Ten-year survival results in metastatic renal cell cancer patients treated with monoimmunotherapy with subcutaneous low-dose interleukin-2.

After more than ten years of clinical investigations, IL-2 immunotherapy appears to constitute the most effective treatment metastatic renal cell carcinoma (RCC),at least in terms of survival time. Moreover, it has been shown that comparable results may be achieved with different schedules of treatment, including intravenous high-dose or subcutaneous (SC) low-dose IL-2. Finally, it has been demonstrated that the association with interferon-alpha does not increase the efficacy of IL-2. Therefore, SC low-dose IL-2 alone may be considered as an adequate therapy for metastatic RCC. In fact, our previous studies with SC low-dose IL-2 alone have shown a 5-year survival time similar to that described with higher and more toxic doses of IL-2. This study was performed to analyze the 10-year survival results with SC low-dose IL-2 in metastatic RCC The study included 44 consecutive metastatic RCC patients, with a minimum follow-up of 120 months. One comlete immunotherapeutic cycle consisted of IL-2 at 3 million IU twice/day SC, 5 days/week for 6 consecutive weeks. In non-progressing patients, a second cycle was planned after a 21-day rest period. Complete response (CR) was achieved in only 2 out of 44 (4%) patients, while partial response (PR) was obtained in 8 out of /44 (18%) patients. Therefore, the response rate (CR + PR) was 10 out of 44 (22%), with a median response duration of 12 months. Stable disease (SD) occurred in 21 out of 44 (48%) patients,whereas the remaining 13 out of 44 (30%) patients had a progressive disease (PD). A 10-year survival was achieved in 2 out of 44 (5%) and the percent of survival at 10 years was significantly higher in patients with response or SD than in those with PD. This study confirms at 10 years the results previously referred to by other authors and by ourselves, in showing that the efficacy of IL-2 immunotherapy in terms of control of cancer growth is associated with a clear prolongation of the overall survival time in metastatic RCC.

Esophagogastroduodenoscopy in chronic hemodialysis patients: 2-year clinical experience in a renal unit.

INTRODUCTION: Upper gastrointestinal (UGI) disorders are frequent in uremic patients and esophagogastroduodenoscopy (OGD) is an important investigation for their management. SUBJECTS AND METHODS: From January 1, 1997 to December 31, 1998, 57 endoscopies were performed in 96 hemodialysis patients (aged 65+/-12 years, 68 M, 28 F, dialysis duration 51+/-58 months) chronically treated in our unit in that period. The reasons for prescribing OGD were: anemia, after exclusion of poor response to EPO, in 26 patients (mean decrease in hemoglobin (Hb) levels 2.6+/-1.3 g/dl: the reference Hb level was the mean value measured before Hb decrease), dyspepsia in 11 and in preparation for renal transplantation in 20 patients. Twelve patients were diabetics, 24 smokers, 41 alcohol drinkers, 13 had hepatitis B or C, 6 were non-steroidal anti-inflammatory drugs (NSAIDs) abusers for bone pain and 21 were taking H2 receptor antagonists or proton-pump inhibitors chronically. Multiple biopsies of gastric mucosa were performed in 38 patients. RESULTS: Endoscopy revealed normal mucosa in 17.5% of cases, whilst chronic gastritis was diagnosed in 30%. Chronic gastritis was also the commonest microscopic abnormality diagnosed in 71.5% of biopsies. Anemic and non-anemic patients were matched and the 2 groups did not show significant differences in endoscopic findings and histological appearance. Thirteen patients had Helicobacter pylori (HP) infection demonstrated by biopsy specimen examination and were treated by metronidazole, clarithromycin and omeprazole. A logistic regression analysis was carried out in all subjects, considering the decrement in Hb as a dependent variable and demographic and clinical characteristics as independent variables. The analysis demonstrates that age (odds ratio 1.05; p < 0.05), NSAIDs abuse (odds ratio 15.6; p < 0.05) and HP infection (odds ratio 16.7; p < 0.01) were independently related to Hb decrease. CONCLUSIONS: In our experience, non-EPO-related anemia and dyspepsia are frequent features in hemodialysis patients. OGD is frequently requested (30% of patients/year) and 83% of patients investigated had abnormal UGI mucosa. Underlying mucosal inflammation might promote UGI bleeding but is not likely to be the cause, making it a necessary superimposed factor such as NSAIDs or HP infection.

