bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intrathecal Administration of Rituximab for the Treatment of Primary Central Nervous System B-Cell Lymphoma.
Authors: Fernandes Flavo B. , Silla Lucia , Friedrisch Jõao R. , Brusius Carlos 
Published: April 2020

Abstract
Background: Patients with a primary central nervous system (CNS) lymphoma are very difficult to be treated. Regarding elderly patients, the side effects of the established strategies are considerable, particularly those caused by radiotherapy. Although with poor long term results, surgery, high dose chemotherapy and focal radiotherapy have been advised for these patients. Thus, new therapeutics strategies are needed. We report two cases of primary CNS B-cell lymphomas treated with rituximab intrathecally (ith). Case 1: In September 2003, a 59-year-old female with headache, paresthesia and weakness of the right limbs presented at our clinic. In August 2003 a brain biopsy of a parenchymal lesion was performed, vasculitis and cerebritis were found. The patient’s condition progressively worsened during the next 3 months and she developed a right-side hemiparesis. A PCR test to ascertain the presence of Mycobacterim tuberculosis in brain tissue was positive and rifampicin was prescribed. The patient presented at our clinic in September 2003, and in December 2003 she underwent another brain biopsy and CD20+ diffuse large B-cell lymphoma was diagnosed. Chemotherapy with high-dose methotrexate (MTX) 3.5 g/m2 iv, MTX 12 mg ith and vincristine 1.4 mg/m2 was scheduled every 15 days for a total of 5 cycles. The patient experienced a partial remission. In February 2004, rituximab 25 mg ith was administered on days 1–2 and days 8–9. There was no toxicity during, or after the rituximab infusions. In March, after a total dose of 200 mg, there was a complete radiological remission of the lymphoma and a consistent clinical improvement. In June 2004, the lymphoma relapsed, affecting the same area of the brain and in July 2004 a re-treatment protocol consisting of MTX 8g/m2 and high dose cytarabine was started, without response. The patient died of sepsis, secondary to mucositis and pancytopenia in August 2004. Case 2: a 67-year-old male with a primary malignant B lymphoma CD20+ of the posterior fossa which relapsed after two surgeries, high dose chemotherapy and focal radiotherapy with lymphomatous meningitis. Complete remission was obtained after one course of high dose MTX (4g/m2) and intrathecal MTX, intercalated with three courses of systemic (350 mg/m2) and intrathecal rituximab (25mg/d - 8 days). The patient presented hepatotoxicity after the first dose of MTX iv. The relapse free survival is seven months until now and the patient is physically and intellectually fully recovered. No major side effects were observed with the administration of rituximab intrathecally.
Conclusion: Intrathecal administration of rituximab had no toxicity and was well-tolerated. Further studies are necessary to establish the best dose and schedule to achieve an improvement in the therapeutic response.
The Bisphosphonate, Incadronate, Inhibits Cell Growth of HTLV-I-Infected T-Cell Lines and Primary ATL Cells by Inhibiting Mevalonate Pathway.
Authors: Ishikawa Chie , Okudaira Taeko , Tomita Mariko , Mori Naoki 
Published: April 2020

Abstract
Bisphosphonates have been used for the treatment of hypercalcemia associated with malignancies and osteoporosis. Recent reports have suggested that bisphosphonates may also exert direct antitumor effects on several cancers, in addition to their therapeutic antiresorptive properties. Adult T-cell leukemia (ATL) is a fatal malignancy of T lymphocytes caused by infection with human T-cell leukemia virus type I (HTLV-I), and remains incurable. ATL is associated with osteolytic bone lesions and hypercalcemia, which are major factors in the morbidity of ATL. Therefore, the search for anti-ATL agents that have antitumor and antiresorptive effects is warranted. The aim of this study was to determine the effect of bisphosphonate, incadronate, on HTLV-I-infected T-cell lines and primary ATL cells. Incadronate prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells, but not of uninfected T-cell lines and normal PBMCs. Incadronate induced S-phase cell cycle arrest and apoptosis in HTLV-I-infected T-cell lines. Treatment of HTLV-I-infected T-cell lines with cell-permeable substrates for mevalonate pathways, geranylgeraniol and farnesol, prevented incadronate-mediated growth suppression. Incadronate also prevented the prenylation of Ras proteins. These results demonstrate that incadronate-induced growth suppression is the result of inhibition of the mevalonate pathway. On the other hand, incadronate did not affect NF-κB and AP-1 pathways. Importantly, treatment with incadronate reduced tumor formation from an HTLV-I-infected T-cell line, HUT-102, when these cells were inoculated s.c. into severe combined immunodeficient mice. These findings indicate that incadronate may become a novel molecular therapeutic class for treatment of ATL.
Immunotherapy with Recombinant Xenogeneic Vascular Endothelial Growth Factor as a Vaccine Combined Low-Dose Adriamycin Induces Synergistic Antitumor Efficacy in EL4 Lymphoma Model.
Authors: Niu Ting , Liu Ting , Jia Yong-qian , Wen Yan-jun , Tian Ling , Liu Ji-yan , Wu Yang , Hu Bing , Wei Yu-quan 
Published: April 2020

