bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intensification of Post-Remissional Treatment in Adult Acute Lymphoblastic Leukemia (ALL) with t(4;11) or t(1;19): Results of the GIMEMA LAL 2000 Study.
Authors: Vignetti Marco , Meloni Giovanna , Morselli Monica , Tedeschi Alessandra , Ferrara Felicetto , Cantore Nicola , Specchia Giorgina , Di Raimondo Francesco , Recchia Anna , Sica Simona , Cascavilla Nicola , Camera Andrea , Fabbiano Francesco , Cimino Giuseppe , Mancini Marco , Fazi Paola , Foà Roberto , Mandelli Franco 
Published: April 2020

Abstract
In the GIMEMA LAL 0496 trial, which has been conducted in Italy between 1996 and 2000, patients with adult ALL received an induction therapy with VCR, DNR and ASP until they reached complete remission (CR). Consolidation therapy with Ara-C and CTX was then administered and, if still in CR, patients received a 3-year maintenance therapy. Ph+ ALL patients were considered at high risk and after the induction phase a stem cell transplant (SCT) was planned, allogeneic for patients with an HLA identical sibling or autologous. A total of 498 patients have been enrolled by 50 GIMEMA Centers. Of these, 29 patients (5.8%) with either t(4;11) or t(1;19), who received the standard post-remissional approach, showed a statistically significant worse prognosis after CR: the projected probabilities of DFS and OS at 2 years were 19% (C.I. 95%: 4.1–34.4) and 31% (C.I. 95%: 14.2–47.9), respectively. Thus, in the new protocol - GIMEMA LAL 2000 - these patients received an intensive post-remissional treatment including SCT. Between 2000 and 2003, a total of 383 patients have been enrolled in this new protocol. Of these, 23 (6.0%) were positive either for t(4;11) or for t(1;19). The clinical characteristics of these patients are comparable to those of the patients enrolled in the previous study and the overall CR rate is also super imposable.
GIMEMA LAL 0496 vs GIMEMA LAL 2000
Fig. 1 shows the comparison in DFS at 2 years between LAL 0496 and LAL 2000; though not statistically significant, a trend towards a better prognosis is clearly seen. The DFS probability projected at 2 years is 52% (95% C.I. 26–78) compared to 19% (95% C.I. 4–35). The OS, projected at 2 years, is 42% (95% C.I. 14–70) compared to 31% (C.I. 95%: 14.2–47.9).
Despite the relatively limited case series, these results suggest that for t(4;11)+ and t(1;19)+ adult ALL intensification of the post-remissional treatment with SCT is a feasible approach that may improve the outcome in this subset of patients at high risk of relapse with standard post-remissional therapies.
Figure Figure GIMEMA LAL 0496 GIMEMA LAL 2000 p Patients t(4;11) or t(1;19) 29 23 0.7626 Sex (M/F) 14/15 8/15 0.3280 Age yrs, median (min-max) 37.8 (14.9–59.4) 39.4 (19.6–59.2) 0.1481 WBC x 109/L median (min-max) 41.2 (2.2–663.0) 50.3 (2.4–300.0) 0.9193 Phenotype (B/T) 29/0 23/0 - CR rate 92.8% 85.7% 0.6392
Pioglitazone Inhibits the Growth of Human Leukemic Cell Lines and Primary Leukemic Cells in Vitro.
Authors: Hatta Yoshihiro , Saiki Minoru , Enomoto Yuko , Aizawa Shin , Sawada Umihiko , Horie Takashi 
Published: April 2020

Abstract
Troglitazone and pioglitazone are one of thiazolidinediones that are high affinity ligand for the nuclear receptor called peroxisome proliferator-activated receptor gamma (PPAR-γ). Troglitazone is a potent inhibitor of clonogenic growth of acute myeloid leukemia cells when combined with a retinoid. However, the effect of pioglitazone to neoplastic cells and normal hematopoietic cells has not been studied yet. Adult T-cell leukemia (ATL), prevalent in western Japan, is a highly aggressive malignancy of mature T lymphocyte. Therefore, we studied antitumor effect of pioglitazone against leukemic cells including ATL as well as normal hematopoietic cells. With 300 μM of pioglitazone, colony formation of ATL cell lines (MT1, MT2, F6T, OKM3T, and Su9T01) was completely inhibited. Colony formation of HUT102, another ATL cell line, was 12 % compared to untreated control. Clonogenic cells of other leukemic cell lines (K562, HL60, U937, HEL, CEM, and NALM1) was also inhibited to 0–30% of control. Colony formation of primary leukemic cells from 5 AML patients was decreased to 15 %. However, normal hematopoietic cells were weakly inhibited with 300 μM pioglitazone; 77 % of CFU-GM, 70 % of CFU-E, and 33 % of BFU-E survived. Cell cycle analysis showed that pioglitazone decreased the ratio of G2/M phase in HL60 cells, suggesting the inhibition of cell division. By Western blotting, PPAR-γ protein level was similar in all leukemic cells and normal bone marrow mononuclear cells. Taken together, pioglitazone effectively eliminate leukemic cells and could be used as an antitumor agent in vivo.
