bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Expression Profiles (GEP) To Predict at Least Very Good Partial Response to Velcade, Doxil, and Dexamethasone in Newly Diagnosed Patients with Multiple Myeloma.
Authors: Hari Malathi , MacDonald James , Friedman Judah , Kendall Tara , Mulligan George , Jakubowiak Andrzej 
Published: April 2020

Abstract
The introduction of novel agents and combination treatments in multiple myeloma (MM) has dramatically improved overall response rates and quality of responses including rates of complete and near complete response (CR/nCR) and very good partial response (VGPR). There is emerging evidence that achieving at least ≥90% disease reduction (≥ VGPR) at some point of treatment is associated with improved outcome and longer survival. Therefore, there is a need to identify patients who will likely achieve this level of reduction of disease and therefore who will have a higher likelihood of benefiting from the specific treatments. In the current study, we evaluated GEP of MM cells obtained from patients who were enrolled in a phase II clinical trial of the frontline therapy with a combination with bortezomib (Velcade), liposomal doxorubicin (Doxil) and dexamethasone (VDD). The primary objective of this research is to develop predictive biomarkers of response to VDD by identifying GEP of patient who achieve ≥ VGPR. Forty newly diagnosed patients were enrolled in the trial. The regimen was given for six 3-week cycles as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and dexamethasone at 40 mg on days 1–4 for the first 10 patients and for the remaining patients at 20 mg on days of Velcade and the day after. Updated results from 40/40 evaluable patients show 93% partial response rate (≥ PR) with 43% CR/nCR and 63% &gt; VGPR (Jakubowiak et al., IMW 2007, Abstract PO-721). Bone marrow aspirates were obtained before therapy from patients who had given an optional consent for research samples. MM cells were negatively selected using RossetteSep myeloma antibody cocktail. Gene expression profiling was performed with 20 samples using Affymetrix Human Genome U133 Plus 2.0 microarray, of which 19 samples were evaluable. These samples were classified based on the modified uniform response criteria with an addition of nCR and minor response (MR) (Durie et al, Leukemia2006;20:1467) as either ≥ VGPR, (includes VGPR and CR/nCR), or &lt;VGPR (includes PR and MR). There were 9 samples classified as ≥VGPR and 10 samples that were &lt;VGPR. GEP analysis revealed 166 genes that were differentially expressed in patients with ≥ VGPR compared with patients with &lt;VGPR (p &lt; 0.001). Further analysis indicated that many of these genes may play a role in cell cycle control, signal transduction, apoptosis, and gene transcription. We plan a comparison of GEP signatures of patients with ≥ VGPR to VDD with those identified in the APEX studies for Velcade alone. The study described here provides evidence that GEPs of samples derived from patients before treatment is a useful tool in clinical trials to prospectively evaluate MM patients for individualized therapy with the goal of minimizing toxicity and maximizing efficacy.
bcl-2 Translocation [t(14;18) (q32;q21)] Does Not Correlate with Poor Clinical Outcome in Multiple Myeloma Patients Treated with Bortezomib.
Authors: Ailawadhi Sikander , Mashtare Terry L. , Coignet Marie V. , DePaolo Dawn M. , Miller Kena C. , Padmanabhan Swaminathan , Wilding Gregory , Starostik Petr , Chanan-Khan Asher A. 
Published: April 2020

Abstract
Background: Overexpression of bcl-2 gene mediated by t(14;18) (q32;q21) results in increased transcription of the anti-apoptotic bcl-2 protein. This is associated with aggressive clinical behavior, resistance to conventional chemotherapy regimens and poor survival in multiple myeloma (MM) patients. Impact of novel therapeutic agents such as bortezomib has not been studied in context with this adverse molecular marker. Thus we investigated the clinical efficacy of bortezomib in MM patients who were positive for bcl-2 translocation.
Methods: All MM patients treated with bortezomib or bortezomib-based therapies were evaluable for this analysis. bcl-2 translocation was studied by a nested PCR-based assay of patient bone marrow samples. The test is reproducibly sensitive to a detection level of 1:100,000 and reported as positive or negative, indicating either the presence or absence of t(14;18). Response to treatment was classified as per EBMT criteria. To study the statistical relationship between pairs of nominal variables, Fisher’s exact test was used. To study the statistical relationship between nominal and ordinal variables, exact Wilcoxon test was used. A 0.05 nominal significance level was used in all testing.
