bluuebunny/crossref_metadata_2025_split huggingface dataset:
The IMiDs® Immunomodulatory Drugs Revlimid® (Lenalidomide) and CC-4047 Induce Growth Arrest and Apoptosis in NHL Tumor Cells In Vitro.
Authors: Corral Laura G. , Zhu Dan , Wang Yuedi , Stein Bernd 
Published: October 2019

Abstract
IMiDs® immunomodulatory drugs are thalidomide analogues that have been developed for improved anti-cancer and anti-inflammatory properties and decreased side effects. Many IMiDs® immunomodulatory drugs have been shown to have activities in hematologic cancers and solid malignancies, as well as having profound effects on the bone marrow microenvironment. Specifically in NHL, it was shown that addition of Revlimid® or CC-4047 to Rituxan enhances anti-tumor activity in a SCID mouse lymphoma model.
Here we tested the direct effects of Revlimid® and CC-4047 on NHL tumor cells by treating Raji cells with each drug alone or with each drug in combination with anti-CD20 antibodies B1 and Rituxan. CC-4047 alone caused up to 40% inhibition of proliferation at 10 μM in Raji cells, which corresponded to G1 arrest. In combination with B1, CC-4047 showed a small additive effect at 10 μM while Revlimid® effects were minimal up to 10 μM. In combination with Rituxan, CC-4047 showed a slight additive effect at 10 μM and Revlimid® at 50 μM.
We have also developed a co-culture assay of PBMC and NHL tumor cells as an in vitro model of tumor-host immune system interaction, to further explore the anti-tumor potential of the drugs in NHL. This assay is non-radioactive and flow cytometry based. In this co-culture system using Raji and PBMC, we have shown that pre-treatment of PBMC with Revlimid® or CC-4047 can enhance the PBMC activity in inducing Raji cell apoptosis in a dose dependent manner. In addition, our data indicate that pre-treatment of Raji cells with Rituxan can further enhance the apoptosis induced by PBMC pre-treated with Revlimid® or CC-4047. Since minimal additive effect between each drug and Rituxan was observed in the Raji single tumor cell model, these studies suggest that the co-culture system is a more appropriate cellular model to assess the anti-tumor activities of certain IMiDs® immunomodulatory drugs. This system can reveal the effects of certain IMiD® immunomodulatory drugs not observable with single tumor cell proliferation models.
In summary, our data clearly demonstrate that Revlimid® and CC-4047 directly induce NHL tumor cell growth arrest and effectively enhance tumor cell apoptosis induced by PBMC. These results support clinical evaluation of Revlimid® and certain IMiDs® immunomodulatory drugs in relapsed B-cell NHL in combination with Rituxan.
Motexafin Gadolinium (Mgd), a Redox Stress Inducer, Lowers p53 Protein but Not Message in Lymphoma Cell Lines: Mechanisms of Reactive Oxygen Species (ROS)-Mediated Apoptosis in Lymphoma.
Authors: Singh Amareshwar , Prachand Sheila , Evens Andrew M. , Schumacker Paul , Gordon Leo I. 
Published: October 2019

Abstract
Disruption of the tumor suppressor p53 is a frequent event in malignant disorders, including lymphomas. Loss of constitutive low-level p53-dependent expression of anti-oxidant proteins could render cells more susceptable to the acute oxidant stress induced by oxidant generating agents such as MGd, bortezomib and rituximab. Alternatively, loss of p53 would render cells more resistant to apoptosis normally seen after strong activation of p53 activity in response to DNA damage. We hypothesized that the ROS generating expanded porphyrin, MGd, which we have previously shown to cause apoptosis in lymphoma and myeloma cells, results in loss of low-level, basal p53 expression, making cells more susceptable to oxidant stress. In order to test this hypothesis, we incubated Ramos, HIF-1 and SUDHL-4 lymphoma cells for 30, 60, 120 and 300 min with MGd (0.1–100 μM) with or without zinc acetate (Zn) and ascorbate. Following incubation, whole cell lysates were collected, electrophoresed on SDS-PAGE gels and blotted with p53-DO1 antibody. GAPDH was used as an internal standard. We found that at 300 min incubation, there was a dose-dependent loss of p53 by immunoblotting in the presence of Mgd and either Zn or ascorbate in Ramos and SUDHL-4 compared with control, and a dramatic loss with MGd/Zn/ascorbate in each of the cell lines. Maximum loss of p53 was observed at 100 μM MGd with both Zn 100 μM and ascorbate 100 μM. MGd, Zn or ascorbate alone had no effect. To determine if p53 message was altered, Ramos cells were treated for 300 min with the same concentrations of MGd, ascorbate and Zn and total RNA isolated by the Qiagen method and dissolved in RNase-free water. 1.0 μg RNA was used for reverse transcription using the Taq DNA polymerase system. PCR amplificatiion was performed at 94° C for 30 sec (denaturation), 58° C (annealing) and 72° C (extension) for 40 cycles. Anti-sense primers and sense primers (IDT Technologies, Coralville, IA) for p53 and GAPDH were used and DNA was identified by 1% agarose gel electrophoresis. We found that there was no loss of p53 message under these conditions in the Ramos cell line.
