bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lymphocyte Count Persistence and Early Recovery Predicts Superior Survival and Is Independent of the International Prognostic Index in Patients Treated with CHOP Chemotherapy for Diffuse Large B Cell Lymphoma.
Authors: Porrata Luis F. , Ristow Kay M. , Markovic Svetomir N. , Persky Daniel , Habermann Thomas M. 
Published: October 2019

Abstract
The peripheral blood absolute lymphocyte count (ALC) post-autologous stem cell transplantation is an independent predictor for survival in non-Hodgkin’s lymphoma. The role of ALC recovery during and after standard CHOP chemotherapy for newly diagnosed diffuse large B cell lymphoma (DLBCL) has not been reported. We hypothesized that ALC recovery during/after CHOP chemotherapy has a direct impact on survival. 135 consecutive newly diagnosed patients with DLBCL treated with CHOP from 1994 through 2000 were retrospectively analyzed. The primary end point was to assess the role of ALC recovery during and after CHOP on progression-free survival (PFS) and overall survival (OS). The ALC recovery before each of the 6 cycles and at 3 months follow-up after completion of therapy were analyzed. Of the 135 patients, 41 patients received concomitant radiation therapy. The median age was 64 years (range: 21–83) and median follow-up was 46 months (range: 1–124). Superior OS and PFS were identified in patients achieving the ALC cut-off value that discriminated clinical outcomes at a high level of significance for blood counts obtained before cycles 1 (ALC ≥ 1.5 x 109/L, OS = not reached vs 54 months, p< 0.0048; PFS = not reached vs 23 months, p <0.0005), 2 (ALC ≥1.5 x 109/L, OS = not reached vs 59 months, p <0.0255; PFS = not reached vs 30 months, p <0.0082), 3(ALC ≥1.2 x 109/L, OS = not reached vs 59 months, p<0.0074; not reached vs 30 months, p <0.0060), and at 3 months (ALC ≥ 1.2 x 109/L, OS = not reached vs 60 months, p< 0.0080; PFS = not reached vs 42 months, p < 0.0017). Similar cut-off points for cycles 4 through 6 could not be identified. The ALC recovery between each cycles 1–3 and at 3 months were not independent of each other. Multivariate analysis demonstrated ALC for cycles 1–3 and at 3 months post CHOP to be independent prognostic factor for OS and PFS when compared to other significant prognostic factors including International Prognostic Index and radiation therapy. Patients were stratified into three groups based on whether or not they achieved cut-off values of ALC in the first 3 cycles: group I= ALC achieved in at least 2 of 3 cycles; group II= ALC achieved in only 1/3 cycles; and group III= ALC cut-off not achieved. A trend towards worse OS (p< 0.0035) (Figure 1) and PFS (p< 0.0003) was identified if patients did not achieve any of the cut-off values of ALC in the first 3 cycles. These data further support the hypothesis that there is a critical role of lymphocyte (immune) recovery during and after CHOP chemotherapy in DLBCL.
FoxP3, a Key Molecule in CD4+CD25+ Regulatory T Cells, Express in Adult T Cell Leukemia/Lymphoma Cells and Relates to Clinicopathological Features.
Authors: Karube Kennosuke , Ohshima Koichi , Suzumiya Junji , Harada Mine , Kikuchi Masahiro 
Published: October 2019

Abstract
AIMES: Adult T cell leukemia/lymphoma (ATLL) is an aggressive neoplastic disease and opportunistic infections often occur in patients with ATLL. However, the underlying mechanisms of such infections remain unknown. Recently, regulatory T cells (Treg), characterized by coexpression of CD4 and CD25, are proposed as a new T cell group with definite function. Treg suppresses normal T cells proliferation in vitro and play an important role to suppress autoimmune disease in vivo. But the deregulated proliferation such immunosuppressive T cells may induce immunodeficient status. We analyzed the expression of forkhead/winged helix transcription factor (FoxP3), known to be important for the function and specific marker of Treg cells, on ATLL cells.