Abstract
We explored the antitumor efficacy of a strategy using recombinant Xenopus laevis vascular endothelial growth factor (xVEGF) as a xenogeneic protein vaccine, which we have demonstrated to have effective antiangiogenic activities in several tumor models, in combination with low-dose adriamycin in lymphoma model. EL4 lymphoma model was established in C57BL/6 mice. Mice were randomly divided into four groups: combination therapy (xVEGF plus adriamycin), xVEGF treatment alone, adriamycin treatment alone, and normal saline (NS) groups, and received relevant treatments. Tumor growth, survival rate of tumor-bearing mice, and potential toxicity of regimens above were investigated. Anti-VEGF antibodies and anti-VEGF antibody-producing B cells (APBCs) were detected by Western blot analysis and enzyme-linked immunospot (ELISPOT) assay, respectively. In addition, microvessel density (MVD) within tumor tissues and tumor cell apoptosis were determined by immunohistochemistry and TUNEL staining, respectively. Our data showed that combination therapy inhibited tumor growth and improved survival of tumor-bearing mice significantly, and complete regression of tumor was observed in 3 of 10 mice in combination group in EL4 lymphoma model.Survival rate of mice was significantly higher in combination group than that in xVEGF alone group,in adriamycin alone group (P&lt;0.05),or that in NS group (P&lt;0.01). Remarkably, the combination treatment resulted in not only significant antiangiogenic effects but also promotion of tumor cell apoptosis. The calculated indexes of combination therapy showed synergistic relationship in terms of inhibition of tumor growth, antiangiogenesis, induction of tumor cell apoptosis. In addition, anti-VEGF antibodies and APBCs were found in mice treated with either xVEGF vaccine alone or combination treatment. No marked toxicities were found in the treated mice. In summary, these findings may provide an effective combination approach for lymphoma therapy in the future.
A Pilot Trial of Imatinib, Low-Dose Cytarabine (ara-C) and Idarubicin (Ida) in Patients (pts) with Chronic Myeloid Leukemia (CML) in Myeloid Blastic Phase (BP).
Authors: Quintas-Cardama Alfonso , Kantarjian Hagop , Ravandi Farhad , Garcia-Manero Guillermo , O’Brien Susan , Wierda William , Faderl Stefan , Cortes Jorge 
Published: April 2020

