Association of Increased Thymidine Uptake Relative to Tumor Cell Proliferation in Low-Grade Follicular Lymphoma and DNA Repair.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3236-3236
Author(s):  
Malik E. Juweid ◽  
Sergei I. Syrbu ◽  
Michelle Bleile ◽  
Andreas Buck ◽  
Marielle Wondergem ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Repair ◽  
Dna Replication ◽  
Follicular Lymphoma ◽  
Germinal Center ◽  
Staining Pattern ◽  
Low Grade ◽  
Ki 67 ◽  
High Contribution ◽  
Thymidine Analogs

Abstract Abstract 3236 Poster Board III-173 We have observed that the uptake of the thymidine analog 18F-fluorothymidine (FLT) is highly disproportional to cellular proliferation in untreated low-grade follicular lymphoma (FL). Since the uptake of thymidine/thymidine analogs is also increased with enhanced DNA repair synthesis, we investigated whether the “excess” uptake of FLT in FL may be related to DNA repair. We stained tumor samples from 20 patients each with grade 1 FL and DLBCL for Ki-67, a marker of cell proliferation and DNA replication but not DNA repair and 2 DNA replication and repair biomarkers: proliferating cell nuclear antigen (PCNA) and replication protein A (RPA). Median %Ki-67-positive cells (Ki-67 index) was 10% (range; 5-20%) in FL compared to 80% (range 60-90%) in DLBCL (P<4×10-20). In contrast, median %positive cells for PCNA and RPA were 90% and 100% in FL and 100% and 100% in DLBCL. In both FL and DLBCL, PCNA showed a characteristic staining pattern with 3+ or 4+ staining of the proliferating Ki-67-positive cells vs. 1+ to 2+ staining of quiescent cells. Similar results were obtained when staining for thymidine kinase I (TK1). Interestingly, similar staining pattern to that seen in lymphoma samples was seen in germinal center but not mantle zone cells of normal tonsils and reactive lymph nodes indicating that the DNA repair seen in both FL and DLBCL is likely related to somatic hypermutations (SHM) generated by error-prone DNA repair known to occur in FL, most DLBCLs and normal germinal center cells. Comparison of FLT uptake in FL and DLBCL indicated that > 70% of FLT uptake in FLs with a Ki-67 index of ≤10% was due to DNA repair. In contrast, contribution of DNA repair to overall FLT uptake in DLBCL with a Ki-67 index of ≥ 80% was <10% presumably due to the 4-fold lower fraction of quiescent compared with proliferating cells with high replicative DNA synthesis. This is the first demonstration of a high contribution of SHM/DNA repair to overall uptake of thymidine/thymidine analogs in low-grade FL. Our data further suggest that FLT use for assessing response to cytostatic therapy in low-grade FL will be confounded by this high contribution and highlights the pitfalls associated with the use of PCNA or RPA to assess proliferative activity in FL and DLBCL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Case Report: Multiple Chromosomal Translocations Including Novel CIITA-CREBBP Fusion and Mutations in a Follicular Lymphoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Huan-You Wang ◽  
Ethan S. Sokol ◽  
Aaron M. Goodman ◽  
Andrew L. Feldman ◽  
Carolyn M. Mulroney
Keyword(s):  
Follicular Lymphoma ◽  
Mhc Class Ii ◽  
Fusion Gene ◽  
B Cell Lymphoma ◽  
Class Ii ◽  
Chromosomal Translocations ◽  
Proliferation Index ◽  
Low Grade ◽  
Creb Binding Protein ◽  
Ki 67

The pathogenesis of follicular lymphoma is a multi-step process, in which chromosomal translocation between immunoglobulin heavy chain (IgH) and anti-apoptotic B-cell lymphoma 2 (BCL2), namely IgH-BCL2, is an earliest step, followed by other genetic/genomic alterations including but not limited to mutation of CREB binding protein (CREBBP). MHC class II transactivator (CIITA) is a transcription regulator responsible for expression of MHC class II molecules including HLA-DR in human. We report herein a novel fusion gene involving CIITA and CREBBP in a patient with a low-grade follicular lymphoma (FL) but with high Ki-67 proliferation index. In addition, our patient also harbors CREBBP mutation. Together, we postulate that total loss of CREBBP function may contribute, in part, to the lymphoma genesis. Furthermore, this patient has addition rare (TBL1XR1-TP63) and common (IgH-BCL2) chromosomal translocations and multiple mutations including BCL2, BRAF, MUTYH, and STAT6.

