bluuebunny/crossref_metadata_2025 huggingface dataset:
VEGF Regulates Leukemia Migration Via FLT-1, Involving Pi3 Kinase, RhoA and Rac1 Activation and Lipid Rafts Formation.
Authors: Fragoso Rita , Casalou Cristina , Dias Sergio
Published: April 2020

Vascular endothelial growth factor (VEGF) and its receptors play a crucial role in malignancy and in disease, regulating the survival, proliferation, and migration of several cell types, such as endothelium and also leukemia cells. We previously demonstrated crucial roles for VEGFR-2 in acute myeloid leukemia, where its blockade showed clinical potential in murine models, by affecting leukemia survival and proliferation. In the present study we focused on a different VEGF receptor, FLT-1, and studied the molecular mechanisms whereby it modulates acute leukemia cell migration in response to VEGF/Placental Growth Factor (PLGF). First, we observed the formation of cell protrusions on ALL cells after VEGF/PLGF stimulation, with evidence for polimerized actin and FLT-1 co-localization (as determined by phalloidin, immunofluorescence staining, and confocal microscopy). Western blot analysis revealed that PLGF/VEGF stimulation resulted in increased RhoA and Rac1 GTPases expression. Co-treatment with LY200942 significantly decreased RhoA and Rac1 induction and cell migration by PLGF/VEGF, demonstrating this effect is modulated via Pi3 kinase. Next, we investigated the mechanisms whereby FLT-1 and actin co-localize at the cell “leading edge” (protrusions), after VEGF/PLGF stimulation, and the relevance of such co-localization for cell migration. We addressed this question using a drug (nystantin) that impairs the formation of lipid rafts, cholesterol and sphingolipid rich membrane domains that modulate the interaction of several proteins (Rho GTPases) with downstream effectors, an event essential to cell migration. Accordingly, co-treatment of leukemia cells with nystantin and PLGF/VEGF blocked cell migration, an effect that was associated with a decrease in FLT-1 polarization and co-localization with actin filaments. Instead, FLT-1 was now found mostly in the cell cytosol (possibly undergoing lysosomal degradation). Taken together, we hypothesize that FLT-1 localization in lipid raft-rich membrane domains allows interaction with the actin cytoskeleton and downstream effectors, resulting in cell migration. Our data reveal for the first time some of the molecular mechanisms involved in VEGF-mediated leukemia migration, which may be crucial for determining the onset of extramedullary disease (the exit of leukemia cells from the bone marrow).
Outcome of the ALL-96 Protocol for Childhood ALL from the Kyushu-Yamaguchi Children’s Cancer Study Group.
Authors: Nagatoshi Yoshihisa , Suminoe Aiko , Matsuzaki Akinobu , Ueda Koichiro , Inada Hiroko , Kawakami Kiyoshi , Yanai Fumio , Nakayama Hideki , Moritake Hiroshi , Itonaga Nobuyoshi , Ayukawa Hiroshi , Fujita Kyoko , Kawano Yoshifumi , Okamura Jun
Published: April 2020

Objective: We conducted a randomized study to compare the effectiveness of two maintenance regimens, namely the 6-MP/MTX-based regimen (A-arm) and the LSA2L2 type regimen (B-arm).

Patients and Methods: A total of 218 newly diagnosed patients between 1 and 15 years of age were enrolled from August 1996 to August 2002. The patients characteristics was as follows: median age, 5; T-cell/B-cell precursor phenotype, 22/196; median WBC, 8,100/μl (range, 600–809, 200). The high-risk group (HR) was defined as having a WBC of over 50,000/μl, a T-cell precursor phenotype, CNS disease, hepatosplenomegaly of more than 5 cm under the costal margin while the standard-risk group (SR) was defined as having no HR features. Any cases with t(9;22) and t(4;11) were excluded from the present protocol. After successful induction treatment, the patients received early intensification, consolidation and late intensification treatment. Before late intensification, the patients were randomly assigned to receive one of two maintenance regimens: the A-arm consisted of daily 6-MP with weekly MTX pulsed with DEX and VCR for 2 weeks irrespective of the risk group. The B-arm consisted of 4 blocks of 6-MP with CPM, 6-MP with CA, 6-MP with VCR and PSL, and intermediate-dose (ID)-MTX in the SR group, while in the HR group, high-dose CA was substituted for ID-MTX. The total treatment duration was 3 years. Eleven cases with t(9:22) and t(4;11), 5 with a disagreement to randomization, while the other 6 did not meet the eligibility criteria and thus were excluded from the protocol. As a result, 196 cases were evaluable (98 cases for each risk-group). Of these, 95 and 94 cases, excluding 7 who developed relapses before randomization, were assigned to the A and B-arms, respectively.

