bluuebunny/crossref_metadata_2025_split huggingface dataset:
VH Gene Usage, Frame Coding and Mutational Status Analysis in Adults with Acute Lymphoblastic Leukaemia (Adult ALL).
Authors: Rai Lena , Casanova Anouska , Hoffbrand A.Victor , Foroni Letizia 
Published: April 2020

Abstract
Analysis of immunoglobulin gene rearrangement for minimal residual disease as a prognostic parameter is a well established test in a variety of leukaemias such as ALL and CLL. The aim of this study was: 1) to analyse VH gene usage, occurrence of in-frame (IF) and out-of-frame (OF) sequences and rate of mutation; 2) to correlate these parameters with overall clinical outcome in adult ALL patients, as this may identify a novel prognostic marker in ALL, especially in the absence of other prognostic indicators.
Patients and methods: DNA from 82 de novo adult ALL patients (31F/51M) was obtained from PB or BM diagnostic samples. Using primers for the FR1 and JH segments, 102 clonal rearrangements were identified. Median WBC was 13.5 × 109/I (range 1.1–550 × 109/I). Sixty-three patients are, to date, in complete clinical remission (median follow up: 7 months; range: 3 weeks–82.5 months), 15 patients have relapsed (median relapse 5.7 mo; range: 2.1–22 mo) and 2 patients had resistant disease. Patients carrying the t(9;22) translocation and patients who received an allogeneic stem cell transplantation were excluded when calculating relapse free survival to avoid bias towards bad and good performance, respectively.
Results: A heterogeneous representation of VH gene usage was demonstrated. Recurrent rearrangements showed preferential use of VH3-66 (4 cases), VH1-2 (7 cases) and VH6 (8 cases; predominant in MLL-AF4 cases), when compared to the non-leukaemic controls (Mortuza et al, 2002; JCO, 20:1094). JH4 and JH6 were found in approximately equal proportions both in control and leukaemic groups, while JH5 (32 cases) was favoured in the leukaemic group. A similar trend was observed with D2-2 (23 cases) when compared to the other D segments in the latter.
There was a predominance of OF sequences (66 alleles; 64%; from 53 patients), although no statistical difference in relapse free survival between IF and OF was observed.
Mutations &gt;1% were observed in 18/82 (22%) patients (18/102 alleles; 18%). These were twice as common in the IF sequences (11/18 patients; 61%) compared to OF sequences (in 6/17 pts, 35.3%). However mutations had no impact on overall survival (p=NS) and neither did immunophenotype (pre B Vs common ALL) (p=NS).
Conclusion: Unique to ALL patients, a considerable proportion of cases carry out-of-frame immunoglobulin rearrangements while a smaller proportion are in-frame, without any apparent clinical impact. In contrast to observations made in other leukemias, such as CLL, occurrence of mutation does not appear to affect clinical outcome in our data set, although a longer follow-up period may be required for this prognostic factor to be fully evaluated.
Clinical Implication of Bone Marrow Angiogenesis in Childhood Acute Lymphocytic Leukemia.
Authors: Won Sung Chul , Rha Sun Young , Oh Seung Hwan , Kim Hwang Min , Lyu Chuhl Joo 
Published: April 2020

Abstract
Purpose: Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are associated with increased angiogenesis, growth, and metastasis in solid tumors. But, until today, the importance of theses factors on leukemia, especially childhood acute lymphocytic leukemia (ALL) has received limited attention. Therefore, this study examined the bone marrow plasma VEGF and bFGF levels in ALL patients and normal controls.
Methods: Bone marrow plasmas at diagnosis from 33 ALL patients (median age 5.97 years; range 1.8–13.9 years) were used for analysis. All ALL patients are divided into 3 groups; one group is standard risk ALL, other group is high risk ALL who did not experience relapse, and the other group is high risk ALL who have experienced relapse during treatment. The bone marrow levels of bFGF and VEGF were determined by enzyme-linked immunosorbent assay (R & D Systems) and compared with the bone marrow levels of 7 healthy control subjects (median age 11.98 years; 6 months–13.6 years).
