bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Molecular Diagnosis of T-Cell Receptor Gene Rearrangement in Thai Patients.
Authors: Kummalue Tanawan , Saesue Teerawat , Pongpruttipan Tawatchai , Sukpanichnant Sanya , Opartkiattikul Nisarat 
Published: October 2019

Abstract
Thirteen Thai patients, seven with pathologic diagnosis of T-cell lymphoma, four with clinical and/or pathological suspicion of T-cell lymphoma, one with lymphadenitis and one with chronic hypertrophic tonsillitis, were investigated for T-cell receptor gene rearrangement (TCR-GR) by polymerase chain reaction (PCR). Clonal TCR-GR was demonstrated in each T-cell lymphoma whereas polyclonal TCR-GR was found in the rest of the patients, including the four cases that were suspected of T-cell lymphoma.
Aim: To identify T-cell receptor gene rearrangement in malignant lymphoma in Thai patients.
Material and method: Thirteen specimens of formalin-fixed, paraffin-embedded tissue were collected from Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University. After conventional morphological evaluation and immunohistochemical studies, DNA in each specimen was extracted from 10μm thick paraffin sections using QIAamp DNA mini kit (QIAGEN) for TCR-GR analysis by multiplex PCR. Two pairs of primers were selected for Vγ11 (VγI), Vγ101(VγIII/IV), Jγ12(Jγ1/2) and Jp12(JPγ1/2). DNA of the four cases suspected of malignant lymphoma were repeated by using IdentiClone™ TCRG Gene Clonality Assay kit (InVivoScribe Technologies).
Results: According to the WHO classification (2001), the seven cases of T-cell lymphoma were angioimmunoblastic type (3 cases) and unspecified type (4 cases). All cases showed monoclonal TCR-GR. Only one of the four cases suspected of T-cell lymphoma was doubtful for nasal NK/T-cell lymphoma while the others were suspected clinically. All of these four cases and the two reactive conditions revealed polyclonal TCR-GR. After using IdentiClone™ kit twice, the four cases suspected of T-cell lymphoma still showed polyclonal TCR-GR.
Conclusion: The molecular analysis of TCR-GR performed in thirteen cases demonstrated the monoclonal TCR-GR in all seven cases of T-cell lymphoma and polyclonal TCR-GR in the four cases suspected of T-cell lymphoma and the two cases of reactive condition. Therefore, this technique is very useful to confirm the diagnosis of T-cell lymphoma and to provide information for further management in patients suspected of malignant lymphoma.
Early Relapses in Primary CNS Lymphoma (PCNSL) without Intraventricular Treatment.
Authors: Schmidt-Wolf Ingo G.H. , Pels Hendrick , Jurgens Annika , Glasmacher Axel , Schulz Holger , Engert Andreas , Linnebank Michael , Schackert Gabriele , Reichmann Heinz , Kroschinsky Frank , Vogt-Schaden Marlies , Egerer Gertlinde , Schaller Carlo , Lamprecht Monika , Bogdahn Ulrich , Deckert Martina , Fimmers Rolf , Bangard Christoph , Schlegel Uwe 
Published: October 2019

Abstract
Background: A systemic and intraventricular polychemotherapy regimen (“Bonn protocol”) with deferred radiotherapy had resulted in durable responses in 75% of patients < 60 years with primary CNS lymphoma (PCNSL), but had been complicated by a high rate of Ommaya reservoir infections.
Purpose: Here, efficacy and toxicity of this regimen but without intraventricular treatment was evaluated in PCNSL.
Patients and Methods : From 08/03 to 11/05, 18 patients with PCNSL < 60 years (median age 53 years) were treated within a phase II trial with a high-dose methotrexate (MTX; cycles 1,2,4 and 5) and cytarabine (Ara-C; cycles 3 and 6) based systemic therapy including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide.
