Trial of oral fumagillin for the treatment of intestinal microsporidiosis in patients with HIV infection. ANRS 054 Study Group. Agence Nationale de Recherche sur le SIDA.

OBJECTIVE: Intestinal microsporidiosis caused by Enterocytozoon bieneusi is a cause of chronic diarrhoea in patients with HIV infection for which there is no current therapy. This study was designed to assess the safety and efficacy of oral fumagillin in this infection. DESIGN: A dose-escalation trial. METHODS: Twenty-nine HIV-infected patients with E. bieneusi infection were consecutively enrolled in the trial. Oral doses of fumagillin were given to four groups of patients for 14 days: 10 mg/day (group 1), 20 mg/day (group 2), 40 mg/day (group 3), and 60 mg/day (group 4). Patients were seen at weeks 1, 2, 4 and 6 to assess safety and efficacy. Efficacy was assessed primarily by the clearance of microsporidia from stools and follow-up duodenal biopsies. RESULTS: Thirteen patients complained of abdominal cramps, vomiting or diarrhoea during the study, and three patients had fumagillin withdrawn because of adverse events. Thrombocytopenia, neutropenia and hyperlipasaemia were the most frequent biological adverse events. Twenty-one out of 29 patients transiently cleared microsporidia from their stools during the study. By week 6, however, all patients in groups 1, 2 and 3 had parasitic relapse. Interestingly, eight out of 11 (72%) patients treated with 60 mg/day (group 4) apparently cleared microsporidia from their gastrointestinal tract and gained weight. No parasitic relapse was documented in these eight patients during a mean follow-up of 11.5 months. CONCLUSION: Treatment with fumagillin at 60 mg/day for 14 days has promise as an effective oral treatment for E. bieneusi infections.

Incidence, clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. The European APL Group.

All trans-retinoic acid (ATRA) syndrome is a life-threatening complication of uncertain pathogenesis that can occur during the treatment of acute promyelocytic leukemia (APL) by ATRA. Since its initial description, however, no large series of ATRA syndrome has been reported in detail. We analyzed cases of ATRA syndrome observed in an ongoing European trial of treatment of newly diagnosed APL. In this trial, patients 65 years of age or less with an initial white blood cell count (WBC) less than 5,000/microL were initially randomized between ATRA followed by chemotherapy (CT) (ATRA-->CT group) or ATRA with CT started on day 3; patients with WBC greater than 5,000/microL received ATRA and CT from day 1; patients aged 66 to 75 received ATRA-->CT. In patients with initial WBC less than 5, 000/microL and allocated to ATRA-->CT, CT was rapidly added if WBC was greater than 6,000, 10,000, 15,000/microL by days 5, 10, and 15 of ATRA treatment. A total of 64 (15%) of the 413 patients included in this trial experienced ATRA syndrome during induction treatment. Clinical signs developed after a median of 7 days (range, 0 to 35 days). In two of them, they were in fact present before the onset of ATRA. In 11 patients, they occurred upon recovery from the phase of aplasia due to the addition of CT. Respiratory distress (89% of the patients), fever (81%), pulmonary infiltrates (81%), weight gain (50%), pleural effusion (47%), renal failure (39%), pericardial effusion (19%), cardiac failure (17%), and hypotension (12%) were the main clinical signs, and 63 of the 64 patients had at least three of them. Thirteen patients required mechanical ventilation and two dialysis. A total of 60 patients received CT in addition to ATRA as per protocol or based on increasing WBC; 58 also received high dose dexamethasone (DXM); ATRA was stopped when clinical signs developed in 30 patients. A total of 55 patients (86%) who experienced ATRA syndrome achieved complete remission (CR), as compared with 94% of patients who had no ATRA syndrome (P = .07) and nine (14%) died of ATRA syndrome (5 cases), sepsis (2 cases), leukemic resistance (1 patient), and central nervous system (CNS) bleeding (1 patient). None of the patients who achieved CR and received ATRA for maintenance had ATRA syndrome recurrence. No significant predictive factors of ATRA syndrome, including pretreatment WBC, could be found. Kaplan Meier estimates of relapse, event-free survival (EFS), and survival at 2 years were 32% +/- 10%, 63% +/- 8%, and 68% +/- 7% in patients who had ATRA syndrome as compared with 15% +/- 3%, 77% +/- 2%, and 80% +/- 2% in patients who had no ATRA syndrome (P = .05, P = .003, and P = .03), respectively. In a stepwise Cox model that also included pretreatment prognostic variables, ATRA syndrome remained predictive for EFS and survival. In conclusion, in this multicenter trial where CT was rapidly added to ATRA in case of high or increasing WBC counts and DXM generally also used at the earliest clinical sign, the incidence of ATRA syndrome was 15%, but ATRA syndrome was responsible for death in only 1.2% of the total number of patients treated. However, occurrence of ATRA syndrome was associated with lower EFS and survival.

