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.     

An indirect method for the estimation of osteoporotic fractures from injury and fracture profiles

Summary Study objective was to develop a valid epidemiological method for the estimation of osteoporotic fracture risk, using administrative databases and accounting for variable baseline risks of injury. Design is the secondary analysis of inpatient and outpatient utilization data. A baseline injury risk was estimated by the incidence of primary utilization of medical services for soft tissue injuries (ICD-9 diagnostic codes 910–929), and the risk profile was compared after normalization with the overall primary utilization rate for fractures (ICD-9 diagnostic codes 800–829). The setting is a county with approximately 100,000 inhabitants in the former East Germany. Participants were all inhabitants of the county who had a physician contact (inpatient or outpatient) during 1987–1988, as well as hospital inpatients for all of Germany in 1989. The number of fractures increased with age, especially in women, when compared to the number of fractures expected from the incidence of soft tissue injury. Similar patterns were identified in hospitalization data from East and West Germany. Estimating the prevalence of osteoporosis directly from certain osteoporotic fracture types associated with higher age is potentially biased, since it neglects the underlying risk of injury. Our model distinguished the osteoporotic fracture risk as the excess risk over an expected injury-related fracture risk for a given age and sex, and may allow a more valid quantification of osteoporotic fractures in different populations.

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Zusammenfassung Studienziel war die Entwicklung einer validen Methode zur Abschätzung des osteoporotischen Frakturrisikos unter Verwendung administrativer Daten und unter Berücksichtigung eines variablen Hintergrundrisikos für Unfälle. Studiendesign ist die sekundäre Analyse von Daten zur stationären und ambulanten Inanspruchnahme. Das Hintergrundrisiko für Unfälle wurde aus der Inzidenz der primären Inanspruchnahme der medizinischen Versorgung für Weichteilverletzungen (ICD-9 Kodierungen 910–929) geschätzt, und das Risikoprofil nach Normalisierung mit der allgemeinen primären Inanspruchnahme wegen Frakturen (ICD-9 Kodierungen 800–829) verglichen. Studienort war ein Landkreis mit etwa 100 000 Einwohnern in der ehemaligen DDR. Studienteilnehmer waren alle Einwohner des Kreises, welche 1987–1988 einen ambulanten oder stationären Arztkontakt hatten, sowie Krankenhausfälle in beiden deutschen Staaten im Jahr 1989. Die Anzahl der Knochenbrüche nahm mit dem Lebensalter zu, vor allem bei Frauen, verglichen mit der Anzahl, welche aus der Inzidenz der Weichteilverletzungen zu erwarten gewesen wäre. Ein ähnliches Muster war bei den Krankenhausfällen in Ost- und Westdeutschland zu beobachten. Die direkte Schätzung der Prävalenz der Osteoporose aus bestimmten osteoporotischen Frakturtypen, welche mit dem höheren Lebensalter verbunden sind, enthält potentiell einen systematischen Fehler, da ein Hintergrundrisiko für Unfälle vernachlässigt wird. Unser Modell identifiziert ein osteoporotisches Frakturrisiko als überschiessendes Risiko über ein nach Alter und Geschlecht zu erwartendes unfallbedingtes Frakturrisiko, und erlaubt potentiell eine validere Quantifizierung osteoporotischer Frakturen in verschiedenen Populationen.

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Résumé L'objective de la recherche était le développement d'une méthode valide pour l'estimation du risque d'une fracture ostéoporotique, utilisant données administratives et tenant compte des risques basales variables concernant les accidents. Le désigne de l'étude est l'analyse secondaire des données hospitalières et ambulatoires. Le risque basale des accidents fut estimé par l'incidence de l'utilisation première des services médicaux pour des blessures non-skeletals (ICD-9 codes 910–929) et cette risque fut comparé après normalisation avec la rate d'utilisation pour des fractures (ICD-9 codes 800–829). La recherche se concentrait sur un département de l'Allemagne de l'Est avec a peu près 100000 habitants. Les participants étaient tous les habitants du département qui avaient un contact avec un médecin (a l'hôpital ou ambulatoire) pendant les années 1987–1988, ainsi que tous les cas hospitalisés dans toute l'Allemagne en 1989. Le nombre de fractures augmentait avec l'âge, en particulier parmi les femmes, comparé avec le nombre attendu de l'incidence des blessures. Des profils de risque pareils ont pu être observés parmi les cas hospitalisés de l'Allemagne de l'Ouest et de l'Est. L'estimation directe de la prévalence de l'ostéoporose a la base de certains types «ostéoporotiques» des fractures, associés avec le troisième âge, peut être incorrecte, parce qu'il néglige le risque basale pour les accidents. Notre modèle distingue le risque ostéoporotique de fracture comme un risque plus haut que le risque de l'accident attendu pour un certain âge et gendre, et permet une quantification plus valide des fractures ostéoporotiques parmi des populations différentes.

