bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Traumatic Lumbar Puncture on CNS Relapse in Children with Acute Lymphoblastic Leukemia.
Authors: Normand Charline , Thébaud-Léculée Estelle , Mazingue Francoise , Lambilliotte Anne , Lepelley Pascale , Nelken Brigitte , Dalle Jean-Hugues 
Published: April 2020

Abstract
Rationnal: In children with de novo acute lymphoblastic leukemia (ALL) event-free survival (EFS) and overall survival (OS) could be decreased when the diagnostic lumbar puncture is traumatic, as showed by two previous studies. The cerebrospinal fluid (CSF) should be contaminated with circulating leukemic blasts.
Purpose: The aim of this study is to further investigate the influence of traumatic diagnostic lumbar puncture (LP) on CNS relapse rate as first endpoint and then on OS in a single center (Lille Academic Hospital, France) from 1989 to 2004.
Patients and Methods: A total of 352 patients were restrospectively evaluated. These patients were treated according to the EORTC pediatric cooperative protocols 58 881 and 58 951. In these protocols, the neuroprophylaxy consisted in high-dose methotrexate (5g/m2/course x 4 to 11 courses according to the risk-group therapy) and intrathecal therapy (methotrexate +/− aracytine and corticosteroids), without any cranial irradiation. Traumatic lumbar puncture was defined as the presence of 10 erythrocytes/mm3 or more in cerebro-spinal fluid.
Results: The median follow-up was 5.9 years (0.05–14). The CNS relapse rate is increased in patients with traumatic diagnostic LP (p=0.023), and their OS is also significantly decreased (p=0.04). However, a “true” CNS involvement (i.e. CNS 3) at diagnostis is a risk factor for further CNS relapse, and in this study, the number of CNS3 child was more important in the traumatic LP group. In order to avoid this major biased error, the analysis was repeated with CNS1 and CNS2 child (n=339)only and without CNS3 patients. In this subgroup, when the diagnostic LP is traumatic, the CNS relapse rate and the OS are not statistically different than in non traumatic LP group (p=0.06 and p=0.087, respectively). However, there is a trend for worse results.
Conclusion: This study does not confirm the pejorative character of the traumatic diagnostic LP. Further investigations in larger study should be conducted to achieve more definitive conclusion. Moreover, an adequate biologic criteria is necessary to discriminate CSF contaminated with circulating leukemic blasts and real CNS primitive involvement to improve prognostic analysis and to adjust the treatment.
A Report of the Event-Free Survival (EFS) and Neurotoxicity for Children with Newly Diagnosed Standard Risk Acute Lymphoblastic Leukemia (ALL) on Pediatric Oncology Group (POG) Protocol 9405.
Authors: Rodes Stephen , Bell Beverly A. , Abish Sharon B. , Pullen Jeanette , Chauvenet Allen , Kurtzberg Joanne , Devidas Meenakshi , Shuster Jonathan , Camitta Bruce M. 
Published: April 2020

Abstract
POG 9405, a randomized phase III study for children with standard risk ALL, opened in 1994. The primary objectives were to determine effects on event-free survival (EFS) of: 1) higher (2.5g/m2) vs. standard (1g/m2) dose methotrexate (MTX) infusions during consolidation (in an attempt to obtain a plasma MTX target of 12 μmol) and (2) once vs. twice daily 6- mercaptopurine (MP) dosing during continuation (to improve the efficacy of MP based on its short half-life and S-phase dependence). Following remission induction, patients were randomized to: Regimens (Reg) A/B (MTX 1 g/m2 IV) or C/D (MTX 2.5 g/m2), all with MP 1g/m2 IV, q2 weeks (wk) x 12. Leucovorin 5 mg/m2 q6h x 5 began at hour 48 and continued until MTX level was &lt;0.3μmol. MTX 20 mg/m2/wk IM and MP 75 mg/m2/day p.o. were given on alternate wks. Continuation was MTX 20 mg/m2/wk IM for all patients and MP 75 mg/m2 daily p.o. for A/C and 37.5 mg/m2 p.o. b.i.d for B/D. CNS prophylaxis was age-adjusted triple intrathecal therapy (TIT) for a total of 14–19 doses due to protocol modifications made because of concerns about neurotoxicity. Total treatment duration was 130 wks. 295 patients entered consolidation therapy. Reg A: 77, Reg B: 77, Reg C: 70, Reg D: 71. The overall 6 year EFS for the study was 80% ±2.4% (s.e.). The study closed prematurely in 1996 due to issues pertaining to neurotoxicity. There was no significant difference in EFS between the two 6-MP dosing regimens [once-daily 78% vs. twice-daily 83%; p = 0.222]. Only 36% of patients on Reg C/D received the full 12 courses of higher dose MTX due to above noted protocol modifications. Neither the efficacy nor the toxicity of higher dose MTX can be fully evaluated for this study. 57 Patients (19%) reported one or more grade 2–4 neurotoxicity event using the Common Toxicity Criteria (CTC) version 2.0. These events included: cortical toxicity 37 events (including 33 seizures), cerebellar 15, cognitive dysfunction 6, headaches 4, motor 3, and significant fatigue in 3 children. Preliminary review indicates no difference in neurotoxicity incidence based on MTX dose. This antimetabolite based study highlights the importance of monitoring for neurotoxicity, as well as other unexpected adverse events on subsequent leukemia treatment protocols.
