5.1–8.6) mmol/L in the placebo group ( p < 0.01). At discharge the hemoglobin concentration was 7.8 (5.9–8.8) mmol/L in the erythropoietin group and 7.2 (5.4–8.6) mmol/L in the placebo group ( p < 0.002). The blood loss during operation was similar in the two groups. In the erythropoietin group the median value was 280 ml (range 25–2000 ml), with the lower and upper quartiles 150 and 500 ml, respectively. In the placebo group the blood loss was median 300 ml (range 50–1800 ml), with the lower and upper quartiles 200 and 750 ml, respectively. The number of blood transfusions given was significantly lower in the erythropoietin group, with a mean of 0.3 (range 0–6) units compared to 1.6 (0–9) units in the control group ( p < 0.05). In conclusion, the hemoglobin concentration at the time of surgery and during the week following surgery was significantly higher in the group of patients receiving r-HuEPO perioperatively compared to the placebo group together with a significant lower use of blood transfusions in the r-HuEPO group. However, the clinical implications of these findings has yet to be proven.RID=" ID=" <E5>Correspondence to:</E5> N. Qvist, M.D., D.Sci.     

Biological monitoring of isocyanates and related amines

Summary Five men were exposed to toluene diisocyanate (TDI) atmospheres for 7.5 h. The TDI atmospheres were generated by a gas-phase permeation method, and the exposures were performed in an 8-m3 stainless-steel test chamber. The mean air concentration of TDI was ca. 40 g/m³, which corresponds to the threshold limit value (TLV) of Sweden. The inhaled doses of 2,4- and 2,6-TDI were ca. 120 g. TDI in the test chamber air was determined by an HPLC method using the 9-(N-methyl-aminomethyl)-anthracene reagent and by a continuous-monitoring filter-tape instrument. After hydrolysis of plasma and urine, the related amines, 2,4- and 2,6-toluenediamine 2,4-, and 2,6-TDA), were determined as pentafluoropropionic anhydride (PFPA) derivatives by capillary gas-chromatography using selected ion monitoring (SIM) in the electron-impact mode. The urinary elimination of the TDAs showed a possible biphasic pattern, with rapid first phases for 2,4-TDA (mean t _1/2 for the concentration in urine, 1.9 h) and for 2,6-TDA (mean t _1/2 for the concentration in urine, 1.6 h). The cumulative amount of 2,4-TDA excreted in urine within 28 h ranged from 8% to 14% of the estimated dose of 2,4-TDI, and the cumulative amount of 2,6-TDA in urine ranged from 14% to 18% of the 2,6-TDI dose. The average urinary level of 2,4-TDA was 5 g/l in the 6 to 8-h sample (range 2.8–9.6 g/l), and the corresponding value for 2,6-TDA was 8.6 g/l (range, 5.6–16.6 g/l). Biological monitoring of exposure to 2,4- and 2,6-TDI by analysis of 2,4- and 2,6-TDA in urine is feasible.     

Biological monitoring of isocyanates and related amines

Summary Two men were exposed to toluene diisocyanate (TDI) atmospheres at three different air concentrations (ca. 25, 50 and 70g/m³) . The TDI atmospheres were generated by a gas-phase permeation method, and the exposures were performed in an 8-m³ stainless-steel test chamber. The effective exposure period was 4h. The isomeric composition of the air in the test chamber was 30% 2,4-TDI and 70% 2,6-TDI. The concentration of TDI in air of the test chamber was determined by an HPLC method using the 9-(N-methyl-amino-methyl)-anthracene reagent and by a continuous-monitoring filter-tape instrument. Following the hydrolysis of plasma and urine, the related amines, 2,4-toluenediamine (2,4-TDA) and 2,6-toluenediamine (2,6-TDA), were determined as pentafluoropropionic anhydride (PFPA) derivatives by capillary gas chromatography using selected ion monitoring (SIM) in the electron-impact mode. In plasma, 2,4- and 2,6-TDA showed a rapid-phase elimination half-time of ca. 2–5 h, and that for the slow phase was > 6 days. A connection was observed between concentrations of 2,4- and 2,6-TDI in air and the levels of 2,4- and 2,6-TDA in plasma. The cumulated amount of 2,4-TDA excreted in the urine over 24 h was ca. 15%–19% of the estimated inhaled dose of 2,4-TDI, and that of 2,6-TDA was ca. 17%–23% of the inhaled dose of 2,6-TDI. A connection was found between the cumulated (24-h) urinary excretion of 2,4- and 2,6-TDA and the air concentration of 2,4- and 2,6-TDI in the test chamber. A connection was also observed between the rate of urinary excretion of 2,4- and 2,6-TDA over the last 2h of exposure and the air concentration of 2,4- and 2,6-TDI in the test chamber. Biological monitoring of exposure to monomeric 2,4- and 2,6-TDI by the analysis of 2,4- and 2,6-TDA in biological media is feasible. A method based on 24-h urine sampling and determination levels of 2,4- and 2,6-TDA in hydrolysed urine is recommended. However, exposure to TDI is often associated with aerosols containing polymeric TDI, and we do not know whether analysis of TDA in urine can also be used as a marker of exposure to TDI prepolymers.     

