Research IndicatorsGraph generated 29 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (3)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: SH2D1A (cancer-related)
Xu P, Xia T, Ling Y, Chen BMiRNAs with prognostic significance in multiple myeloma: A systemic review and meta-analysis.
Medicine (Baltimore). 2019; 98(33):e16711 [PubMed
] Related Publications
BACKGROUND: Multiple myeloma (MM) is a clonal plasma cell malignancy associated with hypercalcemia, bone lesions, and renal failure. The prognostic significance of the mutation of miRNAs, one kind of small noncoding RNA molecules that can modulate gene expression, should be confirmed in non-Hodgkin lymphomas (NHL). This study aimed to identify the prognostic value of miRNAs in patients with MM.
METHODS: A meta-analysis was performed to estimate the pooled hazard ratios and their corresponding 95% confidence intervals for the associations between levels of miRNA expression (predictive factors) and outcomes in patients with MM. We systematically searched the PubMed, Web of Science, and China National Knowledge Infrastructure databases (final search conducted January 1, 2018) to identify eligible studies. Eligible studies were included by certain inclusion and exclusion criteria, whose quality was assessed by Newcastle-Ottawa Scale.
RESULTS: After performing the literature search and review, 10 relevant studies, including 1214 cases, were identified. The results of our meta-analysis revealed that upregulated miR-92a level and downregulated miR-16, miR-25, miR-744, miR-15a, let-7e, and miR-19b expression were associated with poor prognosis in MM.
CONCLUSIONS: This study identified miRNAs could serve as potential prognostic biomarkers in MM. Given the limited research available, the clinical application of these findings has yet to be verified.
Romanchikova N, Trapencieris PWedelolactone Targets EZH2-mediated Histone H3K27 Methylation in Mantle Cell Lymphoma.
Anticancer Res. 2019; 39(8):4179-4184 [PubMed
] Related Publications
BACKGROUND/AIM: Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), possesses histone N-methyltransferase (HMT) activity and plays an essential role in cancer initiation and development. The aim of the present study was to investigate the potential of Wedelolactone (WL) to inhibit the methylation activity of EZH2.
MATERIALS AND METHODS: The mantle cell lymphoma (MCL) cell line, Mino, was treated with WL, while untreated cells were used as control. HMT activity and EZH2 amount were measured in nuclear extracts from WL-treated and control Mino cells.
RESULTS: WL was found to target EZH2-mediated histone H3K27 methylation. Along with the inhibition of H3K27 methylation in vitro (IC50=0.3 μM), WL suppressed HMT activity in Mino cells with an IC50 value of 3.2 μM. We detected a reduced amount of EZH2 in Mino cells treated with WL, compared to untreated control cells.
CONCLUSION: This is the first study to show that WL induces inhibition of H3K27 methylation via EZH2 modulation and decreases cell proliferation in MCL, in vitro. WL is proposed as a promising agent and a novel epigenetic approach in MCL investigation and treatment.
Silva OB, Correia NAA, de Barros FT, et al.3' untranslated region A>C (rs3212227) polymorphism of Interleukin 12B gene as a potential risk factor for Hodgkin's lymphoma in Brazilian children and adolescents.
Tumour Biol. 2019; 41(7):1010428319860400 [PubMed
] Related Publications
Interleukin 12 plays an important role in immunoregulation between the T helper 1/T helper 2 lymphocytes and in the antiviral and antitumor immune response. The aim of this study was to investigate the possible association between the interleukin 12B polymorphism rs3212227 and the risk to develop Hodgkin's lymphoma in childhood and adolescents. A total of 100 patients with Hodgkin's lymphoma and a group of 181 healthy controls were selected at random from a forensic laboratory of the University of Pernambuco. The AA genotype was detected in the controls (53.04%) and the AC genotype was found in the patients (54%). The AC genotype showed an association with the development of Hodgkin's lymphoma (odds ratio = 2.091, 95% confidence interval = 1.240-3.523, p = 0.007). When AC + CC genotypes were analyzed together, an increase in risk of 1.9 times more chances for HL development could be observed (odds ratio = 1.923, 95% confidence interval = 1.166-3.170, p = 0.014). However, there was no association between the AC and CC genotypes of the interleukin 12B polymorphism with the clinical risk group (p = 0.992, p = 0.648, respectively). Our results suggest that the presence of the C allele may be contributing to the development of Hodgkin's lymphoma in children and adolescents.
