Mediastinal (thymic) large B-cell lymphoma: where do we stand?

Mediastinal (thymic) B-cell lymphoma (MBL) is a locally highly aggressive tumour that was first definitively described in the early 1980s. The incidence of MBL is low, which made disease characterisation difficult initially. However, MBL has several peculiar clinical, morphological, immunological, and genetic features. Collectively, these characteristics distinguish it from other diffuse, large B-cell lymphomas. Consequently, MBL has become a defined subtype of diffuse large B-cell lymphoma with its own code (9679/3) in the International Classification of Diseases. New insights into the biological and clinical aspects of MBL have been gained from the study of large numbers of cases. Nevertheless, the histogenesis of the disease is not yet fully understood. We review the available data on MBL with special emphasis on its morphological, immunological, and genetic properties. Also discussed are recent data on molecular genetics, biology, and treatment.     

Beyond genomics – Targeting the epigenome in diffuse large B-cell lymphoma

After decades of intense research on genetic alterations in cancer and successful implementation of genetically-based targeted therapies, the field of cancer epigenetics is only beginning to be fully recognized. The discovery of frequent mutations in genes modifying the epigenome in diffuse large B-cell lymphoma (DLBCL) has highlighted the outstanding role of epigenetic deregulation in this disease. Identification of epigenetically-driven DLBCL subgroups and development of novel epigenetic drugs have rapidly advanced. However, further insights are needed into the biological consequences of epigenetic alterations and the possibility of restoring the aberrant epigenome with specific therapies to bring this treatment concept further into clinical practice. This review will summarize the main epigenetic changes found in DLBCL and their potential for precision medicine approaches.     

Toremifene. where do we stand?

Toremifene is a chlorinated triphenylethylene that is indicated for postmenopausal breast cancer. For advanced disease, toremifene has been found to be as effective and at least as well tolerated as tamoxifen. The same appears to apply for adjuvant setting. After a total cumulative clinical exposure to toremifene of approximately 140000 patient-years, only 9 cases of endometrial carcinoma have been reported. The annual hazard rate (per 1000 patient-years) of developing endometrial carcinoma in breast cancer patients on adjuvant toremifene is 1.14 (versus tamoxifen 2.0 and placebo 0.4). Although toremifene (being a partial agonist) may unmask pre-existing endometrial tumours, there is no clinical data implying that it would per se cause endometrial carcinoma.     

Diagnostics and treatment of diffuse intrinsic pontine glioma: where do we stand?

Journal of Neuro-Oncology - Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of...     

Radiation therapy in the management of diffuse large B-cell lymphoma: still relevant?

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in the United States. Historically, radiation therapy (RT) was the primary treatment for patients with localized disease. Several randomized trials have demonstrated that the addition of systemic therapy improves outcomes. Additional randomized trials have shown that the combination of RT and systemic therapy is superior to systemic therapy alone. The role of RT in advanced-stage DLBCL has not been firmly established, but some prospective phase III trials, as well as retrospective studies, suggest a benefit for advanced disease also. For patients with relapsed or primary refractory disease, autologous stem cell transplantation is the treatment of choice. Here too, consolidation RT appears to improve outcomes compared with autologous stem cell transplant alone. Finally, for patients with advanced DLBCL who are no longer responsive to systemic therapy, RT may provide rapid and durable palliation of local lymphoma-related symptoms.     

Angiogenesis inhibitors in clinical development; where are we now and where are we going?

Angiogenesis is crucial for tumour growth and the formation of metastases. Various classes of angiogenesis inhibitors that are each able to inhibit one of the various steps of this complex process can be distinguished. Results from clinical studies with these agents are summarised. In general, it has been shown that most angiogenesis inhibitors can be safely administered, but that tumour regressions are rare. Combining angiogenesis inhibitors with cytotoxic chemotherapy can enhance anticancer activity. Recently, some promising data with regard to clinical efficacy have been presented. While performing clinical studies with angiogenesis inhibitors, defining biological activity is crucial, but thus far no validated techniques are available. It is conceivable that in the near future various classes of angiogenesis inhibitors will be combined in an attempt to further improve antiangiogenic and anticancer activity.     

Hitting back at lymphoma: How do modern diagnostics identify high-risk diffuse large B-cell lymphoma subsets and alter treatment?

Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease. Diagnostic tools in the clinic can now identify distinct subsets characterized by unique molecular features, which are increasingly transforming how these patients are managed. Activated B–cell-like DLBCL is characterized by NF-κB activation and chronic B-cell receptor signaling and may be targeted with lenalidomide or ibrutinib in the relapsed setting. Germinal center-like DLBCL is enriched for activating EZH2 mutations, and encouraging activity has been observed for the EZH2 inhibitor tazemetostat, which now has a fast-track US Food and Drug Administration designation. Double-hit lymphoma is a high-grade B-cell lymphoma characterized by translocations of MYC and BCL2 and/or BCL6 and carries a poor prognosis. Intensive chemoimmunotherapy strategies appear to be superior to standard R-CHOP (rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone) as initial therapy, and anti-CD19 chimeric antigen receptor T cells are inducing remission in patients with relapsed/refractory disease who previously had few available options. Primary mediastinal (thymic) large B-cell lymphoma is a molecularly distinct large-cell lymphoma with clinical and molecular features that overlap with those of classical Hodgkin lymphoma. R-CHOP has been associated with an unacceptably high rate of primary treatment failure in this young population, whereas dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab) produces durable remissions without the need for radiotherapy in most patients. For relapsed/refractory disease, immune checkpoint inhibitors targeting PD-1 have shown promising activity in chemotherapy-refractory disease, as have anti-CD19 chimeric antigen receptor T cells. Additional therapeutic targets, including JAK2, continue to be evaluated. The identification of discrete biological subsets is steadily moving us away from a “one-size-fits-all” approach in DLBCL.     