CONCLUSIONS: These results suggest that there is post-translational modification of p53 induced by the ROS-generating expanded porphyrin MGd, and that this effect depends on the presence of ascorbate or Zn, similar to the effects of MGd, ascorbate and Zn for lymphoma and myeloma cell apoptosis. These data suggest that oxidant generating agents can result in loss of low-level basal p53 protein expression in lymphoma cells and that this might be important in cellular apoptosis, perhaps through mechanisms that depend on downstream p53 targets.
Quantitative Assessment of Circulating t(14;18) Positive Cells by RQ-PCR at Diagnosis and Follow-Up Correspond to Clinical Characteristics and Predicts Time to Treatment Failure in Follicular Lymphoma.
Authors: Pott Christiane , Boettcher Sebastian , Brueggemann Monika , Raff Thorsten , Ritgen Matthias , Unterhalt Michael , Dreyling Martin , Hiddemann Wolfgang , Hoster Eva , Kneba Michael 
Published: October 2019

Abstract
Follicular lymphoma (FL) is characterized by the t(14;18) translocation and is incurable with standard treatments in advanced stages. However, the prognosis of FL is heterogeneous and there are long term survivor with a slow disease progression. The detection of residual t(14;18) positive cells by PCR has become an important tool in the diagnostic work-up and during the clinical follow-up in patients with FL. Therefore we evaluated the prognostic value of RQ-PCR assessment at diagnosis and follow-up in patients with advanced FL.
Patients and methods: PB and bone marrow (BM) of 80 patients with advanced stage, t(14;18)+ FL treated frontline with CHOP (n=42) or CHOP+ Rituximab (n=28) in a prospective trial of the German Low-Grade Lymphoma Study Group (GLSG) was analysed. t(14;18)+ cells were quantified by RQ-PCR (ABI PRISM 7700).
Results: Patients with stage IV disease (p=0.003), presence of B-symptoms (p=0.002) or >4 involved lymph node regions (p=0.004) had significantly higher level of PB t(14;18)+ cells, whereas the RQ-PCR levels did not correlate with sex, bulky disease, LDH and age. RQ-PCR level seemed to correlate also with the FLIPI defined risk groups (median level 0.00015 low risk, 0.00275 intermediate risk, 0.008 high risk, p=0.059). RQ-PCR values showed a significant influence on TTF (p=0.037, univariate Cox Regression). Circulating lymphoma cells in diagnostic PB above a threshold of 0.01 corresponded to the time to treatment failure (TTF), patients with a high lymphoma load (>0.01) demonstrated a significant lower TTF (median 2.8 years) compared to patients with levels <=0.01 (median not reached at a median observation time of 27 months, p=0.0396).
MRD quantification after CHOP induction demonstrated a significant reduction of about 2 logs of lymphoma cells (p=0.0021) in PB, but the majority of patients (77%) remained MRD positive. R-CHOP removed lymphoma cells more efficiently (>2 logs) inducing a molecular remission (MR) in 76% (p<0.0001). Achievement of MR after induction tended to correlate with improved PFS (PFS at 2 years MRD+ 53%, MRD neg. 90%, p=0.068).
Conclusions: Quantitative assessment of circulating t(14;18)+ in diagnostic PB as well as after treatment has demonstrated prognostic relevance and can be used as a surrogate marker for clinical outcome of patients with FL. The results provide further evidence for the value of RQ-PCR based MRD assessment and demonstrate that achievement of MR is one of the major goals in the therapy of FL.
Serum Free Light Chain (SFLC) Elevation Is Associated with High β2-Microglobulin and with a Shorter Time to Treatment in Waldenström Macroglobulinemia (WM).