Potential efficacy of fumagillin in intestinal microsporidiosis due to Enterocytozoon bieneusi in patients with HIV infection: results of a drug screening study. The French Microsporidiosis Study Group.

OBJECTIVE: Intestinal microsporidiosis due to Enterocytozoon bieneusi is a frequent cause of chronic diarrhoea in patients with HIV infection for which there is no available therapy. This study was designed to search for a drug with activity against this organism. DESIGN: Prospective open-labelled Phase II multicentre study. SETTING: University hospitals. PATIENTS: Sixty HIV-infected men with intestinal E. bieneusi infection. INTERVENTIONS: Ten drug regimens were consecutively tested orally for 3 weeks: albendazole plus metronidazole, sulphadiazine plus pyrimethamine, atovaquone, doxycycline plus nifuroxazide, itraconazole, flubendazole, chloroquine, paromomycin, sparfloxacin and fumagillin. Nine evaluable patients per regimen were required, but each patient could be enrolled up to three times in the study. OUTCOME MEASURE: Efficacy was assessed primarily by the clearance of E. bieneusi from stools and intestinal biopsies. The safety of each regimen was also assessed. RESULTS: Only purified fumagillin was able to clear E. bieneusi from stools as well as intestinal biopsies, whereas all other regimens failed to show antiparasitic efficacy. However, only four patients received fumagillin because of drug-induced thrombocytopenia. The four patients who received fumagillin remained free of E. bieneusi infection after a mean follow-up of 10 months. CONCLUSION: Eradication of E. bieneusi from the intestinal tract of patients with HIV infection and persistent immunosuppression is an achievable goal. Our study allowed the identification of oral fumagillin as a potential treatment for intestinal microsporidiosis due to E. bieneusi.

A randomized comparison of two clarithromycin doses for treatment of Mycobacterium avium complex infections.

Two dosages of clarithromycin were compared for treatment of disseminated Mycobacterium avium disease of AIDS patients: high-dose (HD): 1,000 mg or 750 mg b.i.d. according to body weight, and low-dose (LD): 1,000 mg or 750 mg q.d. Patients with high probability of M. avium positive blood culture on day 0 received a 42-day clarithromycin treatment with HD (n = 27) or LD (n = 28) at random after stratification according to body weight. Assessment procedures, including quantitative blood cultures, were performed at days 14, 28 and 42. Forty-five patients were eligible for clinical and 28 for bacteriological evaluation. Bacteriological success was observed in 12 HD and 11 LD patients, partial success in one HD and two LD and failure in none of the HD and two LD (p = 0.33). Between days 0 and 42, log decreases in CFU counts/ml were (mean +/- SD) 3.13 +/- 0.82 (HD) and 2.67 +/- 1.8 (LD) (p = 0.38). Fever and night sweats significantly improved similarly in both groups; no change in spleen and liver size was observed on CT scans. Eight patients died during the study but no death was reported as drug related. Sixteen patients (HD = 6, LD = 10) discontinued the treatment because of side effects. A trend towards improved bacteriological effectiveness and reduced tolerance was observed in the HD group but the difference was not significant. With a power of 0.70, no dose effect was demonstrated between the two tested dosages. A daily dose of 1,000 mg clarithromycin was tested in drug combinations to treat disseminated M. avium infection in AIDS patients.

