Enhanced Risk Stratification for Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia: A Children's Oncology Group Report.

Current strategies to treat pediatric acute lymphoblastic leukemia rely on risk stratification algorithms using categorical data. We investigated whether using continuous variables assigned different weights would improve risk stratification. We developed and validated a multivariable Cox model for relapse-free survival (RFS) using information from 21199 patients. We constructed risk groups by identifying cutoffs of the COG Prognostic Index (PICOG) that maximized discrimination of the predictive model. Patients with higher PICOG have higher predicted relapse risk. The PICOG reliably discriminates patients with low vs. high relapse risk. For those with moderate relapse risk using current COG risk classification, the PICOG identifies subgroups with varying 5-year RFS. Among current COG standard-risk average patients, PICOG identifies low and intermediate risk groups with 96% and 90% RFS, respectively. Similarly, amongst current COG high-risk patients, PICOG identifies four groups ranging from 96% to 66% RFS, providing additional discrimination for future treatment stratification. When coupled with traditional algorithms, the novel PICOG can more accurately risk stratify patients, identifying groups with better outcomes who may benefit from less intensive therapy, and those who have high relapse risk needing innovative approaches for cure.

Native Valve Infective Endocarditis with Osteomyelitis and Brain Abscess Caused by Granulicatella adiacens with Literature Review.

Granulicatella adiacens is a type of NVS (nutritionally variant streptococci) rarely causing infective endocarditis (IE). NVS are fastidious and unable to sustain growth on routine culture media due to lack of specific nutrients. Endocarditis caused by NVS due to their virulence is associated with higher treatment failures and mortality rates. New antimicrobial susceptibility patterns are indicative of a significant rise in penicillin resistance and susceptibility differences between NVS subspecies. Initial empirical therapy is essential as a delay in using the appropriate agent leads to poor results. We present a case of an immunocompetent young female with recent intravenous drug abuse resulting in native mitral valve endocarditis with ruptured chordae tendineae and septic embolization, causing brain abscess and lumbar spine osteomyelitis. She was transferred to a tertiary center where she underwent mitral valve replacement successfully and treated with six weeks of intravenous vancomycin and ertapenem. To our knowledge, ours is the first case report of G. adiacens endocarditis in an adult with brain abscess and osteomyelitis with an excellent response to antibiotic therapy. Based on our case report, literature review, and new antimicrobial susceptibility patterns, updates to treatment guidelines are suggested to improve the therapeutic outcomes.

Tetracyclines for Treatment of Tularemia: A Case Series.

Tetracyclines for tularemia have been associated with higher failure rates. There were 48 cases of tularemia at the University of Missouri between 1988 and 2015. We retrospectively analyzed 17 patients with tularemia who were successfully treated with tetracyclines, and 9 of these patients also underwent aspiration or incision and drainage.

Primed stimulation of isolated perfused rabbit lung by endotoxin and platelet activating factor induces enhanced production of thromboxane and lung injury.

Bacterial sepsis often precedes the development of the adult respiratory distress syndrome (ARDS) and bacterial endotoxin (LPS) produces a syndrome similar to ARDS when infused into experimental animals. We determined in isolated, buffer-perfused rabbit lungs, free of plasma and circulating blood cells that LPS synergized with platelet activating factor (PAF) to injure the lung. In lungs perfused for 2 h with LPS-free buffer (less than 100 pg/ml), stimulation with 1, 10, or 100 nM PAF produced transient pulmonary hypertension and minimal edema. Lungs perfused for 2 h with buffer containing 100 ng/ml of Escherichia coli 0111:B4 LPS had slight elevation of pulmonary artery pressure (PAP) and did not develop edema. In contrast, lungs exposed to 100 ng/ml of LPS for 2 h had marked increases in PAP and developed significant edema when stimulated with PAF. LPS treatment increased capillary filtration coefficient, suggesting that capillary leak contributed to pulmonary edema. LPS-primed, PAF-stimulated lungs had enhanced production of thromboxane B2 (TXB) and 6-keto-prostaglandin F1 alpha (6KPF). Indomethacin completely inhibited PAF-stimulated production of TXB and 6KPF in control and LPS-primed preparations, did not inhibit the rise in PAP produced by PAF in control lungs, but blocked the exaggerated rise in PAP and edema seen in LPS-primed, PAF-stimulated lungs. The thromboxane synthetase inhibitor dazoxiben, and the thromboxane receptor antagonist, SQ 29,548, similarly inhibited LPS-primed pulmonary hypertension and edema after PAF-stimulation. These studies indicate that LPS primes the lung for enhanced injury in response to the physiologic mediator PAF by amplifying the synthesis and release of thromboxane in lung tissue.