Anticancer Activity and Induction of Multinucleation in Hematologic Cell Lines Mediated by Ganoderma Lucidum.
Authors: Muller Claudia I. , Kumagai Takashi , O’Kelly James , Seeram Navindra , Heber David , Koeffler H. Phillip 
Published: April 2020

Abstract
Over many centuries, herbal remedies have treated a variety of ailments. This empiric observational approach has produced a number of leads for formulated medicines. We have examined five phytochemical herbs with purported anti-cancer activities: Ganoderma lucidum, Isatis indigotica, Dendranthema morifolium, Rabdosia rubescens and Panax pseudoginseng. Ethanol and DMSO extracts were made of each herb, and these were screened for their antiproliferative activities (MTT-assay; doses: 50 μg/ml and 100 μg/ml) using a panel of 26 human cancer cell lines (16 hematologic cell lines). Ganoderma lucidum was the most effective agent, particularly against the 16 hematological cell lines. Further dose- and time-response MTT assays of Ganoderma were performed using the 7 most sensitive hematological cell lines: their ED50’s were 26 μg/ml, HL-60; 63 μg/ml, U937; 50 μg/ml, K562 (all three are myeloid leukemias); 38 μg/ml, Blin-1; 30 μg/ml, Nalm-6 (both are B-ALLs); 40 μg/ml, RPMI8226 (multiple myeloma); 20 μg/ml, Daudi (Burkitt’s lymphoma). Cell cycle analysis revealed a G2/M arrest, most prominently in HL-60 cells (24% in G2/M compared to 12% in control cells cultured with 100 mg/ml Ganoderma for 3 days). Three hematological cell lines (HL-60, U937, Blin-1) were examined for apoptosis, which ranged between 10% – 35% and 30% – 49% compared to &lt;6% in control cells after exposure to 100 and 200 mg/ml Ganoderma for 3 days, respectively (Annexin V staining). Of particular note, cytospin preparations of HL-60 cells revealed that Ganoderma lucidum caused prominent multinucleation. Dose-dependent studies revealed 1% multinucleation in the cells treated with 1 mg/ml, 5% with 10 mg/ml, 10% with 50 mg/ml, 40% with 75 mg/ml and 80% with 100 mg/ml Ganoderma at day 4 of culture. FACS analysis of PI stained HL-60 cells confirmed the increased DNA content of these cells. Of interest, multinucleation did not occur in 6 other hematologic and 6 solid tumor cell lines. In summary, we discovered that 5 phytochemical herbs have growth inhibitory effects on AML, CML, B-ALL, Burkitt’s lymphoma and multiple myeloma cell lines. The most effective drug was Ganoderma lucidum, and it induced cell death by apoptosis. Moreover, multinucleation was observed in HL-60 cells, which may provide interesting insight in the same process in normal cells, like megakaryocytes. Notably, these studies have identified one plant, Ganoderma lucidum, that deserves careful separation techniques to identify its anticancer molecule (s).
ATRA Based (Iraqi) Protocol for Children with Acute Promyelocytic Leukemia (APL) in Baghdad: Results in the First 8 Patients.
