bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Characteristics of JAK2 V617F Mutation Positive Acute Myeloid Leukemia.
Authors: Nahajevszky Sarolta , Andrikovics Hajnalka , Matrai Zoltan , Lovas Nora , Lueff Sandor , Masszi Tamas 
Published: April 2020

Abstract
Chronic myeloproliferative diseases (CMPD) are clonal disorders of pluripotent hematopoietic stem cells. Acquired JAK2 V617F point mutation has recently been identified as disease causing activating genetic abnormality in classic BCR-ABL negative CMPD (80% of polycythemia vera, 35% of essential thrombocythemia and 50% of chronic idiopathic myelofibrosis cases). JAK2 V617F is rare in other myeloid stem cell disorders like acute myeloid leukemia, chronic myelomonocyter leukemia or myelodysplasia with reported frequency of 3–8%. Between January 2001 and December 2005 155 consecutive adult patients [87 females and 68 males, median age of onset was 49±14 (range 18–83) years] were diagnosed with AML in our institute. Peripheral blood or bone marrow samples drawn at the time point of diagnosis were analyzed for the presence of JAK2 V617F by allele-specific PCR. JAK2 V617F mutation was present in 5 patients (3 males and 2 females; 3.2%). 3 of the 5 patients had prior history of CMPD, while 2 patients were diagnosed with de novo AML. The clinical characteristics and laboratory features of JAK2 V617F positive patients are shown in Table 1. FLT3 internal tandem duplication, FLT3 tyrosine kinase domain mutations, AML1-ETO, CBFB-MYH, PML-RARA rearrangements or nucleophosmin mutations were not present at the time point of AML diagnosis. In the case of patient 1, thrombocytosis was present prior the diagnosis of AML, and bone marrow biopsy revealed grade 3 fibrosis at diagnosis of AML, suggesting the presence of an atypical CMPD with the coexistence of del(5q) MDS. Patient 2 had no remarkable disease in his previous medical history. Induction therapy resulted in complete hematological and cytogenetic remission with persistent JAK2 V617F positivity. 10 month later clinical features of CMPD (elevated white blood cell count, left shifted peripheral blood smear, hepatosplenomegaly) appeared. In conclusion, these two cases suggest that acute myeloid leukemia with JAK-2 V617F mutation in fact corresponds to the blastic transformation of a clinically atipical chronic myeloproliferative disorders.
Clinical characteristics and laboratory features of JAK2 V617F positive patients Case Sex AML subtype Age of onset (years) FAB subtype Cytogenetic abnormality Therapy Overall Survival (months) 1 F de novo 52 M1 del(5q) DNR+ara-C, HDara-C 23 2 M de novo 65 M4 t(13;17) DNR+ara-C, HDara-C 12 3 F CMPD blastic transformation 65 M4 trisomy (1q) Supportive 18 4 M CMPD blastic transformation 70 M4 not available Supportive 3 5 M CMPD blastic transformation 71 M4 not available Supportive 6
t(8;21) Positive AML with Favorable Clinical Characteristics, in a Child with Ependymoma after Combined Treatment with Neuroaxis Irradiation and Topoisomerase II Inhibitors.
