Histochemical and immunohistochemical characteristics of elastofibromas.

Elastofibromas are slow-growing and rare soft-tissue tumors. The etiology and pathogenetic mechanisms are still controversial and there are only a few studies in the literature investigating the histochemical, immunohistochemical, and genetic features to determine the pathogenesis. We investigated the cellular composition of lesions with a diagnosis of elastofibroma in 17 patients by using histochemical and immunohistochemical methods. There were 17 cases with a mean age of 53.5 years. Mean lesion diameter was 6.6 cm. The immunohistochemical method showed vimentin and factor XIIIa positivity in all cases. Four cases had focal myoglobin positivity in the spindle-shaped cells between the collagen fibers. Spindle cells were positive for CD34 in 8 cases. Smooth muscle actin, desmin, type 4 collagen and laminin were negative in all cases. The elastic nature of the abnormal fibers was shown histoch with Verhoeff elastin staining and aldehyde fuchsin staining in all cases. Our results have shown that the concurrent positivity of factor XIIIa and CD34 in the cells forming the lesion might show that the lesionoriginates from primitive dermal mesenchymal cells. In addition, the myoglobin positivity found in some cases indicates the possibility of a myofibroblastic origin of elastofibromas.

Treatment of first acute rejection episode: systematic review of level I evidence.

The primary objective of this review was to clarify the efficacy of commercially available and tested agents for the treatment of first acute rejection episode (ARE) and particularly a steroid-resistant rejection (SRR) seeking to provide generalizable level I evidence for clinical practice. The inclusion criteria were restricted to prospective randomized trials (PRT) that (1) reported outcomes of first, biopsy-proven ARE based on Banff 97 diagnostic criteria; (2) excluded borderline changes that were not considered to be acute rejection; (3) included protocol biopsies confirming reversal or recurrence of rejection; (4) utilized calcineurin inhibitor-based double or triple baseline immunosuppression prior to and after the reversal of ARE and possessed Jadad scores at least 3 upon final assessment by both reviewers. Two PRTs compared rabbit-anti-thymocyte globulin (ATG) to low-dose corticosteroids or OKT3, following a first rejection episode in renal transplantation patients. The analysis of pooled data revealed 25% and 31% absolute risk reduction (ARR), in regard to initial treatment failure and recurrence of ARE, respectively, in favor of ATG treatment. Treatment morbidity showed similar long-term graft and patient survival rates in both arms. Three optimal trials compared the efficacy of various polyclonal or polyclonal versus monoclonal (OKT3) antibodies for the treatment of SRR. The estimated efficacy potential of rabbit-ATG appeared to be 11,4% greater than horse-ATG with particularly Banff grade II but also grade III patients demonstrating the greatest benefit. Among two PRTs comparing ATG to OKT3, ATG tended to show better graft function, fewer recurrent rejections (9% ARR), fewer graft losses due to immunologic failure (7% ARR), and better tolerance. The incidence of malignant tumors was similar in both treatment arms. In conclusion, thymoglobulins, especially those of rabbit origin, displayed greater efficacy for the treatment of ARE and SRR. Application of CD3 monitoring using flow-cytometry provided a reliable guid to prevented excessive immunosuppressive administration.

A prudent algorithm for hyperlipoproteinemia in renal transplant recipients.