Results: Study accrual was prematurely stopped in 11/05 due to a high rate of early relapses. Seventeen/18 patients were assessable for response: Nine (53%) achieved complete response (CR), two (12%) complete response/unconfirmed (CRu), two (12%) partial response (PR), four (24%) showed progressive disease (PD); in one treatment was stopped due to toxicity. Median follow-up is 23 months; Kaplan-Meier estimates for median response duration were ten months only in responding patients and for median time to treatment failure (TTF) eight months in the whole group; median overall survival (OS) has not yet been reached. Systemic toxicity was mainly hematologic.
Conclusions: In patients < 60 years with PCNSL polychemotherapy without intraventricular treatment results in a high response rate, but is associated with early relapses in the majority of cases. This is in contrast to the results achieved with the same protocol but with inclusion of intraventricular treatment.
Addition of Rituximab to CHOP Chemotherapy Does Not Improve Clinical Outcome in Patients with Localized Gastric Diffuse Large B-Cell Lymphoma: A Retrospective Study by Ganken Adult Lymphoma Study Group (Single Institute Analysis).
Authors: Yokoyama Masahiro , Ennishi Daisuke , Asai Hiroaki , Ueda Kyoko , Kodaira Makoto , Yamada Shuhei , Myojo Tomohiro , Mishima Yuko , Sakajiri Sakura , Takeuchi Kengo , Saotome Takashi , Terui Yasuhito , Takahashi Shunji , Ito Yoshinori , Hatake Kiyohiko 
Published: October 2019

Abstract
Background: In recent years, it has been reported that addition of rituximab to CHOP chemotherapy significantly improves event-free survival (EFS) and overall survival (OS) compared with standard CHOP alone in patients with diffuse large B-cell lymphoma (DLBCL). On the other hand, gastric DLBCL is a good clinical outcome without surgical excision in the group of primary extranodal DLBCL. Localized gastric DLBCL shows very good EFS and OS treated with standard CHOP plus radiation therapy without rituximab.
Methods: We analyzed retrospectively the prognosis between R-CHOP and CHOP alone in patients with localized gastric DLBCL. All 24 patients diagnosed between July 1999 and July 2006 in our hospital, were included in this study. The pathology was reviewed by a hematopathologist and confirmed to be de novo DLBCL according to the WHO classification. The staging system was using by Lugano meeting classification. Patients with stage IIE and IV were excluded. All patients were initially treated with six cycles of CHOP or R-CHOP regimen consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. If we evaluated partial response after six cycles of chemothrapy, the patients have been added radiation therapy.
Results: Initial characteristics of the 24 patients are summarized in Table 1. The median age of patients at time of inclusion was 67.5 yr (range 30–83 yr). The median follow up of surviving patients was 30 months. CR rates between CHOP and R-CHOP were 91.7% vs. 83.3%, p=1.000, and overall response rates were 100% vs. 83.3%, p=.478, respectively. 2 years progression-free survival and overall survival were no statistical significance difference between two groups (Log rank test: P=.138, P=.739).
Conclusion: These results suggested that addition of rituximab to CHOP chemotherapy does not improve clinical outcome of localized gastric DLBCL. The patients with localized gastric DLBCL did not get the clinical benefits of rituximab. As you know, rituximab needs high costs, so we recommend standard CHOP regimen plus radiation therapy in patients with localized gastric DLBCL, without rituximab combination regimen.
Characteristics of the 24 patients with localized gastric DLBCL Characteristic CHOP (n=12) R-CHOP (n=12) P Age 1.000 =<60 3 4 >60 9 8 Male 7 6 1.000 Stage (Lugano) .890 I 4 3 II 1 7 9 Unknown 1 0 IPI score .867 0,1 7 7 2 4 5 Unknown 1 0
Phase I Study of KW-0761, a Humanized Anti-CCR4 Antibody, in Patients (Pts) with Relapsed or Refractory Adult T-Cell Leukemia-Lymphoma (ATLL) and Peripheral T-Cell Lymphoma (PTCL): Preliminary Results.
