A retrospective study of 37 patients with haematological malignancy (21 acute myeloid leukaemia, 11 acute lymphoid leukaemia, two lymphoma, two hairy cell leukaemia, one Hodgkin's disease) and histologically documented mucormycosis was conducted to evaluate the clinical characteristics and ascertain the factors which influenced the outcome from mycotic infection. Patients were admitted to 18 haematology divisions in tertiary care or university hospitals in Italy between 1987 and 1995.Fever, thoracic pain, dyspnoea and cough were the most frequent presenting symptoms. At the onset, 89% patients were neutropenic (neutrophil counts <0.5 x 10(9)/l) with a median duration of previous neutropenia of 14 d (range 6-60). The most frequent sites of infection were lungs (81%), CNS (27%), sinus (16%), liver (16%) and orbital space (10%). Only three patients were asymptomatic. A correct in vivo diagnosis was made in only 13 (35%) patients. When performed, thoracic and cranial CT scan were the most useful diagnostic investigations. Despite the fact that 26 febrile patients were treated with empirical antifungal treatment, 28 of the 37 patients (76%) died from fungal infection at a median time of 17 d from the onset of clinical symptoms. Nine patients were cured by antifungal therapy plus, in five cases, radical surgery procedures.An analysis of factors influencing outcome demonstrated that the resolution of chemotherapy-induced neutropenia and prolonged treatment with amphotericin B and, if feasible, radical surgical debridement treatment, were significantly correlated with recovery from infection.Mucormycosis, a rare filamentous fungal infection that occurs most frequently in neutropenic acute leukaemia patients, is characterized by a high mortality rate. Extensive and aggressive diagnostic and therapeutic procedures are essential to improve the prognosis in these patients.

Differences among 5-HT3 receptor antagonists have been reported in pharmacological studies with regard to selectivity of receptor binding, potency, duration of action and dose-response curves. However, whether these pharmacological differences can affect clinical efficacy and safety remains to be determined. A careful analysis of the literature revealed 22 comparative studies among the 5-HT3 receptor antagonists available for review. Unfortunately, several of these trials have some important shortcomings especially in the study design, the size of population studied and the type of anti-emetic treatment selected, making their conclusions often difficult to interpret. However, among these studies, seven large, double-blind clinical trials have clearly shown that the antiemetic activity and tolerability of ondansetron, granisetron, tropisetron and dolasetron is almost identical at least in the prevention of cisplatin-induced emesis. Therefore, from the efficacy and safety point of view, there is no reason to prefer one with respect to the other compound. From the economic perspective, instead, differences may exist and they are strictly related to the dose and schedule of administration chosen for each compound. The information available on the use of 5-HT3 receptor antagonists in the prevention of emesis induced by moderately emetogenic chemotherapy is at best scant. Contrasting results have been reported and only one well-conducted study has been published in full. Therefore, the possible differences among the various compounds are difficult to evaluate. More studies should be carried out in this group of patients.

Background In diabetic nephropathy, angiotensin-converting-enzyme (ACE) inhibitors have a greater effect than other antihypertensive drugs on proteinuria and the progressive decline in glomerular filtration rate (GFR). Whether this difference applies to progression of nondiabetic proteinuric nephropathies is not clear. The Ramipril Efficacy In Nephropathy study of chronic nondiabetic nephropathies aimed to address whether glomerular protein traffic influences renal-disease progression, and whether an ACE inhibitor was superior to conventional treatment, with the same blood-pressure control, in reducing proteinuria, limiting GFR decline, and preventing endstage renal disease.Methods In this prospective double-blind trial, 352 patients were classified according to baseline proteinuria (stratum 1: 1-3 g/24 h; stratum 2: greater than or equal to 3 g/24 h), and randomly assigned ramipril or placebo plus conventional antihypertensive therapy targeted at achieving diastolic blood pressure under 90 mm Hg. The primary endpoint was the rate of GFR decline. Analysis was by intention to treat.Findings At the second planned interim analysis, the difference in decline in GFR between the ramipril and placebo groups in stratum 2 was highly significant (p=0.001). The Independent Adjudicating Panel therefore decided to open the randomisation code and do the final analysis in this stratum (stratum 1 continued in the trial). Data (at least three GFR measurements including baseline) were available for 56 ramipril-assigned patients and 61 placebo-assigned patients. The decline in GFR per month was significantly lower in the ramipril group than the placebo group (0.53 [0.08] vs 0.88 [0.13] mL/min, p=0.03). Among the ramipril-assigned patients, percentage reduction in proteinuria was inversely correlated with decline in GFR (p=0.035) and predicted the reduction in risk of doubling of baseline creatinine or endstage renal failure (18 ramipril vs 40 placebo, p=0.04). The risk of progression was still significantly reduced after adjustment for changes in systolic (p=0.04) and diastolic (p=0.04) blood pressure, but not after adjustment for changes in proteinuria. Blood-pressure control and the overall number of cardiovascular events were similar in the two treatment groups.Interpretation In chronic nephropathies with proteinuria of 3 g or more per 24 h, ramipril safely reduces proteinuria and the rate of GFR decline to an extent that seems to exceed the reduction expected for the degree of blood-pressure lowering.