     

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.     

Synthesis and biological activity of new HMG-CoA reductase inhibitors. 3. Lactones of 6-phenoxy-3,5-dihydroxyhexanoic acids.

A group of 43 optically active sodium carboxylates (11a-qq and the corresponding lactones 4 were prepared from respective phenols 8 according to Schemes I-III. Phenols 8 were synthesized from commercially available compounds according to Schemes IV-IX. A number of these HMG-CoA reductase inhibitors 11 exceeded mevinolin's activity in vitro (Tables II and III). Selected lactones 4 effectively inhibited hepatic "de novo" cholesterol synthesis in rats in vivo (Table IV). After po administration to rabbits, 4ff(11ff), 4hh, and notably 11jj reduced plasma cholesterol levels more potently than mevinolin (Table V). Whereas 4ff(11ff) displayed the slight superiority expected according to in vitro data, 4hh and 11jj were considerably more potent than expected. Each of these compounds had only moderate activity after po administration to dogs (Table VI). Compound di-11ii, a hybrid of the structural elements of probucol and HMG-CoA reductase inhibitors, after po administration to rats decreased serum lipoproteins and increased HDL/LDL ratio better than probucol (Table VII). HMG-CoA reductase inhibitor 11ll and phenolic building blocks 8, notably 8jj and 8kk, inhibited LDL oxidation in vitro (Table VIII). Chemical structure-activity relationships (Table IX) and the pharmacological profile of phenoxy-type inhibitors 11 diverged from those of known HMG-CoA reductase inhibitors.     

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.     

In vivo comparison of copper blood-pool agents: potential radiopharmaceuticals for use with copper-62

Two techniques for labeling of albumin with copper-67 (67Cu) and 62Cu were investigated; one using the native Cu(II) binding site of the protein and the other employing a bifunctional chelate, 6-bromoacetamidobenzyl-1,4,8,11-tetraazacyclotetradecane- N,N'N",N"'-tetraacetic acid (Br-benzyl-TETA or BAT), conjugated to the protein. Rat biodistribution experiments with 67Cu demonstrated retention of i.v. 67Cu-benzyl-TETA-albumin in the blood pool identical to co-injected 125I-albumin. By contrast, i.v. administration of either [67Cu]-Cu-acetate or [67Cu]-Cu-acetate pre-mixed with albumin results in relatively rapid clearance of blood-pool radioactivity as the tracer is excreted into the urine. The 62Cu-benzyl-TETA-albumin radiopharmaceutical was obtained in ca. 17% radiochemical yield (end of synthesis, without decay correction) following a procedure that can be completed in 15-18 min. In PET experiments with a baboon, myocardial blood volume images with 62Cu-benzyl-TETA-albumin were identical to those obtained with C15O. Use of the 62Cu-benzyl-TETA-albumin image for blood-pool subtraction of a 62Cu-PTSM myocardial perfusion image is illustrated. Copper-62-benzyl-TETA-HSA should be a useful, generator-produced radiotracer for the detection of the vascular pool at PET facilities without cyclotrons.     

