Effectiveness of antibacterial prophylaxis during induction chemotherapy in children with acute lymphoblastic leukemia.

BACKGROUND: Pediatric patients receiving induction chemotherapy for newly diagnosed acute lymphoblastic leukemia (ALL) are at high risk of developing life-threatening infections. We investigated whether uniform antibacterial guidelines, including mandatory antibacterial prophylaxis in afebrile patients during induction, decreases the incidence of microbiologically documented bacteremia. METHODS: Between 2012 and 2015, 230 patients with newly diagnosed ALL (aged 1-21) were enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 11-001 (DFCI 11-001). Induction therapy, regardless of risk group, included vincristine, prednisone, doxorubicin, methotrexate, and PEG-asparaginase. Afebrile patients received fluoroquinolone prophylaxis at the initiation of induction and those presenting with fever received broad-spectrum antibiotics; antibiotics were continued until blood count recovery. Rates of documented bacteremias and fungal infections on DFCI 11-001 were compared to those on the predecessor protocol (DFCI 05-001), which included the same induction phase without antibiotic prophylaxis guidelines. RESULTS: Sixty-six (28.7%) patients received fluoroquinolone prophylaxis, the remaining patients received broad-spectrum antibiotics. Twenty-four (36.4%) patients on prophylaxis developed fever and seven (10.6%) developed bacteremia. The overall rate of infection during induction on DFCI 11-001 was lower than on DFCl 05-001 (14.3% vs. 26.3%, P < 0.0001) due to a decreased rate of bacteremia (10.9% vs. 24.4%, P < 0.0001). The rate of fungal infections (4.8% vs. 3.6%) and induction death (0.9% vs. 2%) was not significantly different. CONCLUSION: For children with newly diagnosed ALL, uniform antibiotic administration until blood count recovery, including fluoroquinolone prophylaxis for afebrile patients, reduced the incidence of bacteremia during the induction phase. Larger, randomized studies should be performed to confirm these findings.

Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia.

On the basis of the data suggesting that adolescents and young adult patients with acute lymphoblastic leukemia (ALL) have improved outcomes when treated on pediatric protocols, we assessed the feasibility of treating adult patients aged 18-50 years with ALL with the DFCI Pediatric ALL Consortium regimen utilizing a 30-week course of pharmacokinetically dose-adjusted E. coli L-asparaginase during consolidation. Between 2002 and 2008, 92 eligible patients aged 18-50 years were enrolled at 13 participating centers. Seventy-eight patients (85%) achieved a complete remission (CR) after 1 month of intensive induction therapy. With a median follow-up of 4.5 years, the 4-year disease-free survival (DFS) for the patients achieving a CR was 69% (95% confidence interval (CI) 56-78%) and the 4-year overall survival (OS) for all eligible patients was 67% (95% CI 56-76%). The 4-year DFS for the 64 patients who achieved a CR and were Philadelphia chromosome negative (Ph-) was 71% (95% CI 58-81%), and for all 74 Ph- patients the 4-year OS was 70% (95% CI 58-79%). We conclude that a pediatric-like treatment strategy for young adults with de novo ALL is feasible, associated with tolerable toxicity, and results in improved outcomes compared with historical regimens in young adult patients with ALL.

Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia.

Treatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with phosphatase and tensin homolog (PTEN) deletions and resultant phosphatidylinositol 3'-kinase (PI3K)-AKT pathway activation, as well as MYC overexpression, and these pathways repress mitochondrial apoptosis in established T-lymphoblasts through poorly defined mechanisms. Normal T-cell progenitors are hypersensitive to mitochondrial apoptosis, a phenotype that is dependent on the expression of proapoptotic BIM. In a conditional zebrafish model, MYC downregulation induced BIM expression in T-lymphoblasts, an effect that was blunted by expression of constitutively active AKT. In human T-ALL cell lines and treatment-resistant patient samples, treatment with MYC or PI3K-AKT pathway inhibitors each induced BIM upregulation and apoptosis, indicating that BIM is repressed downstream of MYC and PI3K-AKT in high-risk T-ALL. Restoring BIM function in human T-ALL cells using a stapled peptide mimetic of the BIM BH3 domain had therapeutic activity, indicating that BIM repression is required for T-ALL viability. In the zebrafish model, where MYC downregulation induces T-ALL regression via mitochondrial apoptosis, T-ALL persisted despite MYC downregulation in 10% of bim wild-type zebrafish, 18% of bim heterozygotes and in 33% of bim homozygous mutants (P=0.017). We conclude that downregulation of BIM represents a key survival signal downstream of oncogenic MYC and PI3K-AKT signaling in treatment-resistant T-ALL.

