bluuebunny/crossref_metadata_2025_split huggingface dataset:
IELSG Phase II Studies of Bortezomib in Malt Lymphomas.
Authors: Conconi Annarita , Lopez-Guillermo Armando , Martinelli Giovanni , Rigacci Luigi , Vitolo Umberto , Zinzani Pier Luigi , Luminari Stefano , Cavalli Franco , Zucca Emanuele 
Published: April 2020

Abstract
The International Extranodal Lymphoma Study Group (IELSG) is coordinating two phase II multicenter studies aimed to assess the antitumor activity and safety of bortezomib treatment in patients (pts) with relapsed or refractory extranodal marginal zone B-cell lymphoma of MALT-type. The IELSG25A study is evaluating bortezomib in pts previously treated with one prior systemic treatment, and the IELSG25B pts previously treated with more than one prior treatment. Bortezomib 1.3 mg/m2 is administered on days 1, 4, 8, and 11 of a 21-day cycle, for up to 6 cycles. Response and progression are determined by International Workshop Criteria. As of July 2007, 18 pts have been enrolled in the studies: 11 (61%) patients were male, median age was 62 years (range, 38–77). At time of enrolment, the Ann Arbor stages distribution was the following: stage I=5 pts (28%), stage II=5 pts (28%), stage IV=8 (44%). In 10 pts primary gastric localization was present, in 5 cases primary skin, in 2 cases primary subcutaneous, in 1 primary lung lymphoma. All patients had ECOG PS=0; in 2 cases (11%) elevated serum LDH was reported. More than 1 site of extranodal localization was present in 4 pts (22%). Median number of prior therapies was 2 (range, 1–3). Median follow-up was 16 months. Nine pts were assessed for response at the end of treatment plan: 3 pts had a CR (33%); 4 a PR (45%) and 2 SD (22%). Five additional pts, with ongoing therapies, have been evaluated after the first two courses of therapy: one pt achieved a CR and 2 pts a PR, in 2 cases a SD was observed. The safety profile of bortezomib is similar to that observed in multiple myeloma and other subtypes of non-Hodgkin lymphoma. The most relevant adverse events grade 3 or higher were peripheral neuropathy and fatigue. One death, non-related to treatment, was observed during the early follow up. These preliminary results suggest that bortezomib is active and safe in relapsed or refractory MALT lymphomas and encourage us to complete the studies accrual.
Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) Provides Prolonged Safety and Clinical Benefit to Patients with Advanced Cutaneous T-Cell Lymphoma (CTCL).
Authors: Duvic Madeleine , Olsen Elise A. , Breneman Debra , Pacheco Theresa R. , Parker Sareeta , Vonderheid Eric C. , Ricker Justin L. , Rizvi Syed , Chen Cong , Boileau Kathleen , Cooley Paulette , Geskin Larisa J. 
Published: April 2020

Abstract
Background: Vorinostat is a histone deacetylase inhibitor that has been approved by the US FDA for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following 2 prior therapies.
Patients and Methods: A Phase IIb, open-label trial of oral vorinostat 400 mg daily until progressive disease (PD) or intolerable toxicity was conducted in patients with advanced CTCL. Patients must have received at least 2 prior therapies and recovered from all prior treatment-related toxicities. The primary end point was the objective response rate in patients with stage IIB or higher CTCL as measured by the severity weighted assessment tool. Time to response (TTR), duration of response (DOR), pruritus relief, safety, and tolerability were also evaluated. Patients who had received vorinostat therapy for at least 2 years as of August 1, 2007 were further evaluated in this post-hoc subset analysis.
Results: Six of 74 patients originally treated in the study have received vorinostat therapy for at least 2 years as of 8/1/07, including 5 responders (1 complete responder, 4 partial responders) and 1 with prolonged stable disease (Figure 1). The median age was 65 years (range, 57–74), the median number of prior systemic therapies was 2.5 (range, 1–5), and the median time from CTCL diagnosis to enrollment was 1.8 years (range, 0–5.9). The most common drug-related adverse experiences were diarrhea (100%), fatigue (67%), nausea (50%), and alopecia (50%). Grade ≥ 3 drug-related adverse experiences were anorexia (n = 1), pulmonary embolism (PE, n = 1), and thrombocytopenia (n = 1). The PE (Day 144) was a serious adverse experience (SAE) that resolved within 7 days, and this patient is continuing on therapy as of Day 848. The only other SAE was a rash (Day 925). Two patients discontinued due to PD and 4 are continuing on therapy as of August 1, 2007.
Conclusions: Vorinostat has demonstrated prolonged safety and clinical benefit in patients with advanced CTCL.
Figure 1. Time on study of patients on vorinostat therapy for ≥ 2 years (available data as of August 1, 2007). Figure 1. Time on study of patients on vorinostat therapy for ≥ 2 years (available data as of August 1, 2007).
A Panel of Artificial Antigen-Presenting Cells (AAPC) Expressing Prevalent HLA Alleles Permits Generation of Cytotoxic T Cells Specific for Both Subdominant and Dominant Viral Epitopes for Adoptive Therapy.
Authors: Hasan Aisha , Kollen Wouter J. , Selvakumar A. , Trivedi D. , Sadelain M. , O’Reilly Richard J. 
Published: April 2020