Plasmacytoma variant translocation 1 (PVT1) is highly expressed in a variety of cancer tissues and is related to the clinicopathological features and prognosis. However, the prognostic value of PVT1 is still controversial. Therefore, this systematic evaluation and meta-analysis were performed to evaluate the relationship between PVT1 expression and clinicopathological features.PubMed, EMBASE, Web of science, and Cochrane library databases were searched for literature collection according to inclusion criteria and exclusion criteria. The pooled hazard ratios (HRs) or odds ratios (ORs) were used to evaluate the association between PVT1 expression and overall survival, tumor size, tumor-node-metastasis (TNM) stage, lymph node metastasis, and distant metastasis.A total of 39 articles including 3974 patients were included in the study. The results showed that the expression of PVT1 was closely related to the overall survival rate of cancers (HR = 1.64, 95% confidence interval [CI]: 1.50-1.78, P < .000001). Subgroup analysis showed that the high expression of PVT1 was closely related to the low overall survival rate of patients with clear cell renal cell carcinoma, breast cancer, cervical cancer, colon cancer, epithelial ovarian cancer, gastric cancer, lung cancer, and osteosarcoma. In addition, the high expression of PVT1 was positively correlated with tumor size (OR = 1.50, 95% CI: 1.14-1.96, P = .004), TNM stage (OR = 3.39, 95% CI: 2.73-4.20, P < .00001), lymph node metastasis (OR = 2.60, 95% CI: 1.76-3.84, P < .00001), and distant metastasis (OR = 2.94, 95% CI: 1.90-4.56, P < .00001).PVT1 could serve as a marker for the size, TNM stage, metastasis, and prognosis of different type of cancers.
Wińska P, Widło Ł, Skierka K, et al.Simultaneous Inhibition of Protein Kinase CK2 and Dihydrofolate Reductase Results in Synergistic Effect on Acute Lymphoblastic Leukemia Cells.
Anticancer Res. 2019; 39(7):3531-3542 [PubMed
] Related Publications
BACKGROUND/AIM: Recently, we demonstrated the ability of inhibitors of protein kinase 2 (casein kinase II; CK2) to enhance the efficacy of 5-fluorouracil, a thymidylate synthase (TYMS)-directed drug for anticancer treatment. The present study aimed to investigate the antileukemic effect of simultaneous inhibition of dihydrofolate reductase (DHFR), another enzyme involved in the thymidylate biosynthesis cycle, and CK2 in CCRF-CEM acute lymphoblastic leukemia cells.
MATERIALS AND METHODS: The influence of combined treatment on apoptosis and cell-cycle progression, as well as the endocellular level of DHFR protein and inhibition of CK2 were determined using flow cytometry and western blot analysis, respectively. Real-time quantitative polymerase chain reaction was used to examine the influence of silmitasertib (CX-4945), a selective inhibitor of CK2 on the expression of DHFR and TYMS genes.
RESULTS: The synergistic effect was correlated with the increase of annexin V-binding cell fraction, caspase 3/7 activation and a significant reduce in the activity of CK2. An increase of DHFR protein level was observed in CCRF-CEM cells after CX-4945 treatment, with the mRNA level remaining relatively constant.
CONCLUSION: The obtained results demonstrate a possibility to improve methotrexate-based anti-leukemia therapy by simultaneous inhibition of CK2. The effect of CK2 inhibition on DHFR expression suggests the important regulatory role of CK2-mediated phosphorylation of DHFR inside cells.
IGH@ proto-oncogene translocation is a common oncogenic event in lymphoid lineage cancers such as B-ALL, lymphoma and multiple myeloma. Here, to investigate the interplay between IGH@ proto-oncogene translocation and IGH allelic exclusion, we perform long-read whole-genome and transcriptome sequencing along with epigenetic and 3D genome profiling of Nalm6, an IGH-DUX4 positive B-ALL cell line. We detect significant allelic imbalance on the wild-type over the IGH-DUX4 haplotype in expression and epigenetic data, showing IGH-DUX4 translocation occurs on the silenced IGH allele. In vitro, this reduces the oncogenic stress of DUX4 high-level expression. Moreover, patient samples of IGH-DUX4 B-ALL have similar expression profile and IGH breakpoints as Nalm6, suggesting a common mechanism to allow optimal dosage of non-toxic DUX4 expression.
The t(11;14)/CCND1-IGH, t(4;14)/NSD2(MMSET)-IGH, and t(14;16)/IGH-MAF gene rearrangements detected by fluorescence in situ hybridization (FISH) are used for risk stratification in patients with multiple myeloma (MM). Compared with conventional FISH techniques using fresh cells, immunohistochemistry (IHC) is much more cost- and time-efficient, and can be readily applied to routinely prepared formalin-fixed, paraffin-embedded (FFPE) materials. In this study, we performed tissue FISH and IHC employing FFPE specimens, and examined the usefulness of IHC as a tool for detecting CCND1, NSD2, and MAF gene rearrangements. CD138 signals were used to identify plasma cells in tissue FISH and IHC analyses. With cohort 1 (n = 70), we performed tissue FISH and subsequently IHC, and determined IHC cut-off points. In this cohort, the sensitivity and specificity for the 3 molecules were ≥.90 and ≥.96, respectively. With cohort 2, using MM cases with an unknown gene status (n = 120), we performed IHC, and the gene status was estimated using the cut-off points determined with cohort 1. The subsequent FISH analysis showed that the sensitivity and specificity for the 3 molecules were ≥.92 and ≥.98, respectively. CCND1, NSD2, and MAF gene rearrangements were estimated accurately by IHC, suggesting that conventional FISH assays can be replaced by IHC.
