Enhancer of zeste homolog 2 (EZH2), a stemness factor, plays roles in regulation of cell differentiation and embryonic development as well as cancer progression. Deregulation of EZH2 in cancers is correlated with tumor cell invasiveness, metastasis, and the patients’ poor outcome. However, the mechanistic role of EZH2 in cancer is ambiguous. In this study, we aimed to inhibit the expression of EZH2 in a cancer cell line, and evaluate consequence changes in gene expression pattern.
Materials and methods
Using specific retroviral shRNA-EZH2, EZH2 gene was silenced in the KYSE30 cell line. Relative comparative real-time PCR was used to confirm silencing of EZH2 and evaluate expression pattern of selected markers.
Results
Inhibition of EZH2 expression in KYSE30 cells caused significant changes in different genes. Indeed, HIWI and HEY1 genes were over- and underexpressed in KYSE30 cells, respectively, following EZH2 silencing. Other selected cancer stem cell markers were not changed significantly.
Conclusion
To the best our knowledge, there are variety of small molecule inhibitors to target EZH2 in cancer cells as a treatment candidate; therefore, our data in this study helps the researchers to select EZH2 for cancer therapy based on its mechanism and correlation with other markers.
The purpose of this review is to summarize the available literature for the use of small molecule inhibitors in chronic lymphocytic leukemia and B cell non-Hodgkin lymphoma.
Recent Findings
Ibrutinib, idelalisib, and venetoclax are small molecule inhibitors that have revolutionized therapeutic options for patients with CLL, particularly for those with high-risk disease including 17p deletion. These drugs are increasingly finding application in a variety of subtypes of B cell NHL. Intolerance and resistance are concerns for select patients, highlighting the need for continual development of alternate therapies.
Summary
The treatment armamentarium for CLL and NHL is vastly different than it was just a few years ago. Patients have a much wider range of non-chemotherapy treatment options, some of which produce durable responses and have long-term tolerability. Future research directions will likely focus on identifying the optimal sequences and combination strategies for these new targeted therapies.
Lymphomas represent more than 15?% of malignancies in children and adolescents.
Objective
This review article provides an overview on the state of the art diagnostic evaluation and treatment of malignant lymphomas in children and adolescents.
Material and methods
Data obtained from peer reviewed publications of the involved study consortia and by a PubMed search are presented.
Results
According to the World Health Organization (WHO) classification of Hodgkin’s lymphoma a differentation is made between classical (90?%) and nodular, lymphocyte-predominant Hodgkin’s lymphomas. Non-Hodgkin’s lymphomas (NHL) in children and adolescents are classified according to the WHO classification based on the immunophenotype and developmental stage of the lymphoid cells. The mature B?cell NHL (Burkitt lymphoma 46?% and diffuse large cell B?NHL 8?%) represent more than half of pediatric NHL, the other main subtypes are the precursor B and T?cell NHL (lymphoblastic lymphoma 21?%) and anaplastic large cell lymphoma (ALCL 13?%). With increasing age the distribution of subtypes changes towards lymphomas more typical for an adult population. The grey zone lymphomas are entities that cannot be clearly assigned to either HL or NHL and are so defined in the WHO classification. The exact diagnosis of NHL and HL is essential for the subtype-specific treatment. Currently, survival rates of more than 80?% (NHL) and 97?% (HL) can be achieved.
Discussion
Especially in the treatment for HL, the principles are quite different from those used in adult patients. Avoidance of late effects while maintaining high cure rates are the main objectives; therefore, children and adolescents up to the age of 18 years should exclusively be treated within trials provided at pediatric oncology centers.
Diffuse large B cell lymphoma (DLBCL) remains the most common non-Hodgkin lymphoma (NHL) in developed countries. Up to 30–40% of patients experience either refractory or relapsed disease following receipt of front-line chemoimmunotherapy, and the majority of these patients will not be cured following receipt of subsequent therapy.
Recent Findings
Small-molecule inhibitors (SMIs) are an attractive class of therapeutics for patients with chemorefractory DLBCL, and early-phase studies with these agents have typically demonstrated prolonged periods of disease control in responding patients without significant toxicity. Later-phase studies have investigated the combination of SMIs with cytotoxic agents in hopes that exposure to SMIs in the treatment course may improve outcomes for patients who would otherwise develop chemorefractory disease.