Interleukin-2 and interferon-alpha2b as a daily alternating schedule in advanced renal cell cancer

Summary Interferon-alpha (IFN-) and interleukin-2 (Il-2) are effective as single agents in metastatic renal cell cancer (RCC) with response rates of 15–30%. Additionally, IFN- is assumed to act synergistically with Il-2 in the induction of lymphokine-activated killer cells. (LAK cells) in vitro. With the aims of increasing the response rate by combining both cytokines and of reducing side effects, we started a clinical trial with a daily alternating schedule of 10×10⁶ units/m² s.c. rIFN-_2b (Essex, Munich, FRG) and 3×10⁶ Cetus units/m² rIL-2 (EuroCetus, Frankfurt, FRG) in the form of 1 h infusions over a period of 14 days. Patients found to have progressive disease after two cycles of therapy were withdrawn from the study; patients with stable disease or better received two further cycles.Of the 27 patients included in the study, 22 (16 male, 6 female) are evaluable for response. In 1 patient with multiple pulmonary metastases complete remission was achieved, in 5 patients partial remission, and in 2 a minor response. The schedule was practicable; the main side effects were influenza-like symptoms, fatigue and hypotension. Some patients suffered from arthralgias and erythemas up to 3 weeks after finishing the therapy cycle. On the whole, the side effects seem to be less severe than those arising from schedules using continuous Il-2 infusions.This work was supported by Grant No. 01GA8802 of the Bundesministerium für Forschung und Technologie (BMFT)     

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.     

Interleukin-2- and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: a Prospectively Randomized Trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN).

PURPOSE: We conducted a prospectively randomized clinical trial to compare the efficacy of three outpatient therapy regimens in 341 patients with progressive metastatic renal cell carcinoma. PATIENTS AND METHODS: Patients were stratified according to known clinical predictors and were subsequently randomly assigned. Treatment arms were: arm A (n = 132), subcutaneous interferon alfa-2a (sc-IFN-alpha-2a), subcutaneous interleukin-2 (sc-IL-2), and intravenous (IV) fluorouracil; arm B (n = 146): arm A treatment combined with per oral 13-cis-retinoic acid; and arm C (n = 63), sc-IFN-alpha-2a and IV vinblastine. RESULTS: Treatment (according to the standard 8-week Hannover Atzpodien regimen) arms A, B, and C yielded objective response rates of 31%, 26%, and 20%, respectively. Arm B, but not arm A, showed a significantly improved progression-free survival (PFS) compared with arm C (P =.0248). Both arm A (median overall survival, 25 months; P =.0440) and arm B (median overall survival, 27 months; P =.0227) led to significantly improved overall survival (OS) compared with arm C (median OS, 16 months). All three sc-IFN-alpha-2a-based therapies were moderately or well tolerated. CONCLUSION: Our results established the safety and improved long-term therapeutic efficacy of sc-IL-2 plus sc-INF-alpha-2a-based outpatient immunochemotherapies, compared with sc-INF-alpha-2a/IV vinblastine.     

Coamplification of DDX1 correlates with an improved survival probability in children with MYCN-amplified human neuroblastoma.

PURPOSE: Amplification of the MYCN oncogene at chromosome 2p24-25 identifies an aggressive subtype of human neuroblastoma with a poor clinical outcome. Differences in amplicon structure and coamplification of genes telomeric and centromeric to the MYCN oncogene have previously been described. A relevant role of gene coamplification for neuroblastoma pathogenesis remains elusive. PATIENTS AND METHODS: We analyzed 98 primary neuroblastoma tumors with MYCN amplification for coamplification of seven additional genes at chromosome 2p24-25 (DDX1, NAG, NSE1, LPIN1, EST-AA581763, SMC6, and SDC1). Two semiquantitative multiplex polymerase chain reactions were used to obtain the amplification status of the target genes in relation to a reference gene on chromosome 2q (Inhibin-beta-b). Furthermore, mRNA expression pattern of coamplified genes in a subset of tumors was analyzed. RESULTS: Our results show that the frequency of gene coamplification on 2p24-25 in neuroblastoma is correlated directly to the physical distance to MYCN. Coamplification is correlated to an upregulated gene expression for DDX1 and NAG. Coamplification of the DDX1 gene within 400kb telomeric to MYCN identifies a subgroup of advanced stage neuroblastoma tumors with a more favorable outcome (P =.027, log-rank test). A high expression level of DDX1 is associated with a trend towards a better survival probability (P =.058, log-rank test). CONCLUSION: Our results indicate that DDX1 coamplification correlates with a better prognosis and improved patient survival in MYCN-amplified neurobastoma.