Authors: Papadakis Vassilios , Papadhimitriou Stefanos , Paisiou Anna , Parcharidou Agapi , Tourkantoni Natalia , Paterakis George , Belesi Chrysoula , Sambani Constantina , Polychronopoulou Sophia 
Published: April 2020

Abstract
The extensive use of etoposide has been implicated in the development of secondary acute myelogenous leukemia (AML) with unfavorable prognostic characteristics and most often involvement of the 11q23 locus. The case herein being presented exhibits favorable characteristics and poses the question whether it represents a secondary malignancy or a second primary event. A five year old boy was diagnosed with a mass of the posterior fossa representing anaplastic ependymoma of the brain stem (medulla oblongata) without CNS nor distant metastases. After partial resection of the tumor, the patient received 53 Gy to the tumor bed and 30 Gy to the neuroaxis followed by temozolamide p.o. for 4 cycles. Following this treatment, symptoms improved, he was ambulatory and back to school. Two years later he relapsed with unresectable tumor and received etoposide (VP-16) at 100 mg/m2/day for 21 days of 28 cycles, with a palliative intent. The treatment proved efficacious to him and he continued to receive VP-16 for 3 years in total. Six years after initial diagnosis and 3 years on VP-16, he developed ecchymoses, with thrombocytopenia (PLT: 15 k/uL) and leukocytosis (WBC: 25.8 k/uL). Bone marrow evaluation revealed infiltration with AML M2 blasts (&gt;80%), MPO+ (93%), CD 34+ (58%), CD15+ (19%), CD71+ (33%), CD38+ (87%), CD33+ (47%) and CD123+ (52%), karyotype with detection of t(8;21). Bone marrow RT-PCR confirmed the presence of AML1-ETO hybrid gene, the absence of the MLL-AF4 product, and the absence of 11q23 involvement. Results were also confirmed by FISH technique. The patient was started on chemotherapy according to the AML-BFM 98 protocol. Disease remission was rapidly achieved (day +15 BM with no blasts) and treatment schedule was prompt, for the first 4 months of treatment. Severe, long-lasting marrow aplasia followed and pulmonary Aspergillosis was evident (compatible findings on CT and detection of Aspergillus specific proteins in the plasma by PCR), requiring assisted ventilation. However the patient succumbed 5 months following the diagnosis of AML. Childhood ependymomas have a dismal prognosis despite intensive treatment. This child exhibited a similarly good treatment response either to the ependymoma or to the later evolved AML. This AML1-ETO positive AML either representing a second primary malignancy or a rare type of secondary, therapy induced leukemia, is not a common and well described event and it certainly did not present, in our case, the usual dismal course of a secondary AML. Of importance our patient achieved and remained in remission with minimal treatment, for over 5 months, verifying the good prognosis of AML1-ETO positive AML either as a primary or a secondary event.
Compassionate Use of Intrathecal Depot Cytarabine (DepoCyte®) in Central Nervous System (CNS) Involvement in Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma in Spain: Report of 10 Cases.
Authors: Sancho Juan-Manuel , Giraldo Pilar , Romero Maria-Jose , Martin-Reina Victoria , Gimenez Eugenio , Ruiz Elena , Josefa Plaza , Monteserin Carmen , Sanchez-Garcia Eva , Martino Rodrigo , Sarra Jose , Palomera Luis , Ribera Josep-Maria 
Published: April 2020

Abstract
The efficacy of intrathecal (IT) depot formulation of liposomal cytarabine (DepoCyte®) in the treatment of CNS involvement in patients with ALL has been only demonstrated in individual cases or series with a small number of patients. A retrospective review was performed of all cases in which IT depot cytarabine was employed as compassionate therapy of CNS involvement of ALL and lymphoblastic lymphoma in Spain. From February 2004 to March 2006, 10 cases (6 females) were recorded (ALL, 6, lymphoid blast crisis [BC] of Ph’ CML, 2, and lymphoblastic lymphoma, 2). The median (range) age was 31 (5–50) yr. Three patients (2 with ALL and another with BC-CML) had leukemic meningeosis at the time of diagnosis: 2 received IT depot cytarabine as adjuvant therapy after triple IT therapy (TIT) (BC-CML) and TIT plus cranial irradiation (ALL), whereas the remaining case (ALL) only received IT depot