Authors: Testi Anna Maria , Moleti Maria Luisa , Nal-Hadad Salma Abbas , Al-Jadiry Mazin Faisal Farhan , Mandelli Franco , Foa Robert 
Published: April 2020

Abstract
At the Oncology Unit/Al Mansour Teaching Hospital for Pediatrics in Baghdad, Iraq, between January 2002 and January 2003, a total of 11 children (age &lt; 15 years) out of 32 acute myelogenous leukaemia (AML), were morphologically diagnosed as APL. This represents an overall very high incidence (35%) of childhood AML referred to a single institution. Molecular and cytogenetic studies were not feasible. ATRA was not available and most children received combination cytarabine and daunorubicin induction treatment that resulted in more than 50% early fatalities mainly due to hemorrhagic events and in less than 10% survivors. As a consequence of a collaborative project between the Oncology Unit/Al Mansour Teaching Hospital for Pediatrics in Baghdad and the Pediatric Hematology Unit of our Institute at “La Sapienza” University of Rome, a specific ATRA based protocol was designed according to the modern strategies for the management of APL and adapted to the severe local difficulties in Iraq. ATRA was supplied by Roche. The treatment plan consisted of oral induction ATRA (25 mg/m2/day) for 30 days associated to Daunorubicin (DNR 25 mg/m2/day for 2 consecutive days) only if the WBC count was &gt; 10 x 109/L at diagnosis or increased during treatment. Consolidation included three chemotherapy cycles (DNR; DNR+ARA-C; DNR); ATRA was associated to each cycle for patients with a WBC count at diagnosis &gt; 10 x 109/L and/or for those requiring the addition of DNR during ATRA therapy (high-risk). Standard 6-MP and MTX maintenance with 14 days ATRA, every 3 months was administered to all patients in complete remission (CR) for 2 years. Intrathecal MTX prophylaxis (total 3 doses) was given at each consolidation course, for high-risk patients.
Since December 2003, 8 consecutive children with APL (5 male and 3 female; median age: 12 years, range 3–16) were enrolled in the protocol. Seven were defined as high-risk and one as low-risk. Morphological diagnosis was that of classic M3 in 7 children and of M3 variant in 1. The M3v child had a very high WBC count and died the same day of referral due to a massive bleeding, while the other 7 children achieved a CR. One of the 7 responders was lost to follow-up in CR; the other 6 patients are alive and well in CR, on consolidation (1 case) and on maintenance treatment (5 cases).
These preliminary but highly encouraging results represent a substantial improvement over the earlier experience in childhood APL in the main Pediatric Center in Baghdad and demonstrate that modern therapeutic strategies, adapted to the local reality, are a necessity and can be effectively implemented through international collaborative efforts even in countries with limited resources and severe difficulties.
Intracranial Hemorrhage (ICH) in Patients (pts) with Newly Diagnosed Leukemia: Incidence and Effect on Outcome.
Authors: Oki Yasuhiro , Jabbour Elias , Kantarjian Hagop , Estey Elihu , Cortes Jorge E. , Faderl Stefan , Pierce Sherry , Zhou Xian , Bekele B. Nebiyou , Garcia-Manero Guillermo 
Published: April 2020

Abstract
Hemorrhage and infection carry significant morbidity and mortality in pts with leukemia. ICH can be a major clinical problem despite the current advances in supportive care. To analyze the incidence, outcome of ICH, and to identify potential risk indicators, we have conducted a retrospective analysis of pts with leukemia at M.D. Anderson Cancer Center (MDACC). We first reviewed all brain CTs of pts newly referred to MDACC from 1/2003 to 11/2003 with diagnosis of leukemia, myelodysplastic syndrome, or myeloproliferative disorder. Among 1185 pts (275 AML, 78 ALL, 163 CML, 296 CLL, 206 MDS, 47 MPD, 111 Other), 13 (1%) had ICH (8 AML, 3 APL, and 2 CML-myeloid blastic crisis). Based on this preliminary analysis, we limited this analysis to pts with newly diagnosed AML who received induction chemotherapy between 1/1998 and 11/2003. Among 993 such pts, 28 (3%) had ICH (parenchymal bleed in 12, subarachnoid hemorrhage in 4, subdural hematoma in 6, hemorrhagic infarct in 4, subarachnoid hemorrhage + subdural hematoma in 1, subarachnoid hemorrhage + subdural hemorrhage + parenchymal hemorrhage in 1) during the induction period (within 6 months after induction chemotherapy). Pt characteristics are shown in the table. Median time from induction therapy to ICH was 27 (0–122) days. In 16 (57%) pts death occurred before response to therapy could be determined (0–37 days). Thirteen out of 16 (81%) pts died of ICH as an immediate cause of death, and three of 16 (19%) died in the setting of multi-organ failure. Of 12 remaining pts whose disease status was assessed, 8 pts (66%) achieved complete remission (CR). Univariate analysis including age, gender, APL vs non-APL, cytogenetics, performance status, protective environment treatment, presence of antecedent hematologic disorder (AHD) and/or MDS, WBC&lt; hemoglobin, platelet, PT, PTT, b2MG, bilirubin, creatinine, LDH, % of bone marrow blasts, % of peripheral blood blasts, and CR vs non-CR, indicated that APL, cytogenetics, thrombocytopenia, PT, bilirubin, and non-CR were associated with ICH. Differences in PT and bilirubin between the two groups, however, were clinically not significant. In a multivariate logistic regression analysis, APL remained as the only major predictive factor (odds ratio 3.35). In conclusion, ICH is limited to pts with myeloid malignancies, with an incidence of 3% in AML pts receiving induction therapy, with APL pts (13%) at greatest risk. ICH is associated with poor prognosis related to immediate mortality.