Rahimi Babasheikhali S, Rahgozar S, Mohammadi MGinger extract has anti-leukemia and anti-drug resistant effects on malignant cells.
J Cancer Res Clin Oncol. 2019; 145(8):1987-1998 [PubMed
] Related Publications
PURPOSE: Based on the poor prognosis of drug resistance in pediatric acute lymphoblastic leukemia (ALL) and adverse effects of chemotherapy, this study was aimed to evaluate the effect of several herbal extracts on leukemic cells.
METHODS: Two subtypes of T- and B-ALL cell lines, followed by ALL primary cells were treated with cinnamon, ginger, and green tea extracts, alone or in combination with methotrexate (MTX). Possible apoptosis was investigated using Annexin-V/PI double staining. Real-time PCR was applied to evaluate the expression levels of related ABC transporters upon combination therapy.
RESULTS: The IC
CONCLUSION: To the best of our knowledge, this is the first study that reveals the antileukemic effect of ginger extract on both, pediatric ALL cell lines and primary cells.
BACKGROUND: Single-cell gene expression measurements offer opportunities in deriving mechanistic understanding of complex diseases, including cancer. However, due to the complex regulatory machinery of the cell, gene regulatory network (GRN) model inference based on such data still manifests significant uncertainty.
RESULTS: The goal of this paper is to develop optimal classification of single-cell trajectories accounting for potential model uncertainty. Partially-observed Boolean dynamical systems (POBDS) are used for modeling gene regulatory networks observed through noisy gene-expression data. We derive the exact optimal Bayesian classifier (OBC) for binary classification of single-cell trajectories. The application of the OBC becomes impractical for large GRNs, due to computational and memory requirements. To address this, we introduce a particle-based single-cell classification method that is highly scalable for large GRNs with much lower complexity than the optimal solution.
CONCLUSION: The performance of the proposed particle-based method is demonstrated through numerical experiments using a POBDS model of the well-known T-cell large granular lymphocyte (T-LGL) leukemia network with noisy time-series gene-expression data.
The revised WHO classification moved all aggressive B-cell lymphomas with a MYC translocation and a concurrent translocation of BCL2 and/or BCL6 into a single diagnostic category. These are the double- and triple-hit lymphomas. These represent a group with typically a poor outcome to conventional therapy, and as a result, intensification of immunochemotherapy has been explored. The optimal approach is far from clear, and recent insight into the biology suggest that they may represent just a subgroup of molecular high-grade B-cell lymphomas that maybe identified by gene expression profiling. There are a number of novel therapeutic approaches under investigation.
Ioannidou A, Zachaki S, Daraki A, et al.Paraoxonase 1 (PON1) Q192R and L55M Polymorphisms as Potential Predisposition Factors for Chronic Lymphocytic Leukemia.
Anticancer Res. 2019; 39(6):2861-2869 [PubMed
] Related Publications
BACKGROUND/AIM: PON1 gene has an executive role in antioxidant defense, protecting cells from genotoxic factors. Q192R and L55M PON1 polymorphisms reduce catalytic activity of the encoded protein. These polymorphisms were studied in 300 chronic lymphocytic leukemia (CLL) patients and 106 healthy donors. They were also associated with patients' cytogenetic findings, to investigate their possible implication in CLL pathogenesis.
MATERIALS AND METHODS: SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Karyotypic analysis was also performed by chromosome G-banding analysis and fluorescence in situ hybridization.
RESULTS: Genotypic and allelic distribution of Q192R polymorphism showed a statistically significant higher frequency of mutant genotypes and mutant alleles in patients compared to controls. The same observation was noted in patients with abnormal karyotypes and those carrying abn14q32 and del(6q). A statistically increased frequency for the mutant allele was also revealed in patients with del(11q). On the contrary, L55M polymorphism showed a similar distribution between patients and controls.
CONCLUSION: Q192R polymorphism plays a role in CLL predisposition and the formation of specific chromosomal aberrations.
Michalová Z, Čoma M, Kičová M, et al.Overexpression of Galectin-3 in Chronic Lymphocytic Leukemia Is Associated With 17p Deletion: A Short Report.
Anticancer Res. 2019; 39(6):2805-2810 [PubMed
] Related Publications
BACKGROUND/AIM: Galectins belong to the family of galactose-binding proteins known to play an important role in the processes of cell proliferation, differentiation, migration and neoplastic progression. Herein, we studied the expression of galectin-3 (Gal-3) in chronic lymphocytic leukemia (CLL).
MATERIALS AND METHODS: The expression of Gal-3 was analyzed by means of multiparametric flow cytometry in normal and pathological B-cells from peripheral blood and bone marrow samples of 67 patients with CLL.
