Treatment of myelodysplastic syndromes with human granulocytic-macrophage colony stimulating factor (GM-CSF) or GM-CSF combined with low-dose cytosine arabinoside.

In a phase II study, 21 patients with MDS (RAEB, RAEBt, CMML and RA and RAS with severe cytopenia) were randomized to be treated with 3 courses of GM-CSF (3 micrograms/kg/day s.c.) alone (11 patients) or in combination with AraC (20 mg/m2/d s.c.) (10 patients) for 14-d periods, interrupted by 14-d rest periods. Eight patients discontinued the treatment. In the GM-CSF group a marked increase in WBC and neutrophil counts during each course of treatment administration were seen in most patients. Platelet counts decreased in 14 of 24 courses of treatment in the GM-CSF plus AraC group but in none of the GM-CSF group. Although the changes in the circulating blood cells were transient and the counts tended to return to the pretreatment levels during the rest periods, some more durable effects were seen. In 3/6 patients of the GM-CSF group who completed the designed treatment, both WBC and neutrophils remained elevated above the pretreatment levels throughout the 3-month period of treatment, while in one of them thrombocytopenia improved considerably. In the GM-CSF plus AraC group, 4 out of the 7 patients who completed the treatment showed an improvement of neutropenia as well as anaemia. In these 4 patients the BM percentage of blasts was also decreased. In conclusion, the results of this study indicate that GM-CSF given intermittently improves leukopenia in some patients with MDS. In addition, the administration of GM-CSF seems to prevent granulocytopenia of concurrent AraC treatment and may be of benefit in the treatment of these diseases.     

Announcement

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Autoimmune hepatitis type 1 and primary biliary cirrhosis have distinct bone marrow cytokine production

We have recently reported differences in the hematopoiesis between autoimmune hepatitis type 1 (AIH-1) and primary biliary cirrhosis (PBC). In view of the notion that cytokines are regulators of hematopoiesis, we investigated in our tertiary center the cytokine production in the bone marrow (BM) of the same consecutive cohort of patients (13 AIH-1, 13 PBC, 10 healthy and 7 patients with cirrhosis due to chronic hepatitis B). Interferon-gamma (IFN-gamma), interleukin-4 (IL-4), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) were determined in the supernatants of long-term BM cultures by ELISAs. IL-4, TNF-alpha and TGF-beta were found significantly increased in the BM of PBC patients compared to AIH-1 and both control groups. AIH-1 patients had significantly higher BM IL-10 compared to PBC patients and higher IL-10, IL-4 and TNF-alpha compared to controls. BM IFN-gamma was significantly higher in PBC and AIH-1 patients compared to controls. In AIH-1 patients, IL-10 was positively correlated with CD34+, CD34+/CD38- and CD34+/CD38+ cell proportions. In conclusion, the BM cytokine microenvironment of PBC and AIH-1 patients differs significantly compared to that of healthy individuals and cirrhotic patients of non-autoimmune etiology. Differences were also found between patients with PBC and AH-1. The implication of BM in the pathogenesis of autoimmune liver diseases is possible and needs further investigation.     

Pharmacokinetics of teicoplanin in patients undergoing chronic haemodialysis

In order to define a dose regimen of teicoplanin for patients undergoing chronic haemodialysis so that they achieved trough drug serum levels above 10 mg/l, two single doses of 5 and 10 mg/kg were administered intravenously in seven anuric patients immediately after the end of haemodialysis. Concentrations of teicoplanin were determined by a microbiological assay in samples collected from peripheral veins via the arterial and the venous lines of the fistulae and from the dialysate during haemodialysis. The administration of a 5 and 10 mg/kg dose gave mean C(max) of 62.80 and 122.43 mg/l, mean AUC of 526.43 and 1103.98 mg h/l, mean half life (t(1/2)) of 109.09 and 107.06 h, mean clearance rates of 12.85 and 12.44 ml/min, mean apparent volumes of distribution of 1.68 and 1.68 l/kg and mean volumes of distribution at steady state of 0.31 and 0.28 l/kg, respectively. Trough serum levels above 10 mg/l were found for 24 h after the administration of the 5 mg/kg dose and for 48 h after the administration of the 10 mg/kg dose. Teicoplanin was not detected in the dialysate. Its concentrations in both the arterial and the venous lines of the fistulae were similar. Based on the time period after the administration of teicoplanin where the desired trough serum levels were found and on the observed t(1/2), it is proposed that teicoplanin should be administered at a dose of 10 mg/kg at 48-72 h intervals, in patients undergoing chronic haemodialysis for the therapy of infections caused by Gram-positive cocci.     