Characteristics Age Male APL Platelet (x109/L) CR rate Median Survival ICH (n=28) 56 (36–84) 50% 29% 33(4–166) 29% 5 weeks No-ICH (n=965) 58 (17–89) 41% 6% 47(4–635) 54% 42 weeks
Resistance to the Farnesyl Transferase Inhibitor SCH66336/Lonafarnib Caused by Mutations in the Target Protein Farnesyl Transferase Beta.
Authors: Raz Tal , Mohammad Azam , Daley George Q. 
Published: April 2020

Abstract
Farnesyl transferase inhibitors (FTIs) are target specific anti-cancer agents in clinical trials for the treatment of multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), breast cancer, and other malignancies. FTIs were developed to block Ras prenylation; however, their cytostatic properties likely relate to activity against multiple farnesylated targets. The FTI Lonafarnib is showing activity against CML both as a single agent and in combination with the ABL-kinase inhibitor Gleevec. Though Gleevec is remarkably effective, treatment selects for drug-resistant mutations in the BCR/ABL target oncoprotein. Previously, we performed in vitro mutagenesis of BCR/ABL and identified a large catalogue of resistance mutations, anticipating essentially all mutations that have proven to be clinically problematic (Azam et al., Cell 2002). Thus we set out to determine whether FTIs would select for resistance mutations in Farnesyl Transferase Beta (FTase β), a normal target protein in the cell. We mutagenized (FTase β) by plasmid propagation in mutagenic E. coli, thus generating a random, unbiased library of mutated FTase β. This library was then introduced into K-Ras expressing BaF3 cells, which rely on K-Ras activity for cell survival, and undergo apoptotic cell death when treated with Lonafarnib. K-Ras transformed cells carrying mutated FTase (KR/MutFTB) were plated in soft agar in varying Lonafarnib concentrations. Lonafarnib-resistant colonies were harvested, and plasmids carrying mutant FTase βwere recovered and sequenced. Thus far we have identified 14 mutations that confer resistance to Lonafarnib. Among the mutations is W361L, previously shown to confer resistance to SCH56582 and SCH44342, compounds which are structurally similar to Lonafarnib (Del Villar et al. 1999). Most but not all mutations are positioned in the active site of the enzyme. To verify the drug resistant phenotype, 7 mutations were recreated de-novo by site-directed mutagenesis and transduced into BaF3-KRas cells. These cells were tested by a colony forming assay in the presence of drug. FTase activity in the presence of drug was also assessed by immunoblotting of HDJ2, a farnesylated protein. Cells transduced by mutated FTase showed increased ability to grow in the presence of Lonafarnib compared to controls. Interestingly, protein analysis showed reduced inhibition of farnesylation of HDJ2 only in the 361 mutants. This suggests that the mutant FTase may prenylate only a select set of substrates (not including HDJ2), a possibility consistent with previous reports of altered substrate specificity in FTB mutants in yeast (Del Villar et al. 1997). This catalogue of Lonafarnib-resistant FTase mutations will be useful for determining mechanisms of disease refractoriness or relapse in clinical trials, and can be used to profile drug activity of other farnesyl transferase inhibitors to find non-cross-resistant drug combinations.
Reversion of Chemoresistance in Aggressive Lymphoma by Quinine. A Phase II Trial.
