Bruno Cesana

Benefits and risks of protracted treatment with human recombinant erythropoietin in patients having haemodialysis

Fourteen patients with uraemic anaemia and having regular haemodialysis were given human recombinant erythropoietin in increasing doses, beginning with 24 U/kg thrice weekly. One patient was dropped from the study because of recurrent thrombosis of vascular access sites. In the other 13 patients, followed up for a mean of 9.1 months (range 8-11), haemoglobin concentrations increased from 62 (SD 8) to 105 (9) g/l. No antierythropoietin antibodies were detected during the study. The correction of anaemia was associated with a tendency to hyperkalaemia and a mild increase of unconjugated bilirubinaemia. In eight previously hypertensive patients antihypertensive treatment had to be reinforced, but in normotensive patients blood pressure did not change. Thrombosis of arteriovenous fistulas occurred in two patients and a cerebral ischaemic lesion in one. Protracted treatment with human recombinant erythropoietin evidently can maintain normal haemoglobin concentrations in uraemic patients over time. Full correction of anaemia, however, may trigger some vascular problems, particularly in hypertensive patients and those with a tendency to thromboembolism.

Obstructing colonic cancer : Failure and survival patterns over a ten-year follow-up after one-stage curative surgery

BACKGROUND: Large-bowel cancers that present as obstructing lesions have a poor prognosis. However, little is known of the reasons for the dismal survival and of failure patterns after potentially curative treatment. METHOD: An observational study and multivariate analysis were conducted to identify determinants of survival and to compare recurrence patterns between obstructing and nonobstructing tumors after primary resection and anastomosis as curative treatment. RESULTS: Over a period of ten years (1980–1989), 528 patients with colonic cancer were treated at one institution. The cancer was obstructing in 179 cases and nonobstructing in 349. One-stage primary resection and anastomosis as curative treatment were performed in 107 obstructed and 256 nonobstructed patients. Three hundred thirty-six potentially cured survivors (94 in the former group and 242 in the latter) were followed for a median of 55 months. During follow-up, local recurrence occurred in 37 patients (12 obstructed (12.8 percent) and 25 nonobstructed (10.4 percent),P=0.44) and metastatic disease in 68 (25 obstructed (27.6 percent) and 43 nonobstructed (17.8 percent),P=0.029). Multivariate analysis of survival showed that age over 70 years, Dukes stage, histologic grade, and recurrence were the only prognostic factors. No statistically significant determinant turned out for local recurrence, whereas at multivariate analysis for metastatic and overall relapse, Dukes stage, positive nodes, and obstruction remained independent prognostic factors. CONCLUSIONS: After one-stage emergency curative treatment, patients presenting with obstructing tumors of the colon have a smaller survival probability than that of patients with nonobstructing lesions. Local recurrence pattern is similar between groups. Conversely, obstruction, along with pathologic stage and positive nodes, carries a significantly higher risk of metastatic tumor recurrence and death.

Risk factors for late kidney allograft failure

BACKGROUND While graft survival rates in the short term have improved dramatically, only a modest improvement has been shown in long-term graft survival rates. We evaluated the causes of late failure in renal allograft recipients treated with cyclosporine A (CsA). METHODS A total of 864 adults with a functioning graft at one year were evaluated. The end points were dialysis or death with a functioning graft. RESULTS The 13-year patient and graft survival probabilities were 0.82 and 0.64, respectively. The graft half-life was 20.1 years and the pure graft half-life was 31.1 years. At multivariate analysis, plasma creatinine at one year (P = 0.0006; RR 1.72), low-density lipoproteins (LDL) at one year (P = 0.0014; RR 1.65), older age (P = 0.0128; RR 1.50) and delayed graft function (P = 0.0350; RR 1.45) were associated with the end point. Chronic allograft nephropathy was the cause of failure in 97 patients, death in 70, recurrence of glomerulonephritis in 24, other events in 6. Cardiovascular complications were the most frequent cause of death. Post-transplant cardiovascular events were associated with: pre-transplant cardiovascular events (P = 0.0012; RR 2.65), older age (P = 0.0001; RR 2.46), pre-transplant arterial hypertension (P = 0.0249; RR 1.57), smoking (P = 0.0235; RR 1.29), duration of dialysis (P = 0.0229; RR 1.28). Mean serum cholesterol, LDL and triglycerides were each significantly associated post-transplant cardiovascular events. CONCLUSIONS The graft half-life was 20 years. Chronic allograft nephropathy was the leading cause of late failure, followed by death. If the data were censored by death, the projected pure graft half-life would be 31.1 years. Pre-transplant selection and preparation of the candidate as well as appropriate life style are recommended to improve life expectancy and extend graft survival.