RESULTS: Pathological B-cells expressed significantly higher levels of cytoplasmic Gal-3 than normal B-cells. Moreover, overexpression of cytoplasmic Gal-3 was observed in the prognostically poorest subgroup of CLL patients, namely those with 17p deletion.
CONCLUSION: Our results indicate a possible role of galectin-3 in CLL pathophysiology and its potential value as a prognostic marker and therapeutic target.
RATIONALE: Acute lymphoblastic leukemia (ALL) is a malignant disease originating from abnormal proliferation of B or T lymphocytes in bone marrow (BM). Invasion of the pancreas is extremely rare in adults.
PATIENT CONCERNS: In this article, we report a case presenting that ALL invades the pancreas, as well as liver, kidney, and duodenum detected by magnetic resonance image. The patient was misdiagnosed as pancreatic tumor at initial since hemogram was unremarkable.
DIAGNOSES: The diagnosis of ALL was established based on the endoscopic ultrasonography-guided fine-needle aspiration and bone marrow examination, showing BCR/ABL gene positive.
INTERVENTIONS: The patient was actively treated with chemotherapy. Hematological remission was obtained and the lesions in the pancreas disappeared.
OUTCOMES: The patient finally died of complication from fungal pneumonia and central nervous system involvement 12 months after diagnosis.
LESSONS: Under the context of infection, persistent or intermittent fever and complete blood count are not significant prognoses of pancreatic involvement for adult with ALL. We hope that this case will help hepatobiliary and pancreatic surgeon to be aware of this kind of disease as pancreatic carcinoma and pancreas involvement by ALL have totally different treatment strategy.
Fischer K, Al-Sawaf O, Bahlo J, et al.Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions.
N Engl J Med. 2019; 380(23):2225-2236 [PubMed
] Related Publications
BACKGROUND: The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known.
METHODS: In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil-obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated.
RESULTS: In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with
CONCLUSIONS: Among patients with untreated CLL and coexisting conditions, venetoclax-obinutuzumab was associated with longer progression-free survival than chlorambucil-obinutuzumab. (Funded by F. Hoffmann-La Roche and AbbVie; ClinicalTrials.gov number, NCT02242942.).
Deng S, Xiang JJ, Ge HP, et al.The role of MIR-186 and ZNF545 in inhibiting the proliferation of multiple myeloma cells.
J Biol Regul Homeost Agents. 2019 May-Jun,; 33(3):721-729 [PubMed
] Related Publications
This study aimed to investigate the mechanism underlying the inhibitory effect of tumor suppressor gene miR-186 and zinc finger protein 545 (ZNF545) on the proliferation of multiple myeloma (MM) cells. CD138 magnetic beads were used to isolate different types of myeloma cell lines (KM3, U266, RPMI-8226, and H929), which were then infected by lentivirus carrying the miR-186 gene. Using uninfected myeloma cells as the control, MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide] assay was performed to calculate the rate of cell proliferation at different time points. In addition, the correlation between the expression of Jagged 1 and miR-186 was analyzed by real-time Polymerase Chain Reaction (PCR). Furthermore, the effect of 5-Aza-2-deoxycytidine and acetylase inhibitor Trichomycin A (TSA) on the expression of ZNF545 and proliferation/apoptosis of MM cells was investigated using Reverse Transcription-Polymerase Chain Reaction (RT-PCR), Western blotting (WB), MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] cell proliferation assay, and Annexin V-FITC/PI staining. Compared with the control group, the proliferation of miR-186-overexpressing U266 and RPMI-8226 cells was significantly decreased. In cell cloning experiments, miR-186 decreased the number of U266 and RPMI-8226 clones while reducing the protein expression of Jagged 1. The expression level of ZNF545 in myeloma patients was also reduced to some extent. ZNF545 protein also promoted the apoptosis of myeloma cells. By inhibiting the proliferation of myeloma cells, miR-186 gene and ZNF protein may be used as tumor suppressors in the treatment of myeloma.
Li X, Wu N, Li BA high mutation rate of immunoglobulin heavy chain variable region gene associates with a poor survival and chemotherapy response of mantle cell lymphoma patients.
Medicine (Baltimore). 2019; 98(22):e15811 [PubMed
] Related Publications
Immunoglobulin heavy chain variable region (IGHV) gene mutation status is a biomarker for the prognosis of chronic lymphocytic leukemia, whether it is associated with the diagnosis, staging, and prognosis of patients with mantle cell lymphoma (MCL) remains to be determined.The IGHV gene mutations of 52 MCL patients were determined by DNA sequencing and compared with published IGHV germline sequences.DNA sequence alignment of IGHV variable regions with published IGHV germline sequences showed that the coincidence rate was 94% to 100%. Ten cases (21%) were significantly mutated with the rate of 96.9% to 94.0%. The overall survival time of patients was negatively correlated with the degree of IGHV gene mutation. Further survival analysis with log-rank test demonstrated that the patients with significant IGHV gene mutations showed a trend towards poor survival.The mutation rate of the IGHV variant region may be determined to assess the prognosis and overall survival time of MCL patients.