Results: Sixty six patients met the inclusion criteria of MM diagnosis and treatment with bortezomib-based regimens. Of these, bcl-2 analysis was available for 41 patients. Six patients (14.6%) were bcl-2 positive and 35 (85.4%) were bcl-2 negative. Median age was 61 years (range 40–80 years), with 18 (43.9%) females and 23 (56.1%) males. Twenty three patients (56.1%) had Durie-Salmon (DS) stage IIIA disease. Lytic bony lesions were present in 31 (75.6%) patients and most common Ig type was IgG kappa (43.9%). Seven patients (17%) achieved CR, 14 (34%) had PR, 16 (39%) had stable disease (SD) and 4 (10%) had progressive disease (PD). There was no significant association found between t(14;18) result and patient age (p = 0.4985), gender (p = 0.6786), DS stage (p = 0.6117), ISS stage (p = 0.5541), presence of bony lytic lesions (p = 0.1435), patients being paraprotein secretors or non-secretors (p = 1), Ig type (p = 0.0584), or response to treatment (p = 0.1066).
Conclusions: Presence of bcl-2 translocation is associated with aggressive clinical course and suboptimal response to conventional chemotherapy in myeloma patients. Although, the number of patients analyzed in this analysis is small, we did not find the presence of bcl-2 translocation to be an adverse prognostic marker in myeloma patients treated with bortezomib-based regimens.
De Novo CD5+ Diffuse Large B-Cell Lymphoma: Result of a Detail Morphologic Evaluation and Long-Term Follow Up of 128 Patients.
Authors: Yamaguchi Motoko , Nakamura Naoya , Suzuki Ritsuro , Kagami Yoshitoyo , Okamoto Masataka , Ichinohasama Ryo , Yoshino Tadashi , Suzumiya Junji , Murase Takuhei , Miura Ikuo , Hirano Masami , Morishima Yasuo , Shiku Hiroshi , Ueda Ryuzo , Nakamura Shigeo 
Published: April 2020

Abstract
De novo CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is well known to have clinicopathologically and genetically different characteristics from CD5-negative (CD5−) DLBCL and mantle cell lymphoma. To obtain more clinicopathologic information of CD5+ DLBCL, we reviewed specimens from 128 cases of CD5+ DLBCL and analyzed the relationship between the morphologic features and a long-term survival. The current series includes the 109 CD5+ DLBCL cases described in our previous study (Yamaguchi M, Blood 2002). All patients were diagnosed between 1984 and 2002 as having DLBCL according to the WHO classification. They had no past history of any other lymphoproliferative disorders and were immunohistochemically confirmed to be cyclin D1-negative. Four morphologic variants were identified: common (monomorphic) (n=97), pleomorphic (n=15), giant-cell rich (n=14) and immunoblastic (n=2). Intravascular or intrasinusoidal infiltration was seen in 41% of the cases, and bi-nucleated snowman-like cells were seen in 80% of the cases. BCL2 protein expression in CD5+ DLBCL was more frequent than that in CD5− DLBCL (P=0.0009). Immunohistochemical analysis in a serial 45 cases of CD5+ DLBCL revealed that 80% of CD5+ DLBCL cases (36/45) were classified as non-germinal center B-cell type DLBCL. CD10 was positive in 8 cases (18%), and MUM1 was positive in 93% of the cases (42/45). The estimated 5-year overall survival rate was 36% after a median observation time of 79 months. Patients with the common variant showed better prognosis than those with the other three morphologic variants (P=0.018). Multivariate analysis showed that age more than 60 at diagnosis [hazard ratio (HR) 2.25, 95% confidence interval (CI) 1.36–3.73], advanced stage (HR 1.76, 95%CI 1.06–2.93), high serum LDH level (HR 2.2, 95%CI 1.21–4.00), and histopathologic categorization (not common) (HR 1.6, 95%CI 1.00–2.59) were independent prognostic factors for survival. In all, 16 patients (13%) developed central nervous system (CNS) recurrence. Our study revealed the morphologic spectrum and a high incidence of CNS recurrence in CD5+ DLBCL, and confirmed that CD5+ DLBCL shows frequent BCL2 protein expression and it is mainly regarded as non-germinal center B-cell type of DLBCL.
Risk Factors Predisposing to Thromboembolism in Children with Cancer.
Authors: Athale Uma , Siciliano S. , Cox S. , Lathia A. , Khan A. , Pai N. , Armstrong A. , Odame I. , Chan A.K.C. 
Published: April 2020

Abstract
Introduction: Cancer is a major risk factor in children with TE. However, information regarding epidemiology of TE in children with cancer is scant. We conducted a retrospective cohort study to define the epidemiology of TE in children with cancer and to identify potential risk factors.