Background. The pattern and prognostic factors of delayed nausea an d vomiting induced by moderately emetogenic chemotherapy have not yet been adequately studied.Patients and methods. Data are derived from a large and well defined population of patients studied to evaluate the efficacy and tolerability of granisetron: dexamethasone and their combination in the control of acute emesis over repeated cycles of moderately emetogenic chemotherapy. Patients were monitored on days 2-5 without receiving any prophylactic treatment for delayed emesis.Results. There were 395 evaluable patients at the first, 352 at the second and 319 at the third cycle of chemotherapy. Overall, 32.7% patients suffered symptoms of delayed vomiting and/or moderate-severe nausea at the first, 32.1% at the second and 35.1% at the third cycle of chemotherapy. More precisely, the incidence of delayed vomiting was 21.3% at the first, 18.5% at the second and 21.0% at the third cycle of chemotherapy, while the incidence of delayed moderate-severe nausea was 25.1%, 25.0% and 26.0%, respectively. The incidence of delayed vomiting and moderate-severe nausea was very low in patients who obtained good control of acute vomiting and moderate-severe nausea, but it remained substantial in patients who experienced them during the first 24 hours after chemotherapy. In fact, at first/second/third cycle of chemotherapy delayed vomiting occurred in 12.3%/11.8%/ 13.1% of patients who did not suffer from acute vomiting and in 54.1%148.4%/55.9% of those who had acute vomiting, respectively. Similar data were obtained for delayed moderate-severe nausea.Conclusions. Patients without acute vomiting or moderate-severe acute nausea may not need any antiemetic prophylaxis for delayed vomiting or nausea, while those with a history of acute vomiting or moderate-severe acute nausea should always be treated for delayed emesis. Selection bias and dependence effect of delayed emesis on acute emesis can cause misinterpretation of data derived from clinical trials in patients submitted to multiple cycles of chemotherapy.

We retrospectively studied a consecutive series of 100 patients with acute leukemia and aspergillosis to evaluate the clinical findings and risk factors for colonization of the central nervous system (CNS) by Aspergillus species. The diagnosis of CNS aspergillosis was made in 14 patients on the basis of the following criteria: neurological signs of CNS involvement (13 of 14 patients); cerebral CT scan findings (9 of 12); microbiological findings (6 of 12); and histological findings at autopsy (11 of 11). The majority of patients had severe neurological complications (i.e., hemiparesis or seizures), due mainly to brain abscesses or mycetomas. Autopsies were performed on 11 of 14 patients and provided evidence that CNS localization was secondary to invasive aspergillosis; in each case, the most likely primary focus of infection was the lung. Although all patients had received oral antimycotic prophylaxis and had received timely empirical antifungal treatment, they all died within a median time of 5 days from the onset of neurological symptoms. Analysis of the characteristics of patients with invasive aspergillosis did not reveal any difference between those with CNS localization and those without CNS localization.

