REFINE: a randomized trial comparing cyclosporine A and tacrolimus on fibrosis after liver transplantation for hepatitis C.

REFINE was a 12-month, prospective, open-label study in 356 patients receiving de novo liver transplantation for hepatitis C virus (HCV) cirrhosis, randomized to cyclosporine A (CsA) or tacrolimus with (i) no steroids, IL-2 receptor antibody induction and mycophenolic acid, or (ii) slow steroid tapering. The primary analysis population based on availability of liver biopsies comprised 165 patients (88 CsA, 77 tacrolimus). There was no difference in the primary endpoint, fibrosis stage ≥2 at 12 months, which occurred in 63/88 CsA-treated patients (71.6%) and 52/77 tacrolimus-treated patients (67.5%) (odds ratio [OR] 1.11; 95% CI 0.56, 2.21; p = 0.759). Similarly, no significant between-group difference occurred at month 24 (OR 1.15; 95% CI 0.47, 2.80; p = 0.767). Among steroid-free patients, fibrosis score ≥2 was significantly less frequent with CsA versus tacrolimus at month 12 (7/37 [18.9%] vs. 16/38 [42.1%]; p = 0.029). HCV viral load was similar in both the tacrolimus- and CsA-treated cohorts. Mean blood glucose was significantly higher with tacrolimus from day 15 onward. Biopsy-proven acute rejection, graft loss and death were similar. These results showed no differences in posttransplant HCV-induced liver fibrosis between patients treated with CsA or tacrolimus in steroid-containing regimens, whereas CsA in steroid-free protocols was associated with reduced severity of fibrosis progression at 1 year posttransplant.

Polyomavirus BK replication in de novo kidney transplant patients receiving tacrolimus or cyclosporine: a prospective, randomized, multicenter study.

Polyomavirus BK (BKV)-associated nephropathy causes premature kidney transplant (KT) failure. BKV viruria and viremia are biomarkers of disease progression, but associated risk factors are controversial. A total of 682 KT patients receiving basiliximab, mycophenolic acid (MPA), corticosteroids were randomized 1:1 to cyclosporine (CsA) or tacrolimus (Tac). Risk factors were analyzed in 629 (92.2%) patients having at least 2 BKV measurements until month 12 posttransplant. Univariate analysis associated CsA-MPA with lower rates of viremia than Tac-MPA at month 6 (10.6% vs. 16.3%, p = 0.048) and 12 (4.8% vs. 12.1%, p = 0.004) and lower plasma BKV loads at month 12 (3.9 vs. 5.1 log(10) copies/mL; p = 0.028). In multivariate models, CsA-MPA remained associated with less viremia than Tac-MPA at month 6 (OR 0.60; 95% CI 0.36-0.99) and month 12 (OR 0.33; 95% CI 0.16-0.68). Viremia at month 6 was also independently associated with higher steroid exposure until month 3 (OR 1.19 per 1 g), and with male gender (OR 2.49) and recipient age (OR 1.14 per 10 years) at month 12. The data suggest a dynamic risk factor evolution of BKV viremia consisting of higher corticosteroids until month 3, Tac-MPA compared to CsA-MPA at month 6 and Tac-MPA, older age, male gender at month 12 posttransplant.

Efficacy and safety of enteric-coated mycophenolate sodium in combination with two glucocorticoid regimens for the treatment of active lupus nephritis.

Mycophenolic acid, in combination with glucocorticoids, has been shown in a series of trials to be safe and effective for treatment of lupus nephritis. Regimens that permit glucocorticoid dose reduction without loss of efficacy would be advantageous. MyLupus was a 24-week, multicentre, open-label, study in patients with active proliferative lupus nephritis treated with enteric-coated mycophenolate sodium (EC-MPS), randomized to standard-dose (n = 42) or reduced-dose (n = 39) glucocorticoids. Complete response at week 24, the primary endpoint, was achieved in 19.8% (16/81) of patients (19.0% standard-dose, 20.5% reduced-dose; lower limit of 97.5% CI for the difference -15.9%, p = 0.098, i.e. non-inferiority was not shown). Partial response occurred in 42.0% of patients (34/81). From baseline to week 24, the mean global British Isles Lupus Assessment Group (BILAG) score decreased from 14.0 ± 5.4 to 5.0 ± 3.8 (p < 0.001). The incidence of adverse events was 80.2% (65/81), most frequently gastrointestinal complications (31/81, 38.3%). Infections were reported in 57.1% and 35.9% of standard- and reduced-dose glucocorticoid patients, respectively (p = 0.056), with herpes zoster in 16.7% and 0% (p = 0.012). Three patients discontinued study medication due to adverse events. This exploratory study suggests that EC-MPS may facilitate glucocorticoid reduction without loss of efficacy in patients with active lupus nephritis, but results require confirmation in a controlled, longer-term study versus the current standard of care.