Authors: Uike Naokuni , Tsukasaki Kunihiro , Utsunomiya Atae , Tobinai Kensei , Morishima Yasuo , Uozumi Kimiharu , Tomonaga Masao , Matsushima Koji , Shitara Knya , Akinaga Shiro , Ueda Ryuzo 
Published: October 2019

Abstract
Introduction: KW-0761 is a defucosylated humanized IgG1 monoclonal antibody against CC chemokine receptor 4 (CCR4). Previous studies revealed that CCR4 was over-expressed on tumor cells from 88% of pts with ATLL and 38% of pts with PTCL. CCR4 expression was associated with unfavorable prognosis in both diseases. These evidences suggest that CCR4 could be a reasonable molecular target for treatment of CCR4-positive ATLL and PTCL. KW-0761 exerted very potent ADCC but not CDC against cultured ATLL cell lines using normal effecter cells. KW-0761 also exhibited potent ADCC against freshly isolated ATLL cells using the auto-effecter cells.
Methods: KW-0761 is being investigated in a Phase I, single-agent, dose-escalation, multicenter study for relapsed or refractory pts with ATLL or PTCL after undergoing the initial chemotherapy. Eligible pts were required to express CCR4 on their tumor cells by FCM and/or IHC. This phase I trial was designed to evaluate toxicity, pharmacokinetics (PK), immunogenicity and anti-tumor activity. Toxicity was evaluated by NCI CTCAE (v3.0). Pts were planned to receive four weekly intravenous injections of KW-0761 at the doses of 0.01, 0.1, 0.5 and 1.0 mg/kg.
Results: As of August 10, 2007, 6 pts (1 PTCL and 5 ATLL) have been treated with KW-0761 at the dose of 0.01 (N=3) and 0.1 mg/kg (N=3). Three pts were evaluable for toxicity, PK, immunogenicity and 4 pts were evaluable for anti-tumor activity. KW-0761 was well tolerated with no dose-limiting toxicities. Reversible grade (G) 3 toxicities were lymphocytopenia and herpes zoster. G1-2 adverse events were; rash, constipation, nausea, EF decrease, neutropenia, thrombocytopenia, eosinophilia, lymphocytopenia, ALP increase and QT prolongation. In one leukemic ATLL pt with swollen lymph nodes (LNs) treated at 0.01 mg/kg, peripheral ATLL cells disappeared and the LNs were decreased in size, attaining PR. In another leukemic ATLL pt with skin involvement treated at 0.1 mg/kg, peripheral ATLL cells disappeared and the skin achieved PR by Physicians Global Assessment of Clinical Conditions (PGA). One ATLL pt with skin and bone involvement at 0.01 mg/kg showed SD. Preliminary PK analysis at 0.01 mg/kg showed that Cmax and T1/2 after the 4th dosing was 323.7 56.7 ng/ml and 244 117 hrs, respectively. KW-0761 did not exhibit immunogenicity at 0.01 mg/kg.
Conclusions: Preliminary phase I data warrant further investigations of KW-0761, a first-in-class humanized anti-CCR4 antibody, against CCR4-positive peripheral T-cell malignancies including ATLL. Patient accrual is ongoing and the updated results will be presented at the meeting.
Detecting Apoptotic Blocks and Sensitvity to ABT-737 and Conventional Chemotherapy Via BH3 Profiling.