Multiple-dose pharmacokinetics of epirubicin at four different dose levels: studies in patients with metastatic breast cancer

Summary Pharmacokinetic analysis of epirubicin and its metabolites epirubicinol and 7-deoxy-13-dihydro-epirubicinol aglycone during the first and the fourth courses of treatment was performed in 78 patients with metastatic breast cancer. The patients were treated every 3 weeks with epirubicin given as 10-min i.v. infusions at four different dose levels: 40, 60, 90 and 135 mg/m². In most cases (76 of 78 cases), plasma concentration-time curves fitted to a three-compartmental pharmacokinetic model. The terminal half-life of epirubicin was independent of dose and duration of treatment. Large interindividual differences were demonstrated (meant _1/2, 21.6±7.9 h; range, 10.6–69 h;n=110). In two subjects, extremely long half-lives and high serum bilirubin concentrations indicated impaired liver function. No correlation was found between the half-life and levels of liver alanine aminotransferase (ALAT) or serum creatinine. The metabolite epirubicinol appeared quickly after epirubicin administration and its half-lives were shorter than that of the parent compound (meant _1/2, 18.1±4.8 h; range, 8.2–38.4 h;n=105).Formation of the aglycone metabolite was delayed and the half-life of this metabolite was shorter than that of epirubicin (meant _1/2, 13±4.6 h; range, 2.7–29 h;n=104). The AUC of epirubicin and the total AUC (drug and metabolites) were linearly proportional to the dose, with the former value constituting two-thirds of the latter. A correlation was found between AUC and the plasma concentration of epirubicin at two time points (2 and 24 h after administration). The proposed model was AUC=9.44×c ₂+62.5×c ₂₄+157.7 (r=0.953).This work was supported by the Lundbeck Foundation, the Michaelsen Foundation and Farmitalia Carlo Erba Ltd.     

Multivariate Analysis of Risk Factors for Postoperative Complications in Benign Goiter Surgery: Prospective Multicenter Study in Germany

Risk factors for postoperative complications of benign goiter surgery have not been investigated systematically. To this end, a prospective multicenter study (January 1 through December 31, 1998) was conducted involving 7266 patients with surgery for benign goiter from 45 East German hospitals. High-volume providers (>150 operations per year) performed 69% (5042/7266), intermediate-volume providers 27% (50–150), and low-volume providers 4% (258/7266) of operations. Among the hospital groups, the pattern of thyroid disease did not vary significantly, but there was a trend that small-volume providers tended to perform more operations for uninodular goiter and high-volume providers treated more patients with Graves' disease and recurrent goiter. Extent of resection (p < 0.0001) and remnant size (multinodular goiter and recurrent goiter, p < 0.001), differed significantly, with total thyroidectomy being performed more often in hospitals with more than 150 operations compared to hospitals with an operative volume of less than 150 procedures per year. Despite the larger extent of resection and smaller remnant size, rates of recurrent laryngeal nerve (RLN) palsy or hypoparathyroidism were not increased. When the logistic regression analyses were fitted to evaluate the impact of risk factors on transient and permanent RLN palsy and hypoparathyroidism, larger extent of resection [relative risk (RR) 1.5–2.1] and recurrent goiter (RR 1.8–3.4) consistently evolved as independent risk factors. With hypoparathyroidism, additional significant factors included patient gender (RR 2.1–2.4), hospital operative volume (RR 0.8–1.5), and Graves' disease (RR 2.8). Unlike parathyroid gland identification during hypoparathyroidism, RLN identification (RR 1.6) significantly (p= 0.01) reduced permanent RLN palsy rates. The multivariate analyses clearly confirmed the pivotal role of routine RLN identification, independent of the extent of the thyroid resection. These findings might help hospitals with lower operative volumes to identify patients at increased risk whom they might consider for specialist care.     

