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OBJECTIVE: To assess evidence from randomized controlled trials (RCTs) on the safety of isotonic versus hypotonic intravenous (IV) maintenance fluids in hospitalized children. METHODS:We searched PubMed, Embase, Cochrane Library, and clinicaltrials.gov (up to April 11, 2013) for RCTs that compared isotonic to hypotonic maintenance IV fluid therapy in hospitalized children. Relative risk (RR), weighted mean differences, and 95% confidence intervals (CIs) were calculated based on the effects on plasma sodium (pNa). The risk of developing hyponatremia (pNa ,136 mmol/L), severe hyponatremia (pNa ,130 mmol/L), and hypernatremia (pNa .145 mmol/L) was evaluated. We adopted a random-effects model in all meta-analyses. Sensitivity analyses by missing data were also performed.RESULTS: Ten RCTs were included in this review. The meta-analysis showed significantly higher risk of hypotonic IV fluids for developing hyponatremia (RR 2.24, 95% CI 1.52 to 3.31) and severe hyponatremia (RR 5.29, 95% CI 1.74 to 16.06). There was a significantly greater fall in pNa in children who received hypotonic IV fluids (-3.49 mmol/L versus isotonic IV fluids, 95% CI -5.63 to -1.35). No significant difference was found between the 2 interventions in the risk of hypernatremia (RR 0.73, 95% CI 0.22 to 2.48). None of the findings was sensitive to imputation of missing data.CONCLUSIONS: Isotonic fluids are safer than hypotonic fluids in hospitalized children requiring maintenance IV fluid therapy in terms of pNa. Pediatrics 2014;133:105-113

The study reports on the investigation of acute and subacute toxicity and on antineoplastic activity of hexadecylphosphocholine (HPC), the first compound of a new class of antineoplastic chemotherapeutics. In rats, the LD50 of HPC was 606 mumol/kg; the maximum tolerable dose over four weeks was 39 mumol/kg. Symptoms of toxicity were enteritis, spider cell activation in the liver, hemosiderosis in the spleen and reversible transaminase increase. The best therapeutic effect was observed on methylnitrosourea (MNU)-induced mammary carcinoma in the rat. Two transplantable mammary carcinomas in the rat and autochthonous benzo(a)pyrene-induced sarcomas exhibited low-grade sensitivity to HPC. The MXT mammary carcinoma of the mouse, the Walker 256 carcinosarcoma of the rat, and autochthonous acetoxymethylmethylnitrosamine-induced colonic tumors of the rat were not chemosensitive to HPC.

The activity of the newly synthesized ruthenium derivative imidazolium-bis(imidazole)tetrachlororuthenate (III) [ImH(RuIm2Cl4)] was compared with that of 5'-deoxy-5-fluorouridine (5'dFUR) in autochthonous acetoxy-methyl-methylnitrosamine (AMMN)-induced colorectal cancer in SD rats. Following coloscopic diagnosis of colorectal tumors treatment was administered twice weekly for a 10-week period. ImH(RuIm2Cl4) exhibited considerable antitumoral efficacy compared with 5'dFUR (20 T/C % and 60 T/C %, respectively) against the growth of AMMN-induced colorectal adenocarcinoma in SD rats. The mortality rates with ImH(RuIm2Cl4) were dose-related, but its efficacy did not vary in all doses administered.

The prognosis for patients with myeloid-blast (MB) or lymphoid-blast (LB) chronic myeloid leukemia (CML) is poor, with an estimated survival from onset of blast crisis of approximately 3 months. Dasatinib (SPRYCEL®) is a novel inhibitor of BCR-ABL and SRC-family kinases, that has proven to be effective (in terms of complete hematologic and cytogenetic response) for patients with MB- or LB-CML whose disease is either resistant or intolerant to imatinib. Patients were enrolled to the corresponding START studies between January and June 2005, and dasatinib 70 mg BID was administered to 109 patients with MB-CML and 48 patients with LB-CML. All patients had previously failed treatment with imatinib - 90% of whom were resistant to imatinib. Here we present an update with a minimum follow-up of 12 mo. Of the 157 patients, 56% were male and median age was 54 years (range 17–81). Median time from CML diagnosis was 44 mo (range 2–216). Prior therapy included imatinib >600 mg/d in 50% of patients, treatment with imatinib for >3 years in 36%, and stem-cell transplantation in 19%. At baseline, 57% had WBC <20,000/mm3, 69% had platelets <100,000/mm3, and 18% had extramedullary disease outside of the spleen. Major hematologic responses (MaHRs) were induced in 34% of patients with MB-CML (imatinib-resistant 35%, -intolerant 20%) and 35% of LB-CML patients (imatinib-resistant 36%, -intolerant 33%). Major cytogenetic responses (MCyRs) were attained in 33% of patients with MB-CML (imatinib-resistant 34%, -intolerant 20%) and 52% of LB-CML patients (imatinib-resistant 50%, -intolerant 67%), while complete cytogenetic responses (CCyRs) were achieved in 26% (imatinib-resistant 26%, -intolerant 20%) and 46% of patients (imatinib-resistant 43%, -intolerant 67%), respectively. Median progression-free survival was 6.7 mo (MB-CML) and 3.0 mo (LB-CML) while median overall survival was 11.8 mo and 5.3 mo, respectively. Dasatinib was generally well tolerated in this poor prognosis population. Fluid retention events were observed more frequently in the MB-CML cohort, with all grade pleural effusion occurring in 36% and 13% of MB and LB patients, respectively (grade 3–4 - 15% and 6%). Other non-hematologic side effects were primarily grade 1–2. Cytopenias were noted for the majority of patients, and were manageable; grade 3–4 febrile neutropenia was recorded in 8% of patients. Dasatinib doses were reduced in 32% of patients and interrupted in 59%, most typically as a result of non-hematologic toxicities. Doses were escalated in 44% of patients. The median duration of therapy was 3.4 mo (0.03–18) for all patients and 14 mo (6–18) for patients still receiving treatment. Long-term data confirm that dasatinib is highly active, producing rapid and clinically meaningful responses in this poor prognosis patient population. Updated analyses corresponding to a minimum follow-up of 2 years on all patients will be presented.

