bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rearrangement Patterns of Igs and bcl2/IgH and Clinical Significance in Follicular Lymphoma.
Authors: Martinez-Lopez J. , Rivero A. , Montalban C. , de la Serna J. , Fernandez-Sevilla A. , Paz J. , Canales M. , Ona R. , Sanchez-Godoy P. , Martinez R. , Grande S. , Martinez-Sanchez P. , Ayala R. , Tomas Jose F. 
Published: April 2020

Abstract
Objectives: To identify a clonal population by molecular techniques in patients treated with Fluradabine, Cyclophosphamide, Rituximab (CF+R) and included in the LNF-03 clinical trial. To relate these alterations to the clinical variables at diagnosis and response to treatment.
Patients and Methods: Patients: 71 patients from the LNF-03 clinical trial. Their treatment consisted of CF+ Rx6 and posterior maintenance with Rituximab. Peripheral Blood (PB) and Bone Marrow (BM) were studied at diagnosis.
Methods: bcl2/IgH rearrangements were studied by real-time PCR (Olsson et al, Mod Pathol 1999). Ig rearrangement of VDJ IgH, Igs IgL KVJ, Kdel and LVJ was studied according to BIOMED II protocols.
Results: 43 of the 71 patients (60.56%) presented some molecular alteration in PB or BM. 33% of the patients in the study presented t(14;18) in some of its majority forms, bcl2/IgH mayor 19 (26.4%) and minor 3 (4.22%). 13 patients were positive for bcl-2/IgH, both in BM and in PB. The median amount of blc2/IgH in BM was 8.315% (62.9–0.04), Whereas in pb it was 4.775% (92.6–0.06), with no significant differences observed. Nevertheless, monoclonality was detected in BM in eight cases but not in PB, and to the inverse, one it happened in three patients.
Of 71 patients, 38 (53.52%), presented displayed monoclonality in at least one of the Ig genes. Of these patients, 38% presented the clonal rearrangement in IG-L KVJ, 26% in IG-H CDR1, 23% in IG-L KDEL, and 13% rearranged in IG-L LAMBDA. There were 57 patients whose BM was available. 28 of them presented pathological infiltration, and monoclonality was detected in 23 cases; in 29 patients who were not pathologically infiltrated, monoclonality was detected in 12 cases. 83% (6/37) of the patients presented a complete response (CR), 8.1% (3/37) uncertain CR (uCR) and 8.1% (3/37) partial response (PR), after the induction treatment.
No relation was found between the presence of molecular alterations in BM/PB and the achievement of a CR.
Conclusions: The study of the rearrangements of Ig and bcl2/IgH is a good strategy for identifying lymphomatosus disease at diagnosis; bone marrow is more informative than peripheral blood. The presence of molecular alterations in PB and/or BM is not related to a poorer answer to induction treatment. Partially funded by Roche Farma SA.
CD40L Modulates TRAIL-Induced Apoptosis in Germinal Center Derived B Cell Lymphomas.
Authors: Travert Marion , Ame-Thomas Patricia , Fest Thierry , Pangault Céline , Semana Gilbert , Lamy Thierry , Tarte Karin , Guillaudeux Thierry 
Published: April 2020

Abstract
Follicular lymphoma are characterized by the rearrangement of the bcl-2 gene, present in more than 90% of patients. Over-expression of the bcl-2 protein resulting from this translocation is associated with the inability to eradicate the lymphoma, by inhibiting apoptosis. Despite the median survival ranges from 8 to 15 years, leading to the designation of indolent lymphoma, patients with advanced-stage follicular lymphoma are not cured with current therapeutic options. Numerous reports have shown that Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in a wide variety of transformed cell lines of diverse lineage, but does not appear to kill normal cells, even though TRAIL mRNA is expressed at significant levels in most normal tissues. As cell death induced by TRAIL occurs almost exclusively in tumor cells, it suggests that this drug is safe to use as an antitumor therapy. We therefore investigated the efficiency of this cytokine to induce apoptosis in germinal center derived B cell lymphoma, despite bcl-2 over-expression. Our study was also designed to evaluate the role of CD40L, one of the main differentiation signal involved in B cell maturation during the germinal center reaction, on the regulation of TRAIL-induced apoptosis. This study was performed on three germinal center derived tumor cell lines (BL2, VAL and RL), and on normal and tumor primary cells obtained from human tonsils and lymph nodes. Our data show that normal B lymphocytes obtained from tonsil biopsies are resistant to TRAIL-mediated apoptosis, when B lymphoma cells issued from lymph node of numerous patients are significantly sensitive to the cytokine. When we treat these lymphoma cells with trimeric huCD40L, we partly rescue these cells from spontaneous apoptosis which naturally occurs after few days of culture, and reverse by 50% TRAIL-mediated apoptosis when cells were co-treated with huCD40L for 16 hours. Similar results were reproduced on some germinal center derived cell lines. BL2 was indeed found highly sensitive to TRAIL-induced apoptosis following a 24 hour exposure. On the opposite, VAL and RL were almost insensitive. We have demonstrate that apoptosis is exclusively mediated by TRAIL-R1 in BL2. Analysis of signalling pathways revealed that the protection to TRAIL-induced apoptosis by CD40L is due to some specific anti-apoptotic molecules that will be described. Genes encoding these molecules are targets of the NFκB signalling pathway activated by CD40L. Our results suggest that activation of NFκB and induction of anti-apoptotic molecules by CD40L play an important role in the protection of germinal center derived B cell lymphomas against apoptosis. Then, NFκB inhibitors may be wise to use in clinical trials in conjunction with TRAIL against follicular lymphomas.