Summary
SMIs appear to be effective in the treatment of DLBCL. A greater understanding of the molecular features of cases of DLBCL will allow for the more rational and presumably successful utilization of these targeted agents.
This large, population-based U.S. study of lymphoma patients followed for up to four decades enables detailed analysis of second primary mesothelioma risk after radiotherapy.
Methods
U.S. Surveillance, Epidemiology, and End Results data were used to identify second primary mesothelioma among patients diagnosed with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) between 1973 and 2014. Standardized incidence ratios (SIRs) were calculated by radiotherapy. Multivariate adjusted associations were examined using competing risks survival analysis.
Results
Among 47,219 HL patients (19,538 irradiated) and 252,090 NHL patients (52,454 irradiated), second primary mesothelioma developed among 28 lymphoma patients who received radiotherapy and 59 who did not. Mesothelioma risk was increased among HL and NHL patients treated with radiotherapy [SIR = 1.78, 95% confidence interval (CI) 1.18–2.58], but not without radiotherapy. After multivariate adjustment, radiotherapy was associated with increased mesothelioma risk (relative risk = 1.64, 95% CI 1.05–2.57), especially in lymphoma patients diagnosed before 1995 and after a latency of at least 10 years, and apparently with younger age at diagnosis.
Conclusions
The increase in second primary mesothelioma risk following radiotherapy for lymphoma is independent of several patient and disease characteristics, and is higher with earlier treatment era and longer latency.
Advanced basal cell carcinomas (BCCs) suffer from a scarcity of effective treatment options. Previously, we found that the targetable histone methyltransferase EZH2 was upregulated in aggressive BCC subtypes, suggesting that epigenetics may play a role in BCC progression. The purpose of this study was to determine whether EZH2-associated proteins and marks may be employed for the stratification of BCC histologic subtypes.
Methods
Sixty-two specimens (from 61 patients), representing more or less aggressive BCC histologic subtypes and matching non-malignant epidermal cells, were included in this study. Immunohistochemistry of H3K27me3, 5hmC, NSD2, MOF and JARID1B was performed to assess their putative associations with BCC histologic subtypes, as well as with EZH2 and Ki67 expression levels.
Results
We found that H3K27me3 and 5hmC upregulation was positively correlated with the occurrence of a less aggressive BCC histology. The modifications were also positively correlated with each other. Interestingly, we found that they were negatively correlated with the expression of EZH2, a marker for an aggressive BCC histology. The levels of NSD2, MOF, H3K27me3 and 5hmC were found to be universally upregulated in BCCs versus non-malignant epidermal cells.
Conclusions
Our data reveal an EZH2-associated epigenetic marker profile that correlates with histologic signs of BCC aggressiveness. Our findings may have diagnostic and therapeutic implications, and indicate that epigenetic markers may be shared even with relatively less aggressive tumor types, thereby suggesting universal themes.
The present review focuses on key aspects of non-Hodgkin lymphoma (NHL) evasion of immune surveillance and how these can be leveraged to devise effective immunotherapy strategies.
Recent Findings
In recent years, significant progress has been made in the field of cancer immunotherapy. In particular, the remarkable clinical results of anti-programmed death (PD)-1/PD-ligand (L)1 antibodies are revolutionizing the treatment approach to multiple solid and hematologic tumors. In patients with B or T cell NHL, immune checkpoint inhibition has produced mixed results, in part owing to the high complexity of the tumor immune microenvironment. Rationally designed combinations of PD-1/PD-L1 blockers with other antibody- or cell-based immunotherapies, or small molecules are being tested in clinical trials.
Summary
A clearer understanding of the relationship between host immune dysfunction and cancer development and growth, often referred to as cancer “immuno-editing,” has enabled the discovery and successful clinical application of several immunotherapeutic agents, such as the immune checkpoint inhibitors (ICI).
Chemotherapy remains the first-line therapy for aggressive lymphomas. However, 20–30% of patients with non-Hodgkin lymphoma (NHL) and 15% with Hodgkin lymphoma (HL) recur after initial therapy. We want to explore the role of high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) for these patients.