Authors: Letai Anthony , Shipp Margaret , Cin Paola dal , Takeyama Kunihiko , Deng Jing 
Published: October 2019

Abstract
Cancer cells require blocks in apoptosis to survive despite many abnormalities that should trigger apoptosis. Here we demonstrate that BH3 profiling is an effective tool for the systematic investigation of the types of blocks in apoptosis for which cancer cells select. BH3 profiling can segregate lymphoma cell lines into three different classes based on the type of apoptotic block each exhibits. In one class, cells are kept alive via expression of anti-apoptotic proteins of the BCL-2 family. When BCL-2 itself is detected by BH3 profiling as the protein keeping the cell alive, the cell is sensitive to ABT-737, a BCL-2 antagonist compound. Sensitivity to ABT-737 correlates highly with abundance of pro-apoptotic BIM complexed to BCL-2. Knockdown of BIM reduces sensitivity to ABT-737. We describe such cancer cells that maintain survival based on tonic sequestration of large amounts of pro-death molecules by anti-apoptotic proteins like BCL-2 as “primed for death”. “Primed” lymphoma cell lines are more sensitive than “unprimed” cancer cells to conventional agents killing via apoptosis like vincristine, adriamycin, and etoposide. It is important to note that, in general, non-malignant cells are unlikely to be “primed”. Hence “priming” may be an important determinant of the therapeutic window between normal and malignant cells. These results suggest that the degree to which a cell is “primed” can influence sensitivity to chemotherapy agents targeting distinct cellular targets. Therefore, BH3 profiling is a tool potentially useful not only for predicting sensitivity to agents targeting antiapoptotic BCL-2 proteins, but also to conventional cytotoxic agents that use the mitochondrial apoptotic pathway to kill.
The Feature of TCR Zeta Gene in CD4+ and CD8+ T Cells in Patients with CML.
Authors: Chen Si , Li Yangqiu , Chen Shaohua , Yang Lijian , Wu Xiuli , Cen Dongzhi 
Published: October 2019

Abstract
The T-cell receptor (TCR) zeta chain is a master sensor and regulator of lymphocyte responses which plays a critical role in TCR-mediated signal transduction. The abnormal expression of TCR zeta gene was found in some malignancies and immune disease. Cellular immune deficiency is the common feature in patients with chronic myeloid leukemia (CML). Our previous studies had showed that 60% of CML patients displayed an abnormally low expression of TCR zeta chain in peripheral blood mononuclear cells (PBMCs). To further estimate the changes of zeta chain expression of T-lymphocyte subsets in CML, TCR zeta chain gene expression level in purified CD4+ and CD8+ T cells sorted by MACS were detected by real-Time PCR with SYBR Green I technique, CD4+ and CD8+ T cells from both 10 cases with CML and 10 normal individuals were selected to analyze in the study. β2 -microglobulin was used as an endogenous reference. Relative changes in TCR zeta gene expression level were used by the 2−ΔCt×100% method. The relative mRNA expression level of TCR zeta gene in CD4+ and CD8+ T cells from CML was 4.06±4.82% and 3.82±4.25% respectively, whereas 7.75±2.52% and 5.19±1.25% were found in normal individuals. There was a wide range in the TCR zeta gene expression level of CD4+ T cells from CML patients (0.23–15.93%,) with a median value of 1.77%, whereas the a range of (4.74–12.81%) with a median of 7.93% was showed in normal controls (P=0.046). The expression level of TCR zeta gene in CD8+ T cells from controls ranged from 3.47% to 6.75% (median 5.52%) and in CML patients from 0.86% to 15.55% with a median of 2.51% (P=0.340). The results indicated that, compared with normal controls, zeta chain gene expression was obviously down-regulated in CD4+ T cells from patients with CML. However, there was not significant different in expression level of TCR zeta gene of CD8+ T cells between CML patients and normal individuals. Moreover, the expression level of TCR zeta gene is nonsignificant age-associated or gender-link in CD4+ T cells and CD8+ T cells from patients with CML. In conclusions, the results provide at first the difference of TCR-zeta gene expression pattern in CD4+ and CD8+ T cells from patients with CML, this may be reflective of signaling difference between the different T cell subtypes in immunodeficiency state of patients.
Bcl-6 May Be a Survival Factor in Pre-B Cell Ph+ Blast Crisis Cell Lines.
Authors: Batlle Ana , Lam Eric W. , Wagner Simon D. 