Results: CR was successfully achieved in 195 of 196 patients (99%). Relapse occurred in 36 cases (isolated BM, 30; others, 6). No toxic death was observed during the entire treatment period. The event-free survival (EFS) rates in all 196 eligible cases, SR and HR cases were 75.5±5.1 (SE) %, 88.1±3.6% and 62.5±7.5% (p=.0004), respectively. The EFS rates for SR were 86.8±5.6% in the A-arm and 90.6±4.6% in the B-arm (p=ns). In the HR cases, the EFS rate in the A-arm was tended to be superior to that in the B-arm (81.2±5.6% and 52.3±13.1%, p=.13).

Conclusion: No significant difference was observed in the EFS rates between the two maintenance regimens. However, the late adverse effects of each regimen should be carefully evaluated by a long-term follow-up of the patients.
Treatment Outcome of Discontinued L-Asparaginase in Children with Standard-Risk Acute Lymphoblastic Leukemia: Tokyo Children’s Cancer Study Group (TCCSG) Study L99-15.
Authors: Ogawa Chitose , Ohara Akira , Manabe Atsushi , Hanada Ryoji , Takahashi Hiroyuki , Koh Katsuyoshi , Kajiwara Michiko , Maeda Miho , Sugita Kenichi , Kikuchi Akira , Isoyama Keiichi , Noguchi Yasushi , Saito Masahiro , Ota Setsuo , Fukushima Takashi , Yabe Hiromasa , Toyoda Yasunori , Saito Tomohiro , Tsuchida Mahiro
Published: April 2020

BACKGROUND: L-asparaginase (L-asp) is one of the key drugs in the treatment of acute lymphoblastic leukemia (ALL) in children. However, L-asp often produces severe adverse effects including anaphylaxis resulting in its discontinuation.

OBJECTIVE: To evaluate retrospectively the outcome of discontinuation of L-asp in patients with ALL.

PATIENTS AND METHODS: Children newly diagnosed as ALL between 1999 and 2003 were consecutively enrolled on the TCCSG L99-15 study. Risk stratification was based on the age, initial white blood cell count, immunophenotype, cytogenetics and the response to prednisolone monotherapy. Totally, 267 (35%) out of 770 children were categorized into a standard-risk group (SR), 317 (41%) into a high-risk group (HR) and 186 (24%) into a very high-risk group (HEX). Allogeneic stem cell transplantation was indicated approximately in 50% of the HEX patients. L-asp was used 9 times in the induction phase in all the risk groups. The total number of L-asp administration all through the treatment was 19 in SR, 20 in HR and at least 10 in HEX. Patients were divided into two groups in the analysis: group A patients who received at least 50% of scheduled doses of L-asp and group B patients who received less than 50%.

RESULTS: Remission was obtained in 259 (97%) patients in SR, 311 (98%) in HR and 171(92%) in HEX. In the patients who achieved remission and were analyzed, 195 (83.7%) in SR, 223 (78.8%) in HR and 123 (83.7%) in HEX received all the scheduled doses of L-asp. Event-free survival (EFS) (SE) and overall survival (OS) (SE) at 5 years for all the risk groups are shown in the table. Notably, EFS in group A (92.9%) and in group B (74.1%) in SR was significantly different (p=0.025).