cytarabine. The remaining 7 patients (ALL, 4, lymphoblastic lymphoma, 2, and BC-LMC, 1) presented CNS relapse. CNS prophylaxis in these patients consisted of TIT plus cranial irradiation (2 patients with ALL), TIT (2 patients with ALL and 2 with lymphoblastic lymphoma), whereas the patient with BC-LMC did not receive any prophylaxis. IT depot cytarabine was administered as the only treatment for CNS relapse in one patient with ALL, as treatment of a second CNS relapse in 2 ALL patients and as adjuvant to other therapies in 4 patients (to TIT in other patient with ALL, to TIT plus radiotherapy in the patient with BC-CML, and to radiotherapy in the 2 patients with lymphoblastic lymphoma). In the 4 evaluable cases (one patient with ALL and CNS involvement at diagnosis and 3 patients with ALL and CNS relapse, 2 with second CNS relapse) treated with IT depot cytarabine as the only drug, clearance of blasts in cerebrospinal fluid (CSF) was observed with sustained response in two (at 7 and 22 months). The remaining 2 patients presented neurologic and systemic progression at 3 and 2 months, respectively. The median number of IT depot cytarabine administrations was 4 (1–9). Concurrent systemic dexamethasone therapy (4 mg twice/day/5 days) was administered with each dose of IT depot cytarabine. Side effects included headache (5 patients), dizziness (2) vomiting (2) and nausea (1). Depot formulation of cytarabine was effective in achieving CNS remission in ALL patients with CNS involvement or relapse. The administration of depot formulation of cytarabine was well tolerated. This justifies the development of a clinical trial to evaluate the efficacy and safety of IT depot cytarabine in meningeal involvement of ALL.
Intussusception in Childhood Acute T Cell Lymphoblastic Leukemia: An Unusual Complication - Report of 2 Cases.
Authors: Shah Jesika , Barlev Dan , Redner Arlene Sara , Shende Ashok , Karayalcin Gungor 
Published: April 2020

Abstract
Clinically significant gastrointestinal complications in children with acute lymphoblastic leukemia (ALL) have been reported. However, intussusception is a very rare complication. In one study of 286 children with ALL gastrointestinal complications occurred in 5.6% of patients with intussusception seen in only 0.3% of patients. We describe two cases of intussusception during chemotherapy for T-cell leukemia. Patient #1 was an 8 year old girl on chemotherapy for T-cell ALL. Around week 9 following POG 9404 protocol of consolidation chemotherapy, patient presented with severe abdominal pain and vomiting, and had marked, diffuse tenderness of the abdomen with guarding and hypo-active bowel sounds. Abdominal radiograph showed thickening of the descending colon; abdominal sonogram was normal; abdominal computed tomography (CT) scan however, revealed a soft tissue and fluid-filled mass extending from the cecum to the descending colon. These findings were consistent with a large bowel intussusception, which was successfully reduced with a barium enema. Patient #2 was a 15 year old male receiving chemotherapy for T-cell ALL following POG 9404 protocol. At week 14 of consolidation chemotherapy, patient presented with a 2 day history of nausea and colicky peri-umbilical and right lower quadrant abdominal pain. An abdominal CT scan revealed an ileocolic intussusception without bowel obstruction and mild wall thickening of the cecum. Barium enema resulted in successful reduction of the intussusception. Interestingly, both our patients were treated with high dose methotrexate 5gm/m2 during this time period and both experienced delayed excretion of methotrexate. To our knowledge, there is no known reported association between high dose methotrexate and intussusception. We speculate that the two could be related. The increased use of high dose methotrexate therapy in T-cell ALL may result in a higher incidence of intussusception in this population. Although, intussusception in ALL is a very rare complication, awareness of this entity and early recognition with radiological intervention may prevent unnecessary surgery and the associated morbidity and mortality in these patients.
Phenyhexyl Isothiocyanate, a Dual Inhibitor of Histone Deacetylation and Methylation, Inhibit Acute Lymphoblastic Leukemia Cells through Epigenetic Modulation.
