Intravenous BU plus Mel: an effective, chemotherapy-only transplant conditioning regimen in patients with ALL.

We investigated the administration of i.v. BU combined with melphalan (Mel) in patients with ALL undergoing allogeneic hematopoietic SCT. Forty-seven patients with a median age of 33 years (range 20-61) received a matched sibling (n=27) or matched unrelated donor transplant (n=20) for ALL in first CR (n=26), second CR (n=13), or with more advanced disease (n=8). BU was infused daily for 4 days, either at a fixed dose of 130 mg/m² (5 patients) or using pharmacokinetic (PK) dose adjustment (42 patients), to target an average daily area-under-the-curve (AUC) of 5000 µmol/min, determined by a test dose of i.v. BU at 32 mg/m². This was followed by a rest day, then two daily doses of Mel at 70 mg/m². Stem cells were infused on the following day. The 2-year OS, PFS and non-relapse mortality (NRM) rates were 35% (95% confidence interval (CI), 23-51%), 31% (95% CI, 21-48%) and 37% (95% CI, 23-50%), respectively. Acute NRM at 100 days was favorable at 12% (95% CI, 5-24%); however, the 2-year NRM was significantly higher for patients older than 40 years, 58% vs 20%, mainly due to GVHD.

Timidity in Japanese quail: effects of vitamin C and divergent selection for adrenocortical response.

Male Japanese quail chicks of two genetic lines selected for low (LS) or high (HS) adrenocortical responses to mechanical restraint were housed in mixed-line groups of 24 in four compartments of a multitier brooder battery at 20 days of age. Quail in two of the four compartments were given vitamin C (ascorbyl-2-polyphosphate, APP, 1 g L-ascorbic acid/L) solution for 48 h, whereas the other birds received untreated tap water as usual before they were tested at 23 days of age. At test, each quail was placed individually in a dark, sheltered compartment of an emergence box and allowed 1 min to acclimatise before a door was raised allowing access to an illuminated and exposed area. Vocalisation and the latencies to head and full emergence were then recorded to measure its fear levels. More LS quail vocalised than did HS ones. They also emerged more rapidly from the sheltered compartment into the illuminated one than HS birds. These findings further support our hypothesis that decreased fearfulness has accompanied genetic selection for reduced adrenocortical responsiveness. Treatment with APP reduced the latency to emerge fully into the exposed compartment, and there were no line x treatment interactions. These results suggest that vitamin C supplementation alleviated fearfulness, regardless of existing line differences in this behavioural trait.

Treating Japanese quail with vitamin C does not facilitate their capture by the experimenter.

1. Vitamin C supplementation reduces fear of novel situations and of people. The present study examined its effects on the ease of capture of male Japanese quail by the experimenter. 2. At 20 d of age, quail received either vitamin C (ascorbyl-2-polyphosphate, APP, 1 g L-ascorbic acid/l) solution or untreated drinking water (UDW) for 24 h before they were mixed in 2 groups of 40 (20 APP + 20 UDW. All the birds in 1 group were caught individually by an unsighted experimenter whereas a sighted catcher captured the others. The bird's identity was noted each time. This capture/recapture procedure was repeated 6 times for each group (12 capture trials per bird) and an overall capture rank across all 12 trials was assigned to each bird. 3. Regardless of whether the catcher was sighted or unsighted, the mean ranks of neither APP nor UDW quail differed significantly from the value expected by chance. Neither were there any linear trends in the effects of repeated testing. Thus, prior treatment with vitamin C neither facilitated nor hindered capture. 4. Body weights were similar in both treatment groups and there were no significant intra-individual correlations between body weight and capture rank. 5. Highly significant tendencies were found for individual birds to be caught at similar stages of each capture trial regardless of treatment or test situation. This finding sounds a cautionary note for all studies involving putatively random sampling of a population.

White matter disease induced by high-dose chemotherapy: longitudinal study with MR imaging and proton spectroscopy.