Analgesic effect of the somatostatin analogue octreotide in two acromegalic patients: a double-blind study with long-term follow-up.

Two acromegalic patients with severe headache were treated with the somatostatin analogue, octreotide (Sandostatin). A double-blind study of octreotide versus placebo in which pain intensity was measured using a visual analogue scale (VAS) was performed initially with these patients. A rapid (within 4-15 min) pain relief occurred lasting 2-8.5 h after injection of 100 micrograms of octreotide, an effect that was not reversed by intravenous (i.v.) naloxone. These 2 acromegalic patients then received treatment for 71 and 82 months, respectively, with doses starting at 500 micrograms/day and 1500 micrograms/day, respectively, without evidence of either tolerance or dependence, although the effect of octreotide on headache appears to be selective. No unwanted sedative effect has been observed. A screening procedure with injection of 50 micrograms of subcutaneous (s.c.) octreotide was performed in 11 other patients with chronic severe pain associated with various conditions. Only 3 patients (2 with diabetic polyneuropathy and 1 with bone pain associated with myelodysplastic syndrome) reported more than 50% pain relief. In the insulin-dependent diabetic patients the double-blind check was not performed due to the risk of octreotide-induced hypoglycemia. In the patient with bone pain the same double-blind check as in the acromegalic patients could not confirm the analgesic effect. It may thus be concluded that octreotide appears to be useful for the treatment of both chronic and acute severe painful conditions in acromegalic patients. However, since its analgesic effect in our patients was confined to headaches only, further controlled studies must be carried out in order to determine appropriate target groups.

A randomized, double-blind trial of basiliximab immunoprophylaxis plus triple therapy in kidney transplant recipients.

BACKGROUND: A double-blind, placebo-controlled, randomized study was performed to assess whether immunoprophylaxis with basiliximab (Simulect) could reduce the incidence of acute rejection in kidney transplant recipients treated with cyclosporine (Neoral), steroids, and azathioprine. METHODS: Three hundred forty patients received either placebo or basiliximab at a dose of 20 mg, given intravenously on days 0 and 4. All patients received cyclosporine, steroids, and azathioprine. The primary endpoint was the incidence of acute rejection at 6 months. Secondary endpoints included the safety and tolerability of basiliximab and placebo, 1-year patient and graft survival, and significant medical events up to 12 months. RESULTS: During the first 6 months posttransplantation, acute rejection occurred in 20.8% of patients given basiliximab versus 34.9% of patients administered placebo (P=0.005). Similarly, there was a reduction in biopsy-proven acute rejection at 6 months in the patients receiving basiliximab (P=0.023). One-year patient survival was 97.6% with basiliximab and 97.1% with placebo, graft survival was 91.5% versus 88.4%, respectively (NS). The adverse-events profile of patients treated with basiliximab was indistinguishable from that of patients treated with placebo. The number of patients with infections was similar (65.5% for basiliximab vs. 65.7% for placebo), including cytomegalovirus infections (17.3% vs. 14.5%, P=0.245). Nine neoplasms (three in the basiliximab group, six in the placebo arm) were recorded up to 1 year from transplantation. CONCLUSIONS: Basiliximab in combination with cyclosporine, steroids, and azathioprine triple therapy was highly effective in reducing the incidence of acute renal allograft rejection without increasing the incidence of infections and other side effects.

Effects of long-term ergoloid mesylates ('Hydergine') administration in healthy pensioners: 5-year results.

Five-year results are reported of a controlled long-term comparative study to assess the effects of ergoloid mesylates (1.5 mg 3-times daily) and placebo on medical, psychological and electrophysiological variables. Initially, 148 healthy elderly volunteers of both sexes were included. Eighty-nine subjects (48 on ergoloid mesylates and 41 on placebo) are still in the double-blind study; 39 subjects have left the trial for various reasons (6 deaths, 25 drop-outs due to disease, and 8 withdrawals) and 20 subjects are participating under 'open' conditions. Formal statistical comparison of the two groups in terms of 10 medical and psychometric outcome variables did not produce significant differences. However, a number of relevant findings and trends with regard to the effects of ergoloid mesylates were established: the drug was well tolerated objectively and subjectively; subjective complaints such as frequent dizziness, cardiac symptoms and leg cramps were improved; there was less increase than on placebo in the number of subjects with pathological ECG findings; there was less increase than on placebo in the number of subjects taking digitalis; fewer subjects than in the placebo group had an increase in the number of major diagnoses; the decrease in some lipid fractions was more pronounced than on placebo; and performance in some psychometric tests (WAIS Vocabulary, WAIS Performance) was better in the ergoloid mesylates group. None of these findings, by itself, would be evidence of a dramatic effect of ergoloid mesylates on the participants in the double-blind trial. Taken together, however, they fall into a pattern, suggesting that ergoloid mesylates was partly effective in maintaining physical and mental health in these healthy elderly individuals. The finding of more disease-related and symptom-related drop-outs in the placebo group (25 vs. 20 in the ergoloid mesylates group) supports this assumption. Furthermore, the fact that a number of subjects who had left the double-blind trial for medical reasons improved on subsequent ergoloid mesylates administration may be seen as a further argument in favour of a prophylactic effect of ergoloid mesylates on pathological concomitants of ageing.