Dasatinib (SPRYCEL®), a potent inhibitor of BCR-ABL and SRC-family kinases, has been shown to be effective and safe for patients with accelerated-phase chronic myelogenous leukemia (AP-CML) who are resistant or intolerant to imatinib. START-A is a 39-center, international study to which patients with AP-CML who failed prior imatinib therapy were enrolled between December 2004 and July 2005. Here we report an update of the efficacy and safety of dasatinib (70 mg BID) from this open-label study of 174 patients with imatinib-resistant (n=161) or -intolerant (n=13) AP-CML after a median follow-up of 14.1 mo (range 0.1–21.7). Dose escalation (100 mg BID) or reduction (50 or 40 mg BID) were allowed for a lack of response or toxicity, respectively. Median time from original diagnosis of CML was 82 mo (range 4–359). Prior therapy included interferon-α in 72% of patients and stem-cell transplantation (SCT) in 13%; 52% had received prior imatinib doses >600 mg/d and 59% treatment with imatinib for >3 years. Best response to prior imatinib therapy was complete hematologic response (CHR) in 79% of patients, major cytogenetic response (MCyR) in 33%, and complete cytogenetic response (CCyR) in 21%. CHRs were attained by 45% of patients, while MCyRs and CCyRs were seen in 39% and 32%, respectively. Responses were achieved irrespective of imatinib status (with MCyR of 39% for both imatinib-resistant and -intolerant subgroups), prior stem-cell transplantation (26% MCyR), or the presence of prior BCR-ABL mutations (with the exception of T315I) (40% MCyR for both the mutation-positive and -negative subgroups). Twelve-month progression-free survival and overall survival were 66% and 82%, respectively. Dose interruptions were required for 85% of patients and dose reduction for 65%; the average daily dose administered was 126 mg (range 32–196). Grade 3–4 neutropenia and thrombocytopenia were reported in 76% and 82% of patients. Non-hematologic toxicity was generally mild to moderate and consisted primarily of diarrhea (52% all grades, 8% grade 3–4), headache (29%, <1%), nausea (28%, <1%), pleural effusion (27%, 5%), fatigue (26%, 4%), and superficial edema (22%, 1%). Dasatinib is effective in patients with AP-CML following imatinib treatment failure and the overall benefit-risk evaluation is favorable in this poor prognosis population. Updated analyses corresponding to a minimum follow-up of 2 years on all patients will be presented.

Patients with Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) generally have a rapid disease course and a poor overall prognosis that is compounded by resistance to imatinib. Dasatinib is a novel multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases, with in vitro potency some 325-fold greater than imatinib against BCR-ABL and proven efficacy in this patient population. START-L is an open-label, international, multicenter study in which patients with imatinib-resistant or -intolerant Ph+ ALL enrolled from January through July 2005 were treated with dasatinib 70 mg BID. Dose escalation to 100 mg BID and reduction to 50 or 40 mg BID were allowed for inadequate response and toxicity, respectively. At the time of this update, all 46 treated patients (median age 48 years; 59% male) had a minimum follow-up of 12 mo. 96% of patients were imatinib-resistant; 46% had received doses of imatinib >600 mg/d, and 52% had received imatinib therapy for >12 mo. Median time from the initial Ph+ ALL diagnosis was 18 mo (range 3–163) and 37% had undergone prior stem-cell transplantation (SCT). BCR-ABL mutations were present at baseline in 78% of patients. The overall major hematologic response rate (MaHR) was 41% with a complete HR rate of 33%. Major cytogenetic response (MCyR) was achieved in 57% of patients with a complete CyR attained in all but one of these patients (54%). Response rates were consistent irrespective of pre-existing BCR-ABL mutations. The median duration of MCyR was 6.9 mo. Median overall survival (OS) was 8.0 mo and 22% of patients remained alive and progression-free after 1 year of treatment. Outcome was favorable for patients with prior SCT: median OS of 9.0 mo (5.8 mo for patients without prior SCT). As expected in these pre-treated patients, grade 3–4 cytopenias were significant with 78% of patients experiencing severe thrombocytopenia and neutropenia. Non-hematologic side-effects included diarrhea in 33% of patients (grade 3–4 in 9%), pleural effusion in 24% (grade 3–4 in 7%), nausea in 22% (no grade 3-4), and pyrexia in 22% (grade 3–4 in 2%). The dose of dasatinib was reduced in 30% of patients and interrupted in 43%; this was primarily attributable to non-hematologic toxicities. This resulted in a median of the average daily dose of 143 mg. Dasatinib continues to show impressive efficacy in this poor-prognosis patient population with Ph+ ALL after the failure of imatinib. Updated analyses corresponding to a minimum follow-up of 2 years will be presented.

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