BACKGROUND: Modern molecular profiling techniques are yielding vast amounts of data from patient samples that could be utilized with machine learning methods to provide important biological insights and improvements in patient outcomes. Unsupervised methods have been successfully used to identify molecularly-defined disease subtypes. However, these approaches do not take advantage of potential additional clinical outcome information. Supervised methods can be implemented when training classes are apparent (e.g., responders or non-responders to treatment). However, training classes can be difficult to define when assessing relative benefit of one therapy over another using gold standard clinical endpoints, since it is often not clear how much benefit each individual patient receives.
RESULTS: We introduce an iterative approach to binary classification tasks based on the simultaneous refinement of training class labels and classifiers towards self-consistency. As training labels are refined during the process, the method is well suited to cases where training class definitions are not obvious or noisy. Clinical data, including time-to-event endpoints, can be incorporated into the approach to enable the iterative refinement to identify molecular phenotypes associated with a particular clinical variable. Using synthetic data, we show how this approach can be used to increase the accuracy of identification of outcome-related phenotypes and their associated molecular attributes. Further, we demonstrate that the advantages of the method persist in real world genomic datasets, allowing the reliable identification of molecular phenotypes and estimation of their association with outcome that generalizes to validation datasets. We show that at convergence of the iterative refinement, there is a consistent incorporation of the molecular data into the classifier yielding the molecular phenotype and that this allows a robust identification of associated attributes and the underlying biological processes.
CONCLUSIONS: The consistent incorporation of the structure of the molecular data into the classifier helps to minimize overfitting and facilitates not only good generalization of classification and molecular phenotypes, but also reliable identification of biologically relevant features and elucidation of underlying biological processes.
Marcelis L, Tousseyn T, Sagaert XMALT Lymphoma as a Model of Chronic Inflammation-Induced Gastric Tumor Development.
Curr Top Microbiol Immunol. 2019; 421:77-106 [PubMed
] Related Publications
Mucosa-associated lymphoid tissue (MALT) lymphoma, or extranodal marginal zone lymphoma of MALT, is an indolent B-cell non-Hodgkin lymphoma linked with preexisting chronic inflammation. The stomach is the most commonly affected organ and the MALT lymphoma pathogenesis is clearly associated with Helicobacter pylori gastroduodenitis. Inflammation induces the lymphoid infiltrates in extranodal sites, where the lymphoma then subsequently develops. Genetic aberrations arise through the release of reactive oxygen species (ROS), H. pylori-induced endonucleases, and other effects. The involvement of nuclear factor kappa B (NF-κB) pathway activation, a critical regulator of pro-inflammatory responses, further highlights the role of inflammation in gastric MALT lymphoma. The NF-κB pathway regulates key elements of normal lymphocyte function, including the transcription of proliferation-promoting and anti-apoptotic genes. Aberrant constitutive activation of NF-κB signaling can lead to autoimmunity and malignancy. NF-κB pathway activation can happen through both the canonical and non-canonical pathways and can be caused by multiple genetic aberrations such as t(11;18)(q12;q21), t(1;14)(p22;q32), and t(14;18)(q32;q21) translocations, chronic inflammation and even directly by H. pylori-associated mechanisms. Gastric MALT lymphoma is considered one of the best models of how inflammation initiates genetic events that lead to oncogenesis, determines tumor biology, dictates clinical behavior and leads to viable therapeutic targets. The purpose of this review is to present gastric MALT lymphoma as an outstanding example of the close pathogenetic link between chronic inflammation and tumor development and to describe how this information can be integrated into daily clinical practice.
INTRODUCTION: Lymphoma is the third most common cancer among children in the United States and Europe. Hemophilia is a congenital bleeding disorder characterized by deficiency of coagulation factor VIII or IX. Hemophilia B is a consequence of factor IX deficiency and has an incidence of 1 in 20,000 male births. A concurrence of these 2 uncommon diseases is rare except in patients infected with the human immunodeficiency virus (HIV). We report a case of a patient with both Burkitt lymphoma and hemophilia B; this is only such report in China since 1987.
PATIENT CONCERNS: A 3-year-old boy was admitted to our hospital because of melena and jaundice for several days. His older brother had died due to hemophilia B and ventricular septal defect. The patient had not experienced any previous episodes of severe bleeding. Gradual abdominal distention was observed after admission; the patient's superficial lymph nodes were not enlarged. Results of blood routine and bone marrow examinations showed no abnormalities. He was diagnosed with sclerosing cholangitis, abdominal infection, and hepatitis. However, after treatment of reducing enzyme activity and eliminating jaundice, the patient's condition deteriorated. Hydrops abdominis was detected on abdominal ultrasonography. Tumor cells were found by pathological examination of peritoneal effusion. Both a c-myc gene translocation and a c-myc-IgH gene fusion were detected.
DIAGNOSIS: Burkitt lymphoma and hemophilia B.