Beneficial effects of fluvastatin on progressive renal allograft dysfunction

To assess the time-dependent changes in renal function in relation to antioxidant and lipid-lowering effects of fluvastatin in hyperlipidemic renal transplant recipients, 20 patients were treated with fluvastatin 40 mg/d for 12 months, after failure of a dietary program. Plasma malondialdehyde (MDA) levels and lipid profiles were evaluated in relation to serum creatinine and calculated creatinine clearances 18 months before and during the fluvastatin treatment. Mean baseline lipid values were: total cholesterol 318 mg/dL, triglycerides 212 mg/dL, LDL cholesterol 219 mg/dL, HDL cholesterol 58 mg/dL, apolipoprotein A 176 mg/dL, and apolipoprotein B 145 mg/dL. During 12 months of treatment, fluvastatin produced consistent and significant reductions in total and LDL cholesterol (-18.4% and -24.1%), triglycerides (-17.7%), and apolipoprotein B (-22.7%) as well as an increase in HDL cholesterol (12.3%) and apolipoprotein A (9.2%). Plasma MDA levels decreased by 41.8% (from 3.5 +/- 0.3 to 1.8 +/- 0.1 nmol/mL, P =.00002). Creatinine clearance, which had been declining at a rate of 0.32 mL/min/month during the previous 18 months before treatment, progressively improved during treatment, giving a positive slope of the creatinine clearance, which increased by 0.35 mL/min/month, (P =.016; 53.3 +/- 4.2 mL/min vs 49.8 +/- 4.1 mL/min pretreatment). Multiple linear regression analysis revealed that MDA was the parameter most closely associated with the variability in creatinine clearance. In conclusion, renal transplant patients with lipid abnormalities display renoprotective activity of fluvastatin, possibly due to its lipid-lowering and antioxidant effects.     

Visceral leishmaniasis in renal transplant recipients: successful treatment with liposomal amphotericin B (AmBisome).

Visceral leishmaniasis (VL) is a rare disease in renal transplant recipients. Liposomal amphotericin B (AmBisome) is known to be effective against VL. However, previously there has been no experience with administration of such treatment to renal transplant recipients. We report herein four patients with VL complicating renal transplantation who were treated successfully with liposomal amphotericin B (total dose, 23-40 mg/kg). Neither adverse reactions nor clinical relapses of VL were observed.     

Malakoplakia of the colon associated with colonic adenocarcinoma diagnosed in colonic biopsies

Malakoplakia, typically involving the urinary tract, is an uncommon form of chronic inflammation caused by chronic infections and characterized by accumulation of macrophages. It has also been found in many other sites such as the gastrointestinal tract, pancreas, liver, lymph nodes, skin, respiratory tract, adrenal gland, vagina and brain. We present a case of a 64-year-old man referred to our hospital with cachexia and radiologic evidence of metastatic tumor of the liver. Colonoscopy revealed a large malignant - appearing polypoid mass of the ascending colon and multiple distinct polyps throughout the rest of the colon. Biopsies of the ascending colon mass confirmed the diagnosis of adenocarcinoma. Histological examination of two of the other polyps revealed malakoplakia which was characterized by aggregates of granular histiocytes with Michaelis - Gutmann bodies and histochemically confirmed with periodic acid-Schiff and von Kossa stains. This is a rare case diagnosed on endoscopic samples. The majority of reported cases were found in surgical specimens. In addition, the endoscopic appearance of multiple polyps is unusual in rnalakoplakia.     

Radiobiological and dosimetric analysis of daily megavoltage CT registration on adaptive radiotherapy with Helical Tomotherapy

Pre-treatment patient repositioning in highly conformal image-guided radiation therapy modalities is a prerequisite for reducing setup uncertainties. In Helical Tomotherapy (HT) treatment, a megavoltage CT (MVCT) image is usually acquired to evaluate daily changes in the patient's internal anatomy and setup position. This MVCT image is subsequently compared to the kilovoltage CT (kVCT) study that was used for dosimetric planning, by applying a registration process. This study aims at investigating the expected effect of patient setup correction using the Hi-Art tomotherapy system by employing radiobiological measures such as the biologically effective uniform dose (D) and the complication-free tumor control probability (P(+)). A new module of the Tomotherapy software (TomoTherapy, Inc, Madison, WI) called Planned Adaptive is employed in this study. In this process the delivered dose can be calculated by using the sinogram for each delivered fraction and the registered MVCT image set that corresponds to the patient's position and anatomical distribution for that fraction. In this study, patients treated for lung, pancreas and prostate carcinomas are evaluated by this method. For each cancer type, a Helical Tomotherapy plan was developed. In each cancer case, two dose distributions were calculated using the MVCT image sets before and after the patient setup correction. The fractional dose distributions were added and renormalized to the total number of fractions planned. The dosimetric and radiobiological differences of the dose distributions with and without patient setup correction were calculated. By using common statistical measures of the dose distributions and the P(+) and D concepts and plotting the tissue response probabilities vs. D a more comprehensive comparison was performed based on radiobiological measures. For the lung cancer case, at the clinically prescribed dose levels of the dose distributions, with and without patient setup correction, the complication-free tumor control probabilities, P(+) are 48.5% and 48.9% for a D(ITV) of 53.3 Gy. The respective total control probabilities, P(B) are 56.3% and 56.5%, whereas the corresponding total complication probabilities, P(I) are 7.9% and 7.5%. For the pancreas cancer case, at the prescribed dose levels of the two dose distributions, the P(+) values are 53.7% and 45.7% for a D(ITV) of 54.7 Gy and 53.8 Gy, respectively. The respective P(B) values are 53.7% and 45.8%, whereas the corresponding P(I) values are ~0.0% and 0.1%. For the prostate cancer case, at the prescribed dose levels of the two dose distributions, the P(+) values are 10.9% for a D(ITV) of 75.2 Gy and 11.9% for a D(ITV) of 75.4 Gy, respectively. The respective P(B) values are 14.5% and 15.3%, whereas the corresponding P(I) values are 3.6% and 3.4%. Our analysis showed that the very good daily patient setup and dose delivery were very close to the intended ones. With the exception of the pancreas cancer case, the deviations observed between the dose distributions with and without patient setup correction were within ±2% in terms of P(+). In the radiobiologically optimized dose distributions, the role of patient setup correction using MVCT images could appear to be more important than in the cases of dosimetrically optimized treatment plans were the individual tissue radiosensitivities are not precisely considered.     