Methylprednisolone plus Chlorambucil as Compared with Methylprednisolone Alone for the Treatment of Idiopathic Membranous Nephropathy

BACKGROUND AND METHODS Treatment with methylprednisolone and chlorambucil may protect renal function and increase the chance of remission of the nephrotic syndrome in patients with idiopathic membranous nephropathy. To determine whether similar results might be obtained with methylprednisolone alone, we compared the effects of methylprednisolone and chlorambucil with those of methylprednisolone alone in 92 patients with the nephrotic syndrome caused by idiopathic membranous nephropathy. The patients were randomly assigned to receive either alternating one-month courses of methylprednisolone and then chlorambucil for a total of six months (group 1) or methylprednisolone alone for six months at the same cumulative dosage (group 2). RESULTS Four of the 45 patients in group 1 (9 percent) and 1 of the 47 in group 2 (2 percent) stopped treatment because of side effects. At one, two, and three years, the percentage of patients who did not have the nephrotic syndrome was significantly higher in group 1 than in group 2. It was 58, 54, and 66 percent, respectively, in group 1, as compared with 26, 32, and 40 percent in group 2 (P = 0.002, 0.029, and 0.011). By year 4, the difference was no longer statistically significant: 62 percent of the patients in group 1 and 42 percent of those in group 2 did not have the nephrotic syndrome (P = 0.102). The patients in group 1 were in remission longer than those in group 2 (P = 0.008). CONCLUSIONS In patients with the nephrotic syndrome caused by idiopathic membranous nephropathy, treatment with methylprednisolone and chlorambucil for six months induces an earlier remission of the nephrotic syndrome than methylprednisolone alone, but the difference may diminish with time.

Can prolonged treatment improve the prognosis in adults with focal segmental glomerulosclerosis

Eighty nephrotic adults with focal segmental glomerulosclerosis (FSGS) and plasma creatinine lower than 3 mg/dL were given corticosteroids (53 patients) or immunosuppressive agents (27 patients) for a median of 16 and 75 weeks, respectively. Forty-two patients responded with complete remission (29 patients, 36%) or partial remission (13 patients, 16%). Twenty-six patients who did not respond were treated again. Two patients obtained complete remission and 13 partial remission. The probability of remission was associated with treatment with corticosteroids (P = 0.0001; RR, 3. 93; 95% CI, 2.00 to 7.72), absence of arterial hypertension (P = 0. 0023; RR, 2.59; 95% CI, 1.41 to 4.79), and a percentage of hyaline glomeruli lower than 5% (P = 0.0152; RR, 2.04; 95% CI, 1.15 to 3.64). The probability of being alive at 110 months without doubling of plasma creatinine was 69%. The risk of renal insufficiency was correlated with mesangial proliferation (P = 0.0025; RR, 5.50; 95% CI, 1.82 to 16.60) and with interstitial fibrosis (P = 0.0231; RR, 4. 44; 95% CI, 1.23 to 16.08) at initial biopsy. Considering partial or complete remission as a time-dependent variable, only the lack of remission (P = 0.0027; RR, 7.23; 95% CI, 1.98 to 26.33) and mesangial proliferation (P = 0.0069; RR, 4.59; 95% CI, 1.52 to 13. 88) were correlated with renal failure. Major side effects were observed in 11 patients (5 infections, 1 peptic ulcer, 2 diabetes, 3 neoplasias). This study shows that 70% of nephrotic adults with FSGS may obtain complete or partial remission and maintain stable renal function for about 10 years when given a prolonged therapy with corticosteroids or immunosuppressive drugs.

Natural history of hepatitis B and C in renal allograft recipients.

Background. In renal allograft recipients, most cases of liver dysfunction are caused by hepatitis B virus and hepatitis C virus (HCV). The natural history of hepatitis C and B was studied in 286 renal allograft recipients who received a kidney allograft between 1972 and 1989 when tests for anti-HCV became available. Methods. In all patients, hepatitis B (HB) surface (s) antigen (Ag) was tested before and anti-HCV (by enzyme-linked immunosorbent assay II) after transplantation. Results. At enrollment in 1989 (5.5±4 years after transplantation), 209 patients were anti-HCV positive (C+), 42 patients were HBsAg-positive (B+), and 35 patients were both B+ and C+ (C+B+). One hundred four patients were receiving azathioprine (AZA) and 182 were on cyclosporine A (CsA). Since transplantation, the median follow-up was 18 years in AZA-treated and 13 years in CsA-treated patients. Liver biopsy showed chronic hepatitis in 73 patients, cirrhosis in 20 patients, and fibrosing cholestatic hepatitis in 2 patients. In 34 patients, liver biopsy was repeated, and progression of fibrosis was observed in 24 patients. The 12-year patient survival rate was similar in B+, C+, and B+C+ patients (67%, 78%, and 71%, respectively; P=not significant). Liver-related death was the first cause of death in B+ and B+C+ infected patients (58% and 72%, respectively), whereas cardiovascular disease was the leading cause of death in C+ patients (40%). Multivariate analysis showed that older age (>40 years) (relative risk [RR], 2.8), B+ status (RR, 2.36), and C+ status (RR, 1.65) were independently associated with a worse patient survival. Conclusions. In the long term, B+ patients had a higher risk of death related to liver disease than C+ patients, and co-infection did not worsen patient survival.

Iron reduction and sustained response to interferon-α therapy in patients with chronic hepatitis C: Results of an Italian multicenter randomized study

Iron reduction and sustained response to interferon-α therapy in patients with chronic hepatitis C: results of an Italian multicenter randomized study

Clinical relevance of cyclin D1 protein overexpression in laryngeal squamous cell carcinoma.