Neutropenia induced by systemic infusion of 5,12-dihydroxy-6,8,10,14-eicosatetraenoic acid: correlation with its in vitro effects upon neutrophils.

5(S), 12(S)-Dihydroxy-cis-14,trans-6,8,10-eicosatetraenoate (compound I), 5(S),12(R)-dihydroxy-cis-14,trans-6,8,10-eicosatetraenoate (compound II), and 5(S),12(R)-dihydroxy-cis-6,14,trans-8,10-eicosatetraenoate (compound III) were prepared from rabbit peritoneal neutrophils challenged with arachidonic acid plus ionophore A23187. Each arachidonate metabolite caused rabbit neutrophils to aggregate and, in cells treated with cytochalasin B, release granule-bound enzymes. Compound III was 10- to 100-fold more potent than compounds II and I. When intravenously infused into rabbits at doses of 100--1,000 ng/kg, compound III induced abrupt, profound, transient neutropenia associated with a rapidly reversing accumulation of neutrophils in the pulmonary circulation. This in vivo action correlated closely with the ability of the fatty acid to activate neutrophils in vitro: neutropenia, aggregation, and degranulation occurred at similar doses of stimulus and the rapid, reversing kinetics of the neutropenic response paralleled the equally rapid, reversing formation of aggregates. The fatty acid did not alter the circulating levels of lymphocytes or platelets and did not aggregate platelets in vitro. At comparable doses (i.e., 100--1,000 ng/kg), compounds I and II did not cause neutropenia. Thus, compound III possesses a high degree of structural and target-cell specificity in stimulating neutrophils in vitro and in vivo. Clinical and experimental syndromes associating neutropenia with increased levels of circulating arachidonate metabolites may involve compound III as a mediator of neutrophil sequestration in lung.

Gonococcal arthritis in an era of increasing penicillin resistance. Presentations and outcomes in 41 recent cases (1985-1991).

BACKGROUND: To assess the impact of recent reports of disseminated gonococcal infection caused by penicillin-resistant organisms, we reviewed the presenting features, clinical course, and outcomes of a group of patients with gonococcal arthritis treated in recent years. METHODS: We reviewed the records of all cases of acute arthritis associated with a culture positive for Neisseria gonorrhoeae at our institution from July 1985 through December 1991. RESULTS: Forty-one cases were identified. Patients included 34 women and 38 blacks; the mean age was 22.6 years. Duration of symptoms averaged 4.8 days at presentation. Other features included migratory arthralgias (n = 27), urogenital symptoms or signs (n = 26), fever (n = 21), and skin lesions (n = 16). Comorbid conditions included intravenous drug use (n = 8) and systemic lupus erythematosus (n = 3). The knee was the most commonly affected joint. Positive culture results were obtained from 32 urogenital samples (86%), 14 synovial fluid samples (44%), seven rectal samples (39%), four blood samples (12%), and two throat samples (7%). All synovial fluid samples with positive culture results had white blood cell counts higher than 20.0 x 10(9)/L. Response to therapy with penicillin and/or ceftriaxone was prompt, and mean duration of hospitalization was 5.8 days. Patients who required longer hospitalization had a higher mean erythrocyte sedimentation rate and higher frequencies of positive synovial fluid culture results and comorbid conditions. Penicillin sensitivity could be determined in 30 patients on the basis of clinical response or in vitro testing. Among these patients, two cases of penicillin-resistant organisms were identified, one beta-lactamase positive and one beta-lactamase negative. CONCLUSIONS: The clinical features of patients with gonococcal arthritis have changed very little since the last large reported series over a decade ago. Underlying conditions appear to be more common, but response to antibiotic therapy and eventual outcome remain excellent. The finding of penicillin-resistant organisms in at least 5% of patients reinforces recent recommendations that third-generation cephalosporin agents be used as initial therapy for disseminated gonococcal infections until drug susceptibilities are known.

Facile synthesis of platelet-activating factor and racemic analogues containing unsaturation in the sn-1-alkyl chain.

Platelet-activating factor, 1 (PAF, 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine), and octadecyl-PAF were synthesized chemically as the racemates. The sn-1-O-alkyl isomers were isolated after treatment of the racemates with phospholipase A2 and subsequent reacetylation of the 1-O-alkyl-2-lyso-sn-glycero-3-phosphocholines released. Analogues of PAF containing unsaturated alkyl moieties at the sn-1 position (2, 4, 5) were synthesized by utilizing the methoxyethoxymethyl protecting group as a novel method for preparing unsaturated alkyl lipids. This procedure provides a facile means for preparing unsaturated either phospholipids of defined structure that may be tritiated to high radiospecific activity for metabolic studies. Unsaturation in the alkyl chain had minimal effect on the bioactivities examined in this study.

