bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measurement and Clinical Relevance of Proteasome Enzymatic Activity in Plasma of Patients with Acute Lymphoblastic Leukemia.
Authors: Ma Wanlong , Kantarjian Hagop , O’Brien Susan , Jilani Iman , Zhang Xi , Zestrov Zeev , Estey Elihu , Ferrajoli Alessandra , Keating Michael , Giles Francis , Albitar Maher 
Published: April 2020

Abstract
The ubiquitin-proteasome pathway plays a major role in regulating proteins involved in cell cycle regulation and apoptosis. Three different types of enzymatic activity have been reported for proteasomes: chymotrypsin-like (Ch-L), trypsin-like (Tr-L), and caspase-like (Cas-L) (postglutamyl peptide hydrolytic-like). Various proteasome inhibitors affect each of the three activities differently and at different concentrations. For example, NPI-0052 inhibits Ch-L and Tr-L activities at lower concentrations than does bortezomib, while bortezomib inhibits Cas-L at lower concentrations than does NPI-0052. These enzymatic activities are usually measured in normal or tumor cells to monitor therapy with proteasome inhibitors. We developed fluorogenic kinetic assays using peptide-AMC (7-amino 4-methylcoumoran) substrates to measure Ch-L, Tr-L, and Cas-L activities in cell-free plasma. We evaluated plasma activities in 57 patients with acute lymphoblastic leukemia (ALL) and assessed their correlations with clinical behavior. Significantly (P &lt; 0.001) higher Ch-L, Tr-L, and Cas-L activities were detected in patients with ALL (medians: 1.40, 2.06, and 2.04 pmol AMC/sec/mL, respectively) than in healthy volunteers (n = 42) (medians: 0.80, 0.74, and 0.81 pmol AMC/sec/mL, respectively). While there was no significant difference between Ch-L and Cas-L activities in healthy controls, there was a significant difference between the 2 activities in patients with ALL. Cas-L, Tr-L, and Ch-L all correlated positively with lactic dehydrogenase (P &lt;0.01). However, ALL patients with Cas-L activity ≥2.7 pmol AMC/sec/mL had significantly longer survival (P = 0.01) than did patients with lower activity. The increased cell-free circulating proteasome activities most likely reflect the leukemic cells and may represent a marker not only for the disease, but also for monitoring therapy. These data also suggest that patients with ALL may benefit differentially from proteasome inhibitors depending on the specific therapeutic properties of the inhibitor.
Identification of Novel Recurrent Genomic Aberrations by Array-CGH in Adult Acute Lymphoblastic Leukemia.
Authors: Viardot Andreas , Schwanen Carsten , Goekbuget Nicola , Hoelzer Dieter , Dohner Hartmut , Wessendorf Swen , Schmid Mathias 
Published: April 2020

Abstract
In acute lymphoblastic leukaemia (ALL), genomic aberrations like translocations t(4;11) or t(9;22) are associated with an adverse prognostic impact and play an important role in the development of risk adapted treatment strategies. So far, chromosomal banding analysis is the standard cytogenetic procedure for routine diagnosis. Genomic array-comparative genomic hybridization (aCGH) has become a useful technique for genomic screening allowing a more precise delineation of small genomic aberrations. We analyzed 44 patients with ALL, which were treated within the GMALL trials, by aCGH analysis using a genomic 2,8K chip. In 27 patients, clinical data were available. Thirteen patients had a common-ALL with normal karyotype, 10 patients had a common-ALL/Pr-B-ALL with t(9;22), two patients had either pre-B-ALL or T-lineage leukaemia, respectively. Ten patients were classified as very high risk (t(9;22) positive), 2 patient as high-risk (pre-T-ALL; c-ALL with high leukocytes) and 15 patients were standard risk according to the risk stratification of the GMALL-studies. We found genomic aberrations in 30 out of 44 patients (68%). The most frequent aberrations were deletions on chromosome band 9p21 (10 cases; 23%), deletions on chromosome band 7q35 (7 cases; 16%); gains on chromosome X and losses on 7p (6 cases; 14% each), deletions on 13q14 (5 cases; 11%) and gains on 8q24 (4 cases; 9%). The consensus region of the 9p21 deletion was narrowed down to a size of 420 kilobasepairs. This region covers 3 different genes with potential tumor suppressor gene (TSG) function: p14ARF, p15INK4B/p10 and p16INK4A. An additional TSG gene - methylthioadenosine phosphorylase (MTAP) - was found in 9 out of these 10 cases. In 3 cases with 9p21 deletions, none of the patients expressed the p16INK4A protein using western blot analysis. Two patients where also negative for the MTAP protein, whereas another patient whithout a genomic deletion on MTAP remains positive. There was a tendency to a higher number of aberrations per case in the standard risk group in contrast to the t(9;22) positive group (2.1 vs. 1.0 aberrations per case). aCGH analysis is useful for the identification of recurrent genomic aberrations which are not detectable using standard cytogenetic techniques.