Results: The VEGF levels were higher in high risk ALL with relapse (N=7, 171.95 ± 202.54 pg/mL) compared with standard risk (N=9, 9.11 ± 21.47 pg/mL), high risk ALL without relapse (N=17, 37.09 ± 38.77 pg/mL) or normal control (N=7, 72.9 ± 68.22 pg/mL)(P=0.006).
Figure Figure
The bFGF levels were also significantly higher in high risk ALL patients who experienced relapse (high risk with relapse; 37.26 ± 35.73 pg/mL, standard risk ALL; 7.90 ± 12.99 pg/mL, high risk ALL without relapse; 7.27 ± 10.93 pg/mL, normal control; 6.39 ± 6.13 pg/mL) (P=0.003).
Figure Figure
The Pearson correlation coefficient between VEGF and bFGF was 0.775 (P &lt; 0.01). Three patients who showed high levels of both angiogenic markers (VEGF; 366.80 ± 141.29 pg/mL, bFGF; 70.27 ± 5.57 pg/mL) are relapsed and died due to disease progression. The other relapsed patients except these 3 patients are alive without disease after salvage chemotherapy.
Conclusion: Our data suggest that the increased levels of VEGF and bFGF in bone marrow may play an important role in estimating prognosis of childhood ALL.
The Repertoire of Gene Rearrangements in Acute Lymphoblastic Leukemia.
Authors: Morley Alexander A. , Brisco Michael J. , Sykes Pamela J. , Latham Sue , Hughes Elizabeth , Wilczek Vicki , Kuss Bryone J. , Waters Keith 
Published: April 2020

Abstract
Rearrangements of the immunoglobulin and T-cell receptor genes provide molecular markers for clones in acute lymphoblastic leukemia (ALL). Determination of the repertoire of gene rearrangements in ALL aids in understanding the clonal biology of the disease and provides molecular markers which can be used to quantify minimal residual disease (MRD).
We have developed a sensitive PCR-based method for analysing the repertoire of immunoglobulin heavy chain (IgH) rearrangements in ALL. Multiple parallel quantitative PCR’s are performed in microplates using different segment-specific primers in different wells in order to determine the individual V (D) and J segments utilised by each rearrangement. The number of rearrangements detected in 18 children and 10 adults with ALL is shown in the table:
VDJ rearrangements DJ rearrangements No. of rearrangements 1 2 3 4 1 2 Childhood ALL 0 11 3 2 1 1 Adult ALL 7 2 0 1
Since each PCR well contained only 2 ng of DNA, more sensitive repertoire analysis was also performed in samples from 10 of the children and 4 of the adults by using 100 ng of DNA in an initial preamplification, which involved a multiplexed PCR containing primers for all leader and J sequences of the IgH gene and which thus amplified all immunoglobulin sequences. The IgH repertoire of the amplified material was then analysed. This two-step approach should theoretically enable detection of clones which comprise down to approximately 10−4 the leukemic population. It detected all rearrangements previously detected by one-step repertoire analysis and, in addition, it detected 0–5 (mean 1.2) rearrangements marking small clones in childhood ALL and 0–3 (mean 1.0) rearrangements marking small clones in adult ALL. Sequencing showed that most, but not all, small clones had a lineage relationship to the dominant clone present in the leukemic population.
Repertoire analysis of IgH rearrangements is a promising technique for identifying molecular markers for measurement of MRD in B-ALL, particularly childhood ALL, since:
–it is conceptually simple and relatively quick –it detects IgH rearrangements with high efficiency, probably higher than that of current techniques. –IgH rearrangements are the best markers to use for measurement of MRD owing to the specificity and sensitivity that they provide –an enhanced ability to identify markers for both large and small leukemic clones may improve the identification of patients prone to relapse.
Value of Molecular Monitoring for Minimal Residual Disease Preceding Autologous SCT Following Diagnosis of B Cell Acute Lymphoblastic Leukemia in Patients Treated with the MRC UKALL12 Protocol.
Authors: Foroni Letizia , Mitchell Wayne , Rai Lena J. , Casanova Anouska , Patel Bella , Richards Sue , Fielding Adele , Goldstone Anthony H. 