Distinct Cytogenetic Aberrations during the Course of Mantle Cell Lymphoma (MCL).
Authors: Papadhimitriou Stephanos I. , Davea Ageliki , Savvidou Ioanna , Paterakis George , Goumakou Helen , Griva-Kritikou Elpi , Androutsos George , Pavlidis Dimitris , Marinakis Theodoros , Anagnostopoulos Nikolaos I. , Georgiakaki Maria 
Published: April 2020

Abstract
BACKGROUND: Apart from t(11;14)(q13;q32), MCL is also characterized by other nonrandom cytogenetic findings. These additional aberrations are well studied at diagnosis and believed to represent clonal evolution during lymphomagenesis, but little is known about karyotypic changes during the course of the disease.
METHODS: The study included 33 patients with MCL. In all cases, an interphase FISH assay was performed at diagnosis on lymphoma cells from peripheral blood, bone marrow or touch imprints of involved sites. Commercial probes were employed for the detection of t(11;14), +12, 13q−, and abnormalities of ATM, p53, p16, TEL, c-MYC and BCL6 genes. In 14 cases, the same FISH screening was repeated at least once (up to four times) during the course of the disease, at relapse or in the context of partial or no response.
RESULTS: The most frequent additional findings at diagnosis were ATM deletion in 15 cases (45.5%) and 13q− in 12 cases (36.4%), followed by p16 deletion (3 cases; 1 homozygous), p53 deletion (2 cases), and +12, duplication of the CCND1/IGH fusion gene and BCL6 triplication, in one case each. 11 of the 14 cases studied at follow-up showed karyotypic evolution, with acquisition of p16 deletion (6 cases; 4 homozygous), TEL deletion (5 cases; 2 on the basis of monosomy 12), duplication of the CCND1/IGH fusion (3 cases), p53 deletion (2 cases), and c-MYC amplification (1 case). There was no case with acquisition of ATM deletion, 13q− or +12, but in two cases with 13q− in a minor subclone at diagnosis the aberration was estimated to involve the total of the lymphoma cells at relapse. Interestingly, new BCL6 aberrations were seen in 3 cases (triplication in one and amplification in the other two, including the case with gene triplication at diagnosis) and were detected at the third or the fourth repetition of the screening. The longest survival after detection of these aberrations was 3 months.
CONCLUSIONS: Our data suggest that in most cases of MCL clonal evolution also occurs during the course of the disease, with the acquisition of multiple additional chromosomal lesions. Despite the small number of patients in our series, it seems that some of the aberrations (like ATM deletion or 13q−) are most commonly already present at diagnosis, while others (such as monosomy 12 and/or TEL deletion) appear more often or even exclusively on follow-up. From the clinical point of view, we found that the most informative finding is the overrepresentation of the BCL6 gene, apparently associated with aggressive behavior and perhaps the terminal stage of MCL.
Expression of Coxsackie Adenovirus Receptor in Cutaneous T-Cell Lymphoma: Potential for Skin Targeted Gene Therapy.