Familial Malignant Hematological Disorders: A Systematic Assessment in 216 Consecutive Patients with Acute Leukaemia.
Authors: Huiart Laetitia , Lafage Marina , Rabayrol Laetitia , Charbonnier Aude , Bourdeleau Philippe , Sainty Daniele , Coso Diane , Mozziconacci Marie Joelle , Arnoulet Christine , Stoppa Anne-Marie , Murati Anne , Lehucher-Michel Marie Pascale , Sobol Hagay , Esinger François , Vey Norbert 
Published: April 2020

Abstract
Purpose
Our objective was to describe the biological characteristics of acute leukemia (AL) patients with or without a familial form of malignant hematological disorders.
Population
The study population included all newly diagnosed cases of AL treated in the departments of hematology of Institut Paoli-Calmettes between January 2002 and December 2004. We identified 291 eligible patients, of which 216 (74.2%) provided consent to participate in the study and filled a short questionnaire collecting demographic, personal and familial medical data. A face to face interview was arranged for 185 patients (85.7%) and a pedigree compiled for each family and reviewed by 2 familial cancer consultants.
Results
Among the 185 patients with full data on personal and familial history of cancer, 34 (18.4%) had a strong familial history of cancer of which 16 (8.6%) presented a familial form of malignant hematological disorders (at least another case of hematological malignancy in the 1, 2 or 3 degree relatives). Seven families had at least 2 first degree family members with leukemia and 2 families had 5 relatives (1st, 2nd or 3rd degree) diagnosed with leukaemia.
Most index cases were diagnosed with AML in both groups (88.1%). Among familial forms, 7 AML (50%) were classified as FAB M1 or M2. No M3, M6 or M7 were identified. White blood cell count was higher than 30 G/l in 37.5% of familial form as compared to 23.5% in sporadic cases (NS). The mean circulating blast percentage was higher in familial forms (66.6% (SD= 35.5)) than in sporadic cases (36.7% (SD=32.1)) (p=0.001). None of the familial forms were consecutive to pre-existing myelodysplasic or myeloproliferative syndrome. Among familial cases with AML, 43% had normal cytogenetics (vs 36% in sporadic cases); none had a complex karyotype; one presented with a t(3;15)(p26;q11) as a mosaic, a translocation not previously reported. Complete remission (CR) rates after 1st induction and Overall Survival (OS) were similar in both groups (CR in both groups: 61.5% (n=112); OS: median: 16 months (95%CI = 10.2 – 21.8) in familial forms vs 23.9 months (18.8 – 28.9)).
Conclusion
According to our data, among the 15 900 new cases of AL diagnosed every year in the US, 1 370 may correspond to familial forms. This warrants awareness of clinicians who should systematically assess family cancer history. Familial AL tends to present as a proliferative form, with no prior hematologic malignancies and normal cytogenetics. This is consistent with pathogenesis pathways described in other familial cancer syndrome.