BACKGROUND: Hyperlipidemia and particularly low-density lipoprotein cholesterol (LDL-C) have been proposed as independent risk factors predisposing to chronic allograft nephropathy. OBJECTIVE: The primary objective of this prospective randomized study was to evaluate the efficacy of the modified National Cholesterol Education Program (NCEP) Step I Diet to prevent posttransplantation hyperlipidemia. The secondary objective was to assess the impact of fluvastatin on the lipid profile of patients unresponsive to dietary measures. METHODS: The study population consisted of 143 consecutive patients who underwent transplantation between October 1998 and January 2005. Patients who failed to demonstrate total and LDL-C levels below the optimal values of 200 mg/dL and 130 mg/dL respectively, were recruited for fluvastatin treatment. The remaining patients who achieved and maintained the target lipid levels continued on the same dietary regimen. RESULTS: Baseline demographic characteristics were not different among the fluvastatin and modified Step I Diet groups. Mean total cholesterol (231.2 vs 187.3 mg/dL; P < .000), LDL-C (134.5 vs 99.2 mg/dL; P < .000), high-density lipoprotein cholesterol (HDL-C; 62.9 vs 55.7 mg/dL; P = .012), and triglyceride (170.3 vs 138.7 mg/dL; P = .011) levels following the dietary run-in period were significantly different between the patients assigned to fluvastatin treatment and those left on the diet, respectively. Fluvastatin achieved reductions ranging from 12% to 14% in the concentrations of total cholesterol (231.2 +/- 4.29 mg/dL to 202.7 +/- 3.89 mg/dL; P < .000) and LDL-C (134.5 +/- 3.53 mg/dL to 115.6 +/- 3.18 mg/dL; P < .000) among 91% of patients after 1 year of treatment. A substantial decrease in all lipoprotein concentrations occurred in 53 patients in the modified Step I Diet group with significant reductions in total cholesterol (187.3 +/- 4.98 mg/dL to 172.7 +/- 3.8 mg/dL; P < .000) and LDL-C (99.2 +/- 4.0 mg/dL to 96.2 +/- 3.44 mg/dL; P < .000). CONCLUSION: Initiation and education of the Step I Diet should be provided during hospitalization. The 3-month dietary run-in period was deemed sufficient to determine the effect of diet on lipid abnormalities. Reduction of lipoprotein levels by a 40-mg daily fluvastatin dose was sufficient, safe, and tolerable.

Late conversion from calcineurin inhibitor-based to sirolimus-based immunosuppression due to chronic toxicity: a prospective study with protocol biopsy amendment.

BACKGROUND: There is an emerging consensus on conversion from calcineurin inhibitor (CNI)-based regimens to proliferation signal inhibitor (PSI)-based protocols for the prevention of a progressive decline in graft function due to CNI toxicity. METHODS: Thirty-one primary renal transplant recipients within 17-48 years of age (mean, 32.2 +/- 1.6) were enrolled in this dual-center study. Eligible patients had a baseline (pre-engraftment) biopsy and completed at least 12 months of follow-up with deteriorating graft function indicative of chronic CNI toxicity with or without nonspecific interstitial fibrosis/tubular atrophy (IF/TA) on a biopsy specimen. A fast conversion protocol, being defined as a 50% initial reduction followed by complete withdrawal of CNI drug within 2 weeks of introducing rapamycin was performed in all patients. A sirolimus (SRL) loading dose was not prescribed; all subjects directly received maintenance (2-5 mg/d) doses of the drug. The primary endpoint of this study was assessement of renal function using cGFR and renal histology by protocol biopsy at 1 year after conversion. RESULTS: The mean follow-up after conversion was 21.6 months. The difference between cGFR before compared with cGFR after 12 months after conversion (40.8 +/- 2.36 mL/min vs 55.7 +/- 3.6 mL/min; P < .000) and at the last follow-up (40.8 +/- 2.36 mL/min vs 53.8 +/- 2.96 mL/min; P < .000) was significant. The mean IF/TA with glomerulosclerosis and chronic vasculopathy scores of biopsy specimens at baseline, during conversion, and at 12 months of the study were 2.25 +/- 0.3, 3.30 +/- 0.24, and 3.0 +/- 0.30, respectively. The change in scores was indicative of mild progression; however, the difference was not significant. IF/TA, glomerulosclerosis, and chronic vasculopathy scores improved in 8 (30%) subjects, remained unchanged in 11 (42%) and worsened in 7 (28%) after 1 year of SRL therapy. After conversion there was no patient or graft loss in this group. Moreover, SCr and GFR improved in 21 or 29 patients (72%), remained stable in 4 (14%), and decreased in 4 (14%) patients. The predictors of successful conversion in our study were GFR > or = 40.6 mL/min, SCr < or = 2.34 mg/dL, and histological allograft damage score < or =3. CONCLUSION: SRL-MPA/MMF-ST combination may be a good therapeutic strategy against chronic CNI toxicity, particularly for patients whose conversion biopsy specimens demonstrated mild IF/TA, glomerulosclerosis, and chronic vasculopathy scores (< or =3.1 +/- 0.3).