PURPOSE To investigate the prognostic relevance of cyclin D1 gene overexpression in laryngeal squamous cell carcinomas (LSCCs). PATIENTS AND METHODS The overexpression of cyclin D1 was analyzed in 149 LSCC patients with a median follow-up duration of 60 months using the DCS6 monoclonal antibody; only cases that overexpressed cyclin D1 in more than 5% of neoplastic cells were considered positive. RESULTS Forty-eight cases (32.2%) were immunoreactive to the DCS6 antibody. Cyclin D1 overexpression was significantly associated with tobacco smoking and alcohol consumption, tumor extension, advanced clinical stage, and the presence of lymph node metastases. Univariate analysis showed that a shorter disease-free and overall survival were significantly associated with supraglottic site, tumor extension, advanced clinical stage, and cyclin D1 overexpression. At multivariate analysis, tumor extension and cyclin D1 overexpression were significantly associated with tumor recurrence, whereas tumor extension, supraglottic site and, at a borderline level of statistical significance, cyclin D1 overexpression, were associated with reduced overall survival. CONCLUSION The overexpression of cyclin D1 in LSCC is associated with unfavorable clinicopathologic features and represents an independent significant predictor of laryngeal carcinoma prognosis, particularly for disease-free survival. This indicates that cyclin D1 evaluation may be a further useful element for selecting subgroups of patients who should be treated with more aggressive therapies.

Oxidative stress in kidney transplant patients.

Background. Little information is available about the role of oxidative stress in renal transplant patients. To evaluate the prevalence and severity of oxidative stress in renal transplantation, the authors conducted a cross-sectional study. Methods. In 112 cadaver or living-donor kidney transplant recipients with a follow-up of at least 6 months and with plasma creatinine less than or equal to 2.5 mg/dL, complete blood count, serum vitamin B12, serum folate (s-F), reactive oxygen species (ROS), thiol groups (−SH), total antioxidant activity (TAOC), serum homocysteine (Hcy), and intraerythrocyte folate (ery-F) were measured. Results. The mean levels of Hcy (21.1 &mgr;M vs. <10 &mgr;M), ROS (302.7 U. Carr (Carratelli units) vs. 250–300 U. Carr), and TAOC (410.6 &mgr;mol/HclO/mL vs. >350 &mgr;mol/HclO/mL), were higher than the reference interval, whereas −SH groups, vitamin B12, s-F, and ery-F were within the normal range. In the multivariate model, plasma creatinine (P =0.0062), vitamin B12 (P =0.0121), and TAOC (P =0.0007) were independently associated with oxidative stress. At multiple regression analysis, −SH groups and ROS were directly and inversely related to hematocrit (P =0.0007 and P =0.0073). There was also a negative correlation between −SH groups and blood pressure levels (P =0.0095). Conclusions. Renal transplant patients have a pattern of increased oxidant stress that is counterbalanced by an enhancement of the antioxidant mechanisms. Besides the well-known risk factors, the authors found that anemia is an independent risk factor for an increase of ROS. Further studies are needed to evaluate whether the correction of anemia might prevent or reduce the oxidative stress in renal transplant patients.

Clinical relevance of expression of the CIP/KIP cell-cycle inhibitors p21 and p27 in laryngeal cancer.

PURPOSE To investigate the prognostic relevance of p21 and p27 protein expression in laryngeal squamous cell carcinoma (LSCC). PATIENTS AND METHODS We have analyzed by immunohistochemistry p21 and p27 expression in a series of 132 patients who underwent surgical resection of their LSCC and who had previously been investigated for p53 gene mutations and cyclin D1 expression. The tumors were considered low expressors when they had </= 10% of p21 and </= 50% of p27 immunoreactive neoplastic cells. RESULTS In 41 cases (31.1%), p21 was expressed in </= 10% of neoplastic cells; in 91 cases (68.9%), it was expressed in more than 10% of neoplastic cells. In 11 cases (8.3%), p27 was expressed in less than 5% of neoplastic cells; in 39 cases (29.6%), it was expressed in 5% to 50% of neoplastic cells; and in 82 cases (62.1%), it was expressed in more than 50% of the neoplastic cells. Low levels of p21 expression were associated with poor histologic differentiation and lymph node metastases. Low levels of p27 expression were associated with tumor extension and advanced clinical stage. Expression of p21 and p27 was not correlated with p53 gene status, and low p27 expression was more frequently detected in the cyclin D1-positive cases, with a borderline level of statistical significance. At univariate analysis, anatomic site, tumor extension, clinical stage, high cyclin D1 expression, and low p27 expression were significantly associated with reduced disease-free and overall survival rates. At multivariate analysis, high cyclin D1 expression and low p27 expression were the only significant covariates. The patients with a cyclin D1(+)/p27(-) phenotype had the poorest disease-free and overall survival rates. CONCLUSION Our study provides evidence that the immunohistochemical evaluation of p27 expression is a significant independent predictor of prognosis in laryngeal carcinoma.