INTERVENTIONS: The patient was transferred to the Pediatric Hematology Department of our hospital and treated with a modified B-NHL-BFM-95 protocol. During chemotherapy, platelet changes were monitored regularly and blood products were infused timely.
OUTCOMES: The patient died of infection and bleeding after chemotherapy.
CONCLUSION: Concurrent hemophilia and lymphoma are rare, especially in children. When encountering a patient with unexplained obstructive jaundice and massive ascites, the possibility of a tumor should be considered. Early diagnosis and adequate treatment of such tumor may improve prognosis.
Cengiz Seval G, Beksac MA comparative safety review of histone deacetylase inhibitors for the treatment of myeloma.
Expert Opin Drug Saf. 2019; 18(7):563-571 [PubMed
] Related Publications
INTRODUCTION: Dysregulation of histone deacetylase (HDAC) activity is an epigenetic hallmark of multiple myeloma (MM), leading to aberrant gene expression and cellular signaling in myeloma cell growth, survival and resistance to therapy. Hyper-methylation at diagnosis is a frequent observation, which eventually may convert to hypo-methylation during advanced phases.
AREAS COVERED: A literature search on 'HDAC inhibitors' and 'multiple myeloma' was carried out using PubMed and Google Scholar in the preparation of this overview on clinical efficacy and safety data.
EXPERT OPINION: First-generation non-selective HDAC inhibitors have demonstrated minimal single-agent activity in refractory MM. Subsequently, combination therapy has proven an improvement in progression-free survival (PFS) but not response rates. The main concerns are associated with toxicities. Ongoing studies on new and more selective agents, i.e. Romidepsin or Ricolinostat, are promising in terms of better efficacy and less toxicity.
Conant JL, Czuchlewski DRBCR-ABL1-like B-lymphoblastic leukemia/lymphoma: Review of the entity and detection methodologies.
Int J Lab Hematol. 2019; 41 Suppl 1:126-130 [PubMed
] Related Publications
BCR-ABL1-like B-lymphoblastic leukemia/lymphoma (BCR-ABL1-like ALL or Ph-like ALL) is a neoplastic proliferation of lymphoblasts that has a gene expression profile similar to that of B-ALL with t(9;22)(q34.1;q11.2) BCR-ABL1, but lacks that gene fusion. It is associated with poor prognosis and is seen in 10%-20% of pediatric cases and 20%-30% of adult cases of ALL. It is included as a provisional entity in the revised 4th edition of the WHO Classification. A variety of different genetic abnormalities are identified in this entity, but they all converge on pathways that are potentially responsive to the addition of targeted therapy to conventional chemotherapy. Thus, it is important to screen for BCR-ABL1-like ALL, particularly in adults and pediatric patients with high-risk clinical features. Here, we provide a brief overview of the genetic profile and clinical features of BCR-ABL1-like ALL and review laboratory methodologies for routine identification of this genetically heterogeneous entity.
BACKGROUND: Primary central nervous system lymphoma (PCNSL) is the most prevalent brain, spinal cord, eyes, and leptomeningeal lymphoma. It is often misdiagnosed due to an unspecific presentation or unavailable biopsy and results in a poor prognosis. Although the craniocerebral imaging examination of PCNSL has some characteristics, it is limited, and atypical cases are especially difficult to identify with intracranial tumours and other diseases. The biopsy, as the gold standard for PCNSL diagnosis, is not eligible for all patients suspected of having PCNSL.
CASE PRESENTATION: This report documents a woman who presented with a three-month history of numbness and weakness in the right leg. She was treated with drugs at a local hospital for one month. She developed demyelination lesions and her symptoms were aggravated. The patient was admitted to the Department of Nerve Infection and Immunology at Tiantan Hospital. Head magnetic resonance imaging (MRI) enhanced scanning indicated significant inflammatory demyelinating disease, and lymphoma was not excluded. CSF revealed a high protein level and CSF cytology detected abnormal cells, PCNSL was eventually presumed according to positive CSF cytology and cytological detection of the cerebrospinal fluid flow.
CONCLUSIONS: PCNSL is a highly invasive tumour. With the development of technologies such as cerebrospinal fluid cytology and flow cytology, CSF analysis has become one of the definite diagnosis methods, and the tumour cell finding in CSF is the only reliable basis for diagnosis. Flow cytometric analysis and gene rearrangement testing also provide objective evidence.
Mussetti A, Pellegrinelli A, Cieri N, et al.PD-L1, LAG3, and HLA-DR are increasingly expressed during smoldering myeloma progression.