Antibiotic versus maintenance therapy in the prevention of duodenal ulcer recurrence. Results of a multicentric double-blind randomized trial.

OBJECTIVES: Reduction of gastric acid secretion by maintenance therapy and eradication of Helicobacter pylori by antibiotic treatment have been shown to reduce duodenal ulcer relapse. This study compared the effect of two regimens, a 6-month maintenance on an H2 receptor antagonist versus a one-week antibiotic therapy, on the rate of duodenal ulcer relapse in duodenal ulcer patients with gastric H. pylori infection. METHODS: We conducted a 30-week, double-blind, double-dummy, multicentric clinical trial involving 119 patients (97 M, 22 F, mean age 39 +/- 14 years) randomly assigned to a daily dose of 40 mg famotidine for 6 weeks supplemented with, during the first week, either antibiotics (500 mg amoxicillin q.i.d. and 500 mg tinidazole t.i.d.-antibiotic group) or their placebo (maintenance group). Healed patients after 6 weeks entered the 6-month maintenance phase: the maintenance group received 20 mg famotidine at bedtime and the antibiotic group, a placebo. Endoscopy with antral biopsies was performed to allow a rapid urease test, culture and histological examination upon entry, after 6 weeks, 3 months, and 6 months and, whenever symptoms recurred. H. pylori status was regarded as positive if any one of these three tests was positive, and negative if all tests were negative. RESULTS: The 2 treatment groups were well balanced for all baseline characteristics. After 6 weeks, H. pylori was eradicated in 25 (45%) patients in the antibiotic group, and in 1 (2%) in the maintenance group (P < 0.01). In term of intention-to-treat, there was no significant difference in the healing rate after 6 weeks (93 and 83% in the antibiotic and maintenance groups, respectively; P = 0.15) or in the relapse rate after 6 months (13 and 28% in the antibiotic and maintenance groups, respectively; P = 0.17 Log-rank test). However, the overall failure rate (absence of healing, relapse) was lower (P = 0.04, Log-rank test) in the antibiotic group in which all relapses but one were observed in H. pylori positive patients. The rate of ulcer relapse (1/20) in patients of antibiotic group who remained free of H. pylori during the study, was significantly (P < 0.01) lower compared with that of H. pylori positive patients in the maintenance group (11/44). During the first 6-week period, more side effects were observed in the antibiotic group than in the maintenance group (4 vs 1 patient, respectively). CONCLUSIONS: Our results indicate no significant difference between ulcer relapse rates after 6 months following a one-week antibiotic therapy or long-term maintenance therapy. Short-term antibiotic therapy should be considered as a valuable alternative to the long-term maintenance therapy.

Bone densitometry in patients with multiple myeloma.

PURPOSE, PATIENTS, AND METHODS: We performed dual-energy x-ray absorptiometry in 10 selected patients with aggressive multiple myeloma in whom substantial tumor mass reduction was achieved after high-dose chemoradiotherapy followed by autologous blood stem cell transplantation. RESULTS: In most cases, bone mineral density (BMD) of the spine was initially low (Mean Z score: -2.69, SEM 0.76) and dramatically increased after treatment (mean increase 16.4%; 7.7% with 95% confidence interval 2.2 to 12.2, excluding one patient whose spine BMD increased by 94.8%). In contrast, skeletal roentgenograms, computed tomographic scans, and magnetic resonance imaging did not reveal any significant improvement of patients' bone lesions. CONCLUSIONS: In patients with multiple myeloma, bone densitometry could be a useful way to assess the efficacy of treatment on bone status.

Acute carbon monoxide intoxication and hyperbaric oxygen in pregnancy.