The Growth Inhibition and Apoptosis Induction of Acute Myeloid Leukemia Blast Population by the Blocking IGF-IR Pathway.
Authors: Sun Si , He Yanli , Wang Xingbing , Liu Wei , Liu Jun , Huang Shiang 
Published: April 2020

Abstract
The insulin-like growth factor-1receptor (IGF-1R) is overexpressed in a variety of tumors and has been associated with cancer development. Here, we analysis the IGF-IR expression on the bone marrow cells from 45 newly diagnosed patients with acute myeloid leukemia (AML) by flow cytometry. IGF-1R universally expressed on AML blasts and the leukemia cell line HL-60, did not show significant correlation with FAB subtypes. However, the bone marrow cells from AML patients with high myeloblast counts (&gt;80%) generally showed brighter IGF-IR expressions, which indicated the IGF-IR pathway might play an important role for AML blast proliferation and survival. Indeed, blocking the IGF-1R pathway by neutralizing monoclonal antibodies could reduce the proliferation of HL-60 cells by 38.28% at 48 hr. This inhibitory effect on blast growth was observed in 4 of 5 AML samples. In the same IGF-1R blocking treatment, the apoptosis of HL-60 cells was significantly induced, resulting in apoptosis of 57% of the cell population with the measurement of Annexin V vs PI staining by flow cytometry. The control contained only 20% apoptotic cells. We also demonstrated that the blockade of the IGF-1R pathway inhibited the phophorylation of the PI3K pathway component Akt in HL-60 cells when cultured in a serum free system with a supplement of 50ng/ml exogenous IGF. Since PI3K pathway activation greatly contributes to the proliferation, survival and drug resistance of AML, it is of interest to study whether blockading IGF-IR could also inhibit the PI3K pathway in primary AML blasts and synergize other anti-leukemia agents to improve the therapeutic effectiveness.
Conclusions:
IGF-IR may play an important role in the proliferation and survival of the AML blast population; Blocking the IGF-IR pathway could significantly inhibit the growth of AML blasts and considerably induce the apoptosis of AML blasts; IGF-IR could become a critical molecular target in anti-leukemia drug discovery.
Downs Syndrome Patients with Acute Lymphoblastic Leukemia; an Intermediate Outcome with a High Infectious Morbidity.
Authors: Saleh Mahasen , Khairy Ashraf R. , El-Solh Hassan , Al-Mahr Mohammed , Al-Musa Abdulrahman , Al-Seraihy Amel , Al-Ahmari Ali , Belgaumi Asim F. 
Published: April 2020

Abstract
Unlike AML, children with Down syndrome and Acute Lymphoblastic Leukemia (DS-ALL) have been reported to achieve significantly lower rates of remission, with higher mortality and a poorer overall survival. To further study this, we conducted a retrospective review for all DS children who were diagnosed and treated for ALL at our institution from 1997 to 2006. 12 (1.8%) out of 645 children (age 0–14 years) diagnosed with ALL had DS. The median age at diagnosis was 55 months (range 23 – 108 months) and eight were male. The most frequent signs and symptoms were fever (n=11; 91.6%), bleeding tendency (n=8; 75%) and organomegaly (n=9; 83.3%). The median WBC count at diagnosis was 4.99×109/L (range 0.58–500×109/L). The median platelet count and hemoglobin were 255×109/L and 80.5g/L, respectively. None of the patients had CNS disease at diagnosis. Leukemia cell cytogenetics revealed only the additional chromosome 21 for all patients, except in one patient who had 48XY,+X,+21. All cases had a precursor B-cell phenotype, and a DNA index of 1.0. Patients received treatment according to the protocol utilized for intermediate risk ALL at our institution. A good early response to induction therapy by a day-14 bone marrow (BM) evaluation was seen in all patients, and complete remission (CR) was achieved by day 28 of induction for the 11 who completed induction chemotherapy. One patient died toward the end of induction due to severe sepsis. Infection was the most commonly encountered morbidity throughout the course of therapy. Six episodes of febrile neutropenia, two documented bacteremias and one disseminated invasive Aspergillosis were reported during the induction phase. In the post-induction period, 21 episodes of febrile neutropenia were reported, in addition to six documented bacteremias and two patients developed fungal infections, one with fungemia and the other with a nail bed infection. Four patients relapsed at a median time of 13 months from diagnosis. Relapses occurred in the BM for two, as isolated CNS in one, and as combined BM and CNS relapse in one. Seven patients continue in first CR. The overall survival and the relapse free survival at 3 years were 53.7% and 60% respectively.