Abstract
Adoptive transfer of antigen specific T cells can be effective in treating viral infections complicating allogeneic hematopoietic stem cell transplant (HSCT) recipients. However, in practice, generation of T cells is often limited by insufficient supply of autologous antigen presenting cells; therapeutic activity in HLA disparate patients may also be impaired if the immuno- dominant T cells generated are restricted by HLA alleles not shared by the host. AAPCs have theoretical advantages for T cell therapies in terms of sustained supply and capacity to selectively stimulate T cells restricted by HLA alleles shared by donor and host. However, to date, only AAPC systems expressing HLA A*0201 have been characterized. Accordingly, we established a panel of AAPC consisting of NIH 3T3 mouse fibroblast cells, each transduced to express β2- microglobulin and a prevalent HLA class-I allele, specifically HLA A*0201, A*0301, A*2402, B*0702, B*0801 or C*0401, as well as the human co-stimulatory molecules B7.1, LFA-3 and ICAM-1. Novel promotor sequences were introduced to secure stable high expression of the allele on the AAPCs. Sensitization of T cells from seropositive donors with AAPCs expressing each of these alleles (4-8 donors/allele), either loaded with overlapping 15-mer peptides spanning the CMVpp65 sequence or transduced to express the CMV pp65 protein, resulted in 12-35 fold expansions of CD8 + T cells exhibiting CMV pp65 epitope-specific, HLA restricted activity, as quantitated by peptide -HLA tetramer binding, epitope specific production of interferon gamma, and cytotoxic activity against peptide loaded or CMV infected targets. Although both peptide pool loaded and transduced AAPCs induce CMV pp65 epitope specific T cells, yields were higher when transduced AAPCs were employed. In studies of T-cells from 5 donors when sensitized with either peptide pool loaded autologous dendritic cells (DC) or HLA sharing AAPCs, sensitization with DC selectively induced T-cells specific for 1-2 immunodominant CMV pp65 epitopes. In contrast, while sensitization with a panel of peptide loaded or transduced AAPCs expressing shared HLA alleles elicited responses to the same dominant epitopes, we could also regularly generate comparable cytotoxic T cell responses to subdominant epitopes which were either not produced or only present at low frequencies in T cells sensitized with autologous DC. Thus, this panel of AAPCs stably expressing a series of HLA alleles which, in aggregate, are detected in 70% of the patients referred for HSCT, can be employed for rapid generation of CMV-pp65 specific T cells of desired HLA restriction for adoptive therapy.
Serum Evaluation of a Panel of 10 Cytokines in Patients with Follicular Lymphoma: High Serum Level of TGF-β Correlates with Good Prognosis, Independently of the FLIPI Score.
Authors: Ghesquieres Herve , Labidi Sana Intidhar , Caux Christine , Chabaud Sylvie , Gargi Therese , Chassagne Catherine , Sebban Catherine , Biron Pierre , Blay Jean-Yves 
Published: April 2020