Associations between osteoprotegerin and femoral neck BMD in hemodialysis patients

Numerous humoral factors are involved in the development of renal osteodystrophy, causing perturbations in bone mineral density (BMD) in patients with end-stage renal disease (ESRD). The RANKL/OPG cytokine system appears to mediate the effects of many of these factors on bone turnover, contributing to the pathogenesis of renal bone disease. The aim of this study was to evaluate the clinical and biochemical correlations of BMD measurements in patients on chronic hemodialysis. Fifty-four hemodialysis patients underwent measurement of BMD at the proximal femur and the lumbar spine (L2–L4). Intact parathyroid hormone (PTH), osteoprotegerin (OPG), sRANKL, and main bone biochemical markers were also measured in serum samples of all patients. BMD of the femoral neck was negatively correlated with OPG levels (r = 0.333, P = 0.014). OPG levels were significantly different among normal, osteopenic, and osteoporotic tertiles defined according to BMD of the femoral neck. The highest OPG levels were measured in the lowest T-score (osteoporotic) tertile and were higher than in the osteopenic and normal tertiles (P < 0.05). A threshold level for OPG at 21.5 pmol/l enabled the detection of osteoporotic patients with 76.5% sensitivity and 62.2% specificity. BMD values of trabecular bone-rich sites of the skeleton such as lumbar spine (L2–L4), trochanter, and Ward’ s triangle were inversely correlated with total ALP levels (P < 0.05). Hemodialysis patients with low BMD of the femoral neck demonstrated higher OPG levels than patients with normal BMD. Those with lumbar spine (L2–L4), trochanteric, and Ward's triangle BMDs below the normal range presented higher total ALP levels. These results suggest that OPG and total ALP may be clinically useful markers in the detection of significant femoral neck and trabecular bone mineral deficit in hemodialysis patients, warranting further investigations.     

The expression of matrix metalloproteinase-11 protein in various types of glomerulonephritis.

BACKGROUND: Matrix metalloproteinases (MMPs) have been implicated to play important roles in a number of pathological processes such as inflammation. In human glomeruli, the mesangial matrix turnover is controlled by a dynamic equilibrium between synthesis and degradation to which metalloproteinases are known to contribute. Metalloproteinase-11 (MMP-11) was originally discovered as a gene whose expression was associated with tissue remodelling. The aim of this study was to investigate whether MMP-11 protein is expressed in various types of glomerulonephritis and to elucidate the role of this expression. METHODS: Using standard immunohistochemistry, we analysed MMP-11 expression in renal biopsies from 95 patients with primary glomerulonephritis (n = 44) and secondary, either lupus-associated glomerulonephritis (n = 22) or pauci-immune, ANCA-associated glomerulonephritis due to small vessel vasculitis (n = 23) or Wegener's granulomatosis (n = 6). The examined cases were divided into two groups (proliferative and non-proliferative). Anti-Ki67 and -CD68 immunostaining was also performed in order to estimate cell proliferation and number of macrophages, respectively. RESULTS: MMP-11 immunopositivity was detected in the glomeruli of the majority of pathological samples. The highest incidence of MMP-11 immunopositivity (26.3%) was noticed in glomerulonephritides associated with microscopic polyangiitis and Wegener's granulomatosis. Generally, MMP-11 was often expressed in segmental areas of sclerosis, microadhesions, cellular and fibrocellular crescents. Fibrotic crescents and fibrotic glomeruli were constantly MMP-11-immunonegative. In MMP-11 immunoreactive glomeruli, increased numbers of macrophages were often detected in the mesangium (P = 0.001), while no such observation could be made with regard to proliferating cells (P = 0.170). CONCLUSIONS: MMP-11, like an inflammatory mediator, may exert a chemotactic influence on macrophages which aggregate in the mesangium; MMP-11 is not likely to have a parallel mitogenic or antifibrotic effect in diseased glomeruli.