Methods: Records of children (≤18 years of age) with cancer diagnosed and treated at McMaster Children’s Hospital over past 15 years were reviewed for demographics, details of diagnosis and treatment of cancer and of TE, if any. We studied the effect of age (&lt;10 years vs. ≥10 years), gender, type of cancer and presence or absence of intrathoracic disease (defined as mediastinal mass or any primary or metastatic pulmonary disease), type of central venous line (CVL) and CVL dysfunction (defined as persistent or recurrent difficulty of blood draw and/or infusion or documented CVL infection) on the risk of developing TE. Statistical analysis was performed using SPSS version 15.
Results: Overall 49 of 606 children (8.1%) with cancer developed TE (Table 1). Due to very low prevalence of TE in children with brain tumors, regression analyses for risk factors was performed in children with non-CNS cancers. Children with ALL (OR 4.93, 95% CI 1.60, 11.52, p=0.004), lymphoma (OR 4.18, 95% CI 1.37, 12.71, p=0.01), and sarcoma (OR 4.42, 95% CI 1.42, 13.77, p=0.01) had increased risk of TE. Older patients (age ≥ 10 years) were at higher risk of developing TE compared to younger patients (OR 2.2; 95% CI 1.2,3.96; P&lt;0.01). Subgroup analyses showed that patients with CVL-dysfunction (33.3% vs. 9.5%; p&lt;0.0001, 95% CI; 10.1,37.5) and those with intrathoracic disease (17.6% vs.5.7%; p=0.028, 95% CI; 2.2, 21.7) were at significantly higher risk of TE compared to those without CVL dysfunction and intrathoracic disease.
Conclusions: Overall TE is common in children with cancer. We have identified older age and type of cancer are the important risk factors predisposing to TE; children 10 years or older and those with lymphoreticular malignancy and sarcoma are at significantly higher risk of developing TE. In addition presence of mediastinal disease and CVL dysfunction increased the risk of TE. This is one of the largest comprehensive epidemiogical studies of TE in children with cancer identifying different risk factors.
Prevalence of TE according to the tyep of cancer Type of Cancer N Patients with TE % with TE (95% CI) ALL 185 26 14.5 (9.39, 19.91) Brain Tumors 131 1 0.8 (0.02, 4.20) Lymphoma 72 9 12.5 (5.88, 22.41) Sarcoma 70 10 14.3 (7.07, 24.71) AML 51 3 5.9 (1.23, 16.24) Neuroblastoma 45 1 2.2 (0.05, 11.77) Wilms’ Tumor 43 1 1.3 (0.06, 12.3) Other 9 0 - Total 606 49 8.1 (6.1, 10.5)
Corticosteroid Therapy Does Not Increase Relapse Rate after Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myelogeneous Leukemia and Myelodysplastic Syndrome Overt Leukemia.
Authors: Imahashi Nobuhiko , Seto Aika , Watanabe Keisuke , Yanagisawa Mayumi , Nishiwaki Satoshi , Shinba Makoto , Yasuda Takahiko , Miyamura Koichi , Kodera Yoshihisa 
Published: April 2020

Abstract
Corticosteroid is often used after allogeneic hematopoietic stem cell transplantation (AHCT) to control graft-versus-host disease (GVHD). However, it is concerned that corticosteroid therapy may suppress graft-versus-leukemia (GVL) effect and may increase the risk of leukemia relapse after AHCT. The aim of the present study is to determine whether the corticosteroid administration increases the relapse after AHCT for acute myelogeneous leukemia (AML) and myelodysplastic syndrome overt leukemia (MDS overt leukemia). We analyzed 98 patients who received their 1st AHCT for AML (n=78; 47 1st or 2nd complete remission, 31 advanced stage) or MDS overt leukemia (n=20) from related (n=45; 37 HLA matched, 8 HLA mismatched) or unrelated (n=53; 37 HLA matched, 16 HLA mismatched) donors at our institution between 1997 - 2006. The median age was 42 years (range, 18–64). Conventional conditioning regimen was used in 71 patients and reduced-intensity conditioning regimen was used in 27 patients. GVHD prophylaxis was cyclosporine and methotrexate in 48 patients, tacrolimus and methotrexate in 49 patients, and cyclosporine alone in 1 patient. Univariate Cox regression analysis showed AML other than 1st or 2nd complete remission (CR) and HLA mismatch were the significant risk factors for relapse but corticosteroid administration (analyzed in time-dependent fashion) was not: AML other than 1st or 2nd CR (p=0.0230, hazard ratio(HR) 2.373, 95% confidence interval (CI) 1.126–4.999), HLA mismatch (p=0.0045, HR 2.776, 95% CI 1.373–5.613), and corticosteroid administration (p=0.8483, HR 1.067, 95% CI 0.551–2.065). In multivariate analysis, corticosteroid administration did not significantly increase the risk for relapse: HR was 0.760 (95% CI, 0.379–1.524, p=0.4394) after adjusting for disease status and HLA disparity. Corticosteroid is concerned to hamper GVL effect, resulting in increased relapse rate after AHCT. However, in this study, corticosteroid administration after AHCT was not a risk factor for relapse. This may be explained by the fact that among the 54 patients who had corticosteroid administration 45(88.9%) had acute and/or chronic GVHD, resulting in relatively strong GVL effect. On the other hand, there were 7 patients who had neither grade II to IV acute GVHD nor chronic GVHD but had corticosteroid administration. Among them 2 patients relapsed. In conclusion, the result of this study suggests that corticosteroid therapy does not increase relapse rate after AHCT at least in the presence of GVHD. However, larger number of patients is needed to evaluate the effect of corticosteroid therapy on relapse in the absence of GVHD.