Suicide gene therapy in cancer: Where do we stand now?

Suicide gene therapy is based on the introduction into tumor cells of a viral or a bacterial gene, which allows the conversion of a non-toxic compound into a lethal drug. Although suicide gene therapy has been successfully used in a large number of in vitro and in vivo studies, its application to cancer patients has not reached the desirable clinical significance. However, recent reports on pre-clinical cancer models demonstrate the huge potential of this strategy when used in combination with new therapeutic approaches. In this review, we summarize the different suicide gene systems and gene delivery vectors addressed to cancer, with particular emphasis on recently developed systems and associated bystander effects. In addition, we review the different strategies that have been used in combination with suicide gene therapy and provide some insights into the future directions of this approach, particularly towards cancer stem cell eradication.     

EBV-positive diffuse large B-cell lymphoma in young adults: is this a distinct disease entity?

A substantial proportion of Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly can occur in young adults. ‘EBV-positive DLBCL in young adults’ needs to be considered as a clinically distinct disease entity.BackgroundEpstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly is defined only in adults older than 50 years. However, EBV-positive DLBCL can affect younger patients. We investigated the prevalence, clinical characteristics and survival outcomes of EBV-positive DLBCL in young adults.Patients and methodsWe analyzed patients withde novo DLBCL who were registered in the Samsung Medical Center (SMC) retrospective lymphoma cohort and prospective SMC Lymphoma Cohort Study I (ClinicalTrials.gov: NCT00822731).ResultsA total of 571 cases were included in the analysis. The prevalence of EBV positivity was 6.7% (13/195) and 9.3% (35/376) in the young group (≤50 years) and in the elderly group (>50 years), respectively. EBV status was closely associated with unique unfavorable clinical characteristics [older age, more advanced stage, two or more sites of extranodal involvement, higher International Prognostic Index (IPI), and age-adjusted IPI risk] only in the elderly group. Poor prognostic impact of EBV positivity on overall survival was observed only in the elderly group [hazard ratio (HR) 2.86; 95% confidence interval (CI) 1.83–4.47;P < 0.001], but not in the young group (HR 1.17; 95% CI 0.35–3.89;P = 0.801).ConclusionA substantial proportion of EBV-positive DLBCL of the elderly can occur in young adults. EBV positivity of DLBCL in young adults was not associated with unfavorable clinical characteristics or worse outcomes. We suggest that EBV-positive DLBCL should not be confined only in the elderly and ‘EBV-positive DLBCL in young adults’ needs to be considered as a clinically distinct disease entity.ClinicalTrials.govNCT02060435.     

Multinational clinical trials in oncology and post-trial benefits for host countries: where do we stand?

International collaboration has undoubtedly played a key role in the extraordinary progress we have witnessed in some areas of oncology in recent years. It has allowed us, for instance, to design trials large enough to depict very small benefits, as well as high-quality trials in less incident types of cancer. For different reasons, developing countries have also shown growing interest in this international effort and have been participating in many international trials. However, the ever-growing costs of novel anti-cancer treatments and technologies have created unprecedented difficulties for health economies in developing countries. Although the issue of individual benefit for patients must also be taken into account, the actual benefit for their society may be minimal. This paper discusses the ethics of including patients from non-developed countries in clinical trials evaluating the role of treatments that are unlikely to be made available to them after the trial because of prohibitive costs. Upfront arrangements ensuring post-trial access to interventions that have been proven successful might be the best alternative to exclusion from the research.     

Antiangiogenic agents in the management of non-small cell lung cancer: Where do we stand now and where are we headed?

Several therapies targeting angiogenesis are currently in development for non-small cell lung cancer (NSCLC). This review discusses results of recent clinical trials evaluating chemotherapy plus antiangiogenic therapy for NSCLC. Bevacizumab, an anti-VEGF antibody, is currently approved for the treatment of advanced NSCLC in combination with carboplatin and paclitaxel. Completed phase III trials evaluating bevacizumab plus chemotherapy have shown prolonged progression-free survival; however, not all trials showed significant improvement in overall survival (OS). Phase III trials of the tyrosine kinase inhibitors (TKIs) vandetanib and sorafenib and the vascular disrupting agent ASA404 also failed to improve OS compared with chemotherapy alone. Clinical trials are ongoing involving several new antiangiogenic therapies, including ramucirumab, aflibercept, cediranib, BIBF 1120, sunitinib, pazopanib, brivanib, ABT-869, axitinib, ABT-751, and NPI-2358; several of these agents have shown promising phase I/II results. Results from recently completed and ongoing phase III trials will determine if these newer antiangiogenic agents will be incorporated into clinical practice.