Ann Hematol. 2019; 98(7):1713-1720 [PubMed
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Symptomatic multiple myeloma (MM) is a plasma cell neoplasm that represents the final stage of a continuum of clinical conditions that start from monoclonal gammopathy of unknown significance (MGUS), then transits in the more advance, but still asymptomatic, smoldering MM (SMM), with a final evolution in symptomatic MM. To investigate SMM microenvironment modifications, we studied 16 patients diagnosed at our hospital. Eight of them (group A) developed MM within 2 years from diagnosis while the others (group B) had stable SMM. Samples were bone marrow biopsies at diagnosis and after 2 years (± 4 months) and were analyzed by immunohistochemical analysis. Firstly, we found a significant increase in both CD4+ cells (11 vs 17%, p < 0.01) and CD8+ cells (15 vs 18%, p < 0.01) between diagnosis and at follow-up samples (whole cohort). This was associated to an increase in the CD4+/CD8+ ratio (0.74 vs 0.93, p < 0.01). Secondly, we discovered an increased expression of T cell inhibitory molecules during SMM evolution. In fact, plasma cell PD-L1 and microenvironment cell LAG3 expression increased from 1 to 12% (p = 0.03) and 4 to 10% (p = 0.04), respectively, from diagnosis to follow-up. Also, plasma cells and microenvironment cells HLA-DR expression augmented during SMM evolution from 7 to 10% (p = 0.04) and 29 to 39% (p = 0.01), respectively. When comparing group A vs group B, we found an increased CD68-KP1+ cell infiltration in favor of group B at diagnosis (23 vs 28%, p = 0.01) and a greater plasma cell infiltration at follow-up (50 vs 26%, p < 0.01). Our findings suggest how immune escape mechanisms appear earlier during multiple myeloma evolution, and that LAG3 could be a possible immunologic target in this setting.
Non-coding RNAs (ncRNAs) are essential regulators of gene expression. In recent years, it has become more and more evident that the different classes of ncRNAs, such as micro RNAs, long non-coding RNAs and circular RNAs are organized in tightly controlled networks. It has been suggested that deregulation of these networks can lead to disease. Several studies show a contribution of these so-called competing-endogenous RNA networks in various cancer entities. In this review, we highlight the involvement of ncRNA networks in anaplastic-large cell lymphoma (ALCL), a T-cell neoplasia. A majority of ALCL cases harbor the molecular hallmark of this disease, a fusion of the anaplastic lymphoma kinase (ALK) gene with the nucleophosmin (NPM, NPM1) gene leading to a permanently active kinase that promotes the malignant phenotype. We have focused especially on ncRNAs that are regulated by the
Ameri Z, Ghiasi S, Farsinejad A, et al.Telomerase inhibitor MST-312 induces apoptosis of multiple myeloma cells and down-regulation of anti-apoptotic, proliferative and inflammatory genes.
Life Sci. 2019; 228:66-71 [PubMed
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AIMS: The telomerase-based therapy of cancer has received a great deal of attention due to the fact that it is expressed in almost all of the cancer cells while it is inactivated in most of the normal somatic cells. Current investigation was aimed to examine the effects of namely telomerase inhibitor, the MST-312, as a chemically modified derivative of epigallocatechin gallate (EGCG), on human multiple myeloma cell line U-266.
MAIN METHODS: U-266 cells were cultured and then treated by MST-312. The viability of cultured cells was measured by both trypan blue staining and MTT assay techniques. To examine the apoptosis, annexin-V/7-AAD staining using flow cytometry method was employed. To analysis the expression of Bax, Bcl-2, c-Myc, hTERT, IL-6 and TNF-α genes, the quantitative real-time PCR was employed.
KEY FINDINGS: We observed the short-term dose-dependent cytotoxic and apoptotic effect of MST-312 against U-266 myeloma cells. Gene expression analysis indicated that the MST-312-based apoptosis was associated with up-regulation of pro-apoptotic gene (Bax) as well as down-regulation of anti-apoptotic (Bcl-2), proliferative (c-Myc, hTERT) and inflammatory (IL-6, TNF-α) genes.
SIGNIFICANCE: These findings suggest that telomerase-based therapy using MST-312 may represent a novel promising strategy for treatment of multiple myeloma.
BACKGROUND: Mycosis fungoides (MF) is indolent, but may disseminate to leukemia. We reported that C-C motif chemokine ligand 21 (CCL21) is associated with MF invasion and progression. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long noncoding RNA, is associated with several cancer types, however, how it interacts with CCL21 to regulate MF progression, remains unclear.
MATERIALS AND METHODS: Expression of long noncoding RNAs MALAT1, antisense noncoding RNA in the INK4 locus (ANRIL), Hox antisense intergenic RNA (HOTAIR), highly up-regulated in liver cancer RNA (HULC), and leukemia-associated non-coding insulin-like growth factor 1 receptor activator RNA 1 (LUNAR1) in tissues from MF was studied using polymerase chain reaction and RNA interference in MF cell line MyLa were used to address this question.
RESULTS: Expression of MALAT1 was selectively increased in MF tissues. C-C Chemokine receptor type 7 (CCR7) expression was found to be increased in MyLa cells. CCL21 was found not only to mediate migration, but also to enhance MALAT1 and mammalian target of rapamycin (mTOR) activation in MyLa cells. Knockdown of MALAT1 abrogated CCL21-mediated migration, but not mTOR activation. In contrast, mTOR inhibition reduced CCL21-mediated migration and MALAT1 expression.