Association of increase in thymidine uptake relative to tumor cell proliferation in indolent NHLs and DNA repair

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11116-11116
Author(s):  
M. E. Juweid ◽  
A. K. Buck ◽  
L. L. Ponto ◽  
F. M. Mottaghy ◽  
S. Syrbu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Repair ◽  
Tumor Cell ◽  
Treatment Options ◽  
Thymidine Uptake ◽  
Tumor Cell Proliferation ◽  
Ki 67 ◽  
Repair Synthesis ◽  
Standardized Uptake Values ◽  
Dna Repair Synthesis

11116 Background: Uptake of radiolabeled thymidine (tdR) or its analogs is frequently used to assess tumor cell proliferation as well as tumor DNA repair synthesis after inhibition of tumor cell proliferation with certain drugs. We determined whether the relationship between thymidine (td) uptake and tumor cell proliferation may be different between indolent and aggressive NHLs. Methods: Twenty-four patients with histologically confirmed aggressive (n=16; all DLC) or indolent NHLs (n=8; 7 FL gr I-II, 1 MZL) underwent pretherapy imaging with the td analog 18F-fluorothymidine (FLT) and biopsy to determine the proliferative cell fraction by the Ki-67 index. Tumoral FLT uptake was determined by the maximum standardized uptake values (SUVmax) and correlated with the Ki-67 index. The FLT-SUV to Ki-67 ratio was also compared between indolent and aggressive NHLs. Results: Disproportional increase in FLT-SUVmax relative to tumor cell proliferation was found in indolent NHLs: median %Ki-67 was 5% in indolent vs. 80% in aggressive NHL whereas median FLT-SUVmax was 3.6 vs. 9.4, respectively. The disproportional increase in FLT-SUV in indolent NHLs could not be explained by nonspecific FLT uptake in tumor extracellular space estimated to account for <0.2 SUV unit. Difference in the ratio of FLT-SUVmax to Ki-67 index between indolent and aggressive NHLs was highly significant (1.21 ± 0.77 vs. 0.18± 0.20; P=0.006). These data are in line with a previous study using tdR where the ratios of median tdR (in cpm) to median %-Ki-67 or %-S phase cells in indolent were ∼1.5x those in aggressive NHLs which was associated with relatively increased expression of DNA repair proteins (PCNA) in indolent NHLs (Holte et. al. Acta Oncologica, 1999) Conclusions: Disproportional increase in td uptake relative to %proliferating tumor cells in indolent NHLs likely reflects enhanced DNA repair in quiescent cells or, less likely, constitutively increased Tk1 expression. Studies are underway to determine expression of proteins that, unlike Ki-67, are associated with both DNA repair and replication (e.g., RFA, PCNA). If enhanced DNA repair is confirmed in indolent NHLs this could have major implications with respect to understanding their natural course and treatment options. No significant financial relationships to disclose.

Expression Of Histological markers and PET-CT Maximal Standardized Uptake for Follicular Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5058-5058
Author(s):  
Caroline Delette ◽  
Christine Robin ◽  
Jean-Fortuné Ikoli ◽  
Lazhar Saidi ◽  
Anne Parcelier ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Glucose Metabolism ◽  
Follicular Lymphoma ◽  
Tumor Cells ◽  
Glucose Transporter ◽  
Conflicts Of Interest ◽  
Standardized Uptake Value ◽  
Ki 67 ◽  
Glut 1 ◽  
Pet Ct

Abstract Background Follicular lymphoma is the second most common non-Hodgkin lymphoma subtype. PET-CT is a useful tool to evaluate staging and monitoring of follicular lymphoma. Calculation of maximal standardized uptake value (SUV max) is variable and related to the aggressiveness of lymphoma. In tumor cells, there is an increase in uptake and consumption of glucose. Therefore GLUT-1, a membranous glucose transporter, may have an impact on the SUV max. To our knowledge, data regarding eventual correlation between GLUT-1 and SUV in different subtypes of lymphoma is sparse (Hye Kyung Shim et al, Nuclear Medicine and Biology 2009; S. Hartmann et al, BMC Cancer 2012), especially in follicular lymphoma. In addition, Ki67, a marker of cell proliferation is also linked to the metabolism of tumors cells. Only few studies have shown a correlation between SUV max and Ki-67 in follicular lymphoma (Tomas Papjik et al, European Journal of Haematology 2010; Yi shou et al, Journal of Cancer Research and Therapeutics 2012). Elsewhere, it was demonstrated that microenvironment composed of dendritic cells, macrophages, T cells and vascular endothelium play a key role in the prognosis of follicular lymphoma (Pedro Farinha et al, Blood 2005), it could have also an impact on SUV max. The aim of our study was to identify histological markers involved in glucose metabolism, cell proliferation and microenvironment, influencing SUV max in follicular lymphoma. Materials and Methods Lymph node biopsies of 21 patients treated in our hematologic department at diagnosis and/ or relapse were retrospectively included. Patients underwent PET-CT and node biopsy simultaneously. Five histological markers (Ki67, GLUT 1, CD20 for B lymphocytes, CD3 for T lymphocytes, and CD68 for macrophages) were analyzed. Pathologists perform visually the immunostaining analysis without knowledge of the PET-CT results. Percentage of expression of immunological markers was compared with SUV max from the biopsy site. The correlation was analyzed using Spearman’s method to calculate the coefficient of correlation r. Results Ki-67 (median 40, range [3; 80]) and GLUT1 (median 53, range [0; 100]) were not related to the level of expression of the SUV max (respectively r = 0.3603 and p = 0.1086, r = 0.0215 and p = 0.9283). Concerning the microenvironment, CD68 (median 6, range [0; 18]) and CD3 (median 22, range [7; 60]) did not show any correlation (respectively r = 0.1370 and p = 0.5536, r = -0.2115 and p = 0.3708). Interestingly, percentage of CD20 expression (median 79, range [51; 99]) appears to be correlated significantly with the SUV max (r = 0.4924, p = 0.0274). Discussion and Conclusion In this study, it was not possible to identify a specific histological marker influencing the SUV max. Otherwise, interest in glucose metabolism and particularly other isoforms of GLUT receptor or enzymes involved in the metabolism, like hexokinase, appears to be a promising track. Considering that CD20 stains B tumor cell and normal B lymphocyte in the tumor, it could be interesting to analyze the ratio of CD20/CD10, assuming that all tumor cells express CD10. Disclosures: No relevant conflicts of interest to declare.