PURPOSE: The purpose of this study was to determine the time course for development of white matter changes induced by high-dose chemotherapy. METHODS: Eight patients with advanced breast cancer were entered into a prospective, longitudinal trial that included examination by MR imaging and proton MR spectroscopy before chemotherapy and through 12 months after treatment with carmustine, cyclophosphamide, and cisplatin, combined with autologous hematopoietic progenitor cell support (AHPCS). RESULTS: Six patients completed induction chemotherapy, at which time all MR imaging studies appeared normal. At 3 months after the conclusion of high-dose chemotherapy and beyond, three of the four patients remaining in the study showed an increasing volume of white matter changes, which appeared to stabilize during the period from 6 months to 1 year. Maximal volumes of abnormal white matter ranged from 73 to 166 cm3. MR spectroscopy showed little or no change in metabolic ratios through the period of observation, although there was a suggestion of small transient treatment-related decreases in the ratio of N-acetyl aspartate (NAA) to creatine. CONCLUSION: White matter changes are common sequelae of treatment with high-dose chemotherapy combined with AHPCS, occurring early in the period following high-dose chemotherapy, with a rapid and progressive accumulation to about 6 months, but not accompanied by persistent neurologic symptoms. The MR spectroscopic analyses suggest a minimal disturbance of the neuronal marker NAA, a finding that may in part explain the good neurologic outcome.

Decrease in expenditures and selected nosocomial infections following implementation of an antimicrobial-prescribing improvement program.

OBJECTIVE: To evaluate changes in antimicrobial use and expenditures and the rates of selected nosocomial infections due to resistant organisms associated with implementation of an antimicrobial-prescribing improvement program. DESIGN: Before-after trial comparing 1992 (pre-program), 1993 (a transition year), and 1994 (after full implementation of the program). SETTING AND PARTICIPANTS: Academic medical center, all patients and physicians. INTERVENTION: An antimicrobial-prescribing improvement program with prior approval requirement for use of restricted agents. MAIN OUTCOME MEASURES: Antimicrobial use and expenditures, rates of selected nosocomial infection marker events. RESULTS: Between 1992 and 1994, there were substantial decreases in antimicrobial use, from 158,107 to 137,364 defined daily doses, and in expenditures from $2,486,902 ($24.01 per patient day) to $1,701,522 ($18.49 per patient day). After adjusting for changes in purchase prices and census days, we estimated savings attributable to the program of $279,573 in 1993 and $389,814 in 1994. In addition, we found significant decreases between 1992 and 1994 in the rates of enterococcal bacteremia (.34 vs .16 events per 1,000 patient days; P = .016), selected gram-negative bacteremia (.26 vs .11; P = .015), methicillin-resistant Staphylococcus aureus colonization or infection (.66 vs .20; P < .0001), and Stenotrophomonas colonization or infection (.35 vs .17; P = .019). No significant change occurred in rates of nosocomial candidemia or Clostridium difficile toxin-positive diarrhea. Values for 1993 were intermediate between those of 1992 and 1994. CONCLUSION: Implementation of an antimicrobial-prescribing improvement program was associated with substantial savings in antimicrobial use and expenditures and significant decreases in rates of selected nosocomial infections due to resistant organisms.

Histamine H2 receptor antagonist-refractory oesophagitis: the efficacy of long-term omeprazole maintenance treatment.

BACKGROUND: Erosive oesophagitis refractory to high dose histamine H2 receptor antagonists (definition: failure to heal fully after > or = 3 months' treatment with cimetidine 3.2 g or ranitidine 0.9 g) responds well to omeprazole 40 mg daily but frequently relapses when the patients are put back on maintenance H2 receptor antagonists at medium or even high dose (e.g. cimetidine 1.6 g and 3.2 g, respectively). AIM: To investigate the efficacy of maintenance omeprazole 20 mg daily in refractory erosive oesophagitis. PATIENTS & METHODS: In this open, sequential study, patients with H2 receptor antagonist-refractory oesophagitis were healed on omeprazole 40 mg daily and then put on maintenance H2 receptor antagonists (cimetidine 1.6 g or 3.2 g). Relapses were re-treated with omeprazole 40 mg; upon rehealing, patients were put on maintenance omeprazole 20 mg daily for up to 4.5 years. RESULTS: Healing on omeprazole occurred in 38 out of 39 patients (97%) at 12 weeks. Only six of the 38 patients (16%) relapsed (asymptomatic in half) during subsequent maintenance treatment, whereas all had relapsed earlier on high dose H2 receptor antagonists. CONCLUSION: Within the limits of interpretation of an open study, omeprazole 20 mg daily seems effective in maintaining prolonged remission in this group of patients with H2 receptor antagonist-refractory oesophagitis.

Vitamin C supplementation and fear-reduction in Japanese quail: short-term cumulative effects.