Abstract
The course of follicular lymphoma (FL) can be predicted using the FLIPI score but additional prognostic biomarkers are required. The immune microenvironment plays an important role in the physiopathology of FL. As cytokines are involved in the interaction between tumor cells and immune bystander cells, it is relevant to evaluate their prognostic value in FL. Nine cytokines (IL-1ra, IL-6, IL-7, IL-10, IL-13, TNFα, VEGF, PDGF, β-FGF) were measured by multiplex ELISA whereas TGF-β was measured by ELISA sandwich technique in the sera of 60 patients treated for FL (31 at diagnosis, 12 in complete remission (CR) and 21 at first relapse) and 20 healthy persons used as controls. All cytokines but β-FGF were detectable. High IL-6 levels were correlated with increased LDH levels. Increased levels of IL-10 at diagnosis were correlated with advanced stage (p=0.05), bone marrow involvement (p=0.05) and high FLIPI (trend, p=0.07). Levels of IL-10 were higher in FL patients at any time of the disease (diagnosis, relapse or CR) than in controls (respectively p&lt;0.001, p=0.0001 and p=0.04). Levels of TGF-β were significantly lower in FL patients in relapse than in patients in CR (p=0.01) or controls (p=0.001). With a median follow-up of 9 years, overall survival (OS) rates in all patients were 69.9% and 57.5% at 6 and 10 years, respectively. Univariate analysis using clinical prognostic factors (β-2 microglobulin rate, stage, FLIPI score) showed that patients at diagnosis with elevated levels of IL-10 (HR=1.005, p=0.026) and decreased levels of TGF-β (HR=0.929, p=0.01) had shorter survival. In multivariate analysis, Ann Arbor stage I-II and high levels of TGF-β were independent prognostic factors associated with better survival. An elevation by 1ng/ml of TGF-β levels reduced the risk of death by 7%. In follicular lymphoma, a high level of TGF-β is an independent prognostic factor correlated with better survival. As immune microenvironment cells are correlated with survival, we propose to analyse the relationship between immunohistochemical staining of these cells and serum cytokine levels in patients. This is currently being investigated.
Promoter Methylation of Multiple Genes in Diffuse Large Cell Lymphoma (DLCL), Follicular Lymphoma (FL) and Bening Follicular Hyperplasia (BFH).
Authors: Paz-Carreira Jose M. , Losada Raquel , Garcia-Rivero Arantxa , Alvarez Augusto , Bal Fernando , Deben Guillermo , Alba-Losada Jesus 
Published: April 2020

Abstract
Transcriptional silencing of tumor suppressor genes, associated with DNA methylation, is a common epigenetic event in leukemias and myelodisplastic syndromes. Much less is known about the specific methylation changes that occur in DCLC, FL and their normal counterpart BFH. Methylation of cyclin dependent kinase inhibitors is more common in high grade lymphomas and may be an important step in the progression and transformation of follicular lymphoma. We determined the methylation status of 7 tumor suppressor genes in 31 patients with B-cell malignancies. Seven patients with benign follicular hyperplasia were used as normal controls. The target genes chosen are potentially involved in B-cells malignancies and encoding proteins implicated in apoptosis regulation (death associated protein kinase, DAP-K), Jak/STAT3 signalling pathway (SHP1), hormonal response (RARb), DNA repair (O6-methilguanine-DNA methyltranferase, MGMT), cell cycle control (p14ARF and p15INK4b) and detoxification of environmental xenobiotics such as doxorubicin (glutathione S-transferase P1, GSTP1). Genomic DNA extracted from paraffin-embedded samples of thirty one B-cell malignancies (twenty six DLCL and five FL) were analyzed by methylation-specific polymerase chain reaction to determine promoter hypermethylation of DAP-k, SHP1, Rarβ, MGMT, p14, p15 and GSTP1. Samples were obtained mostly from lymph nodes; spleen, stomach, skin, and parathyroid gland biopsies were also included. Specimens were collected at diagnosis before specific therapy. Diagnosis was based on morphology and immunohistochemistry analysis. All cases were matched for age, sex and ethnic origin. DAP-k promoter methylation occurred with similar frequency in DLCL (100%), FL (100%) and BFH (86%). SHP1 was methylated in 75% of DLCL, all FL and the 7 patients with BFH. RARb was methylated in all DLCL and FL patients and 85% of the BFH. Sixteen (50%) DLCL, three (60%) FL and none BFH patients showed MGMT methylation. Promoter hypermethylation of p14 and p15 was detected in 11 (42%) and 13 (50%) DLCL, 2 (40%) and 3(60%) FL, 3(42%) and 5(71%) BFH patients respectively. Methylation of GSTP1 was absent in all samples. Inactivacion of DAP-K, SHP1 and Rarβ is present in B-cell malignancies, DLCL and FL, and BFH. Therefore, it may represent a physiologic event conferring a temporal survival advantage necessary for a BFH response. With our data methylation of Cyclin dependent kinase inhibitors such as p14 and p15 is not a differential pathogenic event in DLCL with respect to FL or BFH. Finally, the absence of GSTP1 methylation in DLCL and FL questions its relevance in B-cell neoplasia development.
Grading Follicular Lymphoma: No Difference between 1, 2 and 3a, but 3b Is Something Else.
Authors: Wahlin Björn E. , Sander Birgitta , Christensson Birger , Kimby Eva 
Published: April 2020