Conclusion: Although DS ALL children do not present with poor-risk features (infancy, T-cell phenotype, adverse cytogenetics, CNS involvement) they tend to have an intermediate treatment outcome even if treated on relatively intensive protocols. Delays in appropriate therapy due to infectious morbidity could contribute to this sub-optimal outcome.
Itraconazole-Enhanced Vindesine Neurotoxicity in Adult Acute Lymphoblastic Leukaemia.
Authors: Chen Suning , Wu De Pei , Sun Aining , Qiu Huiying , Jin Zhengming 
Published: April 2020

Abstract
Severe neurotoxicity following treatment with itraconazole and vincristine has been reported in 25 patients. Here we presented two adult acute lymphoblastic leukemia (ALL) patients developed neurotoxicity after treated with itraconazole and another vinca alkaloids, vindesine. Case 1: A 20-year-old male was diagnosed as having ALL and achieved complete remission (CR) after induction chemotherapy with DVP. He was treated with Hyper-CVAD for consolidation. Because he has a history of pulmonary invasive fungal infection, antifungal prophylaxis with itraconazole solution was started. Nine days after itraconazole was started, some symptom and signs of paralytic ileus were presented. He was diagnosed to have paralytic ileus secondary to neurotoxicity caused by itraconazole and vindesine. After the itraconazole was stopped, his paralytic ileus was improved rapidly. Case 2: A 37-year-old female was diagnosed as having ALL. A diagnosis of B-cell/T-cell biphenotypic acute leukemia was established based on the results of flow cytometry analysis. She was commenced on induction chemotherapy as for ALL (dexamethasone, Idarubicin, and vindesine). The patient presented as pulmonary infection with fever, cough, and expectoration in day 9. Emperical antifungal treatment with itraconazole injection was initiated. Five days after itraconazole injection was started, some symptom of neurotoxicity including limbs anesthesia, and paralytic ileus were presented. After the itraconazole and vindesine were discontinued, these symptoms were resolved. Given the interaction of itraconazole with vinca alkaloids leading to severe and even potentially fatal toxicities, the combination use of these drugs should be avoided.
Phase I Study of Temozolomide and Cisplatin in Patients with Acute Leukemia.