Published: April 2020

Abstract
Introduction and aims. Molecular monitoring of minimal residual disease has provided an independent and prognostically significant parameter in evaluating outcome in adult and childhood acute lymphoblastic leukaemia (ALL). The aim of our study was to assess the impact of MRD measured in bone marrow samples collected at time of harvest or prior to harvest in adult B cell receiving autologous stem cell transplant and correlate MRD with overall clinical outcome.
Patients and Methodology. Patients were selected as de novo adult ALL of B cells. All patients were negative for the t(9;22) or (4;11) and had received chemotherapy followed by an autologous SCT (A-SCT). All patients had at least one molecular marker which was tested by quantitative or semi-quantitative PCR with sensitivity ≥1E4. End points were either clinical relapse or CCR with follow up ≥12 months except for two patients who died in CR following transplant, due to infections. Time point for molecular evaluation was a test preceding A-SCT or harvested BM. Nineteen patients were evaluable prior to/or at time of harvest. Nine were females and nine were males. Median age was 25.2 yrs (range: 15.2–52 yrs), total WCC was 7.1 (range: 2.3–68.9×109/l) at time of diagnosis with common ALL (14 pts) as the predominant phenotype. Patients received an A-SCT at a median period of 6 months from diagnosis (range: 5–18 months). Eight patients relapsed (median period to relapse: 22 mo; range: 8–35 mo) and 8 were in continuous clinical remission (CCR) (median follow up 33 mo; range: 8–139 mo). Median interval between Auto-SCT and relapse was 13.7 mo (range: 3–29 mo).
Results. In seven patients residual disease was demonstrated in the BM prior to A-SCT and 6 of them relapsed. In 12 patients no residual disease was detected at time of harvest or prior to transplant and 10 are at present in CCR. The association between MRD positivity and relapse and MRD negativity and CCR was statistically significant in this cohort of patients (p=0.002)(Figure 1).
Conclusions. Molecular monitoring of MRD can provide a useful tool for the monitoring of residual disease in BM harvest prior to SCT and correlates with outcome. It is therefore important that all BM harvests are tested for residual disease in future clinical trial that may use MRD for patients’ stratification.
MRD tests prior to Auto-SCT and relapse FS MRD tests prior to Auto-SCT and relapse FS
Inhibition of the B Cell Associated Tyrosine Kinase SYK as a Potential Therapeutic Target in Aggressive Lymphomas.
Authors: Bertoni Francesco , Rinaldi Andrea , Sasso Anna , Uccella Silvia , Martin Vittoria , Napoli Sara , Pruneri Giancarlo , Zucca Emanuele , Capella Carlo , Catapano Carlo V. , Tibiletti Maria Grazia , Cavalli Franco 
Published: April 2020

Abstract
By using a combination of genomic and expression profiling (Affymetrix GeneChip Mapping 10k Xba131 and U133 set), we had previously analysed a series of 26 mantle cell lymphoma (MCL) samples to identify regions containing genes that might be relevant to MCL pathogenesis and that could represent new therapeutic targets (Rinaldi et al, Ann Oncol2005; vol. 16 suppl. 5, abstract 447). Of interest, one MCL cell line showed a genomic amplification of 9q22 with concomitant over-expression of SYK, mapped within the region. SYK is a tyrosine kinase involved in B cell receptor signaling, a pathway that is believed to play a major role in B cell lymphoma growth and survival. Western blotting experiments and FISH analysis confirmed the over-expression of SYK and the presence of extra-copies of SYK, respectively. Immunohistochemistry on twelve aggressive lymphomas [MCL and diffuse large B cell lymphomas (DLBCL)] confirmed that SYK is over-expressed in a subset of lymphomas. Based upon all these data, we treated seven established human lymphoma cell lines (four MCL, three DLBCL) with increasing doses of piceatannol (Sigma), a SYK inhibitor. All, but one, cell lines showed arrest of cell proliferation. The JeKo-1 and SU-DHL-6 (MCL and DLBCL) cell lines showed an IC50 of less than 10 μM after 72 hr of drug exposure; four cell lines had an IC50 between 30–50 μM. The two cell lines with a high-sensitivity to SYK inhibition had a constitutively high expression of SYK due to DNA gain, as shown by Western blotting and FISH. A high percentage of necrotic and apoptotic cells (39%) has been shown in JeKo-1 by Annexin V staining. Further, in vitro analyses and more extensive immunohistochemistry and FISH on MCL and DLBCL clinical samples (using tissue microarrays) are under way to elucidate the mechanism of action of cytotoxicity and the clinical relevance of SYK DNA amplification. In conclusion, our in vitro data indicate SYK inhibition as a new therapeutic target for the treatment of a subset of aggressive lymphomas, over-expressing SYK. SYK inhibitors are already in clinical development for treatment of asthma. Work partially supported by the Krebsforschung Schweiz and the Swiss Group for Clinical Research (SAKK).
