Current and future immunotherapies for thyroid cancer

Introduction: Cancer immunotherapies were approved in recent years, including immune checkpoint inhibitors. Experience with ipilimumab (CTLA-4 antagonist), nivolumab and pembrolizumab (PD-1 antagonists), and atezolizumab (PD-L1 antagonist) has shown that the impact on overall survival in cancer patients is paramount. Immune checkpoint inhibitors target the immune system and they can be applied across multiple cancers; the response rate is ranging from 20 to 40%. Many studies have shown that thyroid cancer (TC) cells produce cytokines and chemokines, inducing several tumor-promoting effects. Targeting and/or lowering cytokines and chemokines concentrations within the tumor microenvironment would produce a therapeutic benefit. In TC, increased Treg and PD-1⁺ T cell frequencies are indicative of aggressive disease and PD-L1 expression correlates with a greater risk of recurrence.

Area covered: After performing a literature search, a few pioneering studies have evaluated immunotherapy in thyroid cancer. More recently a case has been described involving anaplastic thyroid cancer treated with vemurafenib and nivolumab, with substantial regression and complete radiographic and clinical remission.

Expert commentary: The use of immune checkpoint inhibitors in aggressive TC has not yet been extensively investigated and further studies in a large number of TC patients are urgently needed.     

Radioimmunotherapy: Strategies for the future in indolent and aggressive lymphoma

The conjugation of radioisotopes to monoclonal antibodies, or radioimmunotherapy (RIT), is a highly active treatment in non-Hodgkin’s lymphoma. RIT has demonstrated high response rates and durable remissions in extensively pretreated patients and has proved highly effective as consolidation after induction chemotherapy in the first-line therapy of follicular lymphoma. Earlyphase clinical trials have shown highly promising results using RIT as part of conditioning regimens in patients who are to undergo transplantation and as consolidation after chemotherapy in patients with aggressive lymphomas. Recent data suggest that integrating RIT with immunochemotherapy and transplant conditioning regimens may further improve outcomes for patients.     

Current and future adjuvant immunotherapies for melanoma: Blockade of cytotoxic T-lymphocyte antigen-4 as a novel approach

The current treatment for melanoma with nodal involvement, but without distant metastasis, is surgical excision and lymph node dissection followed by adjuvant therapy. A number of systemic regimens have been evaluated for melanoma patients with a medium or high risk of disease recurrence following surgery. The only agent approved for the adjuvant therapy of melanoma is high-dose interferon (IFN)-α2b, which prolongs relapse-free survival, but its effects on overall survival remain controversial. Its use is also accompanied by significant toxicity. Thus, despite its approval, high-dose IFN-α2b is not always used for the adjuvant therapy of melanoma, particularly in countries other than the United States. Studies aimed at identifying subgroups of patients that have the greatest benefit-to-risk ratio with this regimen are ongoing. Several vaccines have been studied in the adjuvant setting for melanoma, but none has shown superiority to IFN-containing regimens. The GMK ganglioside vaccine, for instance, has actually been shown to be inferior to high-dose IFN-α2b. Therefore, a therapeutic regimen which improves overall survival with a favorable safety profile would be a major advance in the adjuvant therapy of melanoma. One approach that is currently being investigated is the potentiation of antitumour immune responses through blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4). Here, we provide an overview of the current unmet needs in the adjuvant therapy of melanoma and evaluate the potential of CTLA-4 blockade as a future therapeutic option in this setting.     

原发性渗出性淋巴瘤(附1例报告)

目的探讨原发性渗出性淋巴瘤(PEL)的临床、组织学特点。方法运用组织形态学、免疫组化方法研究1例经临床与病理确诊的PEL病人并结合文献进行讨论。结果该病的临床特点是体腔积液如腹水、胸水和心包积液,但没有可检测到的肿块样病灶,浆膜渗出液中含高度恶性的淋巴细胞。此病多见于爱滋病毒(H IV)感染的病人,也可发生于H IV血清学阴性的病人。结论进一步对本病的病理特征,临床特点加深了解,对提高本病的鉴别诊断、治疗大有裨益。     

Malignant lymphoma and malignant angioendotheliomatosis: one disease

A patient was diagnosed as having angioendotheliomatosis proliferans systemisata (APS) based on characteristic clinical and histologic features. A few days later, malignant lymphoma involving the gut was discovered. Immunohistochemical and electronmicroscopic studies confirmed the nonendothelial and lymphoid nature of intravascular tumor cells. This is the sixth case in which malignant lymphoma has been shown to involve the vessels of the skin (and probably of other organs) in a pattern identical to that seen in APS.     

Current and future therapeutic approaches for the treatment of follicular lymphoma

Introduction: Recent advances in prognostication as well as management of Follicular Lymphoma (FL) are moving to personalized approach.

Areas covered: Prognostic scores as well as consolidated and innovative therapeutic approaches are evaluated according to the various presentation modalities. For asymptomatic, low-tumor burden FL, a ‘watch and wait’ policy is currently the first-choice approach, although possible alternatives are discussed. Early stage FL may be treated with local radiotherapy although the role of minimal residual disease in possible additional agents should be determined. The first line treatment for symptomatic FL is chemo-immunotherapy followed by two years maintenance therapy with anti-CD20 monoclonal antibodies. A deeper knowledge of FL biology has opened new perspectives regarding the timing of therapy and has offered new targets for the development of novel agents that aim to change the therapeutic scenario of FL management.