Authors: Soubeyran Pierre , Masmoudi Amine , Blanc-Bisson Christele , Soubeyran Isabelle , Bellott Ricardo , Monnereau Alain , Eghbali Houchingue , Robert Jacques 
Published: April 2020

Abstract
Multidrug resistance has been one of the most studied mechanisms of cancer cell resistance to chemotherapy. Evidence of its involvement in hematological malignancies is known since many years. One well-designed phase I trial showed that about 20 to 25% of patients strictly resistant to EPOCH schedule could become responsive again by the addition of Dex-verapamil (J Clin Oncol1995; 13:1995–2004). We decided to perform a phase II trial to evaluate whether quinine could reverse resistance to chemotherapy in aggressive lymphoma. Methods: Patients included had all received at least two lines of chemotherapy including CEOP (cyclophosphamide 750mg/m2, epirubicine 60mg/m2, vincristine 1.4mg/m2 IV day 1 and prednisone 40mg/m2 orally day1 to day 7) and were demonstrated as strictly refractory to CEOP i.e. either no change or progression. Q-CEOP was administered as follows: quinine 30-mg/kg/day for two days from d0 to d1 as a continuous infusion, CEOP at the beginning of d1. Results: 15 patients have been included with the following characteristics: median age: 52 years (32–64), 66% stage III–IV, 60% elevated LDH. The median number of previous regimens was 3 (2–5). 13 patients had diffuse large B cell lymphoma including 3 with previous history of follicular lymphoma. Two had mantle cell lymphoma. Seven patients were included directly since they were initially refractory to CEOP while eight were shown refractory after two further cycles of CEOP. Epirubicin pharmacokinetics was not influenced by quinine. Mean dose intensity of epirubicin was 94%. Toxicity was mild. 4 responses were observed at the end of treatment including 2 complete and 2 partial responses (26%, IC 95%: 8–55%). Only the 2 CR patients are still alive with no evidence of disease at 35+ and 61+ months. Conclusion: These results add further arguments to confirm that MDR1 plays a significant role in resistance to chemotherapy in lymphoma. Quinine allowed unexpected long term remission in 2 responding patients.
A Pilot Study of Combined Escalated BEACOPP-ABVD Therapy for Advanced Hodgkin’s Lymphoma Patients with High IPS Score: The Israel Cooperative Lymphoma Group.
Authors: Avigdor Abraham , Bulvik Shlomo , Shemtov Noga , Levi Itai , Berkowicz Miriam , Ben-Yehuda Dina , Blickstein Dorit , Goldschmidt Neta , Gural Alexander , Kornberg Abraham , Libster Dianna , Merkel Drorit , Naparstek Elizabeth , Raanani Pia , Roth Batia , Volchek Yulia , Nagler Arnon , Ben-Bassat Isaac , Polliack Aaron 
Published: April 2020

Abstract
ABVD is widely considered as the gold standard treatment for advanced Hodgkin’s lymphoma (HL), although about 40% of patients relapse or do not respond to initial treatment. Recently, the HD9 trial of the German Hodgkin’s Lymphoma Study Group has shown that escalated (esc) BEACOPP regimen can achieve better disease control than ABVD, but has a high incidence of acute and long-term toxicities including high occurrence of AML/MDS. In an attempt to decrease toxicity while preserving the potential benefit of upfront intensive therapy, we conducted a pilot study, which tested the feasibility, toxicity and efficacy of combined escBEACOPP-ABVD regimen as therapy for newly diagnosed patients with high risk (IPS≥3) stage III–IV HL. Patients initially received 2 cycles of escBEACOPP followed by reevaluation with CT and gallium or PET/CT-FDG scans. When complete response (CR) or partial response (PR) was achieved, patients continued to receive 4 cycles of ABVD, while those failing to achieve a response were withdrawn from the study. Since August 2001, 21 patients entered the study and at the time of present analysis four of them are still receiving therapy. Three (18%) of 17 patients, who completed chemotherapy, received consolidative radiotherapy. Median age at diagnosis was 26 years (range 18–56) and 11 (57%) were males. Stage IV and B symptoms were evidenced in 19 (90%) and 17 (81%), respectively, and 7 (33%) had bulky mediastinal mass. Histology included nodular sclerosis in 18 patients (86%), mixed cellularity in 2 (10%) and lymphocyte predominance in 1 (5%). Following the first 2 cycles of escBEACOPP the overall response rate (CR+PR) was 100%. At the end of all therapy 15 patients (88%) were in CR, one patient in PR and only a single patient had progressive disease. With a median follow-up of 20 months no patient relapsed or died. Toxicity included WHO grade III–IV granulocytopenia in 15 patients (88%) and grade III–IV infection in one patient. Hospitalization for intravenous antibiotics was necessary in 10 patients (59%). Almost all of these events occurred during the first two cycles of escBEACOPP, while acute toxicity during the ABVD phase was mild. In conclusion, the combined escBEACOPP-ABVD regimen is well tolerated and is associated with a high CR rate when used in advanced HL patients with high IPS scores. Further follow-up is obviously required in order to determine long-term survival and late complications of this regimen.