As immunotherapy has gained increasing interest as a new foundation for cancer therapy, some atypical response patterns, such aspseudoprogression and hyperprogression, have garnered the attention of physicians. Pseudoprogression is a phenomenon inwhich an initial increase in tumor size is observed or new lesions appear, followed by a decrease in tumor burden; thisphenomenon can benefit patients receiving immunotherapy but often leads to premature discontinuation of treatment owing tothe false judgment of progression. Accurately recognizing pseudoprogression is also a challenge for physicians. Because of theextensive attention on pseudoprogression, significant progress has been made. Some new criteria for immunotherapy, such asirRC, iRECIST and imRECIST, were proposed to accurately evaluate the response to immunotherapy. Many new detectionindexes, such as ctDNA and IL-8, have also been used to identify pseudoprogression. In this review, the definition, evaluationcriteria, mechanism, monitoring, management and prognosis of pseudoprogression are summarized, and diagnostic andtreatment processes for patients with progression but with a suspicion of pseudoprogression are proposed; these processes couldbe helpful for physicians in clinical practice and enhances the understanding of pseudoprogression. Cite this article as: Jia W, Gao Q, Han A, Zhu H, Yu J. The potentialmechanism, recognition and clinical significance of tumor pseudoprogressionafter immunotherapy. Cancer Biol Med. 2019; 16: 655-70. doi:10.20892/j.issn.2095-3941.2019.0144

http://www.cancerbiomed.org/index.php/cocr/article/download/1502/1494

The potential mechanism, recognition and clinical significance of tumor pseudoprogression after immunotherapy

With the advent of immunotherapy as an integral component of multidisciplinary solid tumor treatment, we are confronted by an unfamiliar and novel pattern of radiographic responses to treatment. Enlargement of tumors or even new lesions may not represent progression, but rather reflect what will ultimately evolve into a clinically beneficial response. In addition, the kinetics of radiographic changes in response to immunotherapy treatments may be distinct from what has been observed with cytotoxic chemotherapy and radiation. The phenomenon of pseudoprogression has been documented in patients receiving immunotherapeutic agents, such as checkpoint inhibitors and cellular therapies. Currently, there are no clinical response guidelines that adequately account for pseudoprogression and solid tumor responses to immunotherapy in general. Even so, response criteria have evolved to account for the radiographic manifestations of novel therapies. The evolution of World Health Organization (WHO) criteria and Response Evaluation Criteria in Solid Tumors (RECIST), along with the emergence of immune-related response criteria (irRC) and the immune Response Evaluation Criteria in Solid Tumors (iRECIST) reflect the need for new frameworks. This review evaluates the relationship between pseudoprogression, clinical outcomes, and our current understanding of the biology of pseudoprogression. To achieve our goal, we discuss unusual response patterns in patients receiving immunotherapy. We seek to develop a deeper understanding of radiographic responses to immunotherapy such that clinical benefit is not underappreciated in individual patients and during clinical investigation.

Challenges in assessing solid tumor responses to immunotherapy.

The vascular endothelial growth factor (VEGF) family, the crucial regulator of angiogenesis, lymphangiogenesis, lipid metabolism and inflammation, is involved in the development of atherosclerosis and further CVDs (cardiovascular diseases). This review discusses the general regulation and functions of VEGFs, their role in lipid metabolism and atherosclerosis development and progression. These functions present the great potential of applying the VEGF family as a target in the treatment of atherosclerosis and related CVDs. In addition, we discuss several modern anti-atherosclerosis VEGFs-targeted experimental procedures, drugs and natural compounds, which could significantly improve the efficiency of atherosclerosis and related CVDs’ treatment.

/pdf/the-role-of-the-vegf-family-in-atherosclerosis-development-2s3jltxg.pdf

The Role of the VEGF Family in Atherosclerosis Development and Its Potential as Treatment Targets

Abstract Tumors are comprised of both cancer cells and surrounding stromal components. As an essential part of the tumor microenvironment, the tumor stroma is highly dynamic, heterogeneous and commonly tumor-type specific, and it mainly includes noncellular compositions such as the extracellular matrix and the unique cancer-associated vascular system as well as a wide variety of cellular components including activated cancer-associated fibroblasts, mesenchymal stromal cells, pericytes. All these elements operate with each other in a coordinated fashion and collectively promote cancer initiation, progression, metastasis and therapeutic resistance. Over the past few decades, numerous studies have been conducted to study the interaction and crosstalk between stromal components and neoplastic cells. Meanwhile, we have also witnessed an exponential increase in the investigation and recognition of the critical roles of tumor stroma in solid tumors. A series of clinical trials targeting the tumor stroma have been launched continually. In this review, we introduce and discuss current advances in the understanding of various stromal elements and their roles in cancers. We also elaborate on potential novel approaches for tumor-stroma-based therapeutic targeting, with the aim to promote the leap from bench to bedside. 