Expert commentary: The introduction of novel agents could question the incurability of FL and change the therapeutic goal from prolonging the complete remission state to eradicating the disease in young/fit patients, as well as improving quality of life in elderly/unfit patients. In the near future, combining new biologic agents and adoptive cell therapies could help in achieving these aims.     

Current therapy and future prospects in lymphoma

Today, lymphoma represents one of the most complex and diverse malignancies in routine clinical practice and huge advances have been made in the pathological classification and treatment of this family of diseases. Progress in treatment means that long-term survival is now an achievable goal for many, although a proportion of patients remain incurable. Developments in both conventional chemotherapy as well as biotechnological advances have opened new therapeutic approaches, many of which have already reached the clinic.     

Current therapy and future prospects in lymphoma

Today, lymphoma represents one of the most complex and diverse malignancies in routine clinical practice and huge advances have been made in the pathological classification and treatment of this family of diseases. Progress in treatment means that long-term survival is now an achievable goal for many, although a proportion of patients remain incurable. Developments in both conventional chemotherapy as well as biotechnological advances have opened new therapeutic approaches, many of which have already reached the clinic.     

Next-generation sequencing in the clinic: Promises and challenges

The advent of next generation sequencing (NGS) technologies has revolutionized the field of genomics, enabling fast and cost-effective generation of genome-scale sequence data with exquisite resolution and accuracy. Over the past years, rapid technological advances led by academic institutions and companies have continued to broaden NGS applications from research to the clinic. A recent crop of discoveries have highlighted the medical impact of NGS technologies on Mendelian and complex diseases, particularly cancer. However, the ever-increasing pace of NGS adoption presents enormous challenges in terms of data processing, storage, management and interpretation as well as sequencing quality control, which hinder the translation from sequence data into clinical practice. In this review, we first summarize the technical characteristics and performance of current NGS platforms. We further highlight advances in the applications of NGS technologies towards the development of clinical diagnostics and therapeutics. Common issues in NGS workflows are also discussed to guide the selection of NGS platforms and pipelines for specific research purposes.     

Statistical controversies in clinical research: early-phase adaptive design for combination immunotherapies

BackgroundIn recent years, investigators have asserted that the 3 + 3 design lacks flexibility, making its use in modern early-phase trial settings, such as combinations and/or biological agents, inefficient. More innovative approaches are required to address contemporary research questions, such as those posed in trials involving immunotherapies.DesignWe describe the implementation of an adaptive design for identifying an optimal treatment regimen, defined by low toxicity and high immune response, in an early-phase trial of a melanoma helper peptide vaccine plus novel adjuvant combinations.ResultsOperating characteristics demonstrate the ability of the method to effectively recommend optimal regimens in a high percentage of trials with reasonable sample sizes.ConclusionsThe proposed design is a practical, early-phase, adaptive method for use with combined immunotherapy regimens. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of two small molecule inhibitors in relapsed/refractory mantle cell lymphoma.     

Treatment of Hodgkin lymphoma: the past, present, and future

Significant advances in the biology and treatment of Hodgkin lymphoma (HL) have been accomplished over the past decades. In a landmark study, DeVita and colleagues showed that half of patients with advanced-stage HL experienced long-term disease-free survival following treatment with a four-drug chemotherapy regimen. Subsequent reports and randomized clinical trials conducted over the past 40 years have defined prognostic categories and refined the treatment options for patients with early-stage and advanced-stage HL. New treatment concepts and regimens have continued to increase the cure rate of HL, while other analyses have documented the acute and long-term morbid and potentially fatal side effects of HL therapy. Increased knowledge of HL biology has been gained, in particular, much has been learnt about the genetic and phenotypic characteristics of malignant cells and the varied oncogenic signaling pathways involved in HL. Continued translational research is needed to improve the long-term survival and to lessen the toxicities associated with therapy. Furthermore, continued clinical-trial involvement by oncologists and patients is imperative to further advance the field of HL.     

血管内T细胞淋巴瘤一例报道并文献复习

目的提高对血管内淋巴瘤（IVL）的认识。方法报道一例IVL的临床表现和诊治经过,并进行文献复习。结果以发热、皮疹和嗜血细胞综合征为表现的IVL少见,该例患者经过积极化疗效果不显著,最后死于肝衰竭和消化道出血。结论IVL少见,患者生前诊断困难,病情进展快,预后差。     

The future of small molecule inhibitors in lymphoma

For the many patients with lymphoma that has relapsed after and/or has become refractory to existing treatments, the development of novel therapeutics is imperative. Investigation into intracellular processes that are dysregulated during lymphomagenesis has uncovered several new potential targets for anticancer agents. Although monoclonal antibodies and other immunotherapeutics have led to dramatic advances in the treatment of patients with lymphoma, the parallel development of small molecule inhibitors has been equally exciting. These agents, whose small size allows direct entry into tumor cells, can target distinct proteins or complexes, thereby disrupting molecular processes on which neoplastic cells depend for survival and growth. This review surveys the published literature on many of these new targeted molecules, focusing on some of the most promising agents for which phase 2 data currently exist. It also explores the potential for incorporating these agents into broader multidrug regimens.