Thrombotic Microangiopathy after Allogeneic Stem Cell Transplantation: A Single Centre Experience.
Authors: Ngirabacu Marie Christine , Kwan John , Leroy Rita , Huynh Phuong , Bron Dominique 
Published: April 2020

Abstract
Introduction Transplant associated microangiopathy (TMA) is a severe complication occurring after allogeneic stem cell transplantation(alloSCT). It is recognized to have a poor prognosis and no effective treatment has been defined.
Methods and Population In this study, we analysed the outcome of patients who developed TMA after alloSCT in our institution from 1996 to 2007. A total 199 patients underwent allogeneic transplantation. To diagnose TMA, we used the criteria proposed by the International Working group of TMA: &gt; 4% schistocytes in blood, de novo or prolonged thrombocytopenia, sudden and persistent increase in lactate dehydrogenase concentration, decrease in serum haptoglobin and decreased haemoglobin.
Results From 1996 to 2006, the overall incidence of TMA in our institution was 19%(37/199). According to the type of transplant, the incidence of TMA was: 18%(14/79) for sibling myeloablative SCT(MSCT); 27%(10/37) for unrelated MSCT; 22.5%(9/40) in haploidentical SCT; 20%(2/10) for sibling non myeloablative SCT(NMSCT) and 20%(2/10) for unrelated NMSCT. Median age of patients was 37 years (range: 16–63). Male to female sex ratio was 1:1.8. As conditioning for transplantation, 60% of patients had received total body irradiation (49% for the alloSCT and 11% for previous treatments). At time of diagnosis of TMA, 35% of patients presented with neurological symptoms (unexplained headache, epilepsy, impaired concentration, drowsiness and/or confusion). Fourty-nine percent (49%) of patients also had cytomegalovirus reactivation; 54% were treated with steroids for acute Graft-versus-host disease and 100% of patients were treated with ciclosporine. The overall mortality rate in the TMA group was 86%, but TMA related mortality was 46%. In patients who died from TMA, median survival post-TMA diagnosis was 16 days(range: 4–60). 88% of those patients had been treated with plasma exchange, 12% by defibrotide. Four of the six patients(66%) treated with defibrotide died from haemorrhagic complications. Only 1 patient treated with defibrotide achieved a complete remission (CR). Of those patients who did not achieve complete remission, 65% had been conditioned with TBI versus 41% in patients who achieved CR.
Conclusion: In our series, the incidence of TMA is significant (19%). The most important risk factors of developing TMA are use of cyclosporine, steroid treatment, CMV reactivation, the use of TBI as conditioning and unrelated donor transplantation. From this study we are unable to define the most effective treatment for TMA. The use of defibrotide was associated with a high risk of haemorrhage in our series and should be used with caution. Because of its incidence and poor prognosis, randomized trials should be utilised to define effective treatment.
Elucidating the Molecular Architecture of the FA-Core Complex Utilizing Biochemical Purification Approach.
Authors: Ali Abdullah M. , Du Changhu , Singh Thiyam R. , Meetei Ruhikanta A. 