A phase II study of chemoneuroimmunotherapy with platinum, subcutaneous low-dose interleukin-2 and the pineal neurohormone melatonin (P.I.M.) as a second-line therapy in metastatic melanoma patients progressing on dacarbazine plus interferon-alpha.

Immunochemotherapeutic combinations containing IL-2 theoretically represent the most effective therapies for metastatic melanoma, particularly in association with cisplatin (CDDP); however, both IL-2 and CDDP have been generally utilized at high doses, with the consequence of considerable toxicity. According to psychoneuroimmunological knowledge, the antitumor activity of IL-2 has been proven to be enhanced by the immunomodulating pineal neurohormone melatonin (MLT), which has also been shown to increase the cytotoxicity of cancer chemotherapy and reduce its toxicity. On this basis, a study was planned with low-dose IL-2 and CDDP in association with MLT as a second-line therapy for metastatic melanoma patients progressing on dacarbazine plus interferon-alpha. The study included 13 evaluable patients. CDDP was injected i.v. at 30 mg/m2/day for 3 days every 21 days. IL-2 was administered s.c. at 3 million IU/day from days 4 to 9 and from days 11 to 16 of the cycle. Finally, MLT was given orally at 20 mg/day in the evening, every day without interruption. One patient obtained a complete response (CR), while partial response (PR) was achieved in 3 other patients. Therefore, the objective tumor response-rate (CR + PR) was 4 out of 13 (31%). A stable disease occurred in 5 patients, whereas the remaining 4 patients had a progressive disease. The treatment was extremely well-tolerated in all patients and, in particular, no CDDP-related neurotoxicity was observed. The results of this preliminary study would suggest that low-dose CDDP and IL-2 in association with the pineal hormone MLT (P.I.M. schedule), given as a second line therapy, is an effective and well-tolerated treatment for metastatic melanoma, with a clinical efficacy at least comparable to that obtained with a first-line therapy of dacarbazine plus interferon-alpha.

Clinical characteristics associated to atrial fibrillation in chronic hemodialysis patients.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia diagnosed in non-uremic patients and its prevalence increases in older subjects, however, information concerning AF in dialysis patients is scarce. Therefore, we carried out a prospective cross-sectional study from September 1996 to December 1996 in order to evaluate the prevalence and some of the clinical characteristics associated to AF in hemodialysis (HD) patients. SUBJECTS AND METHODS: 316 HD patients (age 63 +/- 12 years, dialysis duration 69 +/- 71 months) treated in three different hospital-based units were studied. Standard 12-lead electrocardiograms (ECGs) carried out in the interdialytic day during the study period were reviewed. Data concerning age, history of ischemic heart disease (IHD), cerebrovascular disease (CVD), peripheral vascular disease (PVD), presence of diabetes, smoking history and antihypertensive therapy were collected. Systolic and diastolic blood pressure, fasting cholesterol and triglycerides, albumin and hemoglobin were also derived from the clinical records. Performance status was assessed by Karnofsky index (Ki). RESULTS: 74 patients (23.4%) had persistent AF, i.e. presence of AF in all (at least two) ECGs performed in the study time. Patients with AF were older (age 69 +/- 10 vs 62 +/- 12 years, p < 0.001), had lower Ki (54 +/- 20 vs 68 +/- 17, p < 0.01), cholesterol (182 +/- 46 vs 198 +/- 52 mg/dl, p < 0.01) and albumin (3.9 +/- 0.5 vs 4.1 +/- 0.5 g/dl, p < 0.001) compared to those with no AF. Prevalence of IHD (44.5% vs 19%, p < 0.05) and PVD (23% vs 11%, p < 0.05) was higher among AF patients. Logistic regression analysis showed that IHD (p < 0.001) and Ki (p < 0.01) were independently associated to AF. CONCLUSION: We conclude that AF is a frequent arrhythmia in HD patients treated in hospital-based dialysis units, especially in those with low performance status. It appears to be associated to the atherosclerotic damage of coronary arterial tree. Prospective studies are necessary to assess whether it could contribute to cardiovascular morbidity and mortality in end-stage renal disease.