Factors influencing renal function after liver transplantation. Results from the MOST, an international observational study.

INTRODUCTION: Renal failure, both acute and chronic, is a common complication after liver transplantation and can seriously jeopardise long-term outcome. Given organ shortage it should be essential to determine which patients will experience progressive and severe renal dysfunction after liver transplantation (LT). AIM: To correlate pre-transplant renal function and risk factors for renal failure after liver transplantation with occurrence of renal failure at 1 and 5 years after LT, with particular attention to hepatitis C virus (HCV) infection. METHODS: Data from patients enrolled in the liver section of Neoral MOST (Multinational Observational Study in Transplantation) study were used for the analysis. HCV status, pre-transplant serum creatinine level, recipient gender, recipient age, pre-transplant arterial hypertension, pre-transplant diabetes mellitus, pre-transplant antiviral therapy, the time of the transplant (before or after 2000) and immunosuppressive regimen were collected for each patient. Post-transplant occurrence of renal failure at 1 and 5 years was defined as a GFR<60 mL/min/1.73 m(2) (Stage III of the National Kidney Foundation). RESULTS: Data from 1948 patients enrolled in the study were considered. Glomerular filtration rate (GFR) was evaluated in 406 patients at 1 year and in 233 patients at 5 years after LT. The prevalence of HCV infection was 35% in the former and 37% in the latter. The median GFR was 70 mL/min/1.73 m(2) after 1 year and 69 mL/min after 5 years, significantly lower in HCV-positive (HCV+) than in HCV-negative (HCV-) patients both 1 and 5 years after LT (p<0.001). GFR before transplant correlated with GFR at 1 month, 1 and 3 years (p<0.0001 for all correlations). Multivariate analysis confirmed HCV status, pre-LT serum creatinine levels and recipient gender as significant predictors of 1-year GFR (p<0.001 for all three). Further analysis of the effect of recipient gender indicated that the only significant risk factor observed in both male and female patients was HCV positivity. Only 1-year GFR was an independent predictor of 5-year GFR (p<0.001). HCV+ status, cyclosporine (CsA) exposure, antiviral therapy and diabetes mellitus had no significant influence on 5-year GFR. CONCLUSIONS: HCV status and pre-LT serum creatinine levels were independent predictors of renal function a year after LT, together with GFR before transplant. The negative impact of HCV positivity on renal function was not confirmed in the long term, whereas the prognostic influence of an abnormal renal function in the early post-transplant period was more persistent.

[Normal values for Lactate- and Glutamate dehydrogenate by new optimized methods (author's transl)]. / Normalwerte für Lactat- und Glutamatdehydrogenase, sowie Leucinarylamidase, erstellt mit optimierten Standardansätzen

The activities of the enzymes LDH (Lactatdehydrogenase), HBDH (Hydroxybutyratdehydrogenase), and GIDH (Glutamate dehydrogenase), as well as LAP (Leucine aryl peptidase) were measured in the serum of 934 children in order to get normal values of these enzyme activities in dependence on the age. We used again the optimized methods (Boehringer und Merck). The form of the distribution of the single values of these 4 enzymes can be described by a lognormal distribution. This applies not to newborns and young sucklings. All measured enzyme activities were depended on the age of the children; newborn and sucklings had significantly higher enzyme activities than infants. After the second year of life the enzyme activities for LDH, HBDH, GlDH and LAP remained constantly. The physiological variations are very high in the newborns. The diagnostic selectivity of the enzyme GIDH is very good, this of LDH and HBDH turned out unspecifically. No difference could be supplied for the sex of the children.

Relationship between diseases of the pancreas and hyperplasia of Brunner's glands.