Authors: Huang Yiqun , Ma Xudong , Chiao Dicky J.W. , Liu Delong 
Published: April 2020

Abstract
We have shown that phenyhexyl isothiocyanate(PHI) is a novel histone deacetylase inhibitor and can also modulate histone methylation. In this study we investigated the effect of PHI on human Acute Lymphoblastic leukemia cell line Molt-4 in vitro. The viability of Molt-4 cells was determined by MTT method. Apoptosis and cell cycle arrest were measured by flow cytometry. The expression of bcl-2, caspase-9, caspase-8, caspase-3, PRAP protein, acetylated H3 and H4, methylated H3K9 and H3K4 were detected by Western Blotting. The results showed that PHI inhibited the cell growth and decreased viability of Molt-4 cells. Cell cycle analysis indicated an arrest in G0/G1 phase. The expression of bcl-2, caspase-9, caspase-3, and PRAP was inhibited by PHI in a dose and time dependent manner. In contrast, there was no significant change in the expression of Caspase-8. PHI also significantly increased the level of acetylated histone H3 as well as H4. Interestingly, PHI increased the level of methylated H3k4, but decreased methylated H3K9. These data suggest that ALL cells are sensitive to the novel HDAC inhibitor, and PHI may become a novel agent in ALL therapy.
Laboratory Tumor Lysis Syndrome Complicating LBH589 Therapy in a Patient with Acute Myeloid Leukemia.
Authors: Kalff Anna , Shortt Jake , Farr Julia , McLennan Roger , Scott Jeffrey W. , Liu Angela , Spencer Andrew 
Published: April 2020

Abstract
LBH589 (Novartis) is a potent histone deacetylase inhibitor (HDACi) currently in early phase clinical development. Preliminary data suggests biological activity in a range of malignant hematological disorders including acute myeloid leukemia (AML). To-date, laboratory tumor lysis syndrome (LTLS) has not been described as a complication of LBH589 therapy. We report a case of a 60 year-old man who developed LTLS following treatment for AML with oral LBH589. The patient was diagnosed with refractory anemia with excess blasts (RAEB) in July 2005. Cytogenetic analysis demonstrated trisomy 8 and del(20q). He was initially treated with standard dose cytarabine and idarubicin (7 + 3). Post-induction bone marrow examination revealed ongoing dysplasia but no excess of myeloblasts. He subsequently received further cytarabine and idarubicin as consolidation. This was complicated by prolonged pancytopenia and subsequently by rapid progression to overt AML. Salvage therapy with fludarabine/cytarabine/G-CSF (FLAG) failed and he was referred to our institution for investigational therapy with LBH589. The patient was enrolled in a Phase IA/II trial of oral LBH589 for patients with advanced hematological malignancies and commenced intermittent oral LBH589 (30mg orally Monday, Wednesday and Friday on alternate weeks). He re-presented on day 14 with deteriorating renal function - creatinine 0.28mM/L (baseline 0.12mmol/L) and hyperleukocytosis (WBC 68 × 109/L). He recommenced LBH589 and was also commenced on hydroxyurea 1g bd, allopurinol and hydration. Within 24 hours, associated with a fall in his WBC to 9 × 109/L, he developed LTLS - corrected calcium 1.91mM/L (2.23 – 2.50), phosphate 2.99mM/L (0.70 – 1.30) and uric acid 0.8mM/L (0.15 – 0.50). He recovered uneventfully with the administration of rasburicase, intravenous fluid and electrolytes. Hydroxyurea was ceased and he continued LBH589 as per schedule. On day 28 with a WBC of 60 × 109/L and with prophylactic rasburicase and hyper-hydration, LTLS again recurred within 24 hours of LBH589 administration - WBC fell to 6 × 109/L accompanied by corrected calcium of 2.1 mM/L and serum phosphate of 1.91 mM/L. The patient again recovered uneventfully. This first reported case of LTLS with LBH589 therapy clearly demonstrates the potent anti-leukemic potential of LBH589 and mandates that caution be taken with LBH589 treatment of AML patients exhibiting highly proliferative and/or a high tumor burden disease.
Hematopoietc Stem Cell Targeted Neonatal Gene Therapy Cures oc/oc Mice from Osteopetrosis.
