The impact of platelets on the metastatic potential of tumour cells.

In cancer, activation of platelets by tumor cells is critical to disease progression. Development of precise antiplatelet targeting may improve outcomes from anticancer therapy. Alongside a distinct shift in functionality such as pro-metastatic and pro-coagulant properties, platelet production is often accelerated significantly early in carcinogenesis and the cancer-associated thrombocytosis increases the risk of metastasis formation and thromboembolic events. Tumor-activated platelets facilitate the proliferation of migrating tumor cells and shield them from immune surveillance and physical stress during circulation. Additionally, platelet-tumor cell interactions promote tumor cell intravasation, intravascular arrest, and extravasation through a repertoire of adhesion molecules, growth factors and angiogenic factors. Particularly, the presence of circulating tumor cell (CTC) clusters in association with platelets is a negative prognostic indicator. The contribution of platelets to the metastatic process is an area of intense investigation and this review provides an overview of the advances in understanding platelet-tumor cell interactions and their contribution to disease progression. Also, we review the potential of targeting platelets to interfere with the metastatic process.

Introducing Neoadjuvant Immunotherapy for Colorectal Cancer: Advancing the Frontier.

OBJECTIVE: To give surgeons a review of the current and future use of neoadjuvant immunotherapy in patients with localized colorectal cancer. BACKGROUND: Immunotherapy has revolutionized the standard of care in oncology and improved survival outcomes in several cancers. However, the applicability of immunotherapy is still an ongoing challenge. Some cancer types are less responsive to immunotherapy, and the heterogeneity in responses within cancer types is poorly understood. Clinical characteristics of the patient, the timing of immunotherapy in relation to surgery, diversities in the immune responses, clonal heterogeneity, different features of the tumor microenvironment, and genetic alterations are some factors among many that may influence the efficacy of immunotherapy. RESULTS: In this narrative review, we describe the major types of immunotherapy used to treat localized colorectal cancer. Furthermore, we discuss the prediction of response to immunotherapy in relation to biomarkers and radiological assessment. Finally, we consider the future perspectives of clinical implications and response patterns, as well as the potential and challenges of neoadjuvant immunotherapy in localized colorectal cancer. CONCLUSIONS: Establishing mismatch repair status at the time of diagnosis is central to the potential use of neoadjuvant immunotherapy, in particular immune checkpoint inhibitors, in localized colorectal cancer. To date, efficacy is primarily seen in patients with deficient mismatch repair status and POLE mutations, although a small group of patients with proficient mismatch repair does respond. In conclusion, neoadjuvant immunotherapy shows promising complete response rates, which may open a future avenue of an organ-sparing watch-and-wait approach for a group of patients.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of dopamine-receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting.

INTRODUCTION: Dopamine (D)2,3-receptor antagonists (RAs) were the first antiemetics used in the prophylaxis of chemotherapy-induced nausea and vomiting (CINV). AREAS COVERED: Eight D2,3-RAs, amisulpride, domperidone, droperidol, haloperidol, metoclopramide, metopimazine, olanzapine and prochlorperazine are reviewed focusing on pharmacokinetics, pharmacodynamics, antiemetic effect and side effects. EXPERT OPINION: Since the introduction of D2,3-RAs, antiemetics such as corticosteroids, 5-hydroxytryptamine (5-HT)3-RAs and neurokinin (NK)1-RAs have been developed. The classical D2,3-RAs are recommended in the prophylaxis of CINV from low emetic risk chemotherapy, but not as a fixed component of an antiemetic regimen for moderately or highly (HEC) emetic risk chemotherapy. D2,3-RAs are also used in patients with breakthrough nausea and vomiting. It should be emphasized, that most of these drugs are not selective for dopamine receptors.The multi-receptor targeting agent, olanzapine, is recommended in the prophylaxis of HEC-induced CINV as part of a four-drug antiemetic regimen, including a 5-HT3-RA, dexamethasone and a NK1-RA. Olanzapine is the most effective agent to prevent chemotherapy-induced nausea.Side effects differ among various D2,3-RAs. Metopimazine and domperidone possess a low risk of extrapyramidal side effects. Domperidone and metoclopramide are prokinetics, whereas metopimazine delays gastric emptying and haloperidol does not influence gastric motility. Many D2,3-RAs increase the risk of prolonged QTc interval; other side effects include sedation and orthostatic hypotension.

Digitally assessed lymphocyte infiltration in rectal cancer biopsies is associated with pathological response to neoadjuvant therapy.

A frequently used treatment strategy in locally advanced rectal cancer (RC) is neoadjuvant therapy followed by surgery. Patients treated with neoadjuvant therapy achieve varying pathological response, and currently, predicting the degree of response is challenging. This study examined the association between digitally assessed histopathological features in the diagnostic biopsies and pathological response to neoadjuvant therapy, aiming to find potential predictive biomarkers. 50 patients with RC treated with neoadjuvant chemotherapy and/or radiotherapy followed by surgery were included. Deep learning-based digital algorithms were used to assess the epithelium tumor area percentage (ETP) based on H&E-stained slides, and to quantify the density of CD3+ and CD8+ lymphocytes, as well as the CD8+/CD3+ lymphocyte percentage, based on immunohistochemically stained slides, from the diagnostic tumor biopsies. Pathological response was assessed according to the Mandard method. A good pathological response was defined as tumor regression grade (TRG) 1-2, and a complete pathological response was defined as Mandard TRG 1. Associations between the ETP and lymphocyte densities in the diagnostic biopsies and the pathological response were examined. The density of CD8+ lymphocytes, and the CD8+/CD3+ lymphocyte percentage, were associated with both good and complete response to neoadjuvant therapy, while the density of CD3+ lymphocytes was associated with complete response. The ETP did not correlate with response to neoadjuvant therapy. It is well-known that infiltration of lymphocytes in colorectal cancer is a prognostic biomarker. However, assessment of CD8+ and CD3+ lymphocytes in the diagnostic tumor biopsies of patients with RC may also be useful in predicting response to neoadjuvant therapy.

The role of immunotherapy in the treatment of colorectal cancer.

In Denmark, around 4,500 people are diagnosed with colorectal cancer (CRC) annually. This review investigates that while the efficacy of immunotherapy in CRC is still being studied, immunotherapy is currently only indicated in the treatment of mismatch-repair deficient (dMMR) metastatic CRC, which accounts for 10-15% of patients. Recent studies indicate high rates of pathologic response in dMMR CRC treated with pre-operative immunotherapy while large-scale studies on novel immunotherapy combinations are ongoing.