Abstract
According to WHO’s current criteria, follicular lymphoma is morphologically divided into grades 1, 2, and 3, and grade 3 is further subdivided into 3a and 3b, depending on the presence of centrocytes and solid sheets of centroblasts. The clinical relevance of this grading system is unclear. Although there is consensus that grades 1 and 2 share clinical characteristics of indolent lymphoma, it is debated whether grade 3 should be treated intensively with anthracycline-containing regimens. Furthermore, the 3a/3b subdivision is not universally implemented. We wanted to investigate the clinical relevance of the grading system with respect to clinical characteristics, treatment and survival. Totally, 186 cases were diagnosed between January 1994 and January 2004 in South Stockholm County with de novo follicular lymphoma and without concomitant transformation. The biopsies were re-graded according to the current WHO criteria by two experienced hematopathologists. 129 cases were grade 1 or 2, 44 grade 3a, and 13 grade 3b. Clinical characteristics in the patients with follicular lymphoma grade 1–2 and 3a are shown in Table 1.
The local policy has been to treat all patients with grade 3 disease aggressively. In grade 3a disease, front-line anthracyclines did not seem to improve overall survival (Figure 1).
Grades 1–2 and 3a show similar overall survival curves of indolent and incurable lymphoma, while the 13 patients with grade 3b disease (of whom 12 received aggressive front-line therapy) seem to reach a plateau after four years (Figure 2).
We conclude that follicular lymphoma grade 3a is not clinically different from grade 1 and 2 disease, and that patients with grade 3a do not seem to benefit from front-line anthracyclines. Although our findings are limited by the few cases of grade 3b, it seems that grade 3b is another disease entity and, when treated aggressively, it is maybe curable with chemotherapy. The histopathological distinction between grade 3a and 3b is clinically of great importance.
Table 1 Grade 1–2 Grade 3a P Clinical characteristics in patients with follicular lymphoma grade 1-2 and 3a. Age &gt;60 years 50% 61% NS Elevated LDH 32% 49% 0.046 Stage III or IV 68% 80% NS Front-line anthracyclines 41% 73% 0.0004 Subsequent transformation 21% 19% NS Figure Figure Figure Figure
Hepatitis B and C Virus in Patients with Non-Hodgkin Lymphoma.
Authors: Anderson Lesley A. , Pfeiffer Ruth , Warren Joan , Landgren Ola , Berndt Sonja , Gadalla Shahinaz , Ricker Winnie , Parsons Ruth , Engels Eric A. 
Published: April 2020

Abstract
Background: Hepatitis C virus (HCV) infection has been implicated in the development of Non-Hodgkin lymphoma (NHL), but subtype specific analyses are limited. Although some studies have reported a higher prevalence of hepatitis B virus (HBV) infection in patients with NHL, results are conflicting.
Methods: From the U.S. SEER-Medicare database, we selected 59,824 patients with NHL (aged 65+ years) and 166,057 population-based controls. Participants were classified as having HCV or HBV infection if they had any Medicare record of infection &gt;1 year prior to diagnosis/selection. Polytomous logistic regression analyses were used to compare HCV and HBV infection in cases and controls with adjustment for gender, age (5-year age bands), calendar year of diagnosis/selection (in tertiles), race (white versus non-white) and the number of physician visits (in quartiles).
Results: Overall, 137 (0.23%) NHL cases and 270 (0.16%) controls had HCV infection and 82 (0.14%) cases and 249 (0.15%) controls had HBV infection. HCV infection was significantly associated with NHL overall (OR 1.3, 95% CI 1.1–1.7) and with diffuse large B-cell lymphoma (n=13,330; OR 1.5, 95% CI 1.1–2.2), Burkitt’s lymphoma (n=221; OR 5.7, 95% CI 1.8–17.9), follicular lymphoma (n=6,142; OR 1.9, 95% CI 1.2–3.0) and marginal zone lymphoma (n=1,989; OR 2.3, 95% CI 1.3–4.1). HCV infection was not associated with T-NHL (n=2,362; OR 0.4, 95% CI 0.1–1.6) or NHL not otherwise specified (n=3330; OR0.9, 95% CI 0.3–2.9). HBV infection was not significantly associated with NHL or NHL subtypes.
Conclusions: HCV, but not HBV, infection was associated with elevated risk of high- and low-grade NHLs. HCV may induce NHL development through chronic immune stimulation or other mechanisms.
PU.1 Cooperates with SOX4 in Myeloid Cells.
Authors: Aue Georg , Du Yang , Jenkins Nancy A. , Dunbar Cynthia E. , Copeland Neal G. 
Published: April 2020