The Humanized Anti-CD40 Monoclonal Antibody SGN-40 Targets Hodgkin’s Disease Cells through Multiple Mechanisms.
Authors: Law Che-Leung , McEarchern Julie A. , Cerveny Charles G. , Smith Leia M. , Nesterova Albina , Gordon Kristine A. , Grewal Iqbal S. , Wahl Alan F. 
Published: April 2020

Abstract
CD40 is a member of the TNF receptor superfamily expressed by multiple lineages within the hematopoietic system that carries out essential functions in the maturation of antigen-presenting cells, cross-priming of cytotoxic T cells, initiation of T cell-dependent antibody responses, and Ig class-switching. CD40 is widely expressed by lymphoid malignancies including B-cell precursor acute lymphoblastic leukemia (B-ALL), non-Hodgkin’s lymphoma (NHL), Hodgkin’s disease (HD), and multiple myeloma (MM). SGN-40, a humanized version of the murine anti-CD40 monoclonal antibody S2C6, mediates antibody-dependent cellular cytotoxicity (ADCC) against both NHL and MM cells, directly induces apoptosis in NHL lines, and inhibits the proliferative response of MM cells toward autocrine IL-6 through down-modulation of the IL-6 receptor. Based on these activities, SGN-40 is currently in phase I clinical trials for relapsed and/or refractory MM and NHL. In this study, we examined the expression of CD40 on primary tumors isolated from 93 independent patients with HD. Seventy nine of these 93 cases (85%) demonstrated expression of CD40 by both the Reed-Sternberg cells as well as the infiltrating mononuclear cells. In a 1+ to 3+ scoring system, 35% of cases showed intense 3+ staining, 24% were positive (2+), and 26% were weakly positive (1+). Flow cytometry revealed that 8 of 9 HD cell lines expressed surface CD40, with receptor numbers ranging from 2,000 to &gt; 370,000. SGN-40 induced CD40-positive HD cell lysis through ADCC in a dose-dependent manner, with IC50 values &lt; 10 ng/mL. Fc-dependent effector function of SGN-40 was further exemplified by its ability to enhance macrophage mediated antibody-dependent cellular phagocytosis (ADCP). Specific ADCP against CD40-positive target cells was detected when SGN-40 was present at concentrations &gt; 10 ng/mL. Furthermore, direct anti-proliferation signaling by SGN-40 in HD cells was also observed. In the L-1236 cell line, SGN-40 at doses ≥ 100 ng/ml reduced DNA synthesis to 25% of the untreated cells as measured by 3H-thymidine incorporation assays. Taken together, these data suggest that HD may be a suitable therapeutic target for SGN-40.
Cucurbitacins, a Family of Natural Compounds That Effectively Disrupt Stat3 Signaling in Antigen-Presenting Cells (APCs) Are Promising Agents To Overcome Tumor-Induced CD4+ T-Cell Tolerance.
Authors: Cheng Fengdong , Wang Hongwei , Suarez Alfonso , Horna Pedro , Sebti Said , Sotomayor Eduardo M. 