Lamivudine for treating active hepatitis B in renal transplant recipients: a case report.

AIM: Chronic hepatitis B is still a matter of concern among renal transplantation patients and patients waiting for a renal transplant since it influences negatively morbidity and mortality. Morbidity and mortality are associated with HBV replication. Lamivudine is a new antiviral agent whose use has been advocated to treat HBV-infected liver transplanted patients. SUBJECT AND METHODS: Here we present our experience with an HBV-positive kidney-liver transplanted patient treated with lamivudine after transplantation. RESULTS: After lamivudine was started HBV-DNA became negative (chemiluminescence, Digene Hybrid Capture System, USA 1997) and ALT levels returned to normal. After eighteen months and after steroid pulses treatment for acute rejection, HBV-DNA became positive again, probably due to virus mutation. Lamivudine treatment was not withdrawn since it has been suggested that the mutant form might be less pathogenic than the wild one. To this extent, more than 10 months after, our patient is still in a good clinical general condition and still takes lamivudine 75 mg/day. No lamivudine-related side effects were recorded. CONCLUSIONS: Our case confirms that lamivudine is a safe and useful tool in treating renal transplant recipients with chronic hepatitis B.

Five-year survival results of subcutaneous low-dose immunotherapy with interleukin-2 alone in metastatic renal cell cancer patients.

After the discovery of its essential role in anticancer immunity, IL-2 cancer immunotherapy has shown that comparable results may be obtained with different schedules, including intravenous high-dose IL-2 as a bolus or as a 24-hour intravenous infusion or prolonged subcutaneous injection of low-dose IL-2 with or without IFN-alpha. This study shows the long-term results obtained in 92 metastatic renal cell cancer (RCC) patients with low-dose subcutaneous IL-2, which was given at 3 million IU twice/day for 5 days/week for 6 consecutive weeks. In nonprogressing patients, a second cycle was planned after a 21-day rest period, followed by maintenance therapy consisting of 5 days of treatment every month until disease progression. Complete response (CR) was achieved in only 2/92 (2%) patients, and partial response (PR) was observed in 19 patients (21%). Therefore, the response rate (CR + PR) was 21/92 (23%), with a median duration of response of 25 months. Stable disease (SD) occurred in 37 patients (40%), whereas the other 34 (37%) had a progressive disease (PD). The response rate was significantly higher in patients with a disease-free interval of >1 year than in those with a lower interval, in patients with a high performance status (PS) than in those with a low PS, and in patients with sites of disease other than the liver. A 5-year survival was obtained in 9/92 (9%) patients, and the percent of survival was significantly higher in patients with a response or SD than in those with PD. The treatment was well tolerated in all patients. This study confirms that low-dose subcutaneous IL-2 alone in an effective and well tolerated therapy of metastatic RCC, with results comparable to those described with more aggressive and toxic IL-2 schedules.

The effect of metabolic control on development and progression of diabetic nephropathy.

The progressively growing number of patients with end-stage renal failure (ESRF) associated with diabetes mellitus and requiring renal replacement therapy (RRT) stimulated both nephrologists and diabetologists to investigate the mechanisms linking hyperglycaemia to diabetic renal failure and to set up measures to prevent the onset and slow the progression of diabetic nephropathy. Over the last few decades, a large number of studies have investigated both the incidence of diabetic nephropathy and the relationship between metabolic control and the development of diabetic nephropathy. Chronologically, the first type of diabetes and diabetic nephropathy to be studied was type I, and it is only in recent years that metabolic control has been proven to be a contributor to the development of nephropathy in such patients. Recently, the DCCT demonstrated that metabolic control in the prealbuminuric phase was effective in reducing the incidence of microalbuminuria, even if it was unable to reduce the incidence of overt proteinuria in patients with type I diabetes and established proteinuria. On the other hand, in type II diabetes, the number of studies demonstrating a favourable effect of metabolic control on onset and progression of diabetic nephropathy is only slightly greater than those that failed to show a favourable effect. This feature may suggest that in type II patients, genetic and ethnic differences, nutritional aspects, lifestyle and other confounding factors may play a relevant role in the course of the disease. However, the trials performed and the retrospective analyses generally agree that glycated haemoglobin two standard deviations greater than the mean is related to a worsening in progression of diabetic nephropathy and to an enhanced risk of other complications. In general, a glycated haemoglobin < or =8% seems advisable. Moreover, in both type I and type II, greater emphasis should be placed on the major risk factors such as hypertension, smoking habits and hyperlipidaemia.