This multicentre, randomised, double-blind study was designed to compare the anti-emetic efficacy and safety of single oral doses of dolasetron mesilate with that of the approved oral, multiple-dose regimen of ondansetron in 399 cancer patients receiving moderately emetogenic chemotherapy. Single oral doses of 25, 50, 100 or 200 mg of dolasetron mesilate were administered 1 h prior to the initiation of moderately emetogenic chemotherapy. Multiple doses of ondansetron (8 mg × 3 or 8 mg × 4) capsules, or matching placebo for patients randomised to dolasetron, were given 1.5 h before and 6.5, 14.5 and 22.5 h after the start of chemotherapy (total dose = 32 mg). Efficacy was evaluated for 24 h after the initiation of chemotherapy. The most frequently used moderately emetogenic chemotherapeutic agents included cyclophosphamide, doxorubicin and carboplatin (28.4, 23.1 and 20.6% of patients, respectively). A statistically significant (P < 0.001) linear dose-response relationship was observed over the entire dolasetron dosage range for all efficacy parameters. Complete response rates were 45.0, 49.4, 60.5 and 76.3% for 25, 50, 100 and 200 mg dolasetron mesilate, respectively, and 72.3% of ondansetron patients. A single oral 200 mg dolasetron mesilate dose was therapeutically equivalent to ondansetron for all efficacy parameters and patient satisfaction was high. Overall, there were no significant differences in the incidence of adverse events between any of the dolasetron mesilate doses, or between dolasetron and ondansetron. Headache was most frequently reported (approximately 15% for each drug). No clinically important changes in vital signs or clinical laboratory parameters were observed with either drug. In conclusion, a single oral 200 mg dolasetron mesilate dose was therapeutically equivalent to multiple-dose ondansetron in the prevention of emesis and nausea following moderately emetogenic chemotherapy. Copyright © 1996 Elsevier Science Ltd

Combinations of beta-lactams plus aminoglycosides have been standard therapy for suspected infections in granulocytopenic cancer patients, especially those with profound long-lasting granulocytopenia. With the advent of new broad-spectrum bactericidal antibiotics such as extended-spectrum cephalosporins or carbapenems, the need to combine beta-lactams with aminoglycosides became more controversial. The objective of this prospective randomized multicenter study was to compare the efficacy, safety, and tolerance of meropenem monotherapy with those of the combination of ceftazidime plus amikacin for the empirical treatment of fever in granulocytopenic cancer patients. Of 1,034 randomized patients, 958 were assessable in the intent-to-treat analysis for response to antibacterial therapy, including 483 in the meropenem group and 475 in the ceftazidime-plus-amikacin group. The median durations of neutropenia were 16 and 17 days, respectively. A successful outcome was reported in 270 of 483 (56%) patients treated with monotherapy compared with 245 of 475 (52%) patients treated with the combination group (P = 0.20). The success rates in the monotherapy group and the combination group were similar by type of infection (single gram-negative bacteremia, single gram-positive bacteremia, clinically documented infection, and possible infection). The occurrence of further infections assessed in patients for whom the allocated regimen was not modified did not differ between the two groups (12% in both groups). Mortality due to the presenting infection or further infection was relatively low (8 patients treated with the monotherapy compared with 13 patients treated with the combination). A total of 1,027 patients were evaluable for adverse events; the proportion of those who developed adverse effects was similar between the two groups (29% in both groups), and only 19 (4%) patients in the monotherapy group and 31 (6%) in the combination group experienced an adverse event related or probably related to the study drug. Allergic reactions were the only reason for stopping the protocol antibiotic(s) (3 and 5 patients, respectively). This study confirms that monotherapy with meropenem is as effective as the combination of ceftazidime plus amikacin for the empiric treatment of fever in persistently granulocytopenic cancer patients, and both regimens were well tolerated.

Objective: to evaluate the safety and efficacy of a stable prostaglandin E(1) added to the usual therapeutic practice (either invasive or not) in patients with chronic critical leg ischemia.Design: multicenter, controlled, randomised, open label trial.Setting: a representative sample (56 centers) of vascular and general surgery, angiology and general medicine departments of the Italian National Health Service.Patients: all patients suffering from leg ischemia considered as chronic and critical depending on the presence of persistently recurring rest pain for more than two weeks and/or foot ulceration or gangrene.Intervention: a daily i.v. infusion of 60 mu g of alprostadil alpha-cyclodextrine for the overall hospital stay, up to a maximum of 28 days (as an adjunct to the standard procedures adopted In each center) to patients randomly assigned to the experimental treatment.Measures: the primary evaluation of efficacy is based on the expected reduction of major amputations or persistence of critical leg ischemia at six months, The sum of these ''peripheral'' events, of death and of non-fatal myocardial infarction and stroke is used as a more comprehensive evaluation of the risk/benefit profile of the experimental treatment.Results: a reduction from 40% to 32% of the incidence of the primary end-points is the trial hypothesis, The recruitment of 1500 patients is required to verify this.Conclusions: this large-scale trial aims at providing a reliable estimate of the possibility of modifying hard end-points such as death and amputation in patients with critical leg ischemia.