Impact of calcineurin inhibitors on bone metabolism in primary kidney transplant patients.

OBJECTIVE: Posttransplant bone disease and bone metabolism markers were investigated in primary kidney transplant recipients receiving calcineurin inhibitor (CNI) based triple immunosuppression. We examined the safety profile and independent potential of CNIs on bone formation and bone resorption. The study also attempted to correct for modifiable and nonmodifiable factors that impact on posttransplantation bone metabolism, such as age, renal function, rejection, steroid dosage, and secondary hyperparathyroidism. MATERIALS AND METHODS: Serum alkaline phosphatase and osteocalcin were used as indices of bone formation and urinary deoxypyridinoline as a marker for bone resorption. Bone mineral density (BMD) data were assessed in all patients. Osteocalcin and deoxypyridinoline data were correlated with BMD scores to predict the clinical utility and sensitivity of these tests. Sixty-six patients among 300 kidney transplant recipients were enrolled as eligible candidates based upon more than 12 months' posttransplantation follow-up excellent graft function (GFR values >60 mL/min), and intact parathormone levels <100 pg/mL. RESULTS: Mean follow-up was 1395.3 +/- 179.3 days and 1488.9 +/- 225.1 days for cyclosporine (CsA) and FK506 groups, respectively. Mean values for alkaline phosphatase and osteocalcin were 108.8 +/- 6.0 versus 98.4 +/- 9.7 U/L and 10.1 +/- 1.2 versus 9.8 +/- 1.5 ng/mL for the CsA and FK506 groups, respectively. Both CsA and FK506 caused mild osteoblastic proliferation and matrix mineralization activity, as reflected by increased osteocalcin and alkaline phosphatase levels in 22.6% and 12.5% of patients, respectively. This bone formation activity was counterbalanced by a three-fold increase in urine deoxypyridinoline levels in both groups. Mean deoxypyridinoline levels were, respectively, 13.8 +/- 4.4 versus 11.3 +/- 2.1 nM/mMCr in the CsA and FK506 groups. Thirty-four (68%) patients in the CsA and 10 (62.5%) in the FK506 groups had elevated deoxypyridinoline levels. A strong correlation existed between deoxypyridinoline levels and BMD scores for the CsA group (P < .0001). Despite the presence of relatively greater elevations in deoxypyridinoline and BMD values among CsA-treated patients, there was no significant difference in terms of bone resorption potential of both groups. No correlation existed between iPTH values (<65 pg/mL or among 65 to 98.2 pg/mL) at any time versus osteocalcin, alkaline phosphatase, deoxypyridinoline, or BMD levels. The symptomatic bone disease and fracture rates were 0% in this series. CONCLUSION: Calcineurin inhibitor-based immunosuppression with low maintenance doses of glucocorticoids induces slight bone formation but relatively potent, clinically relevant bone resorption.

Efficacy and safety of enteric-coated mycophenolate sodium in de novo and maintenance renal transplant patients.