Repetitive Cycles of High-Dose Cytarabine Are Effective for Childhood Acute Myeloid Leukemia (AML): Long Term Outcome of the Children with AML Treated on Two Consecutive Trials of Tokyo Children’s Cancer Study Group.
Authors: Tomizawa Daisuke , Tabuchi Ken , Kinoshita Akitoshi , Hanada Ryoji , Kigasawa Hisato , Tsukimoto Ichiro , Tsuchida Masahiro 
Published: April 2020

Abstract
Intensive chemotherapy has contributed to an improved survival in pediatric acute myeloid leukemia (AML). We here report the long term results of the two consecutive AML trials of Tokyo Children’s Cancer Study Group; TCCSG M91-13 and M96-14. Between August 1991 and September 1998, a total of 216 eligible children with newly diagnosed AML entered either of the two trials. In M91-13 trial, patients received 3-drug induction therapy consisted of cytarabine, mitoxantrone, and etoposide, 4 courses of intensive consolidation chemotherapy including 2 courses with high-dose cytarabine. Subsequently, patients received another 4 courses of high-dose cytarabine containing consolidation chemotherapy, or autologous bone marrow or peripheral blood stem cell transplantation (A-BMT/PBSCT) instead. Allogeneic bone marrow transplantation (allo-BMT) was recommended for patients with HLA-matched family donor. In M96-14 trial, the last two courses of consolidation chemotherapy were omitted from the chemotherapy arm, and patients with FAB M3 were treated with all-trans-retinoic acid containing regimen. The remission induction rate, as a whole, was 81% and probability of 5-year overall survival and event-free survival were 62%±6% (95% confidence interval) and 56%±6% by Kaplan-Meier method, respectively. There were no significant differences in survivals among the three types of post-remission therapy (chemotherapy (n = 126), 64%±8%; allo-BMT (n = 34), 76%±14%; A-BMT/PBSCT (n = 32), 80%±13%). Although the number of consolidation chemotherapy courses were reduced from 8 to 6 in M96-14 trial, overall survival rate of each trial was similar (61%±8% vs. 64%±10%, P = 0.48). The overall survival rates of patients with low risk features, namely, t(8;21), inv(16), t(15;17) or FAB M3, and Down syndrome, were significantly better than that of the other patients (75%±9% vs. 55%±8%, P = 0.002). These results suggest that intensive high-dose cytarabine containing treatment was very effective for childhood AML regardless of types of post-remission therapy. As the chemotherapy courses could be safely reduced in number without compromising the results in the latter study, further optimization of AML therapy is required.
Durable Remissions with Single Agent As2O3 in the Treatment of Newly Diagnosed Cases of Acute Promyelocytic Leukemia: Risk Stratification within This Group and Potential Impact on Future Algorithms.
Authors: Mathews Vikram , George Biju , Lakshmi Kavitha M. , Viswabandya Auro , Bajel Ashish , Srivastava Alok , Chandy Mammen 
Published: April 2020

Abstract
There is limited long term follow up data with the use of single agent As2O3 in the treatment of newly diagnosed cases of acute promyelocytic leukemia (APL).
Between January 1998 and December 2004, 72 newly diagnosed patients with APL were treated with single agent As2O3 administered in induction, consolidation and in maintenance at 10mg/day for adults and 0.15mg/kg/day for the pediatric population.