Abstract
Mice that express 20% the normal levels of the Ets transcription factor PU.1 develop AML, unlike mice that express 50% or 80% the normal levels, indicating that PU.1 is a dosage-sensitive tumor suppressor gene. In addition, 3 of 13 AMLs induced by transplanting mice with cells transduced with a Sox4 oncogene-containing retrovirus were found to carry a Sox4 retroviral integration in one PU.1 allele, suggesting that downregulation of PU.1 may cooperate with Sox4 in AML induction. Since the other PU.1 allele remains intact in these AMLs and a 50% decrease in PU.1 expression is not sufficient to induce AML, we hypothesized that Sox4 might further downregulate PU.1 expression in these AMLs. To test this hypothesis, we transfected HL60 cells with an expression vector carrying GFP and Sox4 cDNA or a GFP vector control alone. PU.1 mRNA levels were consistently downregulated 4 to 10 fold in cells transfected with Sox4 cDNA compared to cells transfected with the vector control, confirming that overexpression of Sox4 downregulates PU.1 expression in myeloid cells. The decrease of PU.1 mRNA was observed as early as 8 hours after Sox4 transfection, further suggesting that Sox4 may directly interact with PU.1 in myeloid cells. Consistent with this, analysis of 2 published microarray databases comprising 401 de novo AML patient samples showed that SOX4 expression is significantly negatively correlated with PU.1 expression (coefficient: −0.337, P-value: 1E-07). In order to confirm that downregulation of PU.1 cooperates with Sox4 in AML induction, we infected wild type or PU.1 heterozygous knockout bone marrow cells with the Sox4 retrovirus and then monitored the time of AML development in transplanted mice. Results showed increased penetrance (95%) of myeloid leukemia in mice transplanted with Sox4-infected PU +/– bone marrow compared to mice receiving Sox4-infected wild type marrow (60%). Myeloid leukemia was confirmed by histology in all animals of the Sox4-infected PU +/ cohort while T cell lymphoma was diagnosed in 3 animals of the Sox4 wild type cohort. Together, all experiments support the hypothesis that Sox4 cooperates with the transcription factor PU.1.
SALL4-Dependent Signaling Networks Are Required for Survival of Leukemia Cells.
Authors: Yang Jianchang , Chai Li , Fowles Taylor , Alipio Zaida , Gao Chong , Fink Louis , Ma Yupo 
Published: April 2020

Abstract
Our group and others have recently shown that a murine transcriptional factor, SALL4 plays an essential role in maintaining the properties of embryonic stem cells and in governing the fate of the primitive inner cell mass through regulation of Oct4. Over-expression of SALL4 in mice exhibit myelodysplastic syndrome (MDS) which transforms to acute myeloid leukemia (AML) associated with expansion of leukemic stem cells. Aberrant expression of SALL4 in leukemic blasts is commonly seen in a variety of AML and MDS cases. However, the transcriptional programs downstream of the SALL4 stem cell gene in leukemia are unknown. We mapped its global gene targets using chromatin-immunoprecipitation followed by microarray hybridization (ChIP-on-ChIP). We identified over two thousands high-confidence SALL4 binding sites in the acute leukemic cell line, NB4. Analysis of the SALL4 binding sites revealed that genes involved in cell death, cancer, DNA replication/repair, and cell cycle were highly enriched (p&lt;0.05) when functionally classified. This is consistent with promoter binding of over 280 apoptosis-related genes including important apoptosis and cell-cycle arrest induction genes (DAP3, CARD9, TP53, DAXX, CASP6, CASP9, CYCS, TNF, TAL1, and PTEN) and apoptosis inhibition genes (Bmi-1, BCL2, TEGT and XIAP). This indicates that SALL4 may play a role in leukemogenesis. Reduction of wild type SALL4 mRNA levels by approximately 50 percent resulted in a 21-fold increase in caspase-3 activity from 4.6 percent to 98.3 percent. In addition, suppression of SALL4 expression caused a significant decrease in NB4 cell growth rate. To further study the role of the SALL4 in cell growth, we monitored cell-cycle changes and cellular DNA synthesis in SALL4-suppressed and wild type NB4 cells through flow cytometry analysis and the BrdU incorporation assay. SALL4-reduced NB4 showed about a four-fold decrease in S phase cells and a significant increase in the G1 and G2 phases, which paralleled the drop in DNA synthesis as measurement from the level of BrdU incorporation. Similar results were observed in other cancer cell lines. In addition, SALL4-reduced NB4 cells showed significantly decreased tumorigenicity in immunodeficient mice. Our studies provide a foundation for developing a leukemia stem cell-specific therapy targeting SALL4.