Abstract
Although imatinib is the single most effective agent in CML BP, only approximately 30% to 50% of pts achieve a hematologic response, and it is complete (CHR) and durable in 5% or less. Regimens including high-dose ara-C and daunorubicin are associated with remission rates of 20% to 25% in CML BP, a median survival of 3 months, and significant morbidities. Imatinib is additive or synergistic in vitro with ida and ara-C, particularly in imatinib-resistant cell lines. We thus investigated the efficacy of the combination of imatinib 600 mg daily, ara-C 10 mg daily subcutaneous, and Ida 12 mg/m2 IV every 14 days in pts with CML in myeloid BP. Nineteen pts were treated, including 6 who had BP as their first manifestation of CML. Seventeen pts had failed prior imatinib as a single agent and had received a median of 5 prior therapies (range, 1 to 9). Median age was 54 yrs (range, 27–81) and the median WBC was 28.6 x 109/L (range, 3.7 to 240.5), peripheral blood blasts 18% (range, 0 to 82), and bone marrow blasts 36% (range, 2 to 84). Four pts had extramedullary disease. Pts were treated for a median of 10.5 weeks (range, 4 to 124), receiving a median of 2 cycles (range 1 to 28). Fourteen (74%) pts responded, including 9 (47%) who achieved CHR, and 5 (26%) who returned to chronic phase. Four of the pts who achieved CHR also had a cytogenetic response (CGR) (3 complete, 1 minor). Responses lasted for a median of 10 weeks (range, 2 to 89 weeks). Two of 5 pts who failed to respond had a transient hematological improvement (&gt;50% reduction of blasts in peripheral blood). Six pts were able to receive allogeneic BMT (4 in CHR, 1 in CP and 1 still in BP). Treatment was well tolerated and administered on an outpatient basis. Grade 3–4 non-hematological toxicities consisted of fatigue (n=4), vomiting (n=1), bone pain (n=1) and hyperbilirubinemia (n=1). Sixteen (84%) pts required brief hospitalization for neutropenic fever (n=8), bleeding (n=7), pneumonia (n=6), cellulitis (n=2) and CNS disease (n=2). Thirteen pts died: 4 after BMT and 9 due to disease progression. Among these, 4 had achieved CHR and 2 complete CGR. The median survival was 23 wks and 1 year survival rate 26%. In conclusion, the combination with imatinib + low-dose ara-C + Ida is an outpatient, well tolerated regimen that can induce responses in patients with CML BP who have failed imatinib and can be considered as an option to improve patient’s condition, and as a bridge to allogeneic BMT.
Coordination of Intrinsic, Extrinsic and Endoplasmic Reticulum-Mediated Apoptosis by Imatinib Mesylate Combined with Arsenic Trioxide in Chronic Myeloid Leukemia.
Authors: Zhang Ji , Du Yanzhi , Wang Kankan , Fang Hai , Li Junmin , Xiao Dakai , Zheng Peizheng , Chen Yulong , Fan Huiyong , Zhang Qinghua , Fang Jing , Auffray Charles , Chen Saijuan , Chen Zhu , Zhang Ji 
Published: April 2020

Abstract
A treatment strategy that combines arsenic trioxide (ATO) with the tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec) appears to induce more cell apoptosis than STI571 alone in chronic myeloid leukemia (CML). To understand the mechanisms underlying the synergistic action of these agents, we applied cDNA microarrays, component plane presentation integrated self-organizing maps (CPP-SOM) and methods of protein biochemistry to study proapoptotic and apoptotic activities in programmed cell death induced by STI571, ATO and the combination of the two agents in detail. Numerous features with temporospatial relationship were revealed, indicating the coordinated regulation of molecular networks from various aspects of proapoptotic and apoptotic activities in CML. In consequence, STI571 induces the intrinsic pathway of cell apoptosis, whereas ATO induces the ER stress-mediated pathway of cell apoptosis, and the combination of the two agents induces the intrinsic, extrinsic and ER stress mediated pathways of cell apoptosis, which results in a more effective and efficient induction of programmed cell death in CML. The potential impact of this study on the development of more sophisticated therapy in human malignancy can be substantial.
Characterization of Cancer Stem-Like Cells in a Novel STI571-Resistant Chronic Myeloid Leukemia Cell Line.
Authors: Song Yongping , Fang Baijun , Zhang Yanli , Wei Xudong , Lu Lulu , Zhu Xinghu , Wang Ping , Li Yufu , Gao Qunli , Wang Guiye , Qiu Lugui 
Published: April 2020

