In Search of the Perfect Thrombosis and Bleeding-Associated Cancer Scale.

Thrombosis and bleeding are commonly observed in cancer patients, and their management is crucial for positive patient outcomes. A comprehensive, prophylactic, and therapeutic management of venous thrombosis should focus on identifying the patients who would benefit most from treatment to reduce mortality and minimize the risk of thrombosis recurrence without significantly increasing the risk of bleeding. Existing cancer scales provide valuable information for assessing the overall burden of cancer and guiding treatment decisions, but their ability to predict thrombotic and bleeding events remains limited. With increasing knowledge of the pathophysiology of cancer and the availability of advanced anticancer therapies, new risk factors for cancer-associated thrombosis and bleeding are being identified. In this report, we analyze the current literature and identify new risk factors for venous thrombosis and bleeding which are not included in routinely used risk scores. While some existing cancer scales partially capture the risk of thrombosis and bleeding, there is a need for more specific and accurate scales tailored to these complications. The development of such scales could improve risk stratification, aid in treatment selection, and enhance patient care. Therefore, further research and development of novel cancer scales focused on thrombosis and bleeding are warranted to optimize patient management and outcomes.

The Complex Role of Thrombin in Cancer and Metastasis: Focus on Interactions with the Immune System.

Thrombin, a pleiotropic enzyme involved in coagulation, plays a crucial role in both procoagulant and anticoagulant pathways. Thrombin converts fibrinogen into fibrin, initiates platelet activation, and promotes clot formation. Thrombin also activates anticoagulant pathways, indirectly inhibiting factors involved in coagulation. Tissue factor triggers thrombin generation, and the overexpression of thrombin in various cancers suggests that it is involved in tumor growth, angiogenesis, and metastasis. Increased thrombin generation has been observed in cancer patients, especially those with metastases. Thrombin exerts its effects through protease-activated receptors (PARs), particularly PAR-1 and PAR-2, which are involved in cancer progression, angiogenesis, and immunological responses. Thrombin-mediated signaling promotes angiogenesis by activating endothelial cells and platelets, thereby releasing proangiogenic factors. These functions of thrombin are well recognized and have been widely described. However, in recent years, intriguing new findings concerning the association between thrombin activity and cancer development have come to light, which justifies a review of this research. In particular, there is evidence that thrombin-mediated events interact with the immune system, and may regulate its response to tumor growth. It is also worth reevaluating the impact of thrombin on thrombocytes in conjunction with its multifaceted influence on tumor progression. Understanding the role of thrombin/PAR-mediated signaling in cancer and immunological responses is crucial, particularly in the context of developing immunotherapies. In this systematic review, we focus on the impact of the thrombin-related immune system response on cancer progression.

Inhibitors of immune checkpoints-PD-1, PD-L1, CTLA-4-new opportunities for cancer patients and a new challenge for internists and general practitioners.

The treatment of cancer patients with immune checkpoint inhibitors (ICI) (anti-CTLA-4, anti-PD-1, anti-PD-L1, combined therapy anti-PD-1/PD-L1 with anti-CTLA-4) has without doubt been a significant breakthrough in the field of oncology in recent years and constitutes a major step forward as a novel type of immunotherapy in the treatment of cancer. ICIs have contributed to a significant improvement in the outcome of treatment and prognosis of patients with different types of malignancy. With the expansion of the use of ICIs, it is expected that caregivers will face new challenges, namely, they will have to manage the adverse side effects associated with the use of these drugs. New treatment options pose new challenges not only for oncologists but also for specialists in other clinical fields, including general practitioners (GPs). They also endorse the need for taking a holistic approach to the patient, which is a principle widely recognized in oncology and especially relevant in the case of the expanding use of ICIs, which may give rise to a wide variety of organ complications resulting from treatment. Knowledge and awareness of the spectrum of immune-related adverse events (irAEs) will allow doctors to qualify patients for treatment more appropriately, prevent complications, correctly recognize, and ultimately treat them. Additionally, patients with more non-specific symptoms would be expected, in the first instance, to consult their general practitioners, as complications may appear even after the termination of treatment and do not always proceed in line with disease progression. Dealing with any iatrogenic complications, will not only be the remit of oncologists but because of the likelihood that specific organs may be affected, is likely to extend also to specialists in various fields of internal medicine. These specialists, e.g., endocrinologists, dermatologists, pulmonologists, and gastroenterologists, are likely to receive referrals for patients suffering from specific types of adverse events or will be asked to provide care in cases requiring hospitalization of patients with complications in their field of expertise. In view of these considerations, we believe that there is an urgent need for multidisciplinary teamwork in the treatment of cancer patients undergoing immunotherapy and suffering the consequent adverse reactions to treatment.