Expression of the ELAV-like protein HuR is associated with higher tumor grade and increased cyclooxygenase-2 expression in human breast carcinoma.

PURPOSE: The human ELAV (embryonic lethal abnormal vision)-like protein HuR stabilizes a certain group of cellular mRNAs that contain AU-rich elements in their 3'-untranslated region. Cell culture studies have shown that the mRNA of cyclooxygenase (COX)-2 can be stabilized by HuR. EXPERIMENTAL DESIGN: To investigate a possible contribution of dysregulation of mRNA stability to the progression of cancer and to overexpression of COX-2, we studied expression of HuR in 208 primary breast carcinomas by immunohistochemistry. RESULTS: There were two different staining patterns of HuR in tumor tissue of breast carcinomas: nuclear expression was seen in 61% of cases; and an additional cytoplasmic expression was seen in 30% of cases. Expression of HuR was significantly associated with increased COX-2 expression; this association was particularly significant for cytoplasmic HuR expression (P < 0.0005). We further observed a significant association of cytoplasmic (P = 0.002) or nuclear HuR (P = 0.027) expression with increased tumor grade. Only 13% of the grade 1 carcinomas showed cytoplasmic expression of HuR, compared with 46% of the grade 3 carcinomas. There was no significant correlation between HuR expression and other clinicopathological parameters such as histological type, tumor size, or nodal status as well as patient survival. CONCLUSIONS: Our results suggest that overexpression of HuR in tumor tissue may be part of a regulatory pathway that controls the mRNA stability of several important targets in tumor biology, such as COX-2. Based on our results, additional studies are necessary to investigate whether HuR might be a potential target for molecular tumor therapy.     

High prognostic value of p16INK4 alterations in gastrointestinal stromal tumors.

PURPOSE: Gastrointestinal stromal tumors (GISTs) represent a distinctive (but histologically heterogeneous) group of neoplasms, the malignant potential of which is often uncertain. To determine the prognostic relevance of p16INK4 alterations in GISTs, we investigated a larger group of GISTs and correlated the genetic findings with clinicopathological factors and patient survival. MATERIAL AND METHODS: We evaluated the methylation status of the promotor by methylation-specific polymerase chain reaction (PCR), the presence of mutations by PCR-SSCP-sequencing, the loss of heterozygosity at the p16INK4 locus (using the c5.1 marker), and the immunohistochemical expression of p16INK4 protein in 43 GISTs in 39 patients. RESULTS: p16INK4 alterations were found in 25 of 43 GISTs (58.1%), with benign, borderline, or malignant GISTs showing no differences in the type and frequency of alteration. p16INK4 alterations were correlated with a loss of p16INK4 protein expression (P <.01). Patients who had tumors with p16INK4 alterations had a poorer prognosis than patients with tumors without such alterations (P =.02). There was a high predictive value for p16INK4 alterations only in the group of benign and borderline GISTs (P <.01) with regard to clinical outcome. Univariate Cox's proportional hazard regression analysis revealed a strong correlation between p16INK4 alterations, tumor size, mitotic index, and overall survival (P <.02), whereas multivariate Cox's analysis confirmed only p16INK4 alterations as an independent prognostic factor. CONCLUSION: We believe that the evaluation of p16INK4 alteration status is a helpful prognosticator, particularly in the benign and borderline groups of GISTs.     

Molecular determinants of treatment response in human germ cell tumors.