CONCLUSION: The outcome in patients who received less than 50% of scheduled dose of L-asp was inferior to that in the patients who received more than 50% of the scheduled dose. This suggests that modification or intensification of the treatment should be considered for the patients who discontinued L-asp in SR.

EFS and OS in each group Risk group EFS ± SE(%) OS ± SE(%) (No. in A /B) group A group B p value group A group B p value SR (223 /10) 92.9±2.4 74.1±16.1 0.025 97.8±1.1 88.9±10.5 0.066 HR (269 /14) 78.5±3.2 66.7±19.2 0.969 88.9±2.6 50.0±25.0 0.158 HEX (142 /5) 58.2±5.5 75.5±21.7 0.514 75.6±4.3 80.0±17.9 0.873
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

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

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 <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

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

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 >5000/mm3, Platelet <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 <20,000/mm3 retained its significant adverse impact. Prolonged PT, platelet <20,000/mm3 and WBC >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 <5000/mm3 and Platelet >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

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 < 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 < 0.01) and major bleeding (1.89%/yr vs 3.85%/yr; P < 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 < 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 < 0.01 Total mortality, %/yr 4.20 1.84 1.69 P < 0.01 P < 0.01 P < 0.01 Major bleeding, %/yr 3.85 1.96 1.58 P < 0.01 P < 0.01 P < 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

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 > 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 > 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 > 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

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<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

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 >= 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.
Excellent Outcome with Rituximab-CHOP (R-CHOP) Combined with Radiotherapy (RT) in Primary Mediastinal Large B-Cell Lymhoma (PMLBCL).
Authors: Vassilakopoulos Theodoros P. , Angelopoulou Maria K. , Galani Zacharoula , Sachanas Sotirios , Katsigiannis Andreas , Dimopoulou Maria N. , Kokoris Styliani I. , Michalis Evridiki , Dimitriadou Evangelia M. , Siakantaris Marina P. , Kontopidou Flora N. , Kalpadakis Christina , Sarantopoulos Angelos , Korkolopoulou Pinelopi , Roussou Paraskevi , Pangalis Gerassimos A.
Published: April 2020

Introduction: Combination chemoptherapy regimens such as CHOP and MACOP-B with or without RT are considered the standard first-line treatment for PMLBCL patients. Consolidation with high dose therapy and autologous stem cell support (HDT-ASCT) at first remission is an alternative approach for this young population. However results are not optimal. Given the superiority of R-CHOP over CHOP in elderly patients with diffuse large B-cell lymphoma, the role of Rituximab added to first-line chemotherapy in younger patients is not clear.

Aims: In this study we evaluate the effectiveness of R-CHOP±RT in PMLBCL and we compare the results of this strategy to CHOP±RT in historical controls.

Patients and Methods: A total of 46 patients with PMLBCL were treated in two participating centers between 1994 and 2004. At a given timepoint R-CHOP replaced CHOP in both centers. Thus, 31 consecutive historical controls were treated with CHOP prior to that point and were compared to 15 patients who received R-CHOP thereafter.

Results: The median age of the patients was 31 years (17–58) and 32/46 (70%) were females. Baseline characteristics between the R-CHOP and CHOP groups were well balanced, including age-adjusted IPI [ ≥2 in 40% of R-CHOP and 42% of CHOP-treated patients (p=0.90)]. Complete response (CR) was achieved in 100% in the R-CHOP±RT vs 61% in the CHOP±RT group (p=0.009). No patient has relapsed after R-CHOP, while all relapses after CHOP occurred within 22 months from diagnosis. The 3-year failure free survival (FFS) was 100% and 47±9% for patients treated with R-CHOP±RT and CHOP±RT respectively(p=0.005). Within the subgroup of patients with L/LI risk IPI the corresponding 3-year FFS rates were 100% vs 61±11% (p=0.059), while they were 100% vs 26±13% (p=0.02) among patients with HI/H risk IPI for R-CHOP±RT and CHOP±RT respectively. The 3-year event free survival (EFS) was 93±7% vs 47±9% (p=0.02). The 3-year overall survival was 93±7% vs 47±9% (p=0.27), while the 3-year lymphoma specific survival was 100% vs 67±9% (p=0.049) for the R-CHOP and CHOP groups respectively.