Effect of probenecid on ventricular cerebrospinal fluid methotrexate pharmacokinetics after intralumbar administration in nonhuman primates.

PURPOSE: Intrathecal methotrexate (MTX) achieves high concentrations in the cerebrospinal fluid (CSF) following intralumbar administration. However, peak ventricular CSF MTX concentrations are highly variable and are < 10% of those achieved with intraventricular dosing. The objectives of this study were to evaluate the effect of intralumbar and intravenous probenecid on ventricular CSF MTX concentrations after intralumbar administration of MTX, and to compare the pharmacokinetics of MTX after intralumbar and intraventricular administration. METHODS: Nonhuman primates (Macaca mulatta) with permanently implanted catheters in the lateral and fourth ventricles received 0.5 mg intraventricular (lateral ventricle) MTX, or 0.5 mg intralumbar MTX with and without intralumbar or intravenous probenecid. Animals were kept prone for 1 h after MTX administration, and ventricular CSF was sampled up to 48 h from a fourth ventricular Ommaya reservoir. MTX concentrations were measured using the dihydrofolate reductase enzyme inhibition assay. Area under the ventricular CSF MTX concentration-time curve (AUC) was used as a measure of MTX exposure. RESULTS: Peak ventricular CSF MTX concentrations and AUCs were highly variable after intralumbar MTX administration. Ventricular CSF MTX AUCs increased by a mean of 3.2-fold after the addition of intralumbar probenecid. Intravenous administration of probenecid did not result in an increase in ventricular CSF MTX AUCs. Asymptomatic pleocytosis was observed in all animals after intralumbar probenecid administration. Ventricular CSF MTX concentrations and AUCs were less variable after intraventricular administration of MTX. CONCLUSION: The administration of intralumbar but not intravenous probenecid increases the ventricular CSF MTX exposure after intralumbar MTX administration.

Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984-2001: a report from the children's oncology group.

From 1984 to 2001, the Pediatric Oncology Group (POG) conducted 12 acute lymphoblastic leukemia (ALL) studies. Ten-year event-free survival (EFS) for patients >12 months of age with B-precursor ALL on acute leukemia in children 14, 15 and 16 series were 66.7+/-1.2%, 68.1+/-1.4% and 73.2+/-2.1%, respectively. Intermediate dose methotrexate (ID MTX; 1 g/m(2)) improved outcomes for standard risk patients (10-year EFS 77.5+/-2.7% vs 66.3+/-3.1% for oral MTX). Neither MTX intensification (2.5 g/m(2)) nor addition of cytosine arabinoside/daunomycin/teniposide improved outcomes for higher risk patients. Intermediate dose mercaptopurine (1 g/m(2)) failed to improve outcomes for either group. Ten-year EFS for patients with T-cell ALL, POG 8704 and 9404 were 49.1+/-3.1% and 72.2+/-4.7%, respectively. Intensive asparaginase (10-year EFS 61.8 vs 42.7%) and high-dose MTX (5 g/m(2)) (10-year EFS 78.0 vs 65.8%) improved outcomes. There was a non-significant improvement in EFS for infants (10-year EFS 17.7+/-7.2-31.9+/-8.3%). Prognostic indicators for B-precursor ALL were age and WBC at diagnosis, gender, central nervous system disease, DNA index and cytogenetic abnormalities. Only gender was prognostic in T-cell ALL. In infants, WBC and MLL translocation were linked to inferior outcome.

Calcium-dependent toxic effects of digoxin in isolated myocardial preparations.

On isolated guinea-pig papillary muscles as well as on electrically driven atria digoxin was infused into the bath fluid until cardiac arrest occurred. The concentration of digoxin which caused standstill is defined as the toxic one. The toxicity was determined under various Ca2+-concentrations. On the papillary muscle the increase of extracellular Ca2+ from 0.9 to 7.2 mM increased the toxicity of digoxin, i.e. significantly diminished its toxic concentrations. Likewise, on electrically driven atria an increase of Ca2+ from 0.45 to 7.2 mM increased the toxicity of digoxin. These results demonstrate that with regard to the toxicity Ca2+ and digoxin act synergistically.

Effect of an inhibitor of protein kinase C on human polymorphonuclear leukocyte degranulation.