Examination of 105 duodeno-pancreatectomy specimens showed that 75% of the cases of chronic pancreatitis (n = 74) manifested diffuse hyperplasia of Brunner's glands. In pancreatitis involving part of the pancreas in the presence of ducts of the embryonic type (n = 6), in segmental pancreatitis (n = 16), and in pancreatic cancer (n = 23), no significant difference in the thickness of the layer of Brunner's glands was found as compared with normal specimens. There was no statistically significant correlation between the degree of hyperplasia of Brunner's glands and the degree of scarring of the exocrine pancreatic parenchyma. Nor was there any correlation between existence and extent of scarring of the duodenal wall, inflammatory infiltration of the duodenal mucosa, duration of disease, consumption of alcohol and history of gall stones and ulcers in patients with and without hyperplasia of Brunner's glands. Diffuse hyperplasia of the duodenal glands is probably an adaptive reaction to the exocrine insufficiency of the pancreas or the changes in gastric function (hyperacidity, accelerated emptying of the stomach) caused by chronic pancreatitis. A fact which supports this statement is that the inhibitor hormone urogastrone--an inhibitor of gastric acid secretion--is formed in Brunner's glands. The question is also discussed whether chronic pancreatitis and hyperplasia of Brunner's glands might not also develop simultaneously in the presence of disturbances of the gastrointestinal hormones, themselves either primary or due to alcohol consumption.

[Muscle bridges over the left anterior descending coronary artery: their influence on arterial disease (author's transl)]. / Die koronare Muskelbrücke des Ramus descendens anterior.

A total of 711 hearts was studied and examined for coronary muscle bridges of the left anterior descending (LAD) macroscopically, angiographically and histologically. A muscular overbridging of the LAD was found in 22.9% of all hearts. The average distance from left artery bifurcation was 33.6 mm, the average length was 22.5 mm and the average thickness 2.8 mm. A thin layer of fat tissue is mostly to be found between the overbridged coronary artery and the myocardial bridge. The patient group with and without myocardial overbridging showed no difference in sex or age nor in average stature and the average heart weight. Statistically, there is significantly more atherosclerosis of the coronary artery proximal to the muscle bridge than there is under and distal to the bridge. A difference in frequency and extent of atherosclerosis in hearts with and without coronary muscle bridge could not be shown for this portion of the LAD. Nevertheless, there is a tendency for fewer anterior-wall infarctions in the patient group with a coronary muscle bridge of the LAD, because, when the whole branch is considered, there is a significantly lower incidence of atherosclerosis in hearts with myocardial overbridging of the LAD. The reason for the protective effect of a coronary muscle bridge is yet not clear.

Prognostic significance of the steroid receptor content in primary breast cancer.

Recurrence and survival rates were studied in 222 patients with primary breast cancer with particular reference to relations with the estrogen and progesterone receptor content of the primary tumor, involvement of axillary lymph nodes and menopausal status. The median observation time for these 222 women was 46 months, the longest being 88 months and the shortest for recurrence-free survivors, being 42 months. Within the first 4 years after primary surgery, recurrences occurred more rarely and later in patients with receptor-positive cancers. After 70 and 50 months, respectively, there was no longer any difference between estrogen receptor- and progesterone receptor-positive and receptor-negative cases. The overall survival curve plotted in accordance with Kaplan and Meier [5] was more favourable for patients with estrogen receptor-positive carcinoma than for those with estrogen receptor-negative tumors, even after 6.5 years.

[Prolactin in serum and anamnestic data of women with cystic disease of the breast (author's transl)]. / Serum-Prolaktin und Anamnesevergleich bei Mammazysten und zystischer Mastopathie.

78 women with cysts of the mammary gland--proved by aspiration of cystic fluid--had significantly more hyperprolactinaemia than 42 control-persons. Hyperprolactinaemia was twice as frequently found in 46 women with microscopic cystic disease--proved histological in biopsies--than in control-persons. On the average there was a moderate elevation of prolactin. Individual prolactin-levels were up to four or five times higher than normal. The comparison between prolactin and gynecologic data and anamnestic known endocrine and metabolic lesions was without significance. There was no relation between use of prolactin-stimulating drugs (psychopharmacas a.o.) and cystic disease of the breast. Patients with cystic disease used significantly less oral contraceptiva and more estrogens than control-persons. There was no familiar-genetic disposition significant. Our results show prolactin as an etiologic factor of (gross-) cystic breast disease.

[Topography of posttraumatic fat embolism. Histological and statistical investigation of Gough-sections of the lung (author's transl)]. / Topographie der posttraumatischen Fettembolie. Histologische und statistische Untersuchungen an Lungengrossflächenschnitten.

In 50 fat-stained and foil-mounted Gough-sections of entire lungs in accidental death cases the topographic areas of fat-embolic blood vessel occlusions were estimated. For control, the same investigations were made in cases of nontraumatic death. Accumulation of fat-embolism was found in the arterior thirds of the upper and middle areas of the lung, while in the basal, the central, and the posterior parts the incidence of fat-embolic occlusions is significantly rarer. Similar results, although to a lesser degree, were found in the lungs of non-traumatized patients. A statistical study evaluated whether right or left lobe, sex, age, or time of survival after trauma influence the incidence and intensity of fat-embolic occlusions in the lung. The results were discussed.