Recent Findings
There is some utility of upfront consolidation for-high risk/high-grade B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma, but there is no role of similar intervention for HL. New conditioning regimens are being investigated which have demonstrated an improved safety profile without compromising the myeloablative efficiency for relapsed or refractory HL.
Summary
Salvage chemotherapy followed by HDT and rescue autologous stem cell transplant remains the standard of care for relapsed/refractory lymphoma. The role of novel agents to improve disease-related parameters remains to be elucidated in frontline induction, disease salvage, and high-dose consolidation or in the maintenance setting.
Several investigations have analysed the association between coffee intake and risk of cancer. Contradictory results were reported by the studies conducted in non-Hodgkin’s lymphomas (NHL) few of which report results according to main NHL subgroups. The present study is aimed at evaluating the association between coffee consumption and the risk of NHL by analysing data from a large Italian multicentre case–control study that included 1,418 interviewed cases (1,301 B cell and 117 T cell NHL), diagnosed between 1990 and 1993, and 1,774 population healthy controls.
Methods
The association was evaluated by standard logistic regression analysis. Odds ratio (OR) estimates were adjusted for gender, age, residence area, educational level, previous chemotherapy treatment, smoking habit and exposure to electromagnetic fields, radiation, pesticides and aromatic hydrocarbons.
Results
For all B cell lymphomas, an increased risk (OR 1.6, 95% CI 1.2–2.0) was observed in the highest exposure category (consumption >4 cups per day for at least 30 years), but without a clear dose–response trend. Subgroup analyses highlighted an increased risk for drinkers of at least four cups per day for follicular lymphoma (OR 2.0, 95% CI 1.2–3.4). The risk increased with years of exposure and was more elevated among current smokers.
Conclusions
Consumption of more than four cups of coffee per day enhances the risk of lymphoma, especially the follicular subtype. Further investigations based on large cohorts and accurate measures of exposure are needed to confirm the observed associations.
While dietary factors have been shown to play an important etiologic role in non-Hodgkin lymphoma (NHL), little is known about the association between inflammatory properties of diet and NHL risk.
Methods
We explored the association between the dietary inflammatory index (DII) and NHL risk in a multicenter Italian case–control study conducted between 1999 and 2014. Cases were 536 subjects with incident, histologically confirmed NHL from three areas in Italy. Controls were 984 subjects admitted to the same network of hospitals as the cases for acute, nonmalignant conditions, unrelated to diet. DII scores were computed based on 30 nutrients and food items assessed using a reproducible and validated 78-item food-frequency questionnaire. Odds ratios (ORs) were estimated through logistic regression models adjusting for age, total energy intake, and other recognized confounding factors.
Results
Subjects in the highest quartile of DII scores (i.e., with the most pro-inflammatory diets) had a higher risk of NHL compared with subjects in the lowest quartile (i.e., with the most anti-inflammatory diets) (ORQuartile4vs1 1.61, 95% confidence interval CI 1.07–2.43; p-trend = 0.01). Stratified analyses produced stronger associations between DII and NHL among males (ORQuartile4vs1 2.14; 95% CI 1.25–3.67) with significant heterogeneity (p value = 0.02); when analyzed by histologic subtype, a significant association was observed with diffuse large B-cell lymphoma (ORQuartile4vs1 1.84; 95% CI 1.09–3.10).
Conclusion
A pro-inflammatory diet, as indicated by higher DII scores, is associated with elevated odds of NHL, especially among males.
High intake of meat has been inconsistently associated with increased risk of non-Hodgkin lymphoma (NHL). We carried out a meta-analysis to summarize the evidence of published observational studies reporting association between red meat and processed meat intake and NHL risk.
Methods
Analytical studies reporting relative risks with 95 % confidence intervals (95 % CI) for the association between intake of red and/or processed meat and NHL or major histological subtypes were eligible. We conducted random-effects meta-analysis comparing lowest and highest intake categories and dose–response meta-analysis when risk estimates and intake levels were available for more than three exposure classes.
Results
Fourteen studies (four cohort and ten case–control) were included in the meta-analysis, involving a total of 10,121 NHL cases. The overall relative risks of NHL for the highest versus the lowest category of consumption were 1.14 (95 % CI 1.03, 1.26) for red meat and 1.06 (95 % CI 0.98, 1.15) for processed meat. Significant associations were present when the analysis was restricted to case–control studies but not when restricted to cohort studies. No significant associations were found for major NHL etiological subtypes. Dose–response meta-analysis could be based only on eight studies that provided sufficient data, and compared to no meat consumption, the overall NHL relative risk increased nonlinearly with increased daily intake of red meat.