Enteric-coated mycophenolate sodium (ECMPS) has been developed as an alternative agent to mycophenolate mofetil (MMF), with the aim to provide reduction in gastrointestinal side effects. This open-label, single-arm, two-center prospective study sought to investigate the efficacy and safety of ECMPS used in combination with steroid and cyclosporine (CyA) in de novo and maintenance renal transplant patients with 12 months' follow-up. Twenty-one patients were recruited (mean age, 39 +/- 8 years) into the de novo group. Of these patients, 66% were male and 76.2% underwent living related kidney donation. The induction immunosuppression was ATG in 10 and basiliximab in 6 patients. At 12 months' posttransplantation, there was no graft or patient loss and two (10%) acute rejection episodes. None of the patients in this group discontinued the study medication due to drug-induced adverse events. One patient was excluded from the study because of recurrent oxalosis. Serum creatinine (SCr) levels at 3, 6, and 12 months after renal transplant were 1.30 +/- 0.3, 1.40 +/- 0.3, and 1.40 +/- 0.3 mg/dL, respectively. The maintenance group included 20 patients. Time posttransplantation (mean +/- SD) was 27 +/- 25 months. All patients in this group had been on maintenance azathioprine or MMF in combination with steroid and CyA. These patients were switched to ECMPS. They mean age was 36 +/- 8 years. Sixty-six percent of the patients were male and 57% received living donor kidneys. Acute rejection was nil, whereas two patients lost their grafts owing to chronic rejection in this group. Three patients were excluded from the study, one to discontinuation of the drug because of intractable diarrhea, the second to loss to follow-up, and the last case due to withdrawal of informed consent. Leukopenia was not observed in this group. The SCr levels prior to and at 3, 6, and 12 months after conversion to ECMPS were 1.80 +/- 1.0, 1.95 +/- 1.5, 1.50 +/- 0.8, and 1.60 +/- 0.8 mg/dL, respectively. This is the first phase IV study with ECMPS in the Turkish population. Renal function was preserved in both groups. Only 2.5% of patients were excluded because of side effects. Use of ECMPS in combination with prednisolone and CyA is an effective and safe therapeutic choice for both de novo and maintenance renal transplant patients.

Predictors of mortality and morbidity in acute obstructive jaundice: implication of preventive measures.

BACKGROUND/AIMS: The afferent events in acute obstructive jaundice (AOJ) are characterized by endotoxemia-induced decrease in systemic vascular resistance and bile salt mediated natriuresis and diuresis leading to diminished effective plasma volume. METHODOLOGY: A prospective protocol aimed at preventing those alterations was carried out in 104 consecutive patients with AOJ. The preoperative risk factors that predict postoperative mortality and morbidity were reevaluated and correctable factors were identified. RESULTS: The average duration between the initiation of jaundice and surgery was 9.3 days. The perioperative mortality was 0%. The essentials of the treatment protocol were lactulose and cefazolin administration respectively for the prevention of portal endotoxemia and biliary sepsis and maintenance of body weight with adequately replaced fluid and electrolytes. Clinically relevant nutritional deficit was not observed in any of the patients during the perioperative period. The unique factor that predicted late mortality was the preoperative alanine transaminase value. Renal hemodynamics and hematologic parameters were completely correctable before the operation and patients with malignant or benign biliary strictures benefited and responded to the treatment similarly. CONCLUSIONS: Measures taken to prevent the activation and progression of the afferent events in AOJ, have resulted in excellent clinical outcomes.

Renal failure in obstructive jaundice.