METHODS and RESULTS: FoxP3 expression was detected in both peripheral blood and lymph nodes in part of ATLL cases by real-time PCR and immunostaining (Figure). Next, we immunostained lymph node sections from 112 cases and 36 cases showed positivity for FoXP3. Morphologically, 112 ATLL cases were divided into three variants, namely pleomorphic cell type (61 cases), large cell type (45 cases), and anaplastic large cell type (16 cases). FoxP3 was expressed (more than 30% of the lymphoma cells) in a proportion of pleomorphic cell type (24 cases, 39.4%) and large cell type (12 cases, 26.7%) but no cases of anaplastic type showed positivity. Especially, strong expression (more than 50% of the lymphoma cells) was observed in 15 cases and 12 cases were pleomorphic cell type (Table). A proportion of FoxP3 positive ATLL cases showed intermingled EBV-infected transformed lymphocytes, suggesting local immunodeficient condition (Very few FoxP3 negative cases showed EBV-infected lymphocytes)(Table). Clinically, more proportion of FoxP3 positive ATLL cases showed opportunistic infection, for example Pneumocystis Carinii infections, Herpes zoster virus infection, antibiotics-refractory abscesses (Table).
CONCLUSION: A proliferation of FoxP3 positive lymphoma cells may contribute to the tumor invasion and opportunistic infection by inducing local and diffuse immunodeficient status respectively.
Figure Figure
PKC-beta 2 Protein Expression Predicts for Poor Response to Chemotherapy and Survival in Patients with Low Risk Diffuse Large B-Cell Lymphoma.
Authors: Espinosa Inigo , Briones Javier , Bordes Ramon , Brunet Salut , Martino Rodrigo , Sureda Ana , Prat Jaime , Sierra Jorge 
Published: October 2019

Abstract
The protein kinase C (PKC) superfamily includes conventional PKCs (alfa, beta 1, beta 2, and gamma) and PKC-mu. PKC plays an important role in the activation and survival of B cells. Recent studies using cDNA microarrays found that PKC-beta was overexpressed in refractary diffused large B-cell lymphoma (DLBCL). The purpose of this study is to analyze the clinical significance of PKC-beta 2 protein expression in a homogeneous series of patients with DLBCL. Seventy-six patients with primary DLBCL consecutively diagnosed between 1991 and 2002 were studied. The median age of patients was 58 years (range, 11–18 years), 30 women and 46 men. Advanced stage (III/IV) was observed in 36 cases (47%). Of 71 patients with available date, 36 (50%) presented with high serum lactic acid dehydrogenase (LDH) levels. The distribution according to the International Prognostic Index (IPI) (n = 71) was as follows: low risk, 32 cases (43%); low/intermediate risk, 17 cases (23%); high/intermediate risk, 8 cases (11%); and high risk, 14 cases (19%). All patients received an anthracycline-containing chemotherapy regimen. Formalin-fixed, paraffin-embedded tissue from 76 DLBCL tumors were immunostained with a monoclonal antibody against PKC-beta 2 protein. Tumors were considered positive for PKC-beta 2 if 5% o more of the tumor cells expressed the protein. The main clinical features (B symptoms, Ann Arbor stage, bulky disease, bone marrow disease, high LDH, IPI, and ECOG) of patients within the PKC-positive group were similar to those within the PKC-negative group. Twenty-six cases (34%) were positive for PKC-beta 2 protein. Within the patients whose tumors were PKC-positive, only 8 of 26 (31%) had a complete clinical remission, while that was achieved in the majority (31 of 50; 62%) of the PKC-negative patients (p = 0.015). Patients with PKC-positive tumors had a lower five-year disease free survival (DFS) (30% vs. 60%; p = 0.03) than the PKC-beta 2 negative group. Moreover, patients with low IPI whose tumors expressed PKC-beta 2 protein had an inferior five-year DFS (39% vs. 80%; p = 0.0046). Multivariate analysis confirmed the independent adverse prognostic value of PKC expression (OR = 3.7 [95%CI, 1.4–9.9]; p = 0.007) in patients with DLBCL and low IPI. These results indicate that PKC-beta 2 expression on DLBCL predicts for a low response rate to chemotherapy and unfavorable clinical outcome, specially in those patients with low IPI.
Histologic Subtypes Do Not Confer Unique Outcomes in Early-Stage Lymphoma: Long-Term Follow-Up of SWOG 8736.
Authors: Spier Catherine M. , LeBlanc Michael , Chase Ellen M. , Fisher Richard I. , Miller Thomas P. 