Expression of β-Catenin in Hepatocellular Carcinoma

2001 ◽  
Vol 71 (3) ◽  
pp. 116-125
Author(s):  
Norina Basa ◽  
Daniela Lazar ◽  
Remus Cornea ◽  
Sorina Taban ◽  
Melania Ardelean ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Cell ◽  
Mitotic Index ◽  
Histological Grade ◽  
Proliferation Index ◽  
Tumor Cell Proliferation ◽  
Ki 67 ◽  
B Virus ◽  
Development And Evolution

Alteration of β-catenin expression is involved in the development and evolution of hepatocellular carcinoma (HCC); β-catenin is able to influence tumor cell proliferation. We analyzed the immunohistochemical (IHC) expression of β-catenin on a group of 32 patients diagnosed with HCC using the anti-β-catenin monoclonal antibody (clone E247). We correlated the expression of β-catenin with the proliferation index of Ki-67 (PI Ki-67), the mitotic index (MI) and other clinical and pathological features. We observed an altered β-catenin expression in 58.38% of all HCC cases. This expression was insignificantly correlated with tumor size (]5 cm) (p = 0.683), histological grade G1-G2 (p = 0.307), vascular invasion (p = 0.299) and advanced pT stage (p = 0.453); we obtained a significantly higher MI in HCC with altered β-catenin expression (p = 0.018), as compared to HCC without overexpression (1.66 � 1.37) (p = 0.038) and a PI Ki-67 of 22.49 � 20.1 and 28.24 � 18.2, respectively in tumors with altered β-catenin expression with insignificant differences compared to HCC without overexpression (25.95 � 15.2) (p = 0.682 and p = 0.731, respectively). According to the results we obtained, aberrant β-catenin expression in HCC was correlated with a high mitotic index, therefore playing an important role in tumor progression by stimulating tumor cell proliferation; non-nuclear β-catenin overexpression can have a pathological significance in HCC, especially in cases of HCC associated with hepatitis B virus (HBV) infection.

scholarly journals Inhibition of Glycolysis Suppresses Cell Proliferation and Tumor Progression In Vivo: Perspectives for Chronotherapy

2021 ◽  
Vol 22 (9) ◽  
pp. 4390
Author(s):  
Jana Horváthová ◽  
Roman Moravčík ◽  
Miroslava Matúšková ◽  
Vladimír Šišovský ◽  
Andrej Boháč ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Progression ◽  
Umbilical Vein ◽  
Cell Metabolism ◽  
High Rate ◽  
Ki 67 ◽  
Immunodeficient Mice ◽  
Inhibition Of Glycolysis

A high rate of glycolysis is considered a hallmark of tumor progression and is caused by overexpression of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Therefore, we analyzed the possibility of inhibiting tumor and endothelial cell metabolism through the inhibition of PFKFB3 by a small molecule, (E)-1-(pyridin-4-yl)-3-(quinolin-2-yl)prop-2-en-1-one (PFK15), as a promising therapy. The effects of PFK15 on cell proliferation and apoptosis were analyzed on human umbilical vein endothelial cells (HUVEC) and the human colorectal adenocarcinoma cell line DLD1 through cytotoxicity and proliferation assays, flow cytometry, and western blotting. The results showed that PFK15 inhibited the proliferation of both cell types and induced apoptosis with decreasing the Bcl-2/Bax ratio. On the basis of the results obtained from in vitro experiments, we performed a study on immunodeficient mice implanted with DLD1 cells. We found a reduced tumor mass after morning PFK15 treatment but not after evening treatment, suggesting circadian control of underlying processes. The reduction in tumor size was related to decreased expression of Ki-67, a marker of cell proliferation. We conclude that inhibition of glycolysis can represent a promising therapeutic strategy for cancer treatment and its efficiency is circadian dependent.

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