Authors: Ledet Johnathan , May Joshua , Billelo Seth , Friday Ellen , Nordberg Mary , Turturro Francesco 
Published: April 2020

Abstract
Cutaneous T-cell lymphoma (CTCL) represents a spectrum of diseases characterized by the accumulation of clonal lymphocytes in the skin. It has been well established that primary cutaneous lymphomas of T-cell lineage have shown ALK protein expression. Furthermore, we have previously shown that ALK-ALCL cell lines highly express the coxsackie-adenovirus receptor (CAR), primary receptor for recombinant wild type-fiber adenovirus-derived vectors for gene therapy. Since skin-directed therapies are the preferred first-line treatment the presence of CAR in CTCL may be helpful in developing therapeutic modalities such gene or targeted molecular therapy. By using ALK-immunostaining, we analyzed retrospectively a series of human tissue primarily diagnosed as CTCL [5 mycosis fungoides (MF), 4 (ALCL)] or peripheral T cell lymphoma (1 PTCL) in order to establish the level of CAR expression in primary CTCL tissue. Fluorescence in situ hybridization (FISH) analyses were also performed on these cases using a locus specific DNA probe for the ALK/p2 locus. We used ALK identification because at the time when the primary diagnosis was placed, the samples were not tested for ALK expression. Patients ranged in age from 32–73 years old with a median age of 58. Normal skin biopsies from 8 patients were used as controls. The results of our analysis are illustrated in Table 1.
TABLE 1. DIAGNOSIS SPECIMEN CAR INTENSITY/% ALK INTENSITY/% FISH CD30 ALCL RT ANKLE MASS 0 / 0 N/A N/A POS ALCL RT FLANK MASS 1+/ 80 1+ / 80 32% B-ANEUPLOID ALCL SKIN, LOWER RIGHT EXTREMITY 0 / 0 2+/ 10 NL POS PTCL SKIN, RT ARM 3+ / 95 3 +/ 70 MF SKIN, RT AXILLA 1 + / 5 3+ / 5 ALK POS MF SKIN 1+ / 5 3+ / 5 NL 21% ANEUPLOID MF SKIN, ARM 0 / 0 3+ / 90 NL (18% ANEUPLOID) POS (RARE) MF SKIN, LEFT BACK 2+ / 40 3+ / 95 NL MF SKIN, RT FOREARM 2+ / 30 1 + / 30
In this study, we show that the immunostaining of CAR in combination with classic ALK-immuno or ALK-FISH is feasible and helps in identifying CTCL cases candidate for skin targeted adenoviral-mediated gene therapy.
Reactivity of an Anti NS3-HCV-Induced Autoantibody in HCV-Positive Gastric Tissue by 2D Gel Immunoblot.
Authors: Spina Michele , Caggiari Laura , Cannizzaro Renato , Gloghini Annunziata , De Re Vallì 
Published: April 2020

Abstract
In a previous study we demonstrated an IgM cross reactivity against Fc region of human IgG and HCV-NS3 antigen in HCV-induced type II mixed cryoglobulinemia (MC). We identified NS3 and Fc epitopes recognized by these IgM by epitope excision approach. HLA determination confirms their ability to present these epitopes. The same cross reactivity has been observed with a monoclonal antibody, (mAb B3-18), obtained after immunization of a mouse with one of the identified NS3 epitopes. Previous, observations indicate that HCV may localize in several tissues besides the liver (such as gastric mucosa) possibly inducing some of the extra hepatic manifestations of chronic HCV infection. The aim of this study is to characterize the mAb B3-18 reactivity by an immuno-proteomic approach. Such novel information may be of interest to identify new potential antigens implicated in HCV pathogenesis useful to design new molecules for diagnostic or therapeutic approaches. Proteins were extracted from 12 gastric biopsies of patients with gastric disturb and HCV-infection (one of them with a concomitant malt lymphoma of the stomach) and from 3 patients with gastric disturb but without HCV infection as control. Proteins were analysed by 2D gel electrophoresis and mAb B3-18 immunoblot. Proteins recognized by mAb B3-18 were identified by MALDI-TOF mass spectrometry. Differential protein expression levels between patients and controls were detected by 2D-DIGE. Samples were also tested by immunohistochemistry with the mAb B3-18, by VDJ-BCR and VDJ-TCR genscan analysis and by KIR/ligands haplotypes. MAb B3-18 is functional both in 2D gel electrophoresis and in immunohistochemistry. Two specific proteins were identified by B3-18 immunoblot in HCV-infected patients: 18 kDa antrum mucosa protein (AMP 18) and TFIZ1. Both proteins function as growth factors at least partly responsible for maintaining a functional gastric epithelium by seeking evidence of epithelial cell mitogenic activity. They are expressed and secreted in normal gastric mucosa but down-regulated in gastric cancer. These proteins, as well as some others, also showed an up-regulation in gastric mucosa from HCV-infected patients. Mab B3–18 reactivity in immunohistochemistry was restricted to gastric tissue surrounding the NHL lesion. An oligo/monoclonal B cell pattern was found in 3 patients. The characterization of KIR/ligand is in course. The use of a monoclonal antibody miming IgM autoantibodies from HCV+ patients with type II MC and a concomitant immunocytoma, is useful to identify autoantigens that could sustain HCV-related B cell proliferations and HCV infection-associated antigens.