Authors: Richter Johan , Johansson Maria , de Vries Teun J. , Ehinger Mats , Everts Vince , Karlsson Stefan 
Published: April 2020

Abstract
Infantile malignant osteopeterosis (IMO) is a progressive, rare autosomal recessive disorder affecting osteoclast function. 50% of the affected children have a mutation in the Tcirg1 gene coding for one subunit of an osteoclast specific proton pump, OC116. The non-resorbed dense, sclerotic bones cause symptoms including pancytopenia and progressive visual loss and ultimately death. So far, the only curative treatment is hematopoietic stem cell (HSC) transplantation. The oc/oc mouse has a mutation in the gene homologous to Tcirg1 giving rise to similar symptoms as in patients leading to death of the mice at the age of 3–4 weeks. We have previously shown that the oc/oc mouse can be successfully treated with neonatal transplantation of normal HSC leading to prolonged survival and reversal of osteopetrosis (M. Johansson et al., Exp. Hematology34;242, 2006). In the current study we set out to develop HSC directed gene therapy for osteopetrosis in the oc/oc mouse model. As the bone marrow compartment is severely reduced in the oc/oc mouse fetal liver (FL) cells depleted of Ter119+ erythroid cells were used as a source of hematopoietic stem cells. We first established that wild type Ter119 depleted FL cells marked with a GFP vector and transplanted to newborn oc/oc mice i.p. could correct the osteopetrotic phenotype just as was shown for fresh bone marrow cells previously. Subsequently, Ter119 depleted FL cells from oc/oc mice were transduced with a retroviral vector expressing OC116 and GFP. In vitro transduction efficiency was 60–85%. One-day-old oc/oc mice were irradiated (400cGy) and transplanted i.p. with the transduced FL cells (1–3.5x106). 7 out of 14 mice survived past the expected lifespan and had 8–53% GFP+ cells in the peripheral blood at 3, 6 and 12 weeks. Analysis of bone structure with X-ray and histopathology showed an improvement at 8 weeks and an almost normal structure at 18 weeks, indicating induction of osteoclast activity. In vitro culture of osteoclasts from bone marrow from transplanted animals on bovine bone slices showed GFP marked osteoclasts and bone resorption, albeit at lower levels than for wild type cells. In the oc/oc mouse there is a block in B-lymphopoiesis leading to a reduced number of B-lymphocytes in the peripheral blood. In treated mice a reversal of this deficiency was observed.
In summary we have demonstrated that the osteoclast defect seen in oc/oc mice can be successfully corrected by neonatal transplantation of gene modified hematopoietic stem cells and that this can lead to long-term survival of treated mice. This represents a significant step towards the development of gene therapy for osteopetrosis.
The Effect of Combination of CDK Inhibitor (Roscovitine) and Derivatives of Tetracycline on Human Leukemic Cells.
Authors: Song Hairong , Hassan Zuzana 
Published: April 2020

Abstract
Roscovitine is a 2,6,9- trisubstituted aminopurine analogue that compete with ATP for binding to the active site of Cyclin-dependent kinases (CDKs). It inhibits CDK2/cyclinE, CDK7/cyclinH and CDK9/cyclinT. The cytotoxic effect of roscovitine and its analogues has been reported in several cancer cell lines in vitro and in animal models of cancer xenografts in vivo. The analogues of tetracycline (Doxycycline and Minocycline) possess anti-tumor, anti-metastatic and anti-angiogenesis properties with low toxicity besides acting as antibiotics. The effect of single agent is usually limited in cancer therapy and the use of single agent may mediate drug resistance. We have studied a cytotoxic effect of the CDK inhibitor roscovitine and tetracycline derivatives either alone or in combinations in human leukemia cells lines HL-60 (myeloid), Jurkat (lymphoblastic) and K562 (CML). HL-60, Jurkat and K562 cells were cultured in RPMI 1640 supplemented with 10% FBS. Cells were treated with roscovitine (0.5 – 100 μM), doxycyline (0.5 – 100 μg/ml) or minocycline (0.5 – 100 μg/ml) up to 48 hours alone or in combinations. The cells were examined for viability using AlarmaBlue assay, proliferation using 3H-thymidine