Modalities of oxygen therapy for pregnant women intoxicated with carbon monoxide (CO) are ill defined. Hyperbaric oxygen (HBO) is presumed to be hazardous to the pregnancy. On the other hand CO entails anoxic injuries in the mother and fetus. We have entered 44 pregnant women who sustained an acute carbon monoxide poisoning at home, into a prospective study in order to assess HBO tolerance. They were treated within 5.3 +/- 3.7 h (range: 1-12) of the intoxication with a combination of 2 h of HBO at a pressure of 2 atmospheres absolute (ATA) and 4 h of normobaric oxygen, irrespective of the clinical severity of the intoxication and of the age of pregnancy. Six patients were lost to obstetric follow-up. Only 2 patients sustained a spontaneous abortion: 1 within 12 h and 1 within 15 days of the intoxication. Thirty-four women gave birth to normal newborns. Finally 1 elected to undergo abortion for reasons unrelated to the intoxication and 1 gave birth to a baby with Down's syndrome. There is no evidence that HBO was involved with either abortion of our study. We conclude that HBO may be carried out in pregnant women acutely intoxicated with carbon monoxide.

Trial of normobaric and hyperbaric oxygen for acute carbon monoxide intoxication.

The value of hyperbaric oxygen in the treatment of acute carbon monoxide intoxication was assessed in 629 adults who had been poisoned at home in the 12 h before admission to hospital. In patients without initial impairment of consciousness (group A) the effect of 6 h of normobaric oxygen (NBO) (group A0, n = 170) was compared with that of 2 h of hyperbaric oxygen (HBO) at 2 atmospheres absolute (ATA) plus 4 h NBO (group A1, n = 173). At the 1 month follow-up 66% of A0 and 68% of A1 patients had recovered. In patients with initial impairment of consciousness the effect of one session of HBO (group B1, n = 145) was compared with that of two sessions (group B2, n = 141); all group B patients also received 4 h of NBO. At 1 month of follow-up 54% group B1 and 52% group B2 patients had recovered. The 7 patients left with neuropsychiatric sequelae (3 B1, 4 B2) and the 4 who died (2 B1, 2 B2) had all presented with coma. HBO was not useful in patients who did not lose consciousness during carbon monoxide intoxication, irrespective of their carboxyhaemoglobin level, nor were two sessions of HBO in patients who sustained only a brief loss of consciousness. The prognosis is poorest for those presenting with coma; the trial needs to be pursued in this group of patients until the power of the study is sufficient to demonstrate the value or otherwise of HBO.

Maintenance treatment of psoriasis by Tigason: a double-blind randomized clinical trial.

Extensive lesions on 36 patients with psoriasis were treated by Tigason, I mg/kg/day plus PUVA until skin clearance. A clinical score was calculated for each body area, and erythema, scaling, thickness and pruritus of the lesions were scored from 0 to 3. Skin clearing was defined as a clinical score less than 10% of the initial score. Double-blind maintenance treatment was then started. This was Tigason at half of the maximal dose tolerated during the clearing phase of the treatment v. placebo. Relapse of the disease was defined as the occurrence of a clinical score greater than 50% of the initial score. Among the 36 patients randomized, 20 received placebo and 16 received Tigason. Relapses increased quickly in the patients on placebo, but occurred in few patients treated by Tigason with 60% remaining clear after 1 year (P less than 0.05). Surprisingly, the kinetics of disappearance of the most frequent side effect, cheilitis, was the same in the Tigason group and in the placebo group. This double-blind randomized clinical trial shows that Tigason at low doses is an efficient and well-tolerated maintenance treatment of psoriasis.

Adjvant treatment of tongue and floor of the mouth cancers.

Since January 1974, 95 patients with anterior tongue and floor of the mouth cancers were included in a randomized trial. After stratification according to staging and initial treatment, one-third of the patients received chemotherapy for 2 years (methotrexate 400 mg followed by citrovorum factor 100 mg + bleomycin 60 mg/week, during the first 15 weeks), one-third of the patients received immunotherapy with weekly C. parvum injections during 2 years, while the remaining third did not receive any treatment. If adjuvant treatment seems to delay recurrence it did not significantly decrease the recurrence rate. Survival is also not signigicantly modified by adjuvant treatment and was better for patients with small tumors. Patients who previously received radiotherapy did not benefit from adjuvant therapy.