1. Fear-related behaviour was measured in individually-housed Japanese quail which had received either untreated drinking water (UDW) or a vitamin C solution (ascorbyl-2-polyphosphate, APP, 1 g L-ascorbic acid/1 for 1 or 4 d. Behavioural tests were carried out at 24 or 27 d of age. Water consumption was measured daily and plasma ascorbic acid (AA) content was assayed after differential treatment for 1 or 4 d. 2. The quail in the APP treatment groups drank significantly more than did those receiving untreated drinking water. 3. Supplementation with APP raised plasma AA concentrations substantially above those found in UDW quail. The lower AA concentrations found after APP treatment for 4 d rather than one may have reflected either inter-assay variation or limited intestinal absorption following excess ingestion. 4. Quail treated with APP showed less home-cage avoidance of a novel object and shorter tonic immobility fear reactions than did the UDW birds. The UDW quail showed remarkably similar avoidance and TI scores on test days 1 and 4. Conversely, continued treatment with APP further reduced avoidance scores but, although TI durations fell slightly with continued treatment there were no significant day effects. 5. It was concluded that APP supplementation can reduce underlying fearfulness but that it may not be necessary to continue treatment for longer than 24 h immediately prior to a known frightening event.

MR and proton spectroscopy of white matter disease induced by high-dose chemotherapy with bone marrow transplant in advanced breast carcinoma.

PURPOSE: To determine whether the MR-detectable white matter changes associated with high-dose chemotherapy and bone marrow transplant in patients with advanced breast carcinoma are accompanied by neurochemical disturbances detectable by proton MR spectroscopy. METHODS: MR studies were obtained in 13 patients, and single-voxel proton MR spectra were acquired in vivo in 12 of these 13 for comparison with 13 age- and sex-matched control subjects. RESULTS: Considerable white matter change determined with MR was found in 10 of 13 patients with volume white matter change ranging from 1 to 153 cm3 (mean, 49 cm3; SD, 50 cm3). Single-voxel spectra successfully acquired in 12 patients revealed no significant difference in patients compared with control subjects for the spectral ratios N-acetyl aspartate to creatine or N-acetyl aspartate to choline at either short or long echo times (30 and 136 milliseconds). CONCLUSION: Extensive, late-stage white matter change induced by high-dose chemotherapy is not accompanied by measurable disturbances in the putative neuronal marker N-acetyl aspartate, suggesting that chemotherapy-induced white matter disease is predominantly a water space and possibly an extraneuronal process rather than a primary neuronal (axonal) disease. The MR spectroscopic examination, accomplished at the time of the MR imaging examination, complements the MR imaging study by increasing the specificity of the MR-based clinical evaluation.

Efficacy of 250 mg trospectomycin sulfate i.m. vs. 250 mg ceftriaxone i.m. for treatment of uncomplicated gonorrhea.

BACKGROUND AND OBJECTIVES: Due to the steadily progressive development of resistance to the drugs used for treatment, Neisseria gonorrhoeae remains a medical concern. Trospectomycin sulfate is a 6' propyl analogue of spectinomycin with potent activity against penicillin sensitive and resistant strains of N. gonorrhoeae. GOAL OF THIS STUDY: To compare the efficacy of 250 mg trospectomycin sulfate i.m. versus 250 mg ceftriaxone i.m. for single dose therapy for men and women with uncomplicated gonorrhea. STUDY DESIGN: Dual-center, randomized comparative trial. RESULTS: Among evaluable male patients with urethral gonorrhea, 36 of 40 (90%, 95% confidence interval [95%CI] 76%-97%) who were treated with trospectomycin sulfate were cured, and 22 of 22 patients (100%, [85%-100%]) treated with ceftriaxone were cured. Among evaluable female patients with cervical gonorrhea all were cured following trospectomycin sulfate (23 of 23) and following ceftriaxone therapy (13 of 13). The cure rates for pharyngeal gonorrhea were 67% (8 of 12 patients, 35%-90%) for trospectomycin sulfate therapy, and 100% (2 of 2) with ceftriaxone therapy. CONCLUSIONS: Trospectomycin sulfate, 250 mg i.m., is effective, and well tolerated. However, for treatment of uncomplicated genital and pharyngeal gonorrhea, it is not as reliable for therapy as other recommended regimens.

Effects of ascorbyl-2-polyphosphate on adrenocortical activation and fear-related behavior in broiler chickens.

The effects of supplemental ascorbyl-2-polyphosphate (APP) on adrenocortical function and underlying fearfulness in broiler chickens were assessed in a number of test situations. Chicks pretreated for a minimum of 24 h with APP (1,000 ppm equivalents of L-ascorbic acid) in their drinking water or with no APP (tap water controls; CON) had blood samples taken immediately following water treatment and again after exposure to a capture and cooping stressor for 10 min. First, although the cooping stressor markedly increased plasma corticosterone concentrations, pretreatment with APP failed to attenuate this adrenocortical response. Second, APP-treated chicks showed less freezing and vocalized sooner in an open field (novel environment) than did controls. They also showed nonsignificant tendencies toward accelerated and enhanced ambulation. Third, supplementation with APP reduced the duration of the birds' tonic immobility fear reactions. Collectively, these behavioral effects are indicative of dampened fear. The apparent reduction of nonspecific, underlying fearfulness by APP treatment may have important implications for poultry welfare and performance.