Infection remains the major cause of morbidity and mortality for cancer patients who become granulocytopenic as a result of chemotherapy. Treatment is instituted at the first sign of infection and before the identification of the causative pathogen (empiric treatment). For many years, standard empiric treatment has been combination therapy with beta-lactams and aminoglycosides. The advent of new broad spectrum antibiotics, such as ceftazidime, has introduced the possibility of empiric monotherapy. However, ceftazidime has only modest activity against infections due to Gram-positive organisms, which presently account for at least 50% of infections in neutropenic patients, and resistance to ceftazidime in Gram-negative organisms has been documented. Meropenem is a new carbapenem with a broad antibacterial spectrum with greater in vitro activity than ceftazidime against staphylococci, streptococci and many Gram-negative bacteria. A comparative study of intravenous meropenem (1 g 8-hourly) and ceftazidime (2 g 8-hourly) in the empiric treatment of febrile neutropenic patients with haematological malignancies has been conducted. In an open, randomised trial of the treatment of 338 febrile episodes, all patients survived to 72 hours on both treatments, and meropenem was found to be at least as clinically effective as ceftazidime in eradicating both Gram-positive and Gram-negative infections. Early modification of treatment (48-72 hours) was required for approximately 40% of patients but occurred less frequently in patients treated with meropenem than with ceftazidime. Tolerability of both treatments was good. Meropenem should be compared with standard combination therapy in a large randomised trial before adopting it as empiric monotherapy for febrile neutropenic patients.

In ischaemic stroke, thrombolytic drugs speed the recanalisation of intracerebral arteries. The effects of aspirin are not known. A trial was conducted to determine whether, separately or together, streptokinase and aspirin have clinical benefits in acute ischaemic stroke similar to those in acute myocardial infarction. 622 patients with acute ischaemic stroke within 6 hours of symptom onset were randomised with a 2x2 factorial design to (i) a 1-hour intravenous infusion of 1 . 5 MU streptokinase, (ii) 300 mg/day buffered aspirin for 10 days, (iii) both active treatments, or (iv) neither. Early results raised a question whether the trial should be continued.Streptokinase (alone or with aspirin) was associated with an excess of 10-day case fatality (odds ratio 2 . 7; 95% confidence interval 1 . 7-4 . 3; 2p<0.00001). Of the four groups randomised, only patients allocated to streptokinase plus aspirin had a significantly higher risk of early death than those given neither streptokinase nor aspirin (odds ratio 3 . 5; 95% CI 1 . 9-6 . 5; 2p<0.00001). Streptokinase (alone or with aspirin) and aspirin (alone or with streptokinase) reduced, albeit not significantly, the incidence of combined six-month case fatality and severe disability: odds ratio for streptokinase 0 . 9 (95% CI 0 . 7-1 . 3) and odds ratio for aspirin 0 . 9 (95% CI 0 . 6-1 . 3).The risk of early death with thrombolytic treatments should be weighed against the potential benefit of a marginal reduction of severe disability after the first six months.