It is not just the drugs that matter: the nocebo effect.

The role of psychological mechanisms in the treatment process cannot be underestimated, the well-known placebo effect unquestionably being a factor in treatment. However, there is also a dark side to the impact of mental processes on health/illness as exemplified by the nocebo effect. This phenomenon includes the emergence or exacerbation of negative symptoms associated with the therapy, but arising as a result of the patient's expectations, rather than being an actual complication of treatment. The exact biological mechanisms of this process are not known, but cholecystokinergic and dopaminergic systems, changes in the HPA axis, and the endogenous secretion of opioids are thought to be involved. The nocebo effect can affect a significant proportion of people undergoing treatment, including cancer patients, leading in some cases to the cessation of potentially effective therapy, because of adverse effects that are not actually part of the biological effect of treatment. In extreme cases, as a result of suggestions and expectations, a paradoxical effect, biologically opposite to the mechanism of the action of the drug, may occur. In addition, the nocebo effect may significantly interfere with the results of clinical trials, being the cause of a significant proportion of complications reported. Knowledge of the phenomenon is thus necessary in order to facilitate its minimalization and thus improve the quality of life of patients and the effectiveness of treatment.

PET/MRI-guided GTV delineation during radiotherapy planning in patients with squamous cell carcinoma of the tongue.

PURPOSE: The aim of the study was to evaluate the usefulness and accuracy of 18-fluorine-labeled fluorodeoxyglucose (PET) and magnetic resonance imaging (MRI) hybrid in gross tumor volume (GTV) delineation during radiotherapy planning in patients with carcinoma of the tongue. METHODS: Ten patients with squamous cell carcinoma (SCC) of the tongue underwent computed tomography (CT) and PET/MRI examination. The GTV for primary tumor and lymph nodes (nGTV) were defined on CT (GTV-CT) and compared to GTVs obtained from PET (GTV-PET) and MRI (GTV-MRI) images. Two methods of GTV determination were used: visual interpretation of CT, PET (GTV-PETvis) and MRI images and quantitative automatic method (Syngovia, Siemens) based on a chosen threshold value (20%, 30%, 40%, 50%) of standardized uptake values (SUVmax) from PET examination (GTV-PET20%, GTV-PET30%, etc.). Statistical analysis of differences in GTV values obtained from CT, PET and MRI studies was performed. GTV-CT was used as a reference. RESULTS: In all, 80% of GTV-MRI and 40% of GTV-PETvis were larger than GTV-CT. Respectively, 20% of GTV-MRI and 60% of GTV-PETvis were smaller than GTV-CT. Taking into account all threshold measurements, 70% of volumes were smaller than GTV-CT. GTV-PET30% were the most closely related volumes to GTV-CT from all threshold methods in 50% of patients. GTV-PETvis generated the most similar volumes in relation to GTV-CT from all PET measurements. Statistical analysis confirmed those results. Compared to nGTV-CT, 70% of nGTV-MRI and 20% of nGTV-PETvis were larger. The remaining nGTV-MRI and nGTV-PETvis measurements were smaller than nGTV-CT. Measurements of all thresholds nGTVs were smaller than nGTV-CTV in 52.5% of cases. nGTV-PET20% were the most closely related volumes to nGTV-CT in 40% of the cases. Statistical analysis showed that nGTV-PET20% (p = 0.0468), nGTV-PETvis (p = 0.0166), and nGTV-PET50% (p = 0.0166) diverge significantly from nGTV-CT results. nGTV-MRI (p = 0.1141), nGTV-PET30% (p = 0.2845), and nGTV-PET40% (p = 0.5076) were significantly related with nGTV-CT. CONCLUSION: Combination of PET/MRI provides more information during target tumor mass delineation in radiotherapy planning of patients with SCC of the tongue than other standard imaging methods. The most frequently matching threshold value was 30% of SUVmax for primary tumor delineation and 30-40% of SUVmax for nGTV determination.

Febrile neutropenia (FN) and pegfilgrastim prophylaxis in breast cancer and non-Hodgkin's lymphoma patients receiving high (> 20%) FN-risk chemotherapy: results from a prospective observational study.