Abstract
To characterize a novel chronic myeloid leukemia (CML) cell line and to further elucidate the mechanisms of resistance to STI571, a novel K562 cell line (K562/VP16) was achieved after exposure of the K562 cells in gradually increasing concentrations of VP16 over a period of several months. A small subpopulation (K562/VP16 SP) that was capable of excluding Hoechst 33342 in the K562/VP16 cell line was isolated by flowcytometry sorting. The rest of the K562/VP16 cells were classified as non-SP K562/VP16. The mechanisms involved in K562/VP16 SP cells that became resistant to STI571 were studied. We found that the levels of Bcr-Abl and Abl proteins were similar in the K562 cells and in non-SP K562/VP16 and K562/VP16 SP cells. The MDR-1 gene expression of the 170 kDa P-gp was detected in K562/VP16 non-SP and K562/VP16 SP cells but not in K562 cells. The expression levels of P-gp in the two K562/VP16 cell lines were similar. Furthermore, there were no mutations of Abl in the K562/VP16 SP cells. Compared with non-SP K562/VP16, the K562/VP16 SP cells were more resistant to STI571, and many multidrug resistance inhibitors could hardly reverse this resistance. In addition, in vivo study showed that the K562/VP16 SP cells induced tumorigenesis in mice, while the K562/VP16 non-SP cells failed to do so. These results suggest that a small side population K562/VP16 SP cells in K562/VP16 cell line, had high resistance to STI571 treatment and more tumorigenic than the K562 cells and it may represent the cancer stem cells of the K562/VP16 cell line.
BCR Gene Breakpoint and Type of BCR/ABL-Transcript in Children with Chronic Myeloid Leukemia.
Authors: Suttorp Meinolf , Viehmann Susanne , Claviez Alexander , Martiniak Yvonne , Harbott Jochen 
Published: April 2020

Abstract
The hallmark of chronic myeloid leukemia (CML) is the reciprocal translocation t(9;22)(q34;q11) which creates a hybrid BCR/ABL gene that is transcribed into a chimeric mRNA. In the 8.5-kb mRNA either exon b2 or exon b3 of the major breakpoint cluster region (M-bcr) is coupled to C-ABL exon 2. These two junction variants (b2a2 or b3a2) differ in size by 75 nucleotides and can be selectively amplified by semi-nested PCR. A controversy exists whether or not the type of transcript and/or the breakpoint site exerts an influence on the clinical course of CML in adult patients (Mills KI 1991; Foiretos T 1993; Melo JV 1996). CML is a rare disease in childhood contributing only 2 – 3 % of all pediatric leukemia cases. This may be the reason why there are only scant data from small series of children with CML giving information on the transcript variant present at diagnosis. During an 11 year period (1995 – 2005) 203 pts younger than 19 years (median age: 11.4 yrs; 101 boys, 102 girls) with Philadelphia-chromosome positive CML were treated within the multicenter GPOH-trial “CML-paed”. 85% of the pts were diagnosed in chronic phase (CP). Treatment was performed by hydroxyurea +/− interferon and pts were scheduled for stem cell transplantation (SCT) from an HLA-matched family donor within 6 months after diagnosis and from an unrelated donor within 12 months. Bone marrow and/or peripheral blood specimen for molecular analysis were collected at diagnosis and during follow-up examinations at 3 – 6 months intervals.
RT-PCR with analysis of the breakpoint and transcript type was performed in 154 pts (77.4 % of the total study population). 133 pts exhibited a Major-BCR rearrangement, 5 pts a minor-BCR rearrangement and in 16 pts both rearrangements were present. In pts with M-BCR either 55 pts expressed the b2a2 transcript (37 %) or the b3a2 transcript (37 %), respectively. Both types of transcripts were found either simultaneously or alternately during follow-up examinations in 38 pts (25 %). One pt showed an atypical rearrangement which is awaiting further classification.
No statistical significant differences (p &gt; 0.05) could be found with respect to hematological parameters at diagnosis (white cell count, platelets count, percentage of basophils in peripheral blood), clinical findings (liver size, spleen size) and disease status (CP versus advanced phase). The impact of either transcript upon the course of the disease (e.g. duration of chronic phase) was not analyzed because 70 % of the study population was transplanted early within 1 year after diagnosis.
We conclude that in contrast to some reports in adults the type of BCR breakpoint seems to have no impact in pediatric pts with CML.
Development of a BCR/ABL Real-Time Quantitative RT-PCR Assay and Correlation with an Existing Qualitative Test.
Authors: Howe John Greg , Crouch Jill , Smith Brian R. 
Published: April 2020