Published: April 2020

Abstract
Signal transducer and activator of transcription 3 (Stat3) is a key mediator of several cytokines and growth factors signaling pathways. On myeloid cells, activation of Stat3 to its phosphorylated form (pStat3) has been shown to negatively regulate inflammatory responses. Recently, we have unambiguously demonstrated that Stat3 signaling in APCs also play a central role in the decision leading to immune activation versus immune tolerance of antigen-specific T-cells1. In spite of these advances, there is however a paucity of therapeutic strategies targeting this signaling pathway in immune cells.
Using a high throughput cytoblot screening for phospho-Stat3 inhibition, we have recently identified a family of natural compounds known as Cucurbitacins that effectively disrupt Stat3 signaling at different levels2. Three compounds have been identified, Cucurbitacin A (CuA) that inhibits phospho-JAK-2, Cucurbitacin I (CuI) a dual inhibitor of p-JAK2 and p-Stat3 and Cucurbitacin Q (CuQ) a selective inhibitor of p-Stat3. In vitro treatment of peritoneal elicited macrophages (PEM) and bone marrow-derived dendritic cells (DCs) with increasing concentrations of CuA or CuI resulted in inhibition of p-Stat3 and enhanced antigen presentation to naive CD4+ T cells specific for a MHC class II restricted epitope of influenza hemagglutinin (HA). Indeed, these clonotypic T cells displayed increased antigen-specific proliferation and IL-2 production as compared to clonotypic T cells encountering cognate antigen on untreated APCs. Furthermore, unlike untreated PEM or DCs, which are unable to trigger IFN-gamma production by CD4+ T-cells, Cucurbitacin-treated APCs efficiently trigger the production of this cytokine by naïve CD4+ T-cells in response to cognate antigen. Given the above results, we explored next whether inhibition of Stat3 signaling in B-cell lymphomas by Cucurbitacins might increase the intrinsic antigen-presenting capabilities of these malignant B-cells. Reminiscent of our findings with bone marrow derived APCs, Cucurbitacin-treated A20 lymphoma cells also display enhanced antigen-presenting cell function leading to increased proliferation, IL-2 and IFN-gamma by naive antigen-specific CD4+ T-cells. More importantly, tolerant CD4+ T-cells (isolated from lymphoma bearing mice) exposed to Cucurbitacin-treated A20 B-cells regained their ability to proliferate and produce significant amounts of IL-2 and IFN-gamma in response to cognate antigen stimulation.
Taken together, the ability of Cucurbitacins to inhibit p-Stat3 in normal APCs as well as in malignant B-cells make these natural compounds a promising agents to overcome the remarkable barrier that tolerance to tumor antigens has imposed to cancer immunotherapeutic strategies.
Nongastric Marginal Zone B-Cell Lymphoma: Analysis of 247 Cases - Clinical Presentation and Treatment Outcomes of Nongastric Marginal Zone B-Cell Lymphoma.
Authors: Oh Sung Yong , Ryoo Baek-Yeol , Kim Won Seog , Park Yeon Hee , Kim Kihyun , Kim Hyun Jung , Kwon Jung Mi , Lee Jeeyun , Ko Yong H. , Ahn Yong Chan , Oh Suk Jung , Lee Soon , Kim Hyo Jin , Kwon Hyuk Chan , Bang Soo-Mee , Kim Jung Han , Park Jinny , Lee Seung-Sook , Kim Ho Yong , Park Keunchil 
Published: April 2020

Abstract
Purpose: Nongastric marginal zone B-cell lymphoma (NG-MZL) is a relatively uncommon indolent lymphoma. We report a retrospective analysis of 247 patients with .NG-MZL, presenting their clinical features and therapeutic outcomes.
Methods: From 1990 to 2005, a total of 247 patients with histologically confirmed NG-MZL were analyzed.