Conclusions: R-CHOP±RT exhibited impressive efficacy with no failures among 15 patients. CR and FFS rates were significantly better in favor of R-CHOP compared to CHOP-treated historical controls. EFS and lymphoma specific survival were also improved. Based on these data, our standard approach for PMLBCL patients is the application of R-CHOP±RT. Furthermore the addition of Rituximab to front-line treatment might overcome the need for more aggressive strategies such as consolidation with HDT-ASCT in this patient population.
Clinical Features and Prognostic Factors in 135 NHL of the Head and Neck Treated by the GOELAMS 02 Trial.
Authors: Laccourreye Laurent , Desablens Bernard , Le Maignan Christine , Le Mevel Anne , Berthou Christian , Lamy Thierry , Ghandour Christiane , Guilhot François , Hunault-Berger Mathilde , Jardel Henry , Ifrah Norbert , Colombat Philippe ,   The GOELAMS Group
Published: April 2020

From November 1984 till April 1996 135 patients (67% M, 33% F) presenting a NHL of the head and neck were treated by the GOELAMS 02 trial (3 VCAP + 40 Gy locoregional irradiation). The median age was 48.5 years (17–69) with 36 patients being 60 or over. The main localization was Waldeyer’s ring (57) including tonsil (35), nasopharynx (14), whole Waldeyer (8), neck (49), nasal cavities (14), thyroid (8) salivary gland (5), mandibular bone (2). According to the WFC, histological subtype were as F (21%), G (57%) and H (20%) and unclassified (2%). Ann Harbor classification included 80 stage 1 and 55 stage II. The IPI score was 0 (49.7%), 1 (22.3%), 2 (10.4%), 3 (2.3%) undetermined (16,3%). PS>2 and bulk (= 5 cm) were observed in 7.5% and 43% of patients respectively. 94% achieved CR. 2 patients died during treatment. Relapses occurred in 23/127 (18.1%) at a median time of 31 months (5.5 – 80). 16 of these relapses occurred before 3 years of CR, 5 between 3 and 6 years and 2 after 6 years of CR. With a median follow up of 65 month (7 – 146) OS and EFS were 81.5% and 77% respectively. In univariate analysis age = 60, extension, PS >2, Bulk = 5 cm, erythrocyte sedimentation rate > 40 and high serum LDH significantly decrease EFS (P= 0.01, 0.047, 0.028, 0.0001, 0.004 and 0.03 respectively). In multivariate analysis only the bulk = 5 cm and the localization to salivary gland significantly decrease EFS( P=0.003 and 0.039 respectively). Even if larger studies are needed to confirm these findings, NHL of the head and neck localized to the salivary gland or having a bulk = 5 cm should already be included in new therapeutic trials in order to improve their outcome.
Phase II Study of Sphingosomal Vincristine in CHOP+/ − Rituximab for Patients with Aggressive Non-Hodgkin’s Lymphoma (NHL): Promising 3 Year Follow-Up Results in Elderly Patients.
Authors: Rodriguez Maria Alma , Dang Nam H. , Fayad Luis , Goy Andre , Hagemeister Fredrick , McLaughlin Peter , Pro Barbara , Romaguera Jorge , Younes Anas , Cabanillas Fernando
Published: April 2020

Background: Individuals older than 60 years have a worse prognosis than younger patients with aggressive NHL. Vincristine is an active drug in the treatment of malignant lymphomas. Sphingosomal vincristine (SV) was well tolerated with 45% ORR in patients with multiple relapses of aggressive NHL (ASH abst. 412, 1999). Based on these data, a phase II study of CHOP with rituximab (no rituximab for T-cell histology), and substituting SV for free vincristine, was undertaken in patients with previously untreated aggressive NHL.