Published: October 2019

Abstract
The constitutively active tyrosine kinase Bcr-Abl fusion protein is essential for the development of chronic myeloid leukaemia. Inhibitors of its tyrosine kinase activity e.g. Imatinib, are highly effective in treating chronic phase disease but are only transiently useful in blast crisis, especially lymphoid blast crisis. Bcl-6 is a transcriptional repressor that is required for the formation and maintenance of germinal centre B-cells. Following reports that Imatinib increases expression of Bcl-6 in Ph+ cell lines representative of lymphoid blast crisis we have investigated the regulation of this molecule and its functional importance. We utilised BV173 and Z119. Basal Bcl-6 protein expression was detectable in Z119, but not BV173. As anticipated Imatinib increased Bcl-6 expression in both cell lines. STAT5 is an important target of Bcr-Abl and has been implicated as both a positive and negative regulator of Bcl-6 transcription. Transient transfection with a mammalian expression plasmid bearing a dominant negative STAT5 reduced Bcl-6 expression in Z119 implying that activated STAT5 promotes Bcl-6 expression in this cell line, but also that STAT5 cannot be the main target of Bcr-Abl because Imatinib and dominant negative STAT5 have opposing effects. Next we considered the possibility that phosphorylation status of the transcription factor FoxO3a, which has been shown to bind to the Bcl-6 promoter, correlated with Bcl-6 expression. We found that decreased phosphorylation of Foxo3a, activating this transcription factor, was highly associated with increased Bcl-6 expression suggesting that it is an significant Bcr-Abl target. Next we wished to find out the functional implications of increased Bcl-6 expression. We found that a low concentration of Imatinib (0.25μM) was sufficient to induce Bcl-6 in BV173 and Z119, and caused death of these cell lines over several days. Next we combined Imatinib with a previously reported peptide antagonist of the Bcl-6/SMRT co-repressor interaction. Neither this peptide nor a mutated negative control peptide had an effect on cell numbers or apoptosis over 48 hours of culture when used alone. However, when combined with Imatinib the wild-type peptide, but not the control, reduced cell growth in Z119. We conclude that Bcl-6 may be a survival factor in Ph+ lymphoid blast crisis cell lines following treatment with Imatinib and that specific treatments to abrogate Bcl-6 function may find a place in the treatment of lymphoid blast crisis of CML.
Cardiotoxicity of Imatinib Mesylate - A Prospective Cross-Sectional Study.
Authors: Bittencourt Henrique , Marcolino Milena S. , Clementino Nelma , Xavier Vitor F. , Barbosa Marcia M. , Nunes Maria do Carmo P. , Ribeiro Antonio L. 
Published: October 2019

Abstract
Imatinib Mesylate (IM), a tyrosine kinase inhibitor, has become the first line of therapy for patients with chronic myeloid leukemia (CML) and the standard treatment of advanced gastrointestinal stromal tumors (GIST). A recent publication (Kerkela et al. Nature2006;12:908) suggest that IM might have myocardial toxicity via c-Abl inhibition. Retrospective studies, however, do not show an increase of cardiac hearth failure (CHF) in patients on IM therapy in clinical trials for CML or GIST (Atallah et al. Blood2007;110:1233 and Verweij et al. Eur J Cancer2007; 43:974). In order to prospectively evaluate IM cardiotoxicity we included 101 patients with CML on treatment with IM. As control group, we also included 57 patients with myeloproliferative disorders not treated with IM (essential thrombocytemia= 27, CML=12, policitemia vera=11, other diagnosis=7). After informed consent, all patients had a complete clinical evaluation (interview and physical examination), blood samples for Brain Natriuretic Peptide (BNP) were taken and an echocardiographic study was performed. Groups were similar regarding age (median 48 vs. 54 years), gender distribution and cardiac risk factors, except for hypertension (lower prevalence in IM group: 26% vs. 45.6% in controls, p<0.05). Median time of IM treatment was 805 (range 50–2122) days, mean and median actual IM dose were 463mg and 400 mg, respectively. Cardiac symptoms and signs were equally distributed between groups, except for peripheral edema, more frequent in IM group (25% vs 5%, p<0.05). There was no statistical difference regarding BNP levels (24.4± 7.7pg/mL vs. 26.5± 6.7pg/mL), end diastolic volume of left ventricle (49.4± 10.3mL vs. 48.0 ± 10.8mL) and ejection fraction (EF, 69± 16% vs. 68±13%) for IM and control group, respectively. Four patients presented BNP level above the upper normal limit (UNL = 100pg/mL) in IM group and none in control group. There was a trend for an association between BNP above UNL and a higher IM actual dose (P=0.08). Two patients in IM group and none in control group presented an ejection fraction below normal (<55%). This study shows that a systematic deterioration of cardiac function mediated by IM therapy was not observed. However, since some patients presented with alteration of BNP and/or EF, there is still a possibility for isolate cardiotoxicity associated with IM. BNP, a simple test to perform, might be use to identify patients at risk for subsequent CHF while on IM therapy.