PURPOSE: Prophylaxis for febrile neutropenia (FN) is recommended for the duration of myelosuppressive chemotherapy in high-risk patients; yet, granulocyte-colony-stimulating factor (G-CSF) discontinuation occurs frequently in clinical practice. The objective of this study was to investigate the incidence of FN in real-world settings and the extent and impact of early pegfilgrastim discontinuation. METHODS: This prospective, observational study enrolled patients with any-stage non-Hodgkin's lymphoma (NHL) or breast cancer initiating a new chemotherapy course with a high (> 20%) FN risk, with pegfilgrastim in cycle 1. During routine clinical visits, data were collected on FN events, discontinuation of pegfilgrastim (defined as administration of G-CSF other than pegfilgrastim for ≥ 1 cycle) and all G-CSF (and reasons), neutropenic complications and adverse drug reactions (ADRs). RESULTS: Overall, 943 patients were enrolled; 844 met the eligibility criteria (full analysis set) and 814 (86%) completed the study. Twenty-eight patients (3%) had 31 FN events (NHL, n = 17; breast cancer, n = 11). Twenty-six patients (3%) discontinued pegfilgrastim. Forty-four patients (5%) discontinued G-CSF. The most common reason for pegfilgrastim discontinuation was physician preference for daily G-CSF (n = 14 [2%]), and for discontinuation of all G-CSFs was reduced FN risk (n = 14 [2%]). Patients who continued G-CSF prophylaxis were less likely to experience neutropenic complications (odds ratio [95% confidence interval]: 0.26 [0.09-0.80]). Suspected ADRs to pegfilgrastim occurred in 43 patients (5%) and serious ADRs in 5 (1%). CONCLUSIONS: FN rates were consistent with previous reports with pegfilgrastim in clinical practice. No new ADRs were observed. G-CSF discontinuation was uncommon but appeared to increase the likelihood of neutropenic complications.

Antiplatelet agents for cancer treatment: a real perspective or just an echo from the past?

The association between coagulation and cancer development has been observed for centuries. However, the connection between inflammation and malignancy is also well-recognized. The plethora of evidence indicates that among multiple hemostasis components, platelets play major roles in cancer progression by providing surface and granular contents for several interactions as well as behaving like immune cells. Therefore, the anticancer potential of anti-platelet therapy has been intensively investigated for many years. Anti-platelet agents may prevent cancer, decrease tumor growth, and metastatic potential, as well as improve survival of cancer patients. On the other hand, there are suggestions that antiplatelet treatment may promote solid tumor development in a phenomenon described as "cancers follow bleeding." The controversies around antiplatelet agents justify insight into the subject to establish what, if any, role platelet-directed therapy has in the continuum of anticancer management.

Platelets and cancer angiogenesis nexus.

There has been remarkable insight into the importance of platelets in a wide range of pathophysiologic events, including inflammation and cancer progression. Thrombocytosis in cancer patients is a common finding. Tumor cells induce platelet activation and subsequent aggregation through direct and indirect mechanisms. Platelets are recognized to contribute to metastatic dissemination. There is plenty of evidence that components of the hemostatic system contribute to the process of angiogenesis. Furthermore, there are accumulated data on the substantial influence of blood platelets in the process of blood vessel formation during malignancy. Platelets appear to be the main physiologic transporters of proangiogenic and antiangiogenic factors. Moreover, they influence the process of angiogenesis through platelet-derived microparticles, microRNA, lipids, and variety of surface receptors. Platelets contribute to early and late stages of angiogenesis. Available data support the overall stimulatory effect of platelets on tumor angiogenesis. It raises the possibility that interfering with platelet function may be an effective antineoplastic treatment strategy.

Thrombin-unique coagulation system protein with multifaceted impacts on cancer and metastasis.

The association between blood coagulation and cancer development is well recognized. Thrombin, the pleiotropic enzyme best known for its contribution to fibrin formation and platelet aggregation during vascular hemostasis, may also trigger cellular events through protease-activated receptors, PAR-1 and PAR-4, leading to cancer progression. Our pioneering findings provided evidence that thrombin contributes to cancer metastasis by increasing adhesive potential of malignant cells. However, there is evidence that thrombin regulates every step of cancer dissemination: (1) cancer cell invasion, detachment from primary tumor, migration; (2) entering the blood vessel; (3) surviving in vasculature; (4) extravasation; (5) implantation in host organs. Recent studies have provided new molecular data about thrombin generation in cancer patients and the mechanisms by which thrombin contributes to transendothelial migration, platelet/tumor cell interactions, angiogenesis, and other processes. Though a great deal is known regarding the role of thrombin in cancer dissemination, there are new data for multiple thrombin-mediated events that justify devoting focus to this topic with a comprehensive approach.