Authors: Katragadda Sreedhar , Liu Delong , Halicka Dorota , Kempin Sanford , Ahmed Nasir , Ahmed Tauseef , Seiter Karen 
Published: April 2020

Abstract
We previously demonstrated that temozolomide has significant activity in patients with acute leukemia (Seiter K, et al JCO 2002). Cisplatin can increase the activity of temozolomide through depletion of MGMT, the enzyme that rescues cells from temozolomide toxicity. We performed a phase I study of temozolomide in 17 patients with relapsed or refractory acute leukemia. Median age: 53 (range 26–73); M/F: 9/8; Dx: AML: 12, ALL: 3, biphenotypic: 2; median # of prior regimens: 2 (range 1–7); duration of 1st remission: primary refractory: 8 patients, 1–6 months: 3 patients, 7–12 months: 4 patients, greater than 1 yr: 2 patients; cytogenetics: good: 2, intermediate: 11, poor: 4; prior AHD: 6 patients; Cisplatin (50–100 mg/m2) was given on day 1; temozolomide (200 mg/m2/d for 5–7 days) was administered daily beginning 4 hours after cisplatin. Cisplatin was administered in the inpatient setting. Twenty-one cycles were administered. To date, no dose limiting toxicity has been observed. The median number of hospital days was 10 (range 2–37). Neutropenic fever occurred in 11/21 cycles. Other grade 3 non-hematologic toxicity included orthostatic hypotension, syncope, and constipation in one patient each, and elevated bilirubin in 2 patients. Four patients had grade 2 elevations of creatinine that resolved with hydration. Other grade 1/2 non-hematologic toxicity included fatigue, nausea/vomiting, constipation, bradycardia, diarrhea, hypokalemia and hypomagnesemia. The median number of RBC transfusions was 3U (range 0–8); the median number of platelet transfusions was 3 (range 0–12). No complete remissions were seen. However significant antileukemic activity was seen: the median pretreatment WBC was 3.2 (range 0.3–78.3); the median nadir WBC was 0.4 (range 0.1–9.6). Four patients had a significant reduction in bone marrow blasts: 40 to 22%, 87 to 38%, 69 to 3%, and 87 to 5%, respectively. The three latter patients were treated at the highest dose level. Cisplatin and temozolomide was well tolerated. We are continuing to accrue patients at the highest dose level to further assess efficacy.
Pegylated Recombinant G-CSF after Sequential High Dose Cytarabine Based Induction Chemotherapy in AML - Analysis of Pharmakokinetics and Effect on Neutrophil Recovery of Pegfilgrastim.
Authors: Fiegl Michael A. , Hiddemann Wolfgang , Braess Jan 
Published: April 2020

Abstract
BACKGROUND: The use of hematopoetic growth factors after conventional induction chemotherapy in acute myeloid leukemia (AML) remains controversial. Yet from former studies with sequential high dose AraC (S-HAM) in relapsed and refractory AML it was shown that the use of G-CSF reduced the early death rate significantly in this clinical setting. Pegylated filgrastim (NEULASTA©, Amgen) has shown to have a sustained-duration effect compared to conventional filgrastim due to decreased renal clearance. This analysis focuses on pegfilgrastim pharmacokinetics and effect on neutrophil recovery in AML.
MATERIAL AND METHODS: The ongoing AML CG pilot trial uses sequential high dose AraC as accelerated dose dense induction therapy in AML. It comprises 66 % of the established HAM-HAM double induction regimen (HAM: AraC 3 g/m2 bid for 3 days and mitoxantron 10 mg/m2 for 3 days) given within 2 weeks instead of four. 6 mg of Neulasta© was applied subcutaneously to all patients with complete blast clearance on day 18 after start of S-HAM. Blood samples for measurement of Neulasta plasma levels were obtained before application and afterwards daily up to day 21. Plasma concentrations of pegfilgrastim were measured by ELISA technique. Leukocyte count was obtained daily.
RESULTS: Analyses were performed in 19 patients at two institutions. After injection, peak plasma levels with a mean of 174 ng/ml were achieved within 48 hours after injection and t ½ was 6 days. 7 of these patients received a second injection of Neulasta 10 – 15 days later due to insufficient neutropenic recovery. Here plasma levels of &gt; 200 ng/ml were achieved. Effective plasma levels of Neulasta (&gt; 2.0 ng/ml) were observed up to 14 days after injection. In those patients who remained neutropenic, Neulasta plasma levels were observed even longer (t ½ &gt; 6 days).
Pegfilgrastim clearance was significantly correlated to neutrophil recovery (r=−0.91, p=0.001). Median time to leukocyte recovery of &gt; 1 G/l was 9 days after injection of the first dose in all evaluable patients.
CONCLUSION: In our study, time to neutrophil recovery in primary AML was shortened to 26 days by use of an accelerated, dose dense regimen plus pegfilgrastim application as compared historically to standard double induction therapy (median time to neutrophil recovery 45 days).
Figure Figure
Comparison of Survival Times after Administration of Tipifarnib or Ara-C-Containing Therapy, to Older Patients with Newly-Diagnosed Acute Myeloid Leukemia.