Authors: Itzykson Raphael , Le Garff-Tavernier Magali , Katsahian Sandrine , Diemert Marie-Claude , Guis Laurence , Choquet Sylvain , Musset Lucile , Leblond Veronique 
Published: October 2019

Abstract
WM is a rare lymphoproliferative disorder caracterised by bone marrow lymphoplasmacytic infiltration with IgM monoclonal gammopathy. Assessing the tumor burden in WM is challenging and is not directly related to IgM level or bone marrow infiltration. Thus treatment criteria are based on clinical symptoms related to IgM or pancytopenia. SFLC quantification is a useful tool for the diagnosis and follow-up of gammopathies such as amyloidosis and light chain myeloma. So far its quantification has never been studied in WM. We investigated whether SFLC quantification was correlated with monoclonal component value and established prognostic factors, or was predictive of a shorter time to treatment.
We analyzed 45 untreated WM patients (IgMκ: 37; IgMλ: 8) at the time of diagnosis (n=23) or during the follow-up (n=22). Patients were assessed for physical examination, body CT scan, serum protein electrophoresis with albumin (g/l) and monoclonal component (g/L) measurements, SFLC level (The Binding Site®, cut-off: SFLCκ 19.4 mg/L and SFLCλ 26.3 mg/L), peripheral blood count and β2-microglobulin (β2-m). Cut-off values of prognostic factors were those defined by the International Prognostic Index for WM (Morel ASH 2006) ie. β2-m > 3mg/L, Hb < 115 g/L, platelets < 100 G/L, albumin < 35 g/L. Treatment was initiated at diagnosis in 7 patients or during the follow-up in 23 patients. Median follow-up for the whole population was 15 months (1 – 74).
Median SFLCκ value was 39 mg/L (1.73–399), median SFLCλ was 12.6 mg/L (1.93–19400). 75 % of patients had upper to normal SFLC value (34/45). Table 1 summarizes univariate analysis of (1) the relationship between high SFLC value (SFLC > N) and known biological prognostic factors, and (2) the impact of SFLC > N and other biological parameters on time to treatment. Our results showed that high SFLC correlated with β2-m but not with other biological prognostic factors or with monoclonal IgM value. (2) Patients with SFLC > N had a shorter time to treatment than patients with normal SFLC value. Furthermore, taking SFLC as a continuous variable in patients with SFLC > N, treatment time was strongly correlated to the SFLC quantification (κ: p=0.01; λ: p=0.01). SFLC could thus be used as a new marker of tumor burden in WM and its prognostic value must be tested in larger WM series. The correlation between SFLC variation and response to treatment is still under investigation.
Table 1 SFLC > N (1) time to treatment (2) SFLC > N NA p=0.03 monoclonal IgM value p=0.08 p=0.001 β2-m > 3 mg/L p=0.03 p=0.44 Hb < 115 g/L p=0.43 p=0.009 Platelets < 100 G/L p=1 p=0.36 Albumin < 35 g/L p=0.3 p=0.011
Infectious Disease Associations in Advanced Stage, Indolent Lymphoma (Follicular, FL and Non-Follicular, nFL): Developing a Lymphoma Prevention Strategy.
Authors: Portlock Carol S. , Hamlin Paul A. , Noy Ariela , Palomba Maria Lia , Rosenzweig Lisa , Walker Darren , Corcoran Stacie , Chey William D. , Gaydos Charlotte A. , Schwartz Ira , Papanicolaou Genovefa , Markowitz Arnold 
Published: October 2019

Abstract
Background: The antigen-drive association of gastric MALT lymphoma with H. pylori is well recognized. Successful antibiotic therapy can result in lymphoma remission, and with it, lymphoma prevention. We have sought to prospectively identify possible associated infections in patients with non-bulky, advanced stage indolent lymphoma as the first step to such a lymphoma treatment/prevention strategy. These patients are often candidates for “watch and wait” and it is during this period that a window of opportunity may exist to identify and treat related infections.
Methods: Patients with a new diagnosis of indolent lymphoma (FL and nFL), stages II (intra-abdominal), III and IV fulfilling GELF criteria for observation were eligible. Studies performed: Stool H. pylori, Hepatitis C and Borrelia serologies, Borrelia and Chlamydia fixed tissue PCR, peripheral blood mononuclear cell PCR for Chlamydia, and a hydrogen breath test for small bowel bacterial overgrowth.