Methods: Aggressive NHL histologies eligible for study were diffuse large B-cell lymphoma (DLCL), peripheral T-cell lymphoma (PTCL), follicular lymphoma grade 3 (FL gr3), anaplastic large cell lymphoma (ALCL), and indolent lymphomas with aggressive transformation (TL). Patients were treated with standard dose CHOP that included SV 2.0 mg/m2 without dose capping, ± rituximab 375 mg/m2, given every 21 days for 6 to 8 courses (ASH abst. 338, 2002).

Results: Of 73 patients enrolled on study, 68 were evaluable for response. Median age was 61 (range 22–80), 36 patients (53%) were >60 years old. Overall, 24 patients (23 elderly) had an IPI score ≥3. Patients received a median of 6 study treatments (range 1–8). Diagnoses were: DLCL = 56; FL gr 3 = 4; PTCL = 4; ALCL = 2 and TL = 2. ORR was 92.6% (63/68 pts) with 55 pts achieving CR (80.1%), 7 CRu (10.3%), and 1 PR (1.5%); 3 patients had PD (4.4%) and 2 were not assessed for response (2.9%). ORR was similar in both elderly (>60) and younger pts (≤60): 91.9% and 93.5% respectively. Neuropathy was generally mild (Gr.1–2). Hematological toxicities were as follows: 56% Gr.3–4 neutropenia, 6% Gr.3 anemia, and 13% Gr.3–4 thrombocytopenia. Toxicites were comparable in elderly and younger patients. The median follow up for the study is 39.6 months (mos), and overall survival 94%. There have been 9 relapses (5 DLCL, 3 T-cell, 1 FL gr3, 1 transformed) for elderly patients and 5 relapses (4 DLCL, 1 T-cell) for patients ≤60. The table below shows progression free survival (PFS) at 3 years, for all histologies, and DLCL by age. There is no difference between the age groups.

Conclusions: This regimen, with sphingosomal vincristine in CHOP +/− Rituximab, has a high overall response rate. It is a well-tolerated therapy with mild neurotoxicity for all patients. At 3 years, the PFS in elderly patients with DLCL treated with RCHOP is comparable to that of younger patients, despite a larger fraction of high risk IPI in the older patients. This regimen merits randomized comparison to RCHOP in DLCL.

Age (Yrs) All Histologies (n=68) DLCL (n=56) ≤60 84%, CI [66–93] 85%, CI [66–94] >60 83%, CI [66–92] 86%, CI [66–94]
Ongoing Variability in Transfusion Practices in Cardiac Surgery Despite Established Guidelines.
Authors: Snyder-Ramos Stephanie A. , Moehnle Patrick , Weng Yi-Shin , Boettiger Bernd W. , Kulier Alexander , Levin Jack , Mangano Dennis T.
Published: April 2020

Although blood utilization has been under considerable scrutiny for the past two decades, particularly for surgery, the international evolution of standards remains unknown. Therefore, the objective of this study was to compare the perioperative transfusion of blood components in patients undergoing coronary artery bypass graft (CABG) surgery in different countries. Transfusion practice was investigated prospectively among 16 countries (70 centers). Five-thousand sixty-five (5,065) randomly selected cardiac surgery patients in the Multicenter Study of Perioperative Ischemia Epidemiology II (EPI II) Study were evaluated. Utilization of red blood cells, fresh frozen plasma, and platelets was assessed by day, prior to, during and after surgery until hospital discharge. Intraoperative red blood cell (RBC) transfusion varied from 9 percent to 100 percent among the 16 countries, and 25 percent to 87 percent postoperatively (percent of transfused patients). Similarly, transfusion of fresh frozen plasma (FFP) varied from 0 percent to 98 percent intraoperatively and 3 percent to 95 percent postoperatively, and platelet (PL) transfusion from 0 percent to 51 percent and 0 percent to 39 percent, respectively. An analysis of the EuroSCORE (an internationally validated risk evaluation system for cardiac surgery) risk indices of the countries with the highest and lowest frequencies of use or amounts of each of type blood product failed to demonstrate a correlation between EuroSCOREs and maximum vs minimum frequency of use or amount of blood product administered. Establishment of international guidelines for utilization of blood products in CABG surgery appears necessary.
Survival in Individuals with Profound Anemia Treated without the Use of Blood Transfusions.
Authors: Ford Patricia , Keck Gina , Mastoris Jason
Published: April 2020