Fludarabine, Mitoxantrone and Dexamethasone for the First Line Treatment of Patients with Indolent Non-Hodgkin Lymphoma (NHL): GATLA First Interim Report (Grupo Argentino de Tratamiento de la Leucemia Aguda).
Authors: Milone Gustavo , Rodriguez A. , Milone Jorge , Bezares R.F. , Rudoy S. , Palmer Luis , Cerruti I. , Lastiri Francisco 
Published: April 2020

Abstract
Background: fludarabine (F) is licensed for the management of indolent non-Hodgkin lymphoma in countries such as Canada and Switzerland. Clinical evidence suggests that fludarabine monotherapy is as least as effective, than conventional therapies such as cyclophosphamide, vincristine, prednisone (CVP) for the first and second line treatment of B-cell low grade NHL achieving objective response rates. Better response rates can be achieved combining F with Mitoxantrone (N) and Dexamethasone (D) in indolent NHL patients (pts). The GATLA (Grupo Argentino de Tratamiento de la Leucemia Aguda) started a prospective multicenter national study to evaluate the use FND as a first line treatment for low grade NHL.
Aims: to assess the response rate, safety, disease free survival (DFS) and overall survival (OS) of FND as first line treatment for indolent NHL during (2002–2006).
Methods: Ninety-six patients in the period of January 2002 to April 2006 were recruited. Sixty-nine patients were valuable at the time of analysis. Median age 54 years old (range: 21–79). Gender: male 51% and female 49%. Inclusion criteria for low grade NHL-LG was: non-previous, age &gt; 18 years old with symptomatic disease, ECOG performance status 0–2 and written informed consent. Ann Arbor staging:
5,8%, 14,5%, 24,6% and 55%.
FND treatment consisted of F 25 mg/m2 i.v. (days 1–3), N 10 mg/m m2 i.v. (day 1) and D 20 mg (days 1–5) each 28 days for 6 cycles. All patients received oral antibiotics for intestinal decontamination, antifungal prophylaxis and Trimethoprim-Sulfamethoxazole as P. carinii prophylaxis for one year.
Results: on this low grade NHL cohort the overall response rate (ORR) was 93% (ORR) with 70% (48 pts) with complete response (CR) and 23% (16 pts) with partial response; progressive disease and non-response 7% (5 pts). The probability of event free survival (EFS) and overall survival (OS) at 24 months was 60% and 90% respectively. Two patients developed secondary malignancies after treatment and one died. Only one patient died in CR.
Conclusions: in this population FND treatment demonstrate a high CR rate with low toxicity and high probability of EFS and OS as previous experience published in the literature.
Short Duration Filgrastim (G-CSF) Therapy (2–4 Days) Is Adequate To Maintain Dose Intensity in Hodgkin’s Lymphoma Patients Treated with Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD).
Authors: Kaminer Lynne S. , Bavisi Seema , Lawton Jessica , Uhlig William , Carro George , Grinblatt David L. 
Published: April 2020

Abstract
Maintaining dose intensity in Hodgkin’s Lymphoma (HL) correlates with an improved outcome in patients treated with combination chemotherapy. Filgrastim is commonly used as secondary prophylaxis for neutropenia to avoid dose delays and dose reductions. Results from a retrospective review at the Mayo Clinic (Blood104(11):abs 1317, 2004) demonstrated an increased frequency of pulmonary toxicity in patients with HL treated with bleomycin who had received G-CSF. Thus, using the minimum amount of filgrastim required to maintain dose intensity may be beneficial. We describe below our results using a shortened regimen of filgrastim in conjunction with ABVD chemotherapy.