Results: 55 patients have been enrolled with IRB informed consent: 32 females, 23 males; median age, 54 years (21–77); 30 FL, 25 nFL; stage II (4 pt), III (22), and IV (29). All met GELF criteria for observation. Infections tested include: H. pylori (13 positive: 6 FL, 7 nFL); Hepatitis C (3+; 1 FL, 2 nFL); and small bowel bacterial overgrowth (10+; 4 FL, 6 nFL). Borrelia serologies and tissue PCR were negative in all 13 pts tested. Chlamydia psittaci tissue PCR positive in 1 FL (12 negative). Thus, 20 of 54 (37%) patients have had at least one positive study; and, to date we have observed lymphoma responses after successful antibiotic therapy alone in 6 of 20: H. pylori (1 FL with CRu for 20+ months; 1 nFL with transient near CR); Hepatitis C (1 FL with PR but HCV persistent; 2 nFL (1 CR for 24+ mos; 1 stable, currently on HCV therapy); SBBO (1 FL in PR for 28+ mos). Of interest, the patients with associated infections but without lymphoma response to antibiotics, appear to have required institution of lymphoma treatment sooner than those without initial associated infections (Treatment free survival 48% vs. 87.5%, p=0.08; 33 months median f/u from diagnosis), possibly suggesting a different biology.
Conclusion: Infections are common in advanced stage indolent lymphoma (37% in our series). Anecdotal lymphoma responses have been seen and 2 have been durable CRs (10%) ongoing for 20+ mos following infection eradication alone. The identification and treatment of associated infections may be a first step toward developing a lymphoma prevention strategy.
Acquired Immunodeficiency and Malnutrition in Patients Treated with Bi-Weekly CHOP-Based Chemotherapy for Diffuse Large B-Cell Lymphoma.
Authors: Tholstrup Dorte , Hansen Mads , De Nully Brown Peter , Jurlander Jesper 
Published: October 2019

Abstract
During the recent years CHOP-14/CHOEP-14 in combination with the monoclonal anti-CD20 antibody Rituximab has become the standard choice of treatment for non-localized, poor risk Diffuse Large B-Cell Lymphoma. We, and others, have observed a relative high incidence of opportunistic infections not normally associated with the short neutropenic periods of CHOP-based treatment. We therefore introduced a prospective risk-assessment study in February 2005. The aim of the study is to assess the degree of malnutrition and immunodeficiency that may be associated with bi-weekly regimens. This is a preliminary evaluation of the first 27 patients included. Median age was 60 (31–80), 21 (78%) had CS III/IV disease, 14 (52%) extranodal involvement, 19 (70%) elevated LDH, 9 (33%) a Performance Score ≥2, i.e.13 (48%) presented with IPI 3–5 disease. Furthermore, 7 (26%) had bone marrow involvement, 8 (30%) bulky disease and 17 (63%) B-symptoms. All patients received 6 or 8 cycles of CHOP-14/CHOEP-14, and 15 patients received Rituximab at day 1 of each cycle. Patients were examined four times: 1) before 1st cycle, 2) 14 days after 4th cycle, 3) 14 days after last cycle (i.e. 6th or 8th), and 4) 3 months after treatment. Examination included blood tests, bodyweight and DEXA-scans. 20 patients (74%) had a significant weight loss during treatment. However, 3/4 had regained normal weight three months later. Consistently, DEXA-scans demonstrated a significant reduction in total lean body mass in 12 (44%) patients. P-protein, p-albumin, and selected trace elements were decreased in about 1/4 of patients during treatment. However, most patients had significant declines in T-cell levels during treatment, and interestingly about 1/4 presented with very low T-cell levels at diagnosis. Thus, total CD3-count was low in 7 (26%) patients at diagnosis, and reduced under treatment in 23 (85%). Both CD4- and CD8-count was low in 6 patients at diagnosis, while CD4 was reduced under treatment in 24 and CD8 in 16 patients. Likewise, a significant decrease of IgA, IgM, and IgG subclasses developed during treatment (Table 1). We conclude that patients treated with bi-weekly CHOP-chemotherapy may develop severely decreased levels of T-cells and severe hypogammaglobulinemia, which may be related to an increased incidence of opportunistic infections such as PCP or CMV reactivation.
GMCLI, Goelams Mantle Cell Lymphoma Index, a New Prognostic Index of Survival for MCL Patients Treated with VAD-C and Autologous PBSCT.