Although there is an emerging trend to reduce blood transfusions, there is still very little randomized data outside of the critical care setting that identifies the risks and benefits of transfusion support. Many clinicians base the decision to transfuse primarily on the hemoglobin (Hb) level independent of symptoms. Little is known about the clinical consequences of profound anemia although there is concern that withholding transfusion support will result in adverse outcomes in those with advanced age or underlying cardiovascular conditions. Prior studies have reported a significant mortality rate with Hb levels under 5 g/dL. This in part has led to the use of extreme measures such as hyperbaric chambers, ventilation or paralysis for profound anemia and the establishment of specialized Centers for Bloodless Medicine and Surgery to care for individuals refusing blood products. A retrospective chart review of 128 patients declining blood transfusions with Hb values under 7 g/dL from January 2002 until August 2005 was performed. This population included a broad range of medical, surgical and obstetrical cases with a mean age, Hb and length of stay of 52 years, 5.4 g/dL and 11 days respectively. Table 1 summarizes the survival rates based on the severity of anemia. Our nonblood approach included simultaneous interventions to stimulate erythropoiesis, control bleeding, enhance hemostasis, minimize iatrogenic blood loss and maintain hemodynamic stability. All patients received erythropoietin and iron with antifibrinolytic agents added for any active bleeding. To keep laboratory sampling at a minimum, physicians were required to rely on their basic clinical assessment skills to manage patients. The need for critical care monitoring, volume resuscitation and oxygen support was determined based on changes in blood pressure, heart rate, urine output, and cognitive function. Patients experienced slower recovery times with more frequent cardiac monitoring and increased length of hospital stays. This series demonstrates that the majority of individuals can survive with Hb levels as low as 2.5 g/dL utilizing simple nonblood strategies. The low mortality rate supports the elimination of any predetermined transfusion trigger. Survival Rates in Patients with Profound Anemia

Table 1 Survival Rates in Patients with Profound Anemia Hb Level (g/dL) Proportion Who Survived 2.5–3.0 6/7 (85.7%) 3.1–4.0 9/11 (81.8%) 4.1–5.0 29/32 (90.6%) 5.1–6.0 30/30 (100%) 6.1–7.0 48/48 (100%) Overall 122/128 (95.3%)
Neonatal Alloimmune Thrombocytopenia (NATP) Associated with Maternal-Fetal Incompatibility for Blood Group B.
Authors: Curtis Brian R. , McFarland Janice G. , Fick Andrea , Lochowicz Andrew J. , Ball Robert H. , Richard Aster H.
Published: April 2020