CONCLUSION: CCL21 induced mTOR activation in MyLa cells, followed by expression of MALAT1, causing cell migration. MALAT1 and mTOR are potential therapeutic targets for MF.
Guo L, Wen Z, Su X, et al.Indolent T-cell lymphoproliferative disease with synchronous diffuse large B-cell lymphoma: A case report.
Medicine (Baltimore). 2019; 98(17):e15323 [PubMed
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RATIONALE: Indolent T-cell lymphoproliferative disease (T-LPD) of gastrointestinal tract is a rare recently described disease that seldom progresses. We report a case of T-LPD with synchronous diffuse large B-cell lymphoma (DLBCL) that cause aggravation of disease.
PATIENT CONCERNS: A 46-year-old Chinese male presented with intermittent paraumbilical colic pain, bloating, and occasional diarrhea for 10 years. His condition aggravated with partial bowel obstruction recently. The patient was diagnosed as T-LPD initially based on histological result and T-cell receptor-gamma clonal gene rearrangement test. The patient was followed without chemotherapy. His condition stabilized for 1 year and then deteriorated with small intestine perforation.
DIAGNOSIS: The patient was diagnosed as indolent T-LPD and DLBCL finally.
INTERVENTIONS: The patient had surgery for intestine perforation and received chemotherapy for DLBCL and T-LPD afterward.
OUTCOMES: At 6 months follow-up, the patient continued to have resolution of his symptoms.
LESSONS: Early detection of high-grade transformation of T-LPD or the coexistence of aggressive lymphoma is essential for the patient. DLBCL may coexist in the indolent course of T-LPD. The diagnosis of T-LPD should be made cautiously in case with progressing symptoms such as intestinal obstruction.
Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8), is etiologically linked to the development of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. These malignancies often occur in immunosuppressed individuals, making KSHV infection-associated diseases an increasing global health concern with persistence of the AIDS epidemic. KSHV exhibits biphasic life cycles between latent and lytic infection and extensive transcriptional and posttranscriptional regulation of gene expression. As a member of the herpesvirus family, KSHV has evolved many strategies to evade the host immune response, which help the virus establish a successful lifelong infection. In this review, we summarize the current research status on the biology of latent and lytic viral infection, the regulation of viral life cycles and the related pathogenesis.
BACKGROUND: Little is known about the pathway to diagnosis of lymphoma in Sub-Saharan Africa, despite the increased risk of lymphoma in people living with HIV (PLHIV). The challenges of diagnosis in this setting include diagnostic confusion with extrapulmonary tuberculosis (EPTB), which commonly causes lymphadenopathy in PLHIV.
METHODS: We analysed the time to diagnosis and treatment in patients using predetermined time intervals. Univariate and multivariable analyses were performed to determine the relationship between patient and disease-specific variables with delays to diagnosis. We were particularly interested in the impact of HIV, empiric tuberculosis therapy and fine-needle aspirate for cytology (FNAC) in contributing to delay.
RESULTS: Patients (n = 163), 29% HIV-infected, waited a median of 4 weeks before seeking medical attention. It took a median of 7 weeks for the diagnosis of lymphoma to be made from the time the patient sought medical attention, termed the healthcare practitioner interval. In multivariable logistic regression analysis, diagnostic delay > 6 weeks was associated with late-stage disease (OR 2.3, 95% CI 1.1-5.2) and Hodgkin lymphoma (HL) (OR 3.0, 95% CI 1.1-8.0). HIV status was not associated with diagnostic delay (OR 0.9, 95% CI 0.3-2.2). The median time to diagnosis was a median of 4 weeks longer for patients on tuberculous (TB) therapy (n = 16, p = 0.28) and patients who underwent an FNAC (n = 63, p = 0.04). Where FNAC was performed, it was diagnostic for lymphoma in only 11%. Diagnostic delay was not associated with overall survival.
CONCLUSIONS: Time-to-diagnosis of lymphoma in South Africa was similar to that reported from high-income countries and shows significant periods of delay between the onset of symptoms to diagnosis and treatment. The longest period of delay was in the health practitioner interval. Education regarding the significance of lymphadenopathy for both patients and health care practitioners and appropriate investigative steps preferably by best-practice algorithms specific to TB-endemic areas are needed to shorten the time-to-diagnosis of lymphoma.
Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high risk. Here we analyze structural variants from 795 newly-diagnosed patients as part of the CoMMpass study. We report translocations involving the immunoglobulin lambda (IgL) locus are present in 10% of patients, and indicative of poor prognosis. This is particularly true for IgL-MYC translocations, which coincide with focal amplifications of enhancers at both loci. Importantly, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified. Patients with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that binds the IgL enhancer at some of the highest levels in the myeloma epigenome. These data implicate IgL translocation as a driver of poor prognosis which may be due to IMiD resistance.