Low Dose and Standard Dose of Imatinib Therapy for Patients with Chronic Myeloid Leukemia in Akita Prefecture, Japan.
Authors: Takahashi Naoto , Kameoka Yoshihiro , Saitoh Hirofumi , Fujishima Naohito , Hirokawa Makoto , Sawada Kenichi 
Published: October 2019

Abstract
The IRIS study for CML patients demonstrated the excellent clinical and cytogenetic/molecular effects of imatinib. Patients participating in the IRIS trial were selected according to strict eligibility criteria. The clinical features of patients are usually much more heterogeneous in practical situations than in clinical trials. Sometimes, patients cannot be treated with the standard dose of imatinib because of severe toxicity, especially older patients or patients who had already been treated with the other drugs. In this study, we analyzed whether patients could still be effectively treated using lower doses. Our study analyzed 86 CML patients from 17 hospitals in Akita prefecture. 80 patients were in CP, one patient was in AP, 4 patients were in BC, and one patient had cytogenetic relapse after allo-SCT. All patients were treated with imatinib between December 2001 and July 2007. Initially a dose of 400mg/day was given to almost all patients. Later the dose was decreased in a subset of patients experiencing imatinib-induced side effects. We classified patients into two groups according to the imatinib dosage and analyzed their clinical characteristics [Table 1] and the accumulation of CCR/MMR [Figure 1, 2]. In Group 1, we analyzed 55 patients received 300mg or more of imantiib per day. In Group 2, we analyzed 31 patients received less than 300mg of imatinib per day. Patients in Group 2 were older and had more histories of pretreatment and showed a higher frequency of adverse effects of imatinib than in Group 1. There were no significant differences of CCR/MMR rate between Group 1 and Group 2. This study reproduces the imatinib efficacy results described in the IRIS study, not only for patients treated with standard dose imatinib and for patients who could not take 400mg/day because of imatinib toxicity or other complications. We did not observe an increase in frequency of BCR-ABL point mutations in patients receiving a lower dose of imatinib, suggesting that the low dose imatinib treatment analyzed in our study does not enhance imatinib resistance by increasing BCR-ABL point mutations. In conclusion, we provide data supporting the use of lower doses of imatinib for CML patients that cannot be given sufficient dosage of imatinib for reasons such as severe hematological or non-hematological side effects or other complication.
Clinical Characteristics of Patients in Group I and II Group 1(n=55) Group 2(n=31) P Average doseage 380 mg/day 185 mg/day Average age (% of over 70 yrs) 57.7 yrs (22 %) 68.0 yrs (58 %) .001 (.007) History of treatment with IFN/HU before imatinib therapy 16% 55%. 002 Adverse effect (Grade3/4) 16% 42% .009 PFS to AP/BC at 60 Mo 97.8% 89.6% .28 CCR /MMR rate 78% / 51% 61% / 39% .09 / .27 Point mutation of bcr-abl in patients without MMR 4/17 2/13 .99 Figure Figure Figure Figure