/pdf/targeting-the-tumor-stroma-for-cancer-therapy-sjndz6yj.pdf

Targeting the tumor stroma for cancer therapy

Immune checkpoint inhibitors are associated with clinical benefit in lung cancer. However, response patterns to immunotherapy, including pseudoprogression and hyperprogression, are difficult to diagnose, and their mechanisms remain unclear. This review aimed to describe two response patterns observed in lung cancer, namely pseudoprogression and hyperprogression, including their epidemiology, diagnostic characteristics, and plausible mechanisms. We performed a comprehensive literature search in the PubMed database, using keywords “pseudoprogression”, “hyperprogression”, and “lung cancer”, among others. The literature was examined for pseudoprogression and hyperprogression characteristics and plausible mechanisms. Pseudoprogression manifests in multiple forms; however, the immune system-related response criteria and biopsy data are helpful to make accurate diagnosis. Serological biomarkers, such as neutrophil-to-lymphocyte ratio (NLR) and circulating tumor DNA (ctDNA), might help distinguish pseudoprogression from true progression. The incidence of hyperprogression ranges within 5–19.2%, depending on definition. The unique response pattern of rapid progression is observed not only with immunotherapy, but also with other treatment regimens. Molecular mutations and amplifications may result in hyperprogression; however, the exact mechanism remains unclear. Atypical response patterns, such as pseudoprogression and hyperprogression, are increasingly common in clinical practice. Immune-related response criteria can help diagnose pseudoprogression. Molecular mechanisms of hyperprogression remain unclear. Biomarkers for pseudoprogression and hyperprogression are required.

Pseudoprogression and hyperprogression in lung cancer: a comprehensive review of literature.

The sites of targeted therapy are limited and need to be expanded. The FGF-FGFR signalling plays pivotal roles in the oncogenic process, and FGF/FGFR inhibitors are a promising method to treat FGFR-altered tumours. The VEGF-VEGFR signalling is the most crucial pathway to induce angiogenesis, and inhibiting this cascade has already got success in treating tumours. While both their efficacy and antitumour spectrum are limited, combining FGF/FGFR inhibitors with VEGF/VEGFR inhibitors are an excellent way to optimize the curative effect and expand the antitumour range because their combination can target both tumour cells and the tumour microenvironment. In addition, biomarkers need to be developed to predict the efficacy, and combination with immune checkpoint inhibitors is a promising direction in the future. The article will discuss the FGF-FGFR signalling pathway, the VEGF-VEGFR signalling pathway, the rationale of combining these two signalling pathways and recent small-molecule FGFR/VEGFR inhibitors based on clinical trials.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cpr.13009

Inhibition of FGF-FGFR and VEGF-VEGFR signalling in cancer treatment

Squamous cancer (SqCC) of the lung has a poor prognosis. With the advent of immunotherapy, prognosis has tended to improve; however, pseudoprogression poses a challenge to the management of immunotherapy. Herein, we discuss the case of a 47-year-old heavy smoker with advanced SqCC. The patient had recurrent disease after initial successful control of the tumor by concurrent radiochemotherapy, together with ample pleural effusion. Pleural effusion was well controlled with systematic nivolumab and intra-thoracic recombinant endostatin; however with simultaneous deterioration of performance and tumor progression. Nivolumab was maintained with the addition of nab-paclitaxel. The combination soon led to a partial response and rapid improvement of the patient's performance. During treatment of this case, we advocated the early control of pleural effusion as an indicator for pseudoprogression. Our experience might be helpful to identify pseudoprogression for the clinical management of immunotherapy.

Well-controlled pleural effusion indicated pseudoprogression after immunotherapy in lung cancer: A case report.

Anlotinib hydrochloride is a multi-target tyrosine kinase inhibitor, which has been recently approved for the treatment of advanced non-small cell lung cancer in China. One of its mechanisms of action is the inhibition of angiogenesis and it is similar to other anti-angiogenesis drugs, as it has cardiovascular toxicity, which may damage vascular endothelial cells and result in hypertension and hyperlipidemia. All of the aforementioned factors are considered risk factors for coronary heart disease; however, the risk of developing acute myocardial infarction (AMI) has not been assessed by any previous clinical trials and subsequent research. The present case study, to the best of our knowledge, was the first to report on a patient who developed hypertension, hyperlipidemia and angina pectoris, and eventually experienced AMI, following treatment with anlotinib. This indicates that patients receiving anlotinib may require further observation and monitoring during use.

/pdf/anlotinib-induced-acute-myocardial-infarction-a-case-report-2ktmzd14wx.pdf

Anlotinib-induced acute myocardial infarction: A case report and literature review.

Coronary artery disease is a serious threat to human health. More and more evidences indicate chronic inflammatory plays a key role in the development of this disease. Inflammation markers are gradually used in the diagnosis and treatment. Although the treatment of coronary heart disease with colchicine is still controversial, more and more studies showed that patients can benefit from this medicine. In this review, we discuss and summarize colchicine on essential pharmacology, anti-inflammatory mechanism of action, and the most important and recent clinical studies. According to these literatures, colchicine possibly will possibly become a new valuable and cheap medicine for the treatment of coronary artery disease.

/pdf/colchicine-for-coronary-artery-disease-a-review-1fm436y5.pdf

Guihong Liu

Papers

Inhibition of FGF-FGFR and VEGF-VEGFR signalling in cancer treatment

Well-controlled pleural effusion indicated pseudoprogression after immunotherapy in lung cancer: A case report.

Anlotinib-induced acute myocardial infarction: A case report and literature review.

Colchicine for Coronary Artery Disease: A Review