BACKGROUND/AIMS: The optimal preoperative management of patients with acute obstructive jaundice is still a matter of debate. Reduction in effective plasma volume and systemic endotoxemia are major consequences both in experimental acute bile duct ligation and in patients with acute obstructive jaundice (AOJ). The objective of this study is to show the necessity for adequate preoperative hydration and lactulose administration for the prevention of postoperative renal dysfunction in patients with AOJ. METHODOLOGY: Fifty-five patients (35 male, 20 female) with a mean age of 62 years were entered into the study. There were 23 benign and 32 malignant strictures in this group. All patients received oral lactulose (30-45mL per day) and IV cefazoline (3-4g/day) before surgery. Fluid and electrolyte balance was precisely maintained throughout the hospitalization via daily body weight calculations. High-risk elderly patients with left ventricular systolic dysfunction were assessed by echocardiography and therapeutic measures were undertaken. Renal function was assessed by creatinine clearance (ClCr) measurements and impairment of renal function was defined as a >20% fall in ClCr value post-surgery. RESULTS: Mean preoperative bilirubin level was 11.05mg/dL (range: 3.45-27.0mg/dL). None of the patients developed postoperative renal failure. The difference between pre- and postoperative ClCr value (104.02mL/min vs. 101.0mL/min respectively) was not significant (t=0.698, P=0.489). One patient with mild renal function impairment before surgery (ClCr=45.4mL/min) successfully recovered with 60% rise in creatinine clearance (ClCr=78.1mL/min) after the operation. Three patients with normal functioning kidneys died within 30 days of operation. The principle cause of death was carcinomatosis and pulmonary embolus in two and intraoperative hemorrhagic shock in one patient. CONCLUSIONS: These results further substantiated the importance of adequate preoperative hydration and endotoxin inactivation in terms of acute renal failure prophylaxis in patients with AOJ. This regimen obviates the afferent events in obstructive jaundice and provides prevention of acute renal failure even in high-risk elderly patients.

Adjuvant chemotherapy in a unique population of patients with gastric cancer undergoing surgery.

BACKGROUND/AIMS: Total gastrectomy with D2 dissection theoretically removes the gross primary tumor with its potential route of dissemination, that is locoregional lymph nodes. Complementary therapy for the control of systemic microscopic disease should be taken into consideration in patients whom surgery with curative intent was performed. METHODOLOGY: Twenty-eight patients with moderately differentiated, locally advanced gastric carcinoma underwent total gastrectomy with D2 lymph node dissection. The operative mortality rate was 0% in this series. Fifteen patients received six courses of adjuvant 5-FU + leucovorin in doses of 425 mg/m2/d and 20 mg/m2/d respectively in five-day cycles month ly. The remaining 13 patients constituted the control (surgery only) group. RESULTS: The mean disease-free and overall survival rates were 41 and 48 months (p: 0.78) and 42 and 53 months (p: 0.43) in the control and chemotherapy groups, respectively. The odds ratio for crude mortality was 0.7. CONCLUSIONS: Although statistical significance has not been achieved in this study, a trend toward adjuvant chemotherapy has emerged in that unique group of patients with moderately differentiated (intestinal type) adenocarcinoma of the stomach undergoing curative surgery.

Two-day induction with thymoglobulin in kidney transplantation: risks and benefits.

INTRODUCTION: The aim of this study was to develop an induction protocol to reduce allograft rejection with fewer posttransplant infections and malignancies. METHODS: In this prospective randomized study, a T- and B-cell depletion protocol, consisting of IV thymoglobulin (ATG 5 mg/kg/d) plus methylprednisolone (500 mg/d) plus azathiopurine (2 mg/kg/d), was on days 0 and 1 after renal transplantation. CyA was introduced at day 3.39 among patients undergoing either primary living related (n = 16) or cadaveric (n = 23) transplants excluding recipients of full-HLA-matched sibling, or five- and six-HLA-matched cadaveric donor kidneys. The adequacy of immunosuppression was evaluated by flow cytometric analysis for total, CD3+ (T-cell), and CD19+ (B-cell) lymphocytes. RESULTS: The acute rejection rate was 6% and 37/39 patients are alive with functioning grafts at an average follow-up of 14.5 months. The overall patient and graft survival rate was 95%. Their mean creatinine value was 1.27 mg/dL. Six patients (16%) required hospitalization due to serious infections. The two deaths were attributed to septicemia and brain abcess caused by unusual agents, namely, Rhodococcus equi and Sporobolomyces. One patient presented with a cutaneous Kaposi sarcoma in the 11th month posttransplant. CONCLUSION: A Two-day induction protocol with thymoglobulin yields acceptable acute rejection rates among renal transplants. However, caution is necessary for adverse events, particularly atypical bacterial and fungal infections.