Published: October 2019

Abstract
Analysis of patients with advanced non-Hodgkin’s lymphoma (NHL) suggests unique clinical presentations and outcome according to histologic subtype. Little is known of outcome as it relates to histologic subytpe in patients with limited disease. In a previous report (NEJM1998;339:21–6), 401 patients with limited disease (Stage I or non-bulky II) intermediate or high grade NHL, enrolled in SWOG study 8736, were randomized to chemotherapy or chemotherapy plus radiotherapy. Results at 5 years showed superior survival and less toxicity for those treated with 3 cycles of CHOP chemotherapy plus radiotherapy. These 401 patients, with additional followup and reclassification of histology according to World Health Organization (WHO) criteria, form the basis of the current report. Of the 401 pts, 2 were excluded because of clinical findings and 34 patients were excluded for insufficient pathology material. 365 pts were evaluable. On the basis of hematoxylin-eosin and immunohistochemistry results, pt cases were classified as diffuse large B cell (174pts), follicular, Grade 3 (36), Burkitt-like (27), peripheral T cell, unspecified (9), anaplastic large T cell (4), morphologically consistent with mantle cell (4), morphologically consistent with MALToma (3), morphologically diffuse small cleaved cell (2), unclassifiable (1), suggesting anaplastic large cell CD30+ (1), diffuse large cell without immunohistochemical results (104). At 10 years, there was no significant difference in overall survival (OS) or failure free survival (FFS) between the 2 treatments (OS, p=0.48; FFS, p=0.77) (Blood2001;98:724a). When analyzed by histology, including T lineage, neither OS nor FFS were different for any histologic subytpe (OS, p=0.94; FFS, p=0.99). In addition, the estimated shapes of the survival curves were similar for all histologic subtypes among these 365 evaluable pts. On the basis of these findings it does not appear that either the WHO or the Working Formulation (WF) classification system is able to predict outcome for limited stage disease pts treated with CHOP +/− radiotherapy. Therefore, histologic type should not be a criterion for exclusion for limited stage studies of lymphoma. Further, it does not appear that any histologic subtype presenting as early stage disease needs CNS prophylaxis or a unique chemotherapy treatment strategy. There was only one central nervous system (CNS) relapse (in a patient with testis involvement), and none among the 27 Burkitt-like pts. The lack of an observed survival plateau in the first 10 years of followup for these pts is in contrast to advanced stage pts who achieve a plateau within 6 years. The biology of limited stage lymphoma may be fundamentally different from that of advanced stage disease and more significanct in determining outcome than histologic type.
Clinical Relevance of Soluble HLA-I as Compared to b2-MicroglobulinLevels in Non-Hodgkin’s Lymphoma and Hodgkin’s Disease.
Authors: Albitar Maher , Vose Julie M. , Johnson Marcella M. , Do Kim-Ann , Day Amanda , Jilani Iman , Kantarjian Hagop , Keating Michael , O’Brien Susan M. , Verstovsek Srdan , Armitage James O. , Giles Francis J. 
Published: October 2019

Abstract
Higher levels of b-2 microglobulin (b2-M) have been reported to correlate with poor outcome in non-Hodgkin’s lymphoma (NHL) and Hodgkin’s disease (HD). However, b2-M is a subunit of the human leukocyte antigen-class I (HLA-I) molecule, which is composed of b2-M and the alpha heavy chain. Although soluble HLA-I (sHLA-I) protein has been detected in circulation and is believed to play a role in immunomodulation by inducing apoptosis in cytotoxic T-lymphocytes, the clinical relevance of sHLA-I levels in HD and NHL is not known. Here we report that serum sHLA-I levels are increased in NHL and HD. More importantly, levels of sHLA-I correlate with clinical behavior in NHL in a fashion similar to that of b2-M. In a multivariate model incorporating b2-M, sHLA-I, and IPI (International Prognostic Index), NHL patients with sHLA-I levels >312.60 mg/mL had significantly shorter survival than those with lower levels, independent of IPI score. Moreover, a model incorporating both sHLA-I (cut-point = 312.60 mg/mL) and b2-M (cut-point = 4.16 mg/L) levels were highly predictive of survival (Figure) in NHL patients. In contrast, in HD, b2-M levels correlated with clinical behavior whereas HLA-1 levels did not. These data not only establish the role of sHLA-I as an independent tumor marker in NHL that can be used to stratify patients, but also suggest that, in HD, b2-M and sHLA-I may reflect different processes. The role of sHLA-I as an immunomodulator may be responsible for its divergence from b2-M as an indicator of clinical behavior in HD. Further studies exploring the importance of this role in the biology of HD are needed.