Authors: Estey Elihu H. , Thall Peter F. , Wang X.-M. , Giles Francis , Karp Judith E. 
Published: April 2020

Abstract
Non-cytotoxic (“targeted”) therapies are finding increasing use as initial treatment of older patients with untreated AML. However, the effect of this practice on survival is unknown. We compared survival times in 140 patients age ≥ 65 given the non-cytotoxic agent tipifarnib (T) at 5 centers (C1–C5) not including M.D. Anderson (MDA) with survival in similarly-aged patients treated at MDA with intermediate-dose ara-C + idarubicin (IA, 124 patients) or + agents other than idarubicin (XA, 49 patients). Because there was no randomization between T and IA or XA comparisons were confounded by center effects (C1–C5 versus MDA). This motivated use of Bayesian sensitivity analyses accounting for hypothetical between-center effects as well as age, performance status, cytogenetics, and whether AML was de novo or secondary. These analyses suggested that, while the odds were 7 to 1 that T was associated with shorter survival than IA or XA, it was nonetheless plausible (95% credible interval for relative risk included 1.0) that survival with T was in fact longer than with IA or XA. More importantly, the magnitude of the differences in survival was sufficiently short that a case could be made for use of T given its greater convenience. More generally we suggest that single-arm trials administering experimental therapies to patients with AML should include interim comparison of survival times with those obtainable with standard therapy, and that randomized phase II trials to avoid treatment-trial confounding may be desirable.
No Significant Difference in Therapy Results between Acute Myeloid Leukemia Patients with Myeloblastic Bone Marrow Infiltration within the Range of 20–29% and over 29% at Diagnosis.
Authors: Grosicki Sebastian , Holowiecki Jerzy , Kyrcz-Krzemien Slawomira 
Published: April 2020

Abstract
Definition of acute myeloid leukemia (AML) includes a heterogenous group of disorders differing in cytogenetics, clinical symptoms and prognosis. A common feature is bone marrow infiltration with leukemic clone which is also present in peripheral blood and different organs.
Over thirty years ago the FAB (French-American-British) group defined the morpho-cytochemical classification of acute leukemias and proposed ≥30% leukemic blasts in bone marrow for a threshold between muelodysplastic syndromes and acute leukemias. In 2002 the WHO group of experts decided to decrease this border line to 20%.
The question concerning differences in results of particular treatment programs for AML patient subgroups with original blastic bone marrow infiltration within the range of 20–29% and ≥30% remains disputable.
To address this question we performed an analysis in 405 patients treated according to the PALG (Polish Adult Leukemia Group) protocol DAC and DA. At diagnosis there were 26 patients with myeloblastic bone marrow infiltration ranging 20–29% (group A) and 379 patients with infiltration ≥30% (group B). In 62,5% patients (n=10) of the group A AML was preceding by myelodysplastic syndrome.
In the time period 1999–2002 patients under study received as induction DAC-7 regimen: daunorubicin 60 mg/m2/d iv 1–3; cytarabine 200 mg/m2/d ci 1–7; cladribine 5 mg/m2 2h inf. iv d 1–5 or standard DA-7 regimen (the same regimen without cladribine). Patients achieving CR received two courses of subsequent intensive consolidation:HAM (HD AraC, mitoxantrone)HD AraC with or without cladribine in the DAC-7 or DA-7 arm, respectively.In the case of PR after the first induction course the same regimen was repeated. Post-consolidation therapy was in both arms comparable.
Complete remission (CR) rate was comparable in both populations and reached 73% in the group A and 70% in group B. There were also no statistical differences between overall survival (OS) and leukemia free survival (LFS) between both groups. OS after 5 years equals 34% in group A and 27% in droup B and LFS 42% and 27%, respectively (p=NS).
Our study proves that there are no differences in treatment results between AML patients with original bone marrow infiltration within 20–29% and ≥30% given the same treatment. It confirms that the revised WHO criteria are reasonable.