Results: The median age was 49 years (range, 13–89 years). The study involved 129 males (52.2%) and 118 females (47.8%) The most common involving site was orbit and ocular adnexa (48.6%) followed by lymph node and lymphatic organs (17.8%), bowel (9.3%), lung (6.1%), thyroid gland (4.9%), salivary gland (4.5%) in the decreasing order of frequency. Ann Abor stage I/II disease was present in 78%(167 out of 215). BM involvement was less than 10%(19 out of 211). B symptom was observed in only 2%. One and eighty-six patients out of 208 were in low or low-intermediate risk group (89%) according to international prognostic index(IPI). Eighty percents (172/215) were in low risk group in follicular lymphoma international prognostic index (FLIPI). Patients were treated with a variety of therapeutic strategies. Complete and partial remissions were achieved in 139(92%) and 8(5.3%) of the 151 stage I/II patients, respectively, with an overall response rate of 97.3%. Especially, radiation containing treatment achieved 96% CR rate (108 out of 113). In 38 patients with stage III/IV, CR and PR were achieved in 17(44.7%) and 11(28.9%). The estimated 5-year overall survival (OS) and progression free survival (PFS) were 93.8% and 70.1%, respectively. Although anthracyclin contaning regimen could achieve higher CR rate, it did not improve PFS. Stage III/IV, low hemoglobin, high/high-intermediate IPI, poor risk FLIPI and nodal MZL were poor prognostic factors for PFS in multivariate analysis.
Conclusion: NG-MZL is an indolent disease. For localized disease radiation achieved excellent local control. Anthracyclin containing chemotherapy cannot improve outcome. Both IPI and FLIPI can be applied to predict the prognosis.
Adenovirus-Interferon-g (TG1042) Demonstates Clinical Activity in Relapsing Primary Cutaneous Lymphoma (PCL): A Phase I/II Multicentric Trial.
Authors: Urosevic Mirjana , Luger Thomas E. , Sterry Wolfram , Dreno Brigitte , Dereure Olivier , Baudard Marion , Bagot Martine , Bleuzen Pascal , Rossi Jean-Francois , Dummer Rheinard 
Published: April 2020

Abstract
PCL has been successfully treated with interferons (IFNs), which can offset the Th2 dominance associated with PCL. Intratumoral (IT) injection of TG1042 (a non-replicating recombinant adenovirus with a human IFN-γ cDNA insert) allows high local levels of IFN-γ without severe toxicity induced by systemic delivery. We undertook a multicentric, phase I/II, open-label, trial of repeated, IT injection of TG1042 in patients with advanced primary T cell (CTCL) and multilesional B cell (CBCL) cutaneous lymphoma. The designated lesions were injected on day 1, 8 and 15 with no injection in the fourth week (1 cycle) and thereafter up to 4 cycles. Immunohistochemistry and qPCR were performed on injected lesions biopsied at baseline and after each cycle. In the phase I step, undertaken on a monocentric basis, 9 patients were enrolled in 3 successive cohorts at the doses of 3×109 viral particles (vp), 3×1010 and 3×1011 vp injected in only one lesion and 9 additonal patients were treated at the doses of 3×1011 vp divided in up to 3 lesions. In the phase II step, 18 additional patients have been planned to be treated on a multicentric basis at 3×1011 vp injected in up to 3 lesions. To date, the 36 planned patients (30 CTCL and 6 CBCL) have been enrolled and received a total of 280 injections, 26 patients have completed the treatment. Treatment is well tolerated with only 3 grade III toxicity. Injection site reaction and flue like syndrom are the most commonly observed adverse events. Local clinical response has been observed in 13 (7 complete responses) out of 27 evaluable patients. Disappearance of non-injected lesions was also observed and led to 12 overall responses (6 complete responses) out of 26 evaluable patients. Histology demonstrates pronounced differences in infiltrate patterns following treatment, with signs of vasculitis and increased numbers of eosinophils, neutrophils, CD8 and TIA-1+ve cells. CD4/CD8 ratio decreased in most tumors. Transgene-IFN-γ mRNA was detectable in injected lesions. Gene expression analysis of biopsies and PBMC shows up-regulation of IFN-γ and various immune response-associated genes. Final clinical and immunological data will be presented. In conclusion, these data show that the administration of TG1042 is well tolerated and results in clinical responses associated with in situ immunological changes. These encouraging results demonstrate a potential significant benefit of TG1042 for the treatment of primary cutaneous lymphoma.