Figure Figure
The mean age was 28.6 years (range: 3–75) with 38 (52.8%) males. Six patients (11.1%) received 1 – 2 doses of an anthracycline and 53 (73.6%) received hydroxyurea in induction for either onset of a differentiation syndrome or for leucocytosis. The regimen was well tolerated. Eight (11%) patients developed grade 3 – 4 toxicity (5-hepatic, 2-neuropathy and 1-prolonged neutropenia). None of these toxicities were irreversible or contributed to mortality. Grade 3 – 4 cytopenia did not occur in any patient in remission after the initial induction. Following the initial portion of induction the rest of the protocol was completed on an outpatient basis.
At a mean follow up of 31.4 months (range: 7.8–91) the EFS, DFS and OS was 70.19%, 90% and 81.33% respectively. In a univariate analysis of factors at diagnosis that had an adverse impact on survival a statistically significant effect was seen with a WBC &gt;5000/mm3, Platelet &lt;20,000/mm3 and a prolonged prothrombin time (PT) (p-values: 0.032, 0.020 and 0.023 respectively). In a multivariate analysis only a platelet count &lt;20,000/mm3 retained its significant adverse impact. Prolonged PT, platelet &lt;20,000/mm3 and WBC &gt;5000/mm3 at diagnosis was seen in 12 (16.7%), 43 (59.7%) and 27 (37.5%) respectively. Using the WBC and platelet count at diagnosis two risk groups were identified, one with WBC &lt;5000/mm3 and Platelet &gt;20,000/mm3 (Group A, n=22[30.5%]) and the remaining patients (Group B, n=50[69.5%]). In group A the EFS and OS was 100% while in group B the EFS and OS was 56.5% and 73.33% respectively. Statistical analysis of the survival curves by log rank test between these two groups for EFS and OS was significant (p-values: 0.0019 and 0.0206 respectively) and there was a trend to significance for the DFS (p=0.079).
Conclusion: As2O3 is effective in the management of newly diagnosed cases of APL and can induce durable remissions. The regimen used in this study is well tolerated. Following remission induction it can be administered in the out-patient and has no irreversible or delayed toxicities. A subset that responds well to this regimen which has minimal toxicity can be identified and one could consider adding a synergistic agent such as ATRA or an anthracycline in the remaining patients.
Figure Figure
Outcomes for Ximelagatran Compared with Warfarin According to INR Control: Results from SPORTIF III and V Atrial Fibrillation Trials.
Authors: Kaatz Scott , White Harvey D. , Gruber Michael , Albers Gregory W. 
Published: April 2020

Abstract
Background: Warfarin effectively reduces the risk of stroke in patients with atrial fibrillation, but requires regular monitoring to maintain the target international normalized ratio (INR). Ximelagatran, a novel direct thrombin inhibitor, does not require coagulation monitoring and can be administered at a fixed oral dose.
Methods: Outcomes in warfarin patients (n = 3587) from the SPORTIF III and V trials according to time spent in the therapeutic target INR range of 2–3 (≥ 76% of the time = good INR control [n = 1190]; 60–75% of the time = moderate INR control [n = 1207]; and &lt; 60% of the time = poor INR control [n = 1190]) were compared with ximelagatran patients (n = 3664). The primary endpoint was stroke/systemic embolic event (SEE).
Results: Mean follow-up was 16.6 (± 6.3) months. Outcomes in warfarin patients according to INR control are shown in the table. Ximelagatran patients had numerically lower stroke/SEE rates than the warfarin patients with poor INR control (1.43%/yr vs 2.10%/yr; P = 0.08), as well as lower mortality (2.36%/yr vs 4.20%/yr; P &lt; 0.01) and major bleeding (1.89%/yr vs 3.85%/yr; P &lt; 0.01). The incidence of stroke/SEE and major bleeding did not differ statistically among the moderate INR control, good INR control, and ximelagatran groups. However, major + minor bleeding was more common in the moderate INR control group than the ximelagatran group (41.8% vs 32.5%; P &lt; 0.01).
Conclusions: In warfarin-treated atrial fibrillation patients, the risks of stroke/SEE, mortality, and major bleeding are related to INR control, with a significant reduction in these events with good vs poor INR control. Compared with the one-third of patients who experienced poor INR control, patients randomized to ximelagatran administered at a fixed oral dose without the need for coagulation monitoring had a lower mortality rate and less major bleeding.