Is the red cell morphology really useful to detect the source of hematuria?

Morphological analysis of urinary red blood cells by phase-contrast microscopy to identify the source of bleeding was, and still is, widely used also as a starting point for workup. To evaluate the reliability of this approach, we studied 129 outpatients presenting with persistent isolated microhematuria; 31 subjects also had mild proteinuria (1 g/day), while 21 had pathological albumin levels. All patients were followed for a period of 6 years. During this time, 6 patients underwent renal biopsy for the onset of macrohematuria episodes and proteinuria of 2-3 g/day. Glomerular bleeding was identified in only 14.7% of the patients, despite the persistent microhematuria and the presence of proteinuria or microalbuminuria. The renal origin of the urinary erythrocytes correlated with histological findings in only 2 of 6 patients with dysmorphic erythrocytes who developed proteinuria (exceeding 1 g/day), and none with isomorphic erythrocytes showed urological abnormalities. These results challenge the validity and reliability of morphological analysis to identify the source of bleeding along the urinary tract.

[7-year-follow up (1987-1994) of a population with asymptomatic persistent microhematuria and normal renal function]. / Follow-up di 7 anni (1987-1994) su una popolazione con microematuria persistente asintomatica e funzione renale integra.

A group od 129 patients with persistent asymptomatic microhematuria was studied for 7 years (1987-1994). At the beginning of the study, 31 patients showed mild proteinuria (less than 1 g/day) and in the rest of 98 patients, 21 showed microalbuminuria. At the end of the study none of the patients developed renal failure, urological disease, hypertension. Six patients out of 31 with mild proteinuria (less than 1 g/day), developed an increase of proteinuria over 2 and 3/day and underwent a renal biopsy while 2 out of 21 patients with altered microalbuminuria completely recovered after the follow-up period. The rest of 77 patients at the end of the study still showed isolated microhematuria. The results of this study support the hypothesis that in a population with age range between 16 and 28 years, the presence of persistent microhematuria, also associated with mild proteinuria, even for a long time, does not seem to lead to changes of renal function or to urological diseases.

Carotid artery lesions in patients with nondiabetic chronic renal failure.

Atherosclerotic complications are the leading cause of death in chronic renal failure (CRF) patients. Therefore, we wished to investigate the prevalence of carotid artery lesions (CALs) in these subjects. Two groups were evaluated by high-resolution echo Doppler: group 1 included 103 patients (68 males and 35 females) affected by nonnephrotic CRF and group 2 included 100 control subjects (60 males and 40 females). The prevalence of hypertension was 84% in both groups. The exclusion criteria included diabetes mellitus and symptoms of cerebrovascular disease. In the two groups we evaluated clinical history, physical examination, total cholesterol, triglycerides, fibrinogen, blood cell counts, blood urea nitrogen, creatinine, 24-hour proteinuria, and urine analysis. In group 1 patients the following lipid profile parameters were also evaluated: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, lipoprotein(a), ApoAI, ApoAII, and ApoB. Group 1 had higher triglycerides and fibrinogen than group 2. A lower body mass index was found in group 1 than in group 2. The prevalence of CALs was significantly higher in the CRF patients than in the control subjects (62% v 47%; P = 0.04). The difference between the two groups was more striking among normotensive patients (62% v 19%; P = 0.03). All CRF patients affected by peripheral arterial disease and 86% of those having coronary artery disease had associated CALs. In CRF patients the severity of CALs was positively correlated to age, white blood cell count, triglycerides, and fibrinogen. Nondiabetic CRF patients have a higher prevalence of carotid artery lesions than control subjects. Several factors besides hypertension, including lipids, blood coagulation, and leukocytes, could contribute to the accelerated atherosclerosis of CRF patients.