incorporation assay, apoptosis using morphological criteria in Giemsa staining, cell cycle using propidium iodide and flow cytometry. Mitochondrial membrane permeabilization was assessed using tetramethylrhodamine ethyl ester. Specific proteins were detected by Western blotting. Incubation with roscovitine, doxycycline or minocycline decreased the cell viability in concentration-dependent manner in all three cell lines. Pretreatment of cells with doxycycline and minocycline for 24 hours followed by roscovitine for 24 hours have shown the additional decrease in cell viability. No such effect was observed when the drugs were used concomitantly. Roscovitine alone decreased proliferation in concentration- and time-dependent way in all three cell lines. Apoptotic morphology was firstly observed at 3 hrs after the treatment with roscovitine and markedly increased at 6 hrs in HL60 and Jurkat cells, but not in K562 cells. In HL60 and Jurkat cells, the cell cycle analysis has shown an increase in sub-G1 cells at 6 hours with maximum at 24h without preceding cell cycle arrest. In K562 cells sub-G1 peak increased subsequently to G2/M arrest. A marked loss of ΔΨm was observed at 2 hrs of exposure to 25uM of roscovitine in Jurkat and HL-60 cell lines, respectively. In HL60 and Jurkat cells, release of cytochrome c, AIF and Smac from mitochondria into cytosol were detected along with activation of caspases and PARP. However in K562, no caspase activation was detected at studied time points. Thus, all three agents have a cytotoxic effect in different types of leukemic cells, however, the additional cytotoxic effect of combination of Roscovitine and derivatives of tetracycline might be a potent therapeutic approach in treatment of leukemia.
Treatment of Acute Myeloid Leukemia in a Community Hospital.
Authors: Dhami Mandeep S. , Bulgaru Anca , Jagathambal Kandhasamy , Kapur Dinesh , Slater Dennis E. , Maderazo Eufronio G. , Bauer Frank A. 
Published: April 2020

Abstract
Optimal management of patients with acute myeloid leukemia requires an accurate diagnosis along with cytogenetics and an intensive systemic chemotherapy regimen administered by a multidisciplinary team of experienced physicians, nurses and other support staff. It has been suggested that such complex patients should be treated only at tertiary care centers. However, it is often difficult for patients and families to receive care at teratiary care center which may be at a great distance from their home. Here we present a retrospective review of all patients diagnosed and treated for acute myeloid leukemia at William W Backus Hospital, a 213 bed acute care hospital serving a community of 70,000 in Norwich, Connecticut between the years 2000 and 2005. A total of 44 patients were treated during this period. There were 22 males and 22 females. The median age was 67.5 years. Bone Marrow samples were evaluated by a hematopathologist (histopathology, flowcytometry and cytogenetics) at a near-by tertiary care center. FAB subgroups and cytogenetics were similar to other published studies. APML patients are not included in this analysis. The median survival for the entire group was 14.7 months ranging from 2 days to 113 months. Fourteen patients were alive, all in continued clinical remission except one with relapsed disease and one patient remains transfusion dependent. Median survival was 15.2 months for men compared to 13.2 months for women. Four patients were referred for bone marrow/stem cell transplant after induction therapy.
The limitation of this study is the relatively small number of patients as one would expect from a study done at a small community hospital. Nevertheless, it appears that the median survival of our patients is similar to a pooled analysis of five SWOG trials published by Gundacker et al. We conclude that most patients with acute myeloid leukemia can be managed in a community hospital with commitment and experience to treat such patients.
Treatment outcomes (median survival) Study Number of Patients Under 55 55 – 65 65 – 75 Over 75 *Gundacker et al. Blood, 1 May 2006, volume 107, 3481–3485 Current study 44 17.1 m 18 m 11.7 m 5.7 m Gundacker et al* 968 18.8 m 9.0 m 6.9 m 3.5 m