Figure Figure
CpG Combined with Chemotherapy in the Immunotherapy of Large Tumor.
Authors: Li Jiali , Levy Ronald 
Published: October 2019

Abstract
Unmethylated cytosine-phosphorothioate-guanine nucleotides (CpG) are immuostimulators that can activate both innate and adaptive immunity. By binding to its receptor, TLR9, CpG can activate dendritic cells and B cells by inducing the secretion of cytokines, and increasing the expression of costimulatory molecules, such as CD80 and CD86. In this study, a B type CpG, CpG1826, was given intratumorally in an A20 lymphoma animal model. CpG alone can delay the growth of tumor in this model, however, the majority of the treated tumor-bearing mice still die, and it has very little effect on systemic tumor cells. Here we propose a new therapeutic strategy, a combination of cyclophosphomide (CTX), followed by subsequent intratumoral injection of CpG. BALB/c mice were inoculated s.c. with 107 A20 cells in the lower back, and treatment started on day 17 when tumor reached approximately 1.0 cm in diameter. CTX (100mg/Kg) was given i.p. on day 17 and 18, and for the groups that received CpG, CpG was injected intratumorally on day 19,20,21,24, and 26 with 100μg/dose. As shown in Fig.1, the combination of CTX with CpG could cure well-established large size (>1.2cm in diameter) tumor, and mice remained tumor-free 5–6 months after the initial treatment. Conversely, the majority of mice that received CTX or CpG alone died of lymphoma. Tumor-free mice from this combined maneuver are protected from a lethal dose of A20 challenge even 5 months after the initial treatment. Our studies also showed that this combination is site dependent, as CTX combined with intratumoral injection of CpG had a much better therapeutic effect (100% survival), as compared to injection of CpG into a distant normal site (20% survival). Our studies also indicated that this combined maneuver is CD8+T cell dependent, as no therapeutic effect was observed when we repeated this experiment in a CD8+ T cell knockout model. We also demonstrated the systemic effect of this combination strategy in mice bearing tumors at two different sites. In combination with CTX, injection of one site with CpG controlled the growth of the second site tumor as opposed to a transient effect from chemotherapy or CpG alone. This led to significant prolongation of overall survival (Fig.2). In summary, we have shown that this combined chemoimmunotherapy strategy can cure both local and systemic tumor, which may provide a powerful antitumor therapy in the clinic.
Figure Figure
Development of Effective Immunotherapy for B-Cell Non-Hodgkin’s Lymphoma with CD19-Specific Cytotoxic T Cells.
Authors: Mihara Keichiro , Yanagihara Kazuyoshi , Imai Chihaya , Kimura Akiro , Campana Dario 
Published: October 2019

Abstract
Less than 60% of patients with B-cell non-Hodgkin’s lymphoma (B-NHL) can be cured with contemporary therapy. Using artificial receptors it is possible to redirect the specificity of immune cells to tumor-associated antigens, a strategy that holds great potential as a novel cancer therapy. Since B-NHL cells invariably express CD19, we transduced human peripheral blood T lymphocytes with a recently developed receptor (anti-CD19-BB-ζ), which consists of the single-chain variable domain (scFv) of an anti-CD19 monoclonal antibody, the hinge and transmembrane domains of CD8α, and the signaling domains of CD3ζ and 4-1BB. CD3ζ delivers the primary stimulus upon receptor engagement, while 4-1BB delivers co-stimulatory signals that are crucial for T-cell cytotoxicity. It has been shown that elicitation of 4-1BB signaling enhances the immune response to tumors in vivo, even when an immune response cannot be induced by CD28 stimulation. Retroviral transduction led to anti-CD19-BB-ζ expression in T cells with high efficiency: median percent of transduced cells was 60.3% (range, 25.7%–83.4%; n = 9). T lymphocytes expressing anti-CD19-BB-ζ expanded more vigorously that T cells transduced with receptors lacking 4-1BB and exerted powerful cytotoxicity against the CD19+ B-NHL cell lines Raji, Daudi, RL, and HT in vitro: at a 0.5: 1 effector: target ratio, mean (± SD) cell specific lymphoma cell killing was 96.6% ± 4.6% after 5–7 days of culture (4 experiments in each cell line). Transduced T cells were also effective against freshly isolated cells from patients with diffuse large, follicular large, Burkitt, and mantle cell lymphoma cultured on bone marrow-derived mesenchymal cells: in 10 samples, cell killing was 93.6% ± 5.7% at a 0.5: 1 ratio after 5–7 days of culture. Sensitivity to anti-CD19-BB-ζ-mediated killing was observed regardless of high Bcl-2 expression. T cells expressing anti-CD19-BB-ζ were also effective in a xenograft model of NHL, in which NOD/SCID mice were inoculated subcutaneously with lymphoma cells (1 x 107). Subsequent inoculation of T cells (2 x 106) transduced with anti-CD19-BB-ζ receptors significantly suppressed tumor growth, whereas inoculation of T cells transduced with empty control vector had no effect (3 mice for each treatment). These results provide a rationale for clinical testing of autologous T cells modified with anti-CD19-BB-ζ receptors in patients with aggressive or relapsed B-NHLs refractory to conventional therapy.