Conclusion
The observed positive association between red meat consumption and NHL is mainly supported by the effect estimates coming from case–control studies and is affected by multiple sources of heterogeneity. This meta-analysis provided mixed and inconclusive evidences on the supposed relationship between red and processed meat consumption and NHL.
Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with an unfavorable clinical course. Besides deregulation of the cell cycle, B cell receptor (BCR) signaling, essential for MCL proliferation and survival, is also often deregulated due to constitutive activation of Bruton’s tyrosine kinase (BTK). The BTK inhibitor ibrutinib has been approved as a therapy for refractory MCL, and while it shows some clinical activity, patients frequently develop primary or secondary ibrutinib resistance and have very poor outcomes after relapsing following ibrutinib treatment.
Objective
To overcome ibrutinib resistance, new therapeutic approaches are needed. As checkpoint kinase 1 (Chk1) inhibitors have recently been shown to be effective as single agents in MCL, we assessed the combination of ibrutinib with Chk1 inhibitors.
Methods
We examined the activity of ibrutinib combined with the Chk1 inhibitor PF-00477736 in eight MCL cell lines and analyzed underlying cellular and molecular effects.
Results
The combination was synergistic in all tested cell lines through different mechanisms. The treatment induced apoptosis in ibrutinib-sensitive cell lines, while in ibrutinib-resistant cells the effect was mainly cytostatic and occurred at micromolar concentrations of ibrutinib.
Conclusions
The pharmacological approach of simultaneously targeting cell cycle checkpoints (by Chk1 inhibitors) and pro-survival pathways (by ibrutinib) might offer a promising new therapeutic strategy for MCL patients.
This review summarizes current immunotherapies in breast cancer, with an emphasis on immune checkpoint inhibitors and vaccines.
Recent findings
Combination immunotherapy with checkpoint inhibitors and cytotoxic therapies have shown promising results. Active clinical trials are ongoing in both early stage and metastatic settings for triple negative, HER2+, and hormone-positive breast cancer patients.
Summary
Ongoing challenges remain in defining biomarkers that predict response to immunotherapy, determining the optimal combination immunotherapies, and enhancing the immunogenicity of breast cancer subtypes.
The ligation of PD-1 with PD-L1 activates a critical immune checkpoint leading to T cell dysfunction, exhaustion, and tolerance. Anti-PD-1 or anti-PD-L1 monoclonal antibodies can reverse the immune checkpoint, releasing the brake on T cell responses. We provide a comprehensive review of the literature on the activity of checkpoint inhibitors in lymphoma.
Recent Findings
We discuss the latest findings with checkpoint inhibitors in lymphoma and new promising studies incorporating these agents.
Summary
Classical Hodgkin lymphoma is very sensitive to PD1/PL1 blockade due to genetic alterations in 9p21.1 leading to the high expression of PDL1. Although majority of NHLs have a much lower sensitivity to PD1/PDL1 blockade, a few subtypes such as primary CNS lymphoma, primary testicular lymphoma, primary mediastinal lymphoma harbor 9p21.1 alterations making them vulnerable to PD1 blockade. EBV-associated lymphomas have a virally mediated increased expression of PDL1 making them sensitive to PD1 blockade.
This review discusses novel immunotherapeutic approaches to treat Hodgkin lymphoma (HL), specifically PD-1 inhibitors and cellular immunotherapy.
Recent Findings
PD-1 inhibitors have shown promising results in the treatment of relapsed or refractory HL, leading to FDA approval of nivolumab and pembrolizumab, although complete remissions are rare. Chimeric antigen receptor T cells directed against CD30 have been investigated with preliminary clinical trials showing minimal toxicities and some responses in heavily pre-treated patients with HL.
Summary
HL is unique as it consists of a small percentage of malignant cells (Hodgkin Reed Sternberg cells) surrounded by an inflammatory microenvironment which promotes tumor growth and suppresses immune responses, making it an ideal target for immunotherapeutic approaches, such as PD-1 inhibitors and cellular immunotherapy. Current research is focused on overcoming barriers to efficacy via rational combinations that overcome resistance to therapy.