The electronic and/or paper charts of twenty-one adult patients with HL receiving ABVD at KCCC between January 2002 and May 2005 were reviewed. All patients completed at least 2 cycles of ABVD, with a median of 6 (range 2–8) cycles per patient. Of the 21 patients evaluated, 18 required administration of filgrastim as secondary prophylaxis. The precipitating factor requiring administration of filgrastim was a low ANC, which resulted in treatment being held or delayed in all patients. The filgrastim dosing regimen utilized consisted of a median of 3 doses (range 2–4) given days 6–10 post ABVD treatment. The chart review included 21 patients who received a total of 213 treatments with ABVD. Of these treatments, 78 were not preceded by filgrastim, while 135 included filgrastim. When filgrastim was not given, a subsequent dose delay occurred in 16 instances (20.5%) and dose reduction occurred in one (1.33%) instance. Of the 135 ABVD treatments with filgrastim prior to treatment, a subsequent dose delay occurred only once (0.74%) and there were five (3.7%) dose reductions. Filgrastim was dosed at 5 mcg/kg, rounded to the nearest vial size. Five patients received 300 mcg, while the remaining 13 were dosed at 480 mcg. Using this shorter dosing regimen, there is a potential cost savings of $2420 per treatment when compared to 10 doses of filgrastim. Similarly, when compared to pegfilgrastim, there is a potential cost savings of $2470 per treatment.
In conclusion, using 2–4 doses of filgrastim is a cost effective method that allows patients who are receiving ABVD to sustain dose intensity. This shortened course of filgrastim may also decrease the risk of lung toxicity. These results identify a valuable approach to potentially improve outcomes in patients with Hodgkin’s lymphoma.
Intensive Induction Is Beneficial for High Risk Younger Patients with Aggressive B-Cell Lymphoma, While Frontline ASCT Brings No Benefit: Final Analysis of MegaCHOP-BEAM and MegaCHOP-ESHAP-BEAM Studies.
Authors: Pytlik Robert , Belada David , Kubackova Katerina , Kozak Tomas , Jankovska Milada , Pirnos Jan , Bolomska Ingrid , Vasova Ingrid , Papajik Tomas , Sykorova Alena , Siffnerova Hana , Hamouzova Michaela , Klener Pavel , Trneny Marek 
Published: April 2020

Abstract
Objectives. Both high-dose induction and front-line ASCT have been tested for improvement of treatment results in younger patients with aggressive lymphomas. Since 1998, Czech Lymphoma Study Group is testing these approaches in Phase II prospective studies. We present mature data from two studies conducted in the pre-Rituximab era.
Methods. In 1998–1999, patients up to 65 years of age with all types of aggressive lymphomas except Burkitt and lymphoblastic lymphoma and age-adjusted (aa)IPI 2 or 3 were recruited to MegaCHOP-BEAM protocol, which consisted of 3–4 cycles of high-dose CHOP (cyclophosphamide, 3 g/m2, adriamycine, 75 mg/m2, vincristine, 2 mg and prednisolone 300 mg/m2 + G-CSF every two weeks) followed with BEAM and ASCT. From 2000, 3 cycles of MegaCHOP were followed with 3 cycles of ESHAP and BEAM consolidation. Peripheral blood progenitor cells were collected after 2nd or 3rd MegaCHOP in first and after 1st ESHAP in the second protocol. Analyses were performed on intention to treat principle.
Results. 21 patients were recruited to MegaCHOP-BEAM and 30 patients to MegaCHOP-ESHAP-BEAM protocol, respectively. Median age was 41 years (range, 21–66 years), 29 patients were males (57%). 47% of patients had diffuse large B-cell lymphoma (DLBCL), 33% primary mediastinal B-cell lymphoma (PMBCL), 16% peripheral T-cell lymphoma and 4% grade 3 follicular lymphoma. 53 % of patients had aaIPI 2 and 47% of patients had IPI 3. Overall response rate was 93% and 70% of patients achieved complete remission. Treatment related mortality was 4% (2 patients). 67% of patients proceeded to transplant and in 21%, protocol was changed because of toxicity. Median follow up is 63 months (range, 32–96) for living patients. Median overall survival or progression-free survival have not been reached and actuarial overall survival is 66 ± 13% in three years with no differences between the two protocols. Patients with PMBCL had better outcome than patients with DLBCL and patients of other histologies (3-year survival 94% v. 60% v. 30%, p = 0,001). Interestingly, patients with aaIPI 3 apparently benefited from addition of ESHAP (3-year survival 77% in MegaCHOP-ESHAP-BEAM v. 30% in MegaCHOP-BEAM, p = 0,03) while aaIPI 2 patients had the same survival with both protocols. Omission of ASCT or protocol change because of toxicity did not seem to influence patients outcome.
Conclusions. Full-lenght intensified induction improved treatment results in high-risk patients with aggressive B-cell lymphomas, particularly with aaIPI 3, while ASCT did not seem to have an impact. For T-cell lymphomas, other treatment strategies have to be sought.