GCS-100, a Galectin 3 Antagonist, Is a Novel Caspase-9 Apoptosis Activating Agent for the Treatment of Indolent B-Cell Malignancies.
Authors: Cotter Finbarr E. , Su Bo , Corbo Margherita , Chang Y. , Schindler Joanne , Carver Brad , Fegan Christopher D. , Newland Adrian C. , Auer Rebecca L. 
Published: October 2019

Abstract
Introduction: GCS-100 is a novel polysaccharide agent derived from natural citrus pectin with the ability to inhibit Galectin 3 (Gal-3). It has demonstrated anti-cancer activity and has been administered to patients with solid tumors in a Phase I study demonstrating a good safety profile and a lack of myelosuppression. It has been reported to have three major pharmacological effects: anti-metastatic, anti-angiogenic and pro-apoptotic. This study has investigated the mechanism of induction of apoptosis by GCS-100 for therapeutic benefit in indolent B-cell lymphomas.
Material and Methods: GCS-100 was tested in varying doses with B-cell lymphoma and leukaemia cell lines including the DoHH2 (t(14;18)), Ramos (high and low Bcl-2 expression), BV173 (t(9;22)) and K562 cell lines, primary patient CD19 selected CLL cells and normal B-cells in short term cultures. The addition of chemotherapy post GCS-100 was then undertaken to investigate enhanced anti-tumor activity. Apoptosis was assessed by a number of parameters including mitochondrial transition pore permeability (MTPP) by DiOC6, caspase-8 and -9 activation by western analysis and membrane blebbing by MC540. Gal-3 expression was measured by western analysis and flow cytometry.
Results: The ability of GCS-100 to induce significant apoptosis in both malignant cell lines and primary patient CLL cells in vitro is clearly demonstrated with a minimal effect against normal B-cells (and stem cell cultures). The induced apoptotic pathway is the intrinsic mitochondrial and caspase-9 pathway. In addition, GCS-100 at low dosage will greatly enhance the apoptotic effect of chemotherapy, even in the presence of high levels of anti-apoptotic proteins such as Bcl-2. Immunoprecipitation has shown Bcl-2 binds to Gal-3. Gal-3 expression was increased in the malignant cells compared to the normal B-cells and could explain the selective activity.
Discussion: Gal-3 is a member of the b-galactoside-binding protein family that play significant roles in cellular interactions, cell growth, differentiation, resistance to apoptosis and loss of cell anchorage (anoikis). It shares the highly conserved BH1 functional receptor domain (NWGR) of the Bcl-2 gene family within its carbohydrate binding domain. The potential binding of GCS-100 to this region suggests this as its pro-apoptotic mechanism in B-cell malignancies. As shown in this study, normal B-cells with lower Gal-3 expression do not show significant apoptosis indicating GCS-100 is a selective anti-tumor agent. The possibility of using GCS-100 as an anti cancer agent, either alone or in combination with chemotherapy is suggested by this study. Its activity against indolent B-cell malignancies, such as follicular lymphoma (DoHH2 cell line) and CLL is particularly marked; a Phase 1 study is underway.