Protease-activated receptors (PARs)--biology and role in cancer invasion and metastasis.

Although many studies have demonstrated that components of the hemostatic system may be involved in signaling leading to cancer progression, the potential mechanisms by which they contribute to cancer dissemination are not yet precisely understood. Among known coagulant factors, tissue factor (TF) and thrombin play a pivotal role in cancer invasion. They may be generated in the tumor microenvironment independently of blood coagulation and can induce cell signaling through activation of protease-activated receptors (PARs). PARs are transmembrane G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. They play important roles in vascular physiology, neural tube closure, hemostasis, and inflammation. All of these agents (TF, thrombin, PARs-mainly PAR-1 and PAR-2) are thought to promote cancer invasion and metastasis at least in part by facilitating tumor cell migration, angiogenesis, and interactions with host vascular cells, including platelets, fibroblasts, and endothelial cells lining blood vessels. Here, we discuss the role of PARs and their activators in cancer progression, focusing on TF- and thrombin-mediated actions. Therapeutic options tailored specifically to inhibit PAR-induced signaling in cancer patients are presented as well.

Protease-activated receptors - biology and role in cancer.

The fact that blood coagulation disorders may accompany malignant disease is well established. However, many studies have shown that components of the haemostatic system may also elicit signaling leading to cancer developement and progression. The potential mechanism by which coagulation factors play a role in cancer invasion is not completely understood, but one hypothesis is that protease-activated receptors (PARs) play a prominent role. PARs are transmembrane G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. They have important functions in haemostasis and inflammation but may also be implicated in cancer cell progression. Thrombin, tissue factor (TF) and matrix metalloproteinases (MMPs) are the main activators of these receptors. The mechanism of persistent activation of PARs was also described in cancer cells. Here, we discuss the physiological and pathological role of PARs with a particular focus on PARs' contribution to cancer biology. We also present therapeutic options tailored specifically to inhibition of PAR-induced signalling in cancer patients.

Chemoradiotherapy for locally advanced pancreatic cancer patients: is it still an open question?

Operable pancreatic cancer is characterized by a high risk of recurrence. Efforts are made to incorporate new therapies. Throughout the world there is a lack of uniform recommendations concerning the adjuvant treatment of pancreatic cancer patients, due to confusing evidence-based data. The patients recruited to clinical trials differ from the population of patients treated in everyday practice. These differences have an influence on tolerance of treatment, toxicity and results of therapy. The decision on administration of adjuvant treatment is made individually and differs from center to center. A review of the literature concerning both results and tolerance of postoperative chemoradiotherapy of pancreatic cancer patients is presented.

Pain management during radiotherapy and radiochemotherapy in oropharyngeal cancer patients: single-institution experience.

AIM OF THE STUDY: Radiotherapy (RT) is a radical therapeutic option for patients with oropharyngeal cancer (OPC). It induces an acute postradiation reaction that may cause significant pain. The aim of this study was to analyse pain occurrence and intensity, as well as type and effectiveness of analgesic treatment, in OPC patients undergoing RT or radiochemotherapy (RT-CT). MATERIAL AND METHODS: Retrospective data were obtained for 42 OPC patients at clinical stages I-IVA, treated with adjuvant RT or RT-CT or definite RT or RT-CcT at the Comprehensive Cancer Center in Bialystok, Poland. Pain intensity and type of analgesic treatment during the therapy were analysed and compared with the intensity of the radiation-induced acute reaction, assessed weekly according to the Dische score. RESULTS: Thirty-nine (92.9%) patients received analgesic treatment. Analgesic therapy was started in 27 (64.3%) patients with administration of non-steroidal anti-inflammatory drugs (NSAIDs) and/or paracetamol, in seven (16.7%) with mild opioids and in five (11.9%) with strong opioids. Strong opioids were used during therapy in 21 (50%) patients. Co-analgesics were administered to six patients. Breakthrough pain was observed in 10 (23.8%) patients. CONCLUSIONS: High incidence of pain during RT and RT-CT calls for increased awareness of the importance of pain monitoring and treatment during RT of OPC patients. The analgesic treatment had to be adjusted individually.

[Endothelial microparticles (EMP) in physiology and pathology]. / Mikropecherzyki pochodzenia sródblonkowego (EMP) rola w fizjologii i patologii.