The protein kinase C inhibitor C-I reduced superoxide production by human neutrophils in response to phorbol myristate acetate by greater than 50%. In contrast to its effects in oxidative metabolism, 100 microM C-I caused minimal inhibition (5-18%) of lysozyme release in response to phorbol myristate acetate. Enzyme release produced by the formylated oligopeptide FMLP was enhanced by 23-54% in neutrophils pretreated with 100 microM C-I. These findings suggest that protein kinase C activation is not required for phorbol myristate acetate induced enzyme release. Enhancement of FMLP stimulated degranulation by C-I suggests that protein kinase C activation may have inhibitory effects on the release of granule enzymes by human neutrophils.

Clinical evaluation of moxalactam: evidence of decreased efficacy in gram-positive aerobic infections.

Moxalactam was used as initial, empirical therapy in 69 patients with a variety of serious bacterial infections, 32% of which were accompanied by bacteremia. Overall, the success rate was 83% and drug-related adverse effects were minimal. The drug was less efficacious in infections caused by aerobic gram-positive pathogens than it was in those caused by gram-negative pathogens. The following gram-positive organisms were associated with special problems during moxalactam therapy: Streptococcus pneumoniae (development of meningitis and a relapse of pneumonia with a more resistant strain), Staphylococcus epidermidis (in vivo emergence of moxalactam resistance, and the enterococci (failure of therapy and a fatal superinfection. Moxalactam performed well in infections caused by most gram-negative organisms, including aminoglycoside-resistant strains, but the previously reported emergence of gram-negative bacillary resistance to moxalactam during therapy was reconfirmed in our series with Serratia marcescens. The use of moxalactam in the treatment of gram-negative meningitis was further supported by a patient with meningitis-ventriculitis caused by Bacteroides fragilis who was cured with moxalactam after failure on chloramphenicol.

Platelet-activating factor and analogues: comparative studies with human neutrophils and rabbit platelets.

Platelet-activating factor and 12 structural analogues stimulated rabbit platelets to aggregate and release [14C]-serotonin. They likewise caused human neutrophils to aggregate, degranulate, and take up [3H]-deoxyglucose. Their respective potencies, which varied by 4-5 orders of magnitude, correlated highly (r greater than or equal to 0.93) in all assays. These compounds also selectively desensitized neutrophils to the degranulating actions of platelet-activating factor but not to C5a or a formylated oligopeptide. Three other analogues with structures quite similar to platelet-activating factor were unable to activate or desensitize the cells. Hence, the structure-activity relations of the analogues in several assays of platelet and neutrophil function were similar and they stimulated neutrophils by a common activation mechanism that differed from those used by C5a or formylated oligopeptides. These data are consistent with the notion that platelet-activating factor activates and desensitizes various target cells through stereospecific receptors. Apparently, these putative receptors on neutrophils and platelets have similar structural specificities for platelet-activating factor and its analogues.

Pharmacokinetics and metabolism of the methotrexate metabolite 2, 4-diamino-N(10)-methylpteroic acid.

The novel methotrexate (MTX) rescue agent carboxypeptidase-G(2) (CPDG(2)) converts >98% of plasma MTX to 2, 4-diamino-N(10)-methylpteroic acid (DAMPA) and glutamate in patients with MTX-induced renal failure and delayed MTX excretion. DAMPA is eliminated more rapidly than MTX in these patients, suggesting nonrenal elimination. The pharmacokinetics and metabolism of DAMPA were studied in four nonhuman primates with reverse-phase HPLC with UV, photodiode array detection, and mass spectroscopy. The mean peak plasma DAMPA concentration was 51 microM and the plasma disposition was described by a three-compartment open model with first order elimination. The mean clearance of DAMPA was 1.9 l/kg/h and the mean terminal half-life was 51 min. Forty-six percent of the dose was excreted in the urine as parent compound. Three DAMPA metabolites, hydroxy-DAMPA, DAMPA-glucuronide, and hydroxy-DAMPA-glucuronide, were identified in plasma and urine. These metabolites also were identified in plasma from patients who received CPDG(2) as an MTX rescue agent. The cytotoxicity of DAMPA and its effect on MTX cytotoxicity were assessed in the Molt-4 human leukemic cell line. DAMPA was not cytotoxic and did not significantly alter the cytotoxicity of MTX. In nonhuman primates metabolism of DAMPA is a major route of DAMPA elimination, and metabolism underlies the more rapid elimination of DAMPA versus MTX in patients with MTX-induced renal dysfunction after administration of CPDG(2).