Multicenter, comparative study of cefotaxime and ceftriaxone for treatment of uncomplicated gonorrhea.

BACKGROUND AND OBJECTIVES: Cefotaxime is a third-generation cephalosporin that has in vitro activity against Neisseria gonorrhoeae, including beta-lactamase-producing strains. A single 1-g intramuscular dose is effective and is recommended by the Centers for Disease Control and Prevention as an alternative treatment for uncomplicated gonorrhea. GOAL OF THIS STUDY: This study was conducted to evaluate the efficacy and safety of a lower 500-mg dose of cefotaxime in the treatment of uncomplicated gonococcal infections. STUDY DESIGN: In a randomized multicenter study, patients who had uncomplicated gonorrhea were treated with 500 mg of cefotaxime or 250 mg of ceftriaxone. Both antibiotics were given intramuscularly. Efficacy and safety were assessed four to seven days following treatment. RESULTS: Six hundred thirteen patients were enrolled. Bacteriologic eradication rates for anogenital infection were 97.7% of the patients (213/218) in the cefotaxime group and 99.1% of the patients (221/223) in the ceftriaxone group (P = 0.243). Adverse events occurred in 4.2% and 7.5% of patients in the two groups, respectively. CONCLUSION: Cefotaxime 500 mg appears to be a safe and cost-effective alternative to ceftriaxone 250 mg for the treatment of uncomplicated gonorrhea.

Comparison of ciprofloxacin and ceftriaxone as single-dose therapy for uncomplicated gonorrhea in women.

Although women bear the brunt of gonococcal infection-related morbidity, few large studies of gonorrhea treatment in women have been conducted. In a multicenter, double-blind, placebo-controlled trial, 181 evaluable women with uncomplicated gonorrhea were treated with ciprofloxacin (250 mg orally; 94 women) or ceftriaxone (250 mg intramuscularly; 87 women). Twenty-four percent of the participants were infected with antibiotic-resistant Neisseria gonorrhoeae. Cervical gonorrhea was cured in 100% (93 of 93) of the women treated with ciprofloxacin and 99% (83 of 84) receiving ceftriaxone. All pharyngeal (n = 5) or rectal (n = 20) infections treated with ciprofloxacin were cured, as were ceftriaxone-treated patients with pharyngeal (n = 6) or rectal (n = 21) infection. Geometric mean MICs (range) for 248 pretreatment isolates were: penicillin, 0.28 (0.015 to 8.0); tetracycline, 0.46 (0.06 to 4); ciprofloxacin, 0.003 (0.002 to 0.015); and ceftriaxone, 0.004 (0.001 to 0.125) microgram/ml. Both drugs were well tolerated. Despite the high prevalence of antibiotic-resistant gonococci in these populations, 250 mg of oral ciprofloxacin was as effective as an injection of ceftriaxone.

New strategies in marrow purging for breast cancer patients receiving high-dose chemotherapy with autologous bone marrow transplantation.

High-dose chemotherapy and autologous bone marrow transplantation (ABMT) are commonly used to treat selected patients with high-risk breast cancer. A limitation of ABMT is that clonogenic cancer cells could be collected with the bone marrow and produce a relapse of diseases when reinfused into patients. Purging the marrow ex vivo may eliminate the tumor cells, but it can also delay engraftment. We employed two different purging methods whereby breast cancer cells were depleted without delaying engraftment. The addition of WR-2721 (amifostine) to 4-hydroperoxycyclophosphamide (4-HC) reduced the time to engraftment by 10 days compared with marrow purged with 4-HC alone (26 versus 37 days, respectively). The positive selection of CD34+ hematopoietic progenitors produced engraftment within 21 days. The use of granulocyte colony-stimulating factor (G-CSF) accelerated the engraftment time of CD34+ hematopoietic progenitors to 11 days.

Responses to isolation in Japanese quail genetically selected for high or low sociality.