(90)Y-ibritumomab tiuxetan followed by reduced-intensity conditioning and allo-SCT in patients with advanced follicular lymphoma.

Reduced-intensity conditioning (RIC) hematopoietic SCT (HSCT) is a potentially curative therapeutic option for patients with advanced follicular lymphoma (FL), but disease relapse remains the most common cause of failure. Radioimmunoconjugates administered before RIC allo-HSCT may enhance cytoreduction and allow more time for GVL effect to develop without the associated toxicity of a myeloablative HSCT. We performed a retrospective study to describe the outcomes of patients with relapsed, refractory or transformed FL who received yttrium-90 ((90)Y)-ibritumomab tiuxetan followed by fludarabine and low-dose BU RIC allogeneic HSCT at the Dana-Farber Cancer Institute between 2006 and 2009, inclusively. Twelve patients were identified with a median age of 55 (40-66) years and a median number of lines of therapy of 5 (2-10). Two patients (17%) had transformed to a more aggressive histology and five (42%) had chemorefractory FL. Cumulative incidences of grade II-IV acute GVHD at 100 days were 17% (±11%) and chronic GVHD at 12 months were 63% (±19%). Two-year non-relapse mortality was 18% (±12%). Two-year OS and PFS were 83% (±11%) and 74% (±13%), respectively. This treatment is associated with favorable outcomes including acceptable rates of GVHD and relapse in advanced FL patients, and warrants prospective studies.

Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-2000).

The Dana-Farber Cancer Institute (DFCI) acute lymphoblastic leukemia (ALL) Consortium has been conducting multi-institutional clinical trials in childhood ALL since 1981. The treatment backbone has included 20-30 consecutive weeks of asparaginase during intensification and frequent vincristine/corticosteroid pulses during the continuation phase. Between 1985 and 2000, 1457 children aged 0-18 years were treated on four consecutive protocols: 85-01 (1985-1987), 87-01 (1987-1991), 91-01 (1991-1955) and 95-01 (1996-2000). The 10-year event-free survival (EFS)+/-s.e. by protocol was 77.9+/-2.8% (85-01), 74.2+/-2.3% (87-01), 80.8+/-2.1% (91-01) and 80.5+/-1.8% (95-01). Approximately 82% of patients treated in the 1980s and 88% treated in the 1990s were long-term survivors. Both EFS and overall survival (OS) rates were significantly higher for patients treated in the 1990s compared with the 1980s (P=0.05 and 0.01, respectively). On the two protocols conducted in the 1990s, EFS was 79-85% for T-cell ALL patients and 75-78% for adolescents (age 10-18 years). Results of randomized studies revealed that dexrazoxane prevented acute cardiac injury without adversely affecting EFS or OS in high-risk (HR) patients, and frequently dosed intrathecal chemotherapy was an effective substitute for cranial radiation in standard-risk (SR) patients. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.

Is raised intraocular pressure a bad prognostic sign in acute corneal graft rejection?

One hundred and forty acute corneal rejection episodes in 94 patients were studied retrospectively. Sixteen episodes in 15 eyes were associated with raised intraocular pressure (IOP) on admission, three of whom had had previously elevated IOP. At six weeks, six (37.5%) still required hypotensive therapy. Five eyes with raised IOP at rejection had lost vision at six weeks. Five of the six eyes with graft failure at review had raised IOP either pre-graft, at rejection or at follow-up. Eyes grafted for herpes simplex keratitis with hypertensive rejection episodes had a higher mean admission IOP, with a more short-lived rise than other eyes.

Local extraocular extension of retinoblastoma following intraocular surgery.

Three cases of local extraocular extension of retinoblastoma following intraocular surgery via a transscleral approach have been seen in one centre during a 12-month period. This number represents a significant increase on the previous incidence of this serious complication, which may be related to more widespread use of vitrectomy techniques. Orbital and local lymph node recurrence of retinoblastoma have been associated with a very poor survival rate in the past, and steps must be taken to limit the chance of this happening should an intraocular surgical procedure be performed inadvertently on an eye containing a retinoblastoma. Early enucleation without implant is advised, and adjuvant orbital radiotherapy is strongly recommended, even when there is no histopathological evidence of local extraocular tumour spread.

Respiration and viability of thermally injured Saccharomyces cerevisiae.