In most individuals, A and B blood group antigens are weakly expressed on platelets, allowing ABO incompatible platelets to be tolerated when transfused. However, in a minority of normal subjects (high expressers, H-Exp), platelets carry 10–20 times the usual number of A or B epitopes (up to 20,000/platelet, Blood2000;96:1574). Post-transfusion survival of incompatible H-Exp platelets has not been systematically studied. We recently encountered a family in which NATP in two infants appears to have been caused by maternal anti-B reacting with H-Exp fetal platelets inherited from a father with the group B H-Exp trait. The first two children (C1 and C2) born to a G4P2 group O mother and A2B father were positive for blood group B, and had neonatal thrombocytopenia (TP) (C1 = 33K/μL, C2 = 61K/μL), anemia, positive direct antiglobulin test, elevated reticuloytes and hyperbilirubinemia requiring phototherapy. C1 required 3 platelet transfusions and RBC transfusion, and C2 required RBC transfusion. Both recovered in the immediate neonatal period. A third child (C3) inherited blood group A2 from the father and was born with a normal platelet count. The parents were incompatible for HPA-2b and -3b, but no platelet-specific antibodies were detected in maternal serum. High titer IgG antibodies were detected in maternal serum against father’s platelets in both flow cytometry and modified antigen capture ELISA. This activity was completely removed by absorption with normal, washed group B RBCs. When tested by flow cytometry with monoclonal anti-B and anti-A, the father’s platelets were shown to carry 17 times the normal level of B antigen, and only trace amounts of A antigen. We previously showed that the potent glycosyltransferase activity associated with the H-Exp trait causes essentially all H antigen on platelets and RBCs to be converted to A and/or B antigen. Consistent with this, father’s platelets and RBCs were found to express no detectable H. Quantitation of B and H antigens on platelets and RBCs from C1 and C2 is pending receipt of samples. Findings made in this family indicate that maternal anti-B (and presumably anti-A) IgG antibodies can cause NATP in infants with the ABO “high expresser” trait. Maternal-fetal ABO incompatibility should be considered as a cause of NATP when maternal antibodies against platelet-specific antigens cannot be demonstrated. The possibility that ABO incompatibility can aggravate thrombocytopenia caused by antibodies against recognized platelet-specific antigens also deserves consideration.
Different Histopathological Subtypes of Hodgkin Lymphoma Have Significantly Different Levels of FDG Uptake.
Authors: Hutchings Martin , Jakobsen Annika L. , Hansen Mads T. , Ralfkiaer Elisabeth , Specht Lena
Published: April 2020

Background: Functional imaging with positron emission tomography using 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) is an important tool in the staging of Hodgkin lymphoma (HL). FDG-PET enables quantitative information about the tumour metabolism, most commonly measured as the semiquantitative standardised uptake value (SUV). The aim of this study was to investigate if the level of FDG uptake varies between the different subtypes of HL.

Methods: Sixty consecutive patients with newly diagnosed HL were prospectively included in the protocol. At least one lymph node biopsy was obtained from each patient and all patients underwent an FDG-PET/CT scan along with other staging procedures. The highest SUV in each patient (SUVmax/total) and in each affected region or organ (SUVmax) was recorded. Differences in SUVmax between histopathological subgroups were analysed with independent-samples student’s t-test and one-way analysis of variance (ANOVA).

Results: 38 patients had nodular sclerosis (NS), 11 patients had mixed cellularity (MC), seven patients had nodular lymphocyte predominance (NLP) and four patients had classical HL, not otherwise specified (CHL-NOS). Mean SUVmax/total was 9.3 g/ml in NLP patients, 16.3 g/ml in NS patients, 20.8 g/ml in MC patients, and 19.5 g/ml in CHL-NOS patients (Figure 1). The difference between the histopathological subgroups was highly significant (ANOVA, p = 0.011). Out of 780 potential sites of disease (600 lymph node regions plus 180 organs), 208 sites were affected with HL. Mean SUVmax was 8.3 g/ml in the 12 sites affected with NLP, 11.2 g/ml in the 147 sites affected with NS, 14.6 g/ml in the 36 sites affected with MC, and 13.1 g/ml in the 13 sites affected with CHL-NOS (ANOVA, p = 0.011, Figure 2). Mean SUVmax in sites with NS was significantly higher than in sites with NLP (t-test, p = 0.042) and significantly lower than in sites with MC (t-test, p = 0.011).

Conclusion: There is a significant difference in FDG/glucose uptake between the different histopathological subtypes of HL. The SUVs in NLP, NS and MC lymphomas are significantly different, while the uptake in CHL-NOS lymphomas resembles the uptake in MC lymphomas. SUV analysis is frequently used in situations where the qualitative evalutation of a site on FDG-PET is uncertain. In those situations, it is helpful to know that the level of uptake varies from subtype to subtype. Since the subtypes have different FDG metabolism, they should ideally be regarded separately in future studies of FDG-PET and FDG-PET/CT in HL.

1. Highest SUV anywhere in the body of each patient 1. Highest SUV anywhere in the body of each patient