PURPOSE: Germ cell tumors (GCTs) are highly sensitive to cisplatin-based chemotherapy. This feature is unexplained, as is the intrinsic chemotherapy resistance of mature teratomas and the resistant phenotype of a minority of refractory GCTs. Various cellular pathways may influence the efficacy of chemotherapy. Their impact has not been investigated in a comprehensive study of tumor samples from clinically defined subgroups of GCT patients. EXPERIMENTAL DESIGN: We investigated proteins involved in regulation of apoptosis (p53, BAX, BCL-2, and BCL-X(L)), cell cycle control [p21 and retinoblastoma protein (RB)], and drug export and inactivation [P-glycoprotein, multidrug resistance-associated protein (MRP) 1, MRP2, breast cancer resistance protein, lung resistance protein, metallothionein, and glutathione S-transferase pi] immunohistochemically in samples of unselected GCT patients (n = 20), patients with advanced metastatic disease in continuous remission after first-line chemotherapy (n = 12), and chemotherapy-refractory patients (n = 24). Mature teratoma components (n = 10) within tumor samples from all groups were analyzed separately. The apoptotic index was studied by terminal deoxynucleotidyl transferase-mediated nick end labeling assay. RESULTS: Invasive GCTs of all groups showed a correlation between wild-type p53 and apoptotic index (r(s) = 0.66; P < 0.001). The levels of the antiapoptotic proteins BCL-2 and BCL-X(L) were generally low. p21 was hardly detectable and did not correlate with p53 (r(s) = 0.29; P = 0.07). No significant differences among the three patient groups were identified regarding any of the investigated parameters (all Ps were >0.08), even though only individual samples from chemotherapy-resistant cases showed a strong staining for MRP2 and GSTpi. In contrast to other components, mature teratomas showed an intense p21 and RB staining and were mostly positive for MRP2, lung resistance protein, and GSTpi. CONCLUSIONS: Our results indicate a multifactorial basis for the chemosensitivity of GCTs with lack of transporters for cisplatin, of antiapoptotic BCL-2 family members, of p21 induction by p53, and of RB and an intact apoptotic cascade downstream of p53. These findings suggest a preference for apoptosis over cell cycle arrest after up-regulation of p53. None of the examined parameters offers a general explanation for the chemotherapy-resistant phenotype of refractory tumors. The up-regulation of various factors interfering with chemotherapy efficacy and ability for a p21-induced cell cycle arrest may explain the intrinsic chemotherapy resistance of mature teratomas.     

Increased fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) uptake in childhood CNS tumors is correlated with malignancy grade: a study with FDG positron emission tomography/magnetic resonance imaging coregistration and image fusion.

PURPOSE Positron emission tomography (PET) has been used in grading of CNS tumors in adults, whereas studies of children have been limited. PATIENTS AND METHODS Nineteen boys and 19 girls (median age, 8 years) with primary CNS tumors were studied prospectively by fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) PET with (n = 16) or without (n = 22) H(2)(15)O-PET before therapy. Image processing included coregistration to magnetic resonance imaging (MRI) in all patients. The FDG uptake in tumors was semiquantitatively calculated by a region-of-interest-based tumor hotspot/brain index. Eight tumors without histologic confirmation were classified as WHO grade 1 based on location, MRI, and clinical course (22 to 42 months). Results Four grade 4 tumors had a mean index of 4.27 +/- 0.5, four grade 3 tumors had a mean index of 2.47 +/- 1.07, 10 grade 2 tumors had a mean index of 1.34 +/- 0.73, and eight of 12 grade 1 tumors had a mean index of -0.31 +/- 0.59. Eight patients with no histologic confirmation had a mean index of 1.04. For these 34 tumors, FDG uptake was positively correlated with malignancy grading (n = 34; r = 0.72; P < .01), as for the 26 histologically classified tumors (n = 26; r = 0.89; P < .01). The choroid plexus papilloma (n = 1) and the pilocytic astrocytomas (n = 3) had a mean index of 3.26 (n = 38; r = 0.57; P < .01). H(2)(15)O-uptake showed no correlation with malignancy. Digitally performed PET/MRI coregistration increased information on tumor characterization in 90% of cases. CONCLUSION FDG PET of the brain with MRI coregistration can be used to obtain a more specific diagnosis with respect to malignancy grading. Improved PET/MRI imaging of the benign hypermetabolic tumors is needed to optimize clinical use.