Outcome Poor INR Control Moderate INR Control Good INR Control Poor vs Moderate Poor vs Good Good vs Moderate Stroke/SEE, %/yr 2.10 1.34 1.07 P = 0.09 P = 0.02 P &lt; 0.01 Total mortality, %/yr 4.20 1.84 1.69 P &lt; 0.01 P &lt; 0.01 P &lt; 0.01 Major bleeding, %/yr 3.85 1.96 1.58 P &lt; 0.01 P &lt; 0.01 P &lt; 0.01
Low Molecular Weight Heparin and Bleeding in Patients with Severe Renal Failure: A Meta-Analysis.
Authors: Lim Wendy , Dentali Francesco , Eikelboom John , Crowther Mark A. 
Published: April 2020

Abstract
Background: Dose adjustment or monitoring of low molecular weight heparin (LMWH) is commonly recommended in patients with severe renal insufficiency (creatinine clearance [CrCl] ≤ 30 ml/min) but little evidence supports this recommendation.
Purpose: To compare the risk of major bleeding in LMWH-treated patients with CrCl ≤ 30 ml/min versus &gt; 30 ml/min using standard weight-adjusted therapeutic LMWH doses, empirically adjusted LMWH doses and prophylactic LMWH doses.
Data sources: Electronic databases (MEDLINE, EMBASE, Cochrane Library), reference lists and contact with experts.
Study selection: Observational or subgroups of randomized studies that included non-dialyzed patients with varying degrees of renal function who were treated with LMWH and which reported CrCl and major bleeding.
Data extraction: Two reviewers independently selected studies and extracted data on patient characteristics, renal function, LMWH treatment and major bleeding. The pooled relative risk (RR) of major bleeding in patients with CrCl ≤ 30 versus &gt; 30 ml/min was calculated by the Mantel-Haenszel method.
Data synthesis: In 12 studies involving 4971 patients (10 studies of 4741 patients using enoxaparin; 2 studies of 230 patients using tinzaparin), LMWH significantly increased the risk of major bleeding in patients with CrCl ≤ 30 compared with &gt; 30 ml/min (5.0% vs. 2.4%, RR 2.34, 95% confidence interval [CI]: 1.46 to 3.74; P = 0.0004; number needed to harm [NNH] = 38). When analyzed according to LMWH preparation, increased major bleeding was evident in studies of standard weight-adjusted therapeutic dose enoxaparin (8.3% vs. 2.4%, RR 2.96; 95% CI: 1.63 to 5.37, NNH = 17) but not in studies using empirically adjusted enoxaparin doses (0.9% vs. 1.9%, RR 1.06; 95% CI: 0.23 to 4.97), P for heterogeneity = 0.82. There were insufficient studies using tinzaparin and prophylactic doses of enoxaparin.
Limitations: Only 2 LMWH preparations were evaluated and only 2 studies used tinzaparin. Data are observational and the potential for confounding cannot be excluded.
Conclusions: Non-dialysis dependent patients with CrCl ≤ 30 ml/min who are treated with therapeutic doses of enoxaparin have an increased risk of major bleeding. Empiric dose reduction of enoxaparin may reduce the risk of bleeding and merits further evaluation. No conclusions can be drawn regarding other LMWHs.
Event Rate for Patients with Atrial Fibrillation with and without Low Molecular Weight Heparin Bridging.