Authors: Gressin Remy , Maugendre Sylvie Caulet , Deconinck Eric , Tournilhac Olivier , Dartigeas Martine , Moles Marie Pierre , Lepeu Gerard , Guyotat Denis , Legouffe Eric , Dugay Jacqueline , Martin Claude , Casassus Philippe , Pierre Jean , Ghandour Christiane , Grulois Isabelle , Maloisel Frederic , Le Maignan Christine , De Jaureguiberry Jean Pierre , Thyss Antoine , Lucas Virginie , Cailleres Sylvie , Rodon Philippe , Dutel Jean Luc , Colombat Philippe , Gyan Emmanuel 
Published: October 2019

Abstract
The treatment of Mantle Cell Lymphoma (MCL) and the predictive variables of response to chemotherapy and survival are largely discussed. The French Goelams group conducted between 1996 and 2000, a first line phase II prospective trial for MCL patients to test the efficacy of the VAD+C regimen, explore the effect of ASCT on patients under 60 and identify prognostic factors.
Treatment: it consisted for the first step of 4 cycles of VAD+C regimen (classical VAD with vincristine, adriblastine, dexamethasone associated with chlorambucil 12 mg/D from D20 to D29. interval between two cycles 35 days). The responders (cheson criteria) went to the second step wich consisted of 4 other VAD+C regimen for patients over 60 years or for patients under 61 years, 2 other VAD+C regimen followed by a ASCT with preparative regimen including Alkeran 140 and a 8 grays TBI.
Results: 90 patients were included and finally 74 retained after the pathologic review. Fifty (78%) were common forms and 24 blastoid variants. For the 74 eligible patients (40 under 61years and 34 over 60), the ORR after 4 cycles of VAD+C was 73% and 46% of the patients were in CR/CRu. ASCT influenced significantly the PFS, with a median survival of 20 months for non transplanted patients versus 37 months for ASCT recipients (p=0,001) and showed a tendency for a better OS (p=0.07). Six independent prognostic factors (PF) were identified as influencing OS: blastic variants, LDH level, lymphocytosis>5G/L, MIB1proliferation index, performance status and B symptoms. This allows to propose a new prognostic index which stratifies patients at diagnosis into 3 prognostic groups, with 0 or 1 PF (n=34, 46%), 2 or 3 PF (n=29, 39%) and 4 or more PF (n=11, 15%). For these three groups, median OS was respectively of 68, 41 and 7 months (p=0.0001).
Conclusion: The VAD+C regimen thus appears as a good regimen for MCL with few prognosis factors, which can effectively be completed by an ASCT for young responders’ patients.
FcγRIIIa Gene Polymorphisms May Correlate with Response to Frontline R-CHOP Therapy for Diffuse Large B-Cell Lymphoma.
Authors: Kim Dong Hwan , Jung Hee Du , Sohn Sang Kyun , Lee Je-Jung , Yang Deok-Hwan , Park Yeon Hee , Do Young Rok , Shin Ho Jin , Hyun Myung Soo 
Published: October 2019

Abstract
Background: The precise mechanism of rituximab (R) plus CHOP (R-CHOP) therapy in diffuse large B-cell lymphoma (DLBCL) is not fully elucidated. Besides overcoming bcl-2 mediated chemoresistance, antibody-dependent cellular cytotoxicity (ADCC), which is activated by effector cells via IgG fragment C receptors (FcR), was also proposed as a mechanism of Rituximab. The current study evaluated the impact of FcR polymorphism on the response to R-CHOP therapy for DLBCL with the basis that FcR polymorphism can affect R’s affinity for ADCC effector cells.
Patients and Methods: The FcγRIIIa and FcγRIIa gene polymorphisms were determined in DLBCL patients receiving R-CHOP (n=113) comparing to CHOP therapy (n=85).
Results: The FcγRIIIa valine (V) allele was significantly correlated with higher complete response rate to R-CHOP compared to phenylalalnine (F) allele (88% in V/V versus 79% in V/F versus 50% in F/F, p=0.002), while no difference was found between FcγRIIa polymorphism. In addition, V/V allele was associated with faster achievement of response than other alleles. The impact of FcγRIIIa gene polymorphism on response rate was not noted in CHOP group. In terms of overall or event-free survival, no difference was found according to FcγRIIIa or FcγRIIa alleles.
Conclusion: The FcγRIIIa SNP is predictive of response to R-CHOP, but does not correlate with survival in DLBCL patients.