Abstract
Introduction: With the recent introduction of imatinib (Gleevec) as a therapeutic agent for chronic myeloid leukemia (CML), the need for quantitation of the level of tumor cells after treatment has become essential. Our lab has for a number years tested for CML using a sensitive qualitative nested RT-PCR assay for BCR/ABL. We wanted to develop a quantitative test that retained the sensitivity of our qualitative test and contained an initial screen to prevent unnecessary quantitative testing as well as develop quantitative tests for the various breakpoints.
Methods: The new test is divided into three parts. A real-time multiplex qualitative RT-PCR screen containing specific primers for the p190, p210 and p230 BCR/ABL forms and a common labeled probe. If a patient sample is positive in the screen, the original nested RT-PCR test is performed to determine which BCR/ABL form is present. This is followed by a real-time quantitative RT-PCR test for the identified BCR/ABL translocation. Subsequent follow up tests require only the specific quantitative test.
Results: Comparing negative results from 82 patient (various clinical presentations) samples tested by the previous qualitative test with the new qualitative screen showed completely correlation. Out of 31 CML patients studied, both test strategies gave the same result for 20 positive and 13 negative samples. Patients with multiple samples collected over time showed complete correlation between the two assays.
Conclusions: The new quantitative BCR/ABL testing strategy yielded results that correlated with the previous qualitative BCR/ABL assay.
High Dose Zevalin (90Yttrium Ibritumomab Tiuxetan) Treatment with PBSC Support in Refractory-Resistant NHL Patients: Preliminary Results of a Phase I/II Study.
Authors: Vanazzi Anna , Ferrucci Pierfrancesco , Ferrari Mahila , Calabrese Liliana , Cremonesi Marta , Bartolomei Mirco , Paganelli Giovanni , Martinelli Giovanni 
Published: April 2020

Abstract
Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT or for those pts relapsing after ABMT. Zevalin has been already demonstrated active in elderly pts with resistant-primary refractory DLBCL at dose of 0.4 mCi/kg, however duration of response is short. Increasing RIT dose intensity might improve efficacy. There are no data about the use of Zevalin at myeloablative dosage. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. Three Zevalin dose-levels were fixed: 0.8, 1.2, 1.5 mCi/kg; from April 2004 to July 2005 12pts were enrolled, 4pts at each dose level. Median age was 66,5 ys (28–73), 83% male. All pts had stage III/IV at diagnosis; 7DLBCL; 3MCL, 1FL, 1transformed MZL. 7pts had received more than 3 previous CT regimens. All pts had received prior rituximab, 3pts RT, 6pts HD-CT. BM was negative in all pts before RIT. 1Week prior to Zevalin all pts underwent dosimetry and if no abnormal uptake was observed they received the planned dose. On Day −7 and 0 imaging and therapeutic doses were preceded by rituximab 250mg/mq. On Day13 pts were reinfused with PBSC previously harvested. On Day28 from reinfusion engraftment was considered to be delayed if WBC/ANC were&lt;1.0x109/L or PLT&lt;20x109/L. All pts engrafted promptly after PBSCT with median time to WBC/ANC&gt;1.0x109/L and PLT&gt;20x109/L of 19 (range 0–23) and 12 days (0–22) from PBSCT. PLT and ANC count nadirs were observed at 21 (0–24) and 25 (0–31) days after Zevalin with median values of 11x109/L(4–35) and 0.24x109/L(0.01–1.09). Median time to recovery from nadir was 16,5 days (4–175) for PLT and 17days (7–175) for ANC. 8pts required PLT transfusions, 4pts RBC transfusions; median number of PLT transfusions:1(1–4). No G-CSF was administered. No significant differences in terms of haematologic toxicity were observed among the 3 levels. No pulmonary, renal or cardiac toxicity was observed. 11/12 pts are now evaluable for response: 5pts experienced a CR (2 at 0.8mCi/kg, 2 at 1.2mCi/kg, 1 at 1.5mCi/kg), 1 pt receiving 1.5 mCi/kg a PR (ORR 50%); to date 4 pts maintain CR at 12, 11, 9 and 8 months after treatment.
Conclusion: Zevalin at dosage higher than MTD is feasible with PBSC support. Even at dosage 4 times higher than standard, HD-Zevalin could be safely delivered in elderly and heavily pretreated pts, including those who previously received HD-CT. Clinical activity and mild treatment-related toxicities suggest that HD-Zevalin is an interesting modality treatment to be further investigated as an alternative therapeutic options for resistant-refractory NHL.