Background. Serotonin-receptor antagonists seem to be as effective as corticosteroids in preventing emesis induced by moderately emetogenic antineoplastic agents. We compared the antiemetic effect of a combination of granisetron and dexamethasone with that of granisetron or dexamethasone administered alone.Methods. From December 1992 to January 1994, 428 consecutive patients who were to receive moderately emetogenic chemotherapy for the first time (600 to 1000 mg of cyclophosphamide per square meter of body-surface area, greater than or equal to 50 mg of doxorubicin per square meter, greater than or equal to 75 mg of epirubicin per square meter, or greater than or equal to 300 mg of carboplatin per square meter, alone or in some combination) were enrolled in a double-blind, randomized, multicenter study evaluating the efficacy and toxicity of three antiemetic regimens. The following antiemetic regimens were used: 8 mg of dexamethasone given intravenously before chemotherapy plus 4 mg given orally immediately before chemotherapy and then every six hours for a total of four doses, 3 mg of granisetron given intravenously be fore chemotherapy, or a combination of granisetron and dexamethasone given in the doses used for the single-drug regimens.Results. We evaluated 408 patients (136 receiving dexamethasone, 137 receiving granisetron, and 135 receiving both drugs), In the first 24 hours after chemotherapy, complete protection from vomiting and complete protection from nausea were achieved in 70.6 and 55.1 percent, respectively, of the patients receiving dexamethasone, in 72.3 and 48.2 percent of those receiving granisetron, and in 92.6 and 71.9 percent of those receiving granisetron combined with dexamethasone (P<0.001 for all comparisons). Patients who received granisetron alone had less protection from delayed vomiting and nausea than those who received dexamethasone alone or the two drugs combined. All the regimens were equally well tolerated.Conclusion. Granisetron combined with dexamethasone was the most effective regimen for the prevention of emesis induced by moderately emetogenic chemotherapy.

The most common complication of the vascular access sites in patients on chronic hemodialysis is represented by thrombotic occlusions. The STOP Study is a large, prospective, multicenter, double-blind, placebo-controlled study involving; over 800 patients to be treated for one year with either picotamide, a new antiplatelet agent, or with placebo. The aim of the study is to assess whether an antithrombotic treatment with picotamide can prevent the occurrence of thrombotic occlusions of the arterial venous shunts in a general population of patients undergoing hemodialysis under current management procedures. The rationale and design of the study, which is the first trial large enough to provide reliable information on thrombotic occlusion in patients on chronic hemodialysis with permanent internal vascular accesses, are described.

This 24-hour trial randomized 398 cancer patients at 26 centers to 25, 50, 100, 200 mg DM or OND (8 mg × 4; 8 mg × 3 at four centers) prior to IV CT primarily with cyclophosphamide (≥ 600 mg/m2), doxorubicin (≥ 40 mg/m2), or carboplatin (≥ 300 mg/m2), Efficacy was assessed by complete response (CR: 0 emetic episodes [EE] and no rescue medication [RM]); CR + major response (CMR: 1–2 EE and no RM); and patient ratings of nausea and satisfaction on a 100 mm visual analog scale (VAS). A statistically significant linear trend with dose was observed across the 25, 50, 100, 200 mg doses of DM (P < 0.0001) both for CR (45.0%, 49.4%, 60.5%, and 76.3%), respectively, and for CMR. The CR rate for OND was 72.3%. CR and CMR rates for DM 200 mg were equivalent to OND. Linear trends across the four DM doses were statistically significant for median time to first EE/RM, for patient VAS nausea-level scores, and for the combined parameter of CR + no nausea (< 5 mm VAS), (P < 0.0001 for all parameters). For the stringent CR + no nausea test, DM 200 mg (63.8%) was numerically superior to OND (49.4%). DM and OND were equivalent in the safety analysis and there was no statistically significant trends with dose for adverse events with DM. In conclusion, a single oral dose of DM 200 mg was equivalent to multiple doses of OND in preventing nausea and emesis induced by moderately emetogenic CT. This 24-hour trial randomized 398 cancer patients at 26 centers to 25, 50, 100, 200 mg DM or OND (8 mg × 4; 8 mg × 3 at four centers) prior to IV CT primarily with cyclophosphamide (≥ 600 mg/m2), doxorubicin (≥ 40 mg/m2), or carboplatin (≥ 300 mg/m2), Efficacy was assessed by complete response (CR: 0 emetic episodes [EE] and no rescue medication [RM]); CR + major response (CMR: 1–2 EE and no RM); and patient ratings of nausea and satisfaction on a 100 mm visual analog scale (VAS). A statistically significant linear trend with dose was observed across the 25, 50, 100, 200 mg doses of DM (P < 0.0001) both for CR (45.0%, 49.4%, 60.5%, and 76.3%), respectively, and for CMR. The CR rate for OND was 72.3%. CR and CMR rates for DM 200 mg were equivalent to OND. Linear trends across the four DM doses were statistically significant for median time to first EE/RM, for patient VAS nausea-level scores, and for the combined parameter of CR + no nausea (< 5 mm VAS), (P < 0.0001 for all parameters). For the stringent CR + no nausea test, DM 200 mg (63.8%) was numerically superior to OND (49.4%). DM and OND were equivalent in the safety analysis and there was no statistically significant trends with dose for adverse events with DM. In conclusion, a single oral dose of DM 200 mg was equivalent to multiple doses of OND in preventing nausea and emesis induced by moderately emetogenic CT.