Published: April 2020

Abstract
FA is a rare, recessive disorder characterized by progressive bone marrow failure, developmental abnormalities, chromosome instability, cellular hypersensitivity to DNA cross-linking agents, and predisposition to cancer, mainly leukemias and squamous cell carcinomas of the head and neck. FA is genetically heterogeneous, represented by at least thirteen different complementation groups. The genes corresponding to groups A, B, C, D1 (BRCA2), D2, E, F, G, I, J, L, M and N have been cloned. The Fanconi proteins FANC -A, -B, -C, -E, -F, -G, -L, -M along with another newly discovered protein FAAP100 forms a core complex (CC) in the nucleus that is required for the monoubiquitination of two other Fanconi proteins FANCD2 and FANCI. In addition to their presence in nucleus, most of the Fanconi proteins are also found in the cytosol however their role in cytosol is not clear. Also, whether the FA-core complex proteins exist as a single complex or sub-complexes in the cytosol is not clear. The goals of this study are to
develop a method of purification of FA core complex from nuclear and cytosol identify individual components of cytosolic and nuclear complex(s) of the FA proteins.
We have established a two-step purification method using 6XHis and FLAG tags for the biochemical and functional characterization of the FA core complex proteins. In an attempt to isolate interacting partners of FANCC, FANCG, FANCL and FAAP100 proteins; we have established four different HeLa cell lines; HeLa-HF-FANCC, HeLa-HF-FANCG, HeLa-HF-FANCL and HeLa-HF-FAAP100, stably expressing HF-FANCC, HF-FANCG, HF-FANCL and HF-FAAP100 recombinant proteins respectively. Affinity purification was carried out to isolate the complexes from the cytosol and nuclear extracts prepared from stable cell lines. The polypeptides purified from the complexes were identified by mass spectrometry. The results suggest that, in addition to the existence of the FA-core complex containing FANC -A, -B, -C, -E, -F, -G, -L and 100, the FA proteins also exists as sub-complexes in the cytosol. FANCL was found to form a sub-complex with FANCB and FAAP100 in cytosol. Also FANCC, a predominantly cytosolic protein was found to form a sub-complex with FANCE in cytosol. We found several novel proteins that interact with FA proteins.
Responses and Outcome Following Immunosuppressive Therapy in Large Granular Lymphocyte Leukemia-Associated Pure Red Cell Aplasia: A Nationwide Cohort Study in Japan for the PRCA Collaborative Study Group.
Authors: Fujishima Naohito , Sawada Ken-ichi , Hirokawa Makoto , Oshimi Kazuo , Matsuda Akira , Teramura Masanao , Karasawa Masamitsu , Nakao Shinji , Urabe Akio , Omine Mitsuhiro , Ozawa Keiya 
Published: April 2020

Abstract
Background: Large granular lymphocyte (LGL) leukemia accounts for a significant part of secondary PRCA. Cyclophosphamide (CPA) therapy has been reported as being useful in the literature. However, because of its rarity, the long-term response and relapse rate after immunosuppressive therapy including CPA in LGL leukemia-associated PRCA are largely unknown, and optimal management of this disorder remains unclear.
Objectives: We conducted a nationwide survey of immunosuppressive therapy for PRCA in Japan to elucidate the long-term response and overall survival (OS) of this disorder. This report is a summary focusing on CPA therapy for LGL leukemia-associated PRCA.
Methods: The questionnaires were sent to 109 medical institutions in Japan to estimate the number of patients with newly diagnosed acquired PRCA. From a total of 185 patients consisting of 73 idiopathic and 112 secondary PRCA cases, we evaluated 14 patients with LGL leukemia for this report. Endpoints of this study were the response rate and the duration of the response to immunosuppressive therapy and overall survival.
Results. Efficacy of the first remission induction therapy was seen in 6 out of 8 patients treated with CPA (75%), 1 out of 4 patients with cyclosporine (CsA) (25%), and 0 of 2 with corticosteroid (0%), respectively. The median initial dose of CPA for the responding patients (n=6) was 100 mg. The initial dose of CsA for the responding patient was 3.7 mg/kg. Two patients, who failed to respond to the initial CPA therapy, received CsA therapy resulting in the response in one patient. Three patients, who failed to respond to the initial CsA therapy, received CPA therapy resulting in the response in all of three patients. Two patients, who failed to respond to the initial prednisolone therapy, received CsA therapy resulting in the response in one patient. We classified the patients with LGL-associated PRCA into the CPA-group (n=9) and the CsA-group (n=3) according to the response to initial or salvage therapy. Relapse was seen in two CPA-responders following discontinuation of maintenance therapy (23, 45 months), whereas no patients relapsed on maintenance CPA therapy. The estimated median duration of the response to CPA was 125 months. The median OS has yet been reached with the median observation period of 89 months.
Conclusion: CPA showed an excellent response in LGL leukemia-associated PRCA and CPA-containing regimens were effective to prevent relapse of anemia. However, most patients are still receiving CPA for maintenance therapy, and it remains uncertain whether CPA can induce maintenance-free hematological response.