Endothelial microparticles (EMP) are released from endothelial cells (ECs) in the process of activation and/or apoptosis. They harbor adhesive molecules, enzymes, receptors and cytoplasmic structures and express a wide range of various constitutive antigens, typical for ECs, at their surface. Under physiological conditions the concentration of EMP in the blood is clinically insignificant. However, it was reported that under pathological conditions EMP concentration in the blood might slightly increase and contribute to blood coagulation, angiogenesis and inflammation. It has been shown that EMP directly and indirectly contribute to the activation of blood coagulation. Endothelial microparticles directly participate in blood coagulation through their surface tissue factor (TF) - a major initiator of blood coagulation. Furthermore, EMP exhibit procoagulant potential via expression of negatively charged phospholipids at their surface, which may promote assembly of coagulation enzymes (TF/VII, tenases and prothrombinase complexes), leading to thrombus formation. In addition, they provide a binding surface for coagulation factors: IXa, VIII, Va and IIa. Moreover, it is possible that EMP transfer TF from TF-bearing EMP to activated platelets and monocytes by binding them through adhesion molecules. Also, EMP express von Willebrand factor, which may facilitate platelet aggregation. Apart from their procoagulant properties, it was demonstrated that EMP may express adhesive molecules and metalloproteinases (MMP-2, MMP-9) at their surface and release growth factors, which may contribute to angiogenesis. Additionally, surface presence of C3 and C4 - components of the classical pathway - suggests pro-inflammatory properties of these structures. This article contains a summary of available data on the biology and pathophysiology of endothelial microparticles and their potential role in blood coagulation, angiogenesis and inflammation.

Erythropoietin receptor and tissue factor are coexpressed in human breast cancer cells.

PURPOSE: Erythropoiesis-stimulating agents (ESAs) are recommended for treating chemotherapy-induced anemia in breast cancer patients. Reduced survival rates in ESAs-treated patients have been reported, possibly due to thromboembolic complications, however the exact mechanism remains obscure. The principal activator of blood coagulation in cancer is tissue factor (TF). There are data that erythropoietin receptor (EPO-R) is expressed in tumor cells. The purpose of this study was to evaluate the expression of EPO-R and TF in loco in breast cancer. METHODS: The expression of EPO-R and TF was investigated in 24 invasive breast carcinoma specimens. Immunohistochemical (IHC) methodologies according to ABC technique and double-staining IHC procedure were employed utilizing antibodies against EPO-R and TF. RESULTS: Expression of EPO-R and TF was demonstrated in the tumor cells in all breast cancer specimens. No staining for EPO-R and TF was visualized in normal breast tissue. Double staining studies revealed co-expression of both EPO-R and TF in breast cancer cells and endothelial cells. CONCLUSIONS: EPO-R and TF expression and their coexpression in breast cancer cells suggest a possibility that EPO-R might be responsible for some adverse effects and reduced survival observed in ESAs-treated breast cancer patients with anemia, possibly due to the interaction with TF. Further experimental studies are warranted to determine the role of both EPO-R and TF in the treatment with ESAs of breast cancer patients with chemotherapy-induced anemia.

Protein Z/protein Z-dependent protease inhibitor system in loco in human gastric cancer.

In gastric cancer, hemostatic system components contribute to cancer progression, as activation of factor X (FX) was observed. The protein Z (PZ)/protein Z-dependent protease inhibitor (ZPI) complex inhibits factor Xa proteolytic activity. The purpose of this study was to determine the distribution of ZPI and PZ in relation to FX, and prothrombin fragment (F1 + 2), a standard marker for blood coagulation activation, in human gastric cancer tissue. ABC procedures and a double staining method employed polyclonal antibodies against PZ, FX, and F1 + 2 and a monoclonal antibody against ZPI. In situ hybridization (ISH) methods employed biotin-labeled 25-nucleotide single-stranded DNA probes directed to either PZ or ZPI mRNAs. FX and components of PZ/ZPI coagulation inhibitory system were observed in cancer cells. F1 + 2 was observed in gastric cancer cells as well. Double staining studies revealed FX/PZ, FX/ZPI, and PZ/ZPI co-localization on gastric cancer cells. ISH studies demonstrated the presence of PZ mRNA and ZPI mRNA in gastric cancer cells indicating induced synthesis of these proteins. The co-localization of PZ/ZPI and FX in gastric cancer cells indicates in loco that these proteins may play a role in anticoagulant events at the tumor tissue.

Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial.

BACKGROUND: Regorafenib inhibits VEGF receptors 1, 2, and 3 and PDGF receptors like other anti-angiogenic tyrosine-kinase inhibitors approved for treatment of advanced renal-cell cancer. Regorafenib also inhibits other potentially important angiogenic kinases like TIE2, activation of which is thought to be important in tumour escape mechanisms. This phase 2, open-label, non-