Resting cells of Saccharomyces cerevisiae Y25 were heated at 56 degrees C for 0 to 2 min. Respiratory activity of the cells reflected the severity of the heat stress. The endogenous respiration was approximately 50 microliter of O2/mg per h for cells heated for 2 min at 56 degrees C as compared with 2 microliter of O2/mg per h for nonheated cells. There was a distinct decrease in respiration after 1 to 3 h, and after 20 h the respiration rate of heated cells was less than that of nonheated cells. Along with increased rates of endogenous respiration, respiratory quotients of cells were altered after heat stress. Addition of 2,4-dinitrophenol stimulated O2 (uptake) in nonheated cells but decreased O2 (uptake) of heated cells. Due to the high rate of endogenous respiration, addition of glucose resulted in no substantial change in the rate of respiration of heated cells. However, addition of glucose prolonged the presence of the high rates of respiration observed in heated cells.

Automated fluorometric determination of thiamine and riboflavin in infant formulas.

Commercial infant formulas were analyzed simultaneously for thiamine and riboflavin by an automated fluorometric method and by the AOAC manual fluorometric methods. For 10 products, the mean thiamine and riboflavin results determined using the automated method ranged from 104 to 113% and 90 to 112%, respectively, of those by the AOAC manual methods. The coefficients of variation for thiamine and riboflavin ranged from 1.05 to 3.90% and 0.60 to 2.48%, respectively, for the automated methods, and 1.48 to 3.86% and 0.69 to 10.9%, respectively, for the manual methods. Using the automated method, mean recoveries of thiamine and riboflavin added to samples were 103 and 104%, respectively. The automated method used a common sample preparation to determine both thiamine and riboflavin, and gave results equivalent to, or better than, those obtained by the manual methods.

Comparison of semiautomated and manual methods for the determination of thiamine in baby cereals and infant and dietary formulas.

Using a semiautomated method, the mean thiamine content of specific products ranged from 88 to 101% and 83 to 93% for baby cereals and infant and dietary formulas, respectively, of those obtained with the AOAC manual method. The best results were obtained when data for the semiautomated method were calculated from a standard curve obtained by using thiamine solutions which had been digested and hydrolyzed along with the samples.

Effect of beef broth protein on the thermal inactivation of staphylococcal enterotoxin B1.

Enterotoxin B produced by Staphylococus aureus 243 in brain heart infusion broth was concentrated by dialysis against 40% polyethylene glycol (20 M), partially purified on a Sephadex G-100 column and heated at 110 degrees C in thermal death time cans. Various heating menstrua included 0.04 M Veronal buffer (pH 7.4), beef broth, and fractions of beef broth obtained by ultrafiltration or precipitation with ammonium sulfate. The toxin was assayed serologically using the microslide gel double-diffusion method. The time requiring for 90% inactivation at 110 degrees C (D110 value) obtained in buffer and in beef broth was 18 and 60 min, respectively. When the concentration of beef broth was increased fivefold, the D110 increased to 78 min. The apparent protective effect or protein was further investigated using beef broth protein obtained by precipitation with (NH4)2SO4. The D110 values were 51 and 70 min when the protein concentration in the heating menstruum was 3.8 and 7.7 mg/ml, respectively. However, when the beef broth protein was dialyzed against buffer before use as a heating menstrum, the D110 was only 39 or 41 min at comparable protein concentrations. Results indicated a dialyzable factor, whose protective effect was partially destroyed by trypsin and chymotrypsin but did not by disodium ethylenediaminetetraacetate, was involved in the protection of enterotoxin B during heating.

Exosporium formation in sporulating cells of Clostridium botulinum 78A.

In sporulating cells of Clostridium botulinum type A (NCA strain 78A), formation of exosporia was initiated laterally in the sporangia before the synthesis of the spore cortex. Mature spores were enveloped by multilayered exosporia; the layers were uniform in appearance, approximately 3 nm thick, with a center-to-center distance of 7 nm.

Fixation of mature spores of Clostridium botulinum.

A triple fixation method using a sequential application of 15 or 30% formaldehyde, 6% glutaraldehyde, and 1% osmium tetroxide resulted in excellent fixation of mature spores of Clostridium botulinum.

Fermenting yeasts associated with softening and gas-pocket formation in olives.

Fermenting, pectolytic yeasts were isolated from a massive commercial outbreak of softening and gas-pocket formation in olives that had been stored in acidified, low-salt brines in an attempt to reduce the problem of brine disposal. The suspected yeasts represented three different species: Saccharomyces oleaginosus, S. kluyveri, and Hansenula anomala var. anomala. All pectolytic cultures produced pectin esterase and polygalacturonase but no pectic acid trans-eliminase when grown in nutrient glucose broth. Crude, cell-free dialyzed enzyme preparations measured viscosimetrically exhibited optimal activity on sodium polygalacturonate at pH 6.0 and 45 C and were active in the range of pH 4.0 to 9.0 and 10 to 60 C.