The adrenocortical, behavioral, and leucocytic responses to isolation, for 1, 3, or 72 h, of 7-10-day-old Japanese quail chicks, of lines selected for high (HSR) or low (LSR) levels of social reinstatement (SR) behavior, were studied. Isolation had no effect on plasma corticosterone levels of heterophil/lymphocyte measures in LSR line chicks. Conversely, circulating corticosterone levels were increased after 1 h of isolation in the HSR line, although they fell to control levels thereafter. Heterophil/lymphocyte ratios of HSR line chicks were also increased after 3 h of isolation but decreased to control levels thereafter. Isolated HSR line chicks were consistently more active and showed more peeping and jumping than LSR line chicks in which sitting and lying were more frequent. However, no such behavioral divergence was observed when HSR and LSR line chicks were housed in same-line groups. These results indicate that selection for SR behavior has influenced both underlying social motivation and responses to short-term isolation. Social separation appeared to be more stressful for HSR than LSR line chicks.

4-Hydroperoxycyclophosphamide purging of breast cancer from the mononuclear cell fraction of bone marrow in patients receiving high-dose chemotherapy and autologous marrow support: a phase I trial.

We designed an ex vivo bone marrow treatment for breast cancer patients receiving high-dose chemotherapy and autologous bone marrow support (ABMS), using 4-hydroperoxycyclophosphamide (4-HC), an active derivative of cyclophosphamide with known activity against breast cancer. This phase I bone marrow purging trial used ficoll-separated mononuclear cells (MNC) (devoid of granulocytes and RBCs), as opposed to the buffy coat. Twenty-five patients with metastatic breast cancer were studied. Patients received three cycles of the Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), fluorouracil, and methotrexate (Duke AFM) regimen, followed by marrow harvest. An MNC fraction of marrow was prepared and treated with 4-HC in concentrations of 20 micrograms/mL (four patients), 40 micrograms/mL (four patients), 60 micrograms/mL (nine patients), or 80 micrograms/mL (eight patients) and cryopreserved. Patients then received high-dose systemic cyclophosphamide, cisplatin, and carmustine, followed by infusion of the purged marrow. The study end point was marrow engraftment, defined as WBC count greater than 1,000 cells per microliter. At the first three dose levels (20, 40, and 60 micrograms/mL 4-HC), there was no significant delay in time to engraftment (19, 20, and 23 days, respectively) compared with the unpurged historical controls (17 days). At 80 micrograms/mL, engraftment was significantly delayed compared with the lower concentrations (P = .027), and further escalation of 4-HC was not attempted. A significant correlation was observed between the time of leukocyte engraftment and the 4-HC concentration (P = .017). With a methylcellulose-based tissue culture assay, we demonstrated a statistically significant correlation between the colony-forming unit-granulocyte-macrophage (CFU-GM) content in the purged marrow and the days to engraftment. Ninety-five percent of patients responded clinically to the entire program, 55% of them completely. Longer follow-up is required to assess the ultimate benefit of intensive therapy on long-term survival.

The Duke AFM Program. Intensive induction chemotherapy for metastatic breast cancer.

Forty-five patients have completed treatment with AFM, an intensive induction chemotherapy regimen composed of Adriamycin (doxorubicin, Adria Laboratories, Columbus, Ohio), 5-fluorouracil, and methotrexate with folinic acid rescue. This regimen was designed to produce rapid and extensive tumor shrinkage prior to high-dose alkylating agent chemotherapy with autologous marrow support. The overall response rate was 91%, and 38% of patients achieved complete clinical responses after a mean of 70 days on treatment. Hematologic and mucosal toxicity were extensive, but no toxic deaths were noted. AFM is a potent remission induction regimen for metastatic breast cancer, but its considerable toxicity suggests caution in its use for routine breast cancer treatment.

Omeprazole in the treatment of erosive oesophagitis refractory to high dose cimetidine and ranitidine.

Forty five patients with refractory oesophagitis, defined as persisting erosive changes or ulceration despite a minimum of three months' treatment with cimetidine 3.2 g daily or ranitidine 0.9 g daily, were treated in an open trial with omeprazole 40 mg daily for up to eight weeks. Endoscopically defined healing was observed in 73% of patients after four weeks' treatment and in 91% after eight weeks' treatment. Symptoms were completely relieved in 60% of patients, improved in 34%, unchanged in 4%, and worsened in 2%. After healing patients returned to maintenance treatment with cimetidine 1.6-3.2 g daily, depending on the severity of their illness before treatment with omeprazole. By six months and 12 months only 55% and 33% of patients respectively were still in remission. This study suggests that when erosive oesophagitis is refractory to treatment with high dose cimetidine or ranitidine, treatment with omeprazole 40 mg daily for up to eight weeks is effective in inducing healing and relieving symptoms.