Authors: Billett Henny Heisler , Madsen Eileen M. , Giannattasio Emily 
Published: April 2020

Abstract
The benefit of ’bridging’ atrial fibrillation patients with low molecular weight heparin until their INRs are at therapeutic levels with coumadin is unclear. Using a replicative hospital database available for IRB approved protocols and quality control analyses, we compared a cohort of patients over 65 years of age discharged with a diagnosis of atrial fibrillation (index date) who had been bridged (n=201) with a cohort of patients over 65 years of age who were not bridged on discharge but who achieved a therapeutic INR within 30 days of coumadin initiation (nonbridged and early INR, NB-E, n=1376). Log rank Mantel Haenszel two group comparisons were used to test for differences in time to event rate for admission for CVA, admission for hemorrhage, and number of laboratory INRs in therapeutic range (NLTR). The incidence of CVA admissions in the bridged group at 15, 30, 60, 90, 180 and 365 days was 0%, 0%, 0%, 0%, 0.5% and 1.2% whereas for the NB-E it was 0.1%, 0.3%, 0.8%, 1.3%, 1.8% and 2.8%. This difference did not reach statistical significance (p=0.19). No difference was noted in the time to admission for hemorrhage (3.5% at day 15, remaining unchanged at 30, 60 and 90 days for the bridged patients vs. 1.0%, 1.9%, 3.1% and 4.2% for NB-E patients, p=0.67). When NLTR were expressed as dichotomous variables (INR&lt;1.9=bad, 2–3.5=good, 3.6–20=bad) and assessed for one year from index date, there was no significant difference (good = 55.3% NLTR for bridged vs. 52.3% for NB-E). When either of these groups were compared to patients with AF who did not achieve therapeutic INRs until after 30 days (but less than one year, NB-L, n=2061), there was a difference in the incidence of admissions for CVA that was significant (0.2%, 0.7%, 1.1%, 1.2%, 2.5% and 4.8% at day 15, 30, 60, 90, 180, 365, p=0.025 vs. bridged, and p=0.048 vs. NB-E), NLTR (45.2%), but not in the incidence of admission for hemorrhage at 90 days (0.7%, 1.4%, 2.6% and 3.9% at 15, 30, 60 and 90 days). Because no risk factors prompting the decision to bridge patients were examined, the non-significant decreased incidence of CVA admissions in bridged patients may be important, since it may be that patients who were bridged were at higher risk for stroke than those who were not bridged (early or late). Future randomized trials with risk group stratification will be necessary to elucidate this but these data demonstrate there is no significant additional hemorrhagic risk for patients with atrial fibrillation who are bridged with low molecular weight heparin and suggest a potential benefit to early effective anticoagulation.
Absolute Lymphocyte Count Recovery Predicts Superior Survival and Is Independent of the International Prognostic Index in Patients Treated with CHOP or R-CHOP Chemotherapy for Diffuse Large B Cell Lymphoma.
Authors: Porrata Luis F. , Ristow Kay M. , Geyer Susan M. , Markovic Svetomir N. , Persky Daniel O. , Colgan Joseph P. , White William L. , Witzig Thomas E. , Inwards David J. , Ansell Stephen M. , Micallef Ivana N. , Johnston Patrick B. , Habermann Thomas M. 
Published: April 2020

Abstract
Absolute lymphocyte count (ALC) recovery post-autologous stem cell transplantation has been documented as an independent predictor for survival in non-Hodgkin lymphoma. The effect of ALC recovery on survival during standard CHOP or R-CHOP chemotherapy for newly diagnosed diffuse large B cell lymphoma (DLBCL) is unknown. To participate in the study, patients required to receive their full treatment with complete blood count determinations at the Mayo Clinic College of Medicine. Of 1633 DLBCL cases seen at the Mayo Clinic College of Medicine between February 1994 through August 2004, 212 consecutive DLBCL patients were eligible for the study. We study ALC recovery as a prognostic factor for progression-free survival (PFS) and overall survival (OS) in DLBCL patients treated with at least 3 cycles of CHOP or R-CHOP. 57% were male and the median age was 66 years (range: 20 – 87); 42% had elevated LDH, only 11% had a PS of 2 or higher; 58% were low stage (I or II); 88% of pts achieved a complete response. ALC was evaluated at the beginning of each treatment cycle, focusing on cycles 1–3 and the 3 month post treatment sample. ALC for each of the cycles were significantly correlated with PFS and OS, with cycle 1 ALC most significantly correlated when accounting for inherent differences based on treatment (Rx) type (i.e. CHOP vs. R-CHOP) as well as high vs. low IPI (PFS: p = 0.0012; OS: p = 0.005). Also, 74 pts achieved an ALC of at least 1,000 during all three cycles, where there was no significant relationship with this incidence and Rx type; this incidence was significantly associated with higher PFS (p = 0.0007) and OS (p = 0.0006), even when accounting for Rx type and high vs. low IPI. In the 179 pts who had 3-month post-Rx ALC data, this was also significantly associated with PFS (p = 0.002) and OS (p = 0.0009), while still accounting for Rx type and IPI status. Achievement of ALC &gt;= 1,000 post-Rx was also significant for PFS (p = 0.0014) and OS (0.003). Also of note, only cycle 1 ALC was significantly different in high vs. low IPI pts (p = 0.008). In summary, these data support the hypothesis that there is a critical role of lymphocyte (immune) recovery during CHOP/R-CHOP chemotherapy in DLBCL.