Purpose: To evaluate antiemetic efficacy and tolerability of granisetron, dexamethasone, and their combination over repeated courses of moderately emetogenic chemotherapy, and the influence of the prognostic factors on occurrence of nausea and vomiting.Patients and Methods: Four hundred twenty-eight consecutive cancer patients were entered onto multicenter, randomized, double-blind study to compare granisetron 3 mg intravenously, dexamethasone 8 mg intravenously, and 4 mg orally every 6 hours for four doses, or the combination of dexamethasone plus granisetron al the same doses, administered for three consecutive cycles. Occurrence of nausea, retching, and vomiting was monitored for 24 hours after chemotherapy administration by a diary card.Results: Three hundred ninety-eight patients were assessable for clinical efficacy at the first cyle, 354 were assessable at the second cycle, and 322 were assessable at the third cycle of chemotherapy. Dexamethasone plus granisetron induced significantly greater complete protection from vomiting, nausea, and both nausea and vomiting than granisetron alone in all three cycles. With respect to dexamethasone alone, complete protection from vomiting was significantly greater at the first and second cycle, and complete protection from nausea and from both nausea and vomiting only at the first cycle. Complete protection did not differ significantly among the three cycles in patients receiving dexamethasone plus granisetron or dexamethasone alone, whereas it decreased significantly, at least for vomiting, in patients receiving granisetron alone. Protection obtained in the previous cycle of chemotherapy wets the most important prognostic factor in the occurrence of nausea and vomiting.Conclusion: The combination of dexamethasone plus granisetron offers the best antiemetic protection because of its greater efficacy with respect to the other two regimens at first cycle, and because its activity is maintained in the subsequent cycles of chemotherapy. (C) 1995 by American Society of Clinical Oncology.

The efficacy and toxicity of teicoplanin and vancomycin in the initial empirical antibiotic regimen in febrile, neutropenic patients with hematologic malignancies were compared in a prospective, randomized, unblinded, multicenter trial in the setting of 29 hematologic units in tertiary-care or university hospitals. A total of 635 consecutive febrile patients with hematologic malignancies and chemotherapy-induced neutropenia were randomly assigned to receive intravenously amikacin plus ceftazidime plus either teicoplanin at 6 mg/kg of body weight once daily or vancomycin at 1 g twice daily. An efficacy analysis was done for 527 evaluable patients: 275 treated with teicoplanin and 252 treated with vancomycin. Overall, successful outcomes were recorded for 78% of patients who received teicoplanin and 75% of those who were randomized to vancomycin (difference, 3%; 95% confidence interval [CI], -10 to 4%; P = 0.33). A total of 102 patients presented with primary, single-agent, gram-positive bacteremia. Coagulase-negative staphylococci accounted for 42%, Staphylococcus aureus accounted for 27%, and streptococci accounted for 21% of all gram-positive blood isolates. The overall responses to therapy of gram-positive bacteremias were 92 and 87% for teicoplanin and vancomycin, respectively (difference, 5%; CI, -17 to 6%; P = 0.22). Side effects, mainly represented by skin rash, occurred in 3.2 and 8% of teicoplanin- and vancomycin-treated patients, respectively (difference, -4.8%; CI, 0.7 to 8%; P = 0.03); the rate of nephrotoxicity was 1.4 and 0.8% for the teicoplanin and vancomycin groups, respectively (difference, 0.6%; CI, -2 to 1%; P = 0.68). Further infections were caused by gram-positive organisms in two patients (0.7%) treated with teicoplanin and one patient (0.4%) who received vancomycin (difference, 0.3%; CI, -0.9 to 1.0%; P = 0.53). Overall mortalities were 8.5 and 11% for teicoplanin- and vancomycin-treated patients, respectively (difference, -2.5%; CI, - 2 to 7%; P = 0.43); death was caused by primary gram-positive infections in three patients (1%) in each treatment group. When used for initial empirical antibiotic therapy in febrile, neutropenic patients, teicoplanin was at least as efficacious as vancomycin, but it was associated with fewer side effects.