Cellular therapy using T cells modified to express chimeric antigen receptors (CAR-T cells) has had striking success in patients that have failed previous treatment for CD19+ B cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or acute lymphoblastic leukemia (ALL). Curative therapy for this group of diseases has previously been limited to allogeneic hematopoietic cell transplantation HCT (alloHCT). The recent results of CAR-T cell therapy raise the question of how best to integrate CAR-T cell therapy and alloHCT in the care of these patients.
Recent Findings
Within the past 2 years, results from larger trials and increased follow-up of patients treated with CD19 CAR-T cell therapy suggest that some may achieve durable remission without transplant.
Summary
The balance of efficacy and toxicity for CAR-T cell therapy and alloHCT vary by disease type, disease status at the time of treatment, patient characteristics, and the specific therapy employed. There are early signals that subsequent transplantation of patients who have achieved remission with CAR-T may be a potentially viable (though expensive) strategy.
Survival rates among patients with lymphoma continue to improve. Strategies aimed at reducing potential treatment-related toxicity are increasingly prioritized. While radiological procedures play an important role, ionizing radiation exposure has been linked to an increased risk of malignancy, particularly among individuals whose cumulative radiation exposure exceeds a specific threshold (75 millisieverts).
Methods
Within this retrospective study, the cumulative radiation exposure dose was quantified for 486 consecutive patients with lymphoma.
Results
The median estimated total cumulative effective dose (CED) of ionizing radiation per subject was 69 mSv (42–118). However, younger patients (under 40 years) had a median CED of 89 mSv (55–124).
Conclusion
This study highlights the considerable radiation exposure occurring among patients with lymphoma as a result of diagnostic imaging. To limit the risk of secondary carcinogenesis, consideration should be given to monitoring cumulative radiation exposure in individual patients as well as considering imaging modalities, which do not impart an ionizing radiation dose.
Lymphomatous meningitis is generally fatal. Specific diagnostic tools are required to optimize therapeutic decisions and to improve patient prognosis. Discriminating between secondary and primary central nervous system (CNS) involvement of lymphoma is important due to differing prognosis and therapeutic consequences.
Objectives
Incidence, diagnostic tools and therapeutic options for lymphomatous meningitis are presented.
Materials and methods
Review of the scientific literature regarding incidence, diagnostic tools and therapeutic options of lymphomatous meningitis.
Results
In addition to lymphomas with known particularly higher risk of CNS involvement, lymphomatous meningitis occurs in DLBCL (diffuse large B-cell lymphoma). Recent investigations revealed ECOG (Eastern Cooperative Oncology Group), IPI (International Prognostic Index), > 1 extranodal involvement, LDH (lactate dehydrogenase), and renal involvement as risk factors for CNS involvement. Specific diagnostic workup of cerebrospinal fluid with conventional cytology, flow cytometry, and magnetic resonance imaging improves the possibility of early diagnosis. Recent protocols including autologous stem cell transplantation are promising, providing curative options.
Conclusions
Flow cytometry offers obvious improvement in detecting lymphoma cells in cerebrospinal fluid. The value of detected lymphoma cells in asymptomatic patients is still unclear and the optimal CNS prophylaxis in DLBCL firstline therapy for reducing central nervous relapse is unknown. Nevertheless recent publications are offering promising data even in curing lymphomatous meningitis.
The use of circulating tumor DNA (ctDNA) for the purposes of diagnosis, prognosis, assessment of treatment response, and monitoring for relapse is a new and developing field in lymphoma. This review aims to summarize many of the most recent advances in ctDNA applications.
Recent Findings
Recent studies have demonstrated the use of ctDNA assessment across many lymphoma subtypes including diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, and T-cell lymphoma. In addition, many novel applications of ctDNA assessment have been described such as the development of new prognostic models, investigation of clonal evolution and heterogeneity, early assessment of treatment response, and prediction of response to targeted therapy as a form of personalized medicine.
Summary
The use of ctDNA has been shown to be feasible across many lymphoma subtypes and has shown significant promise for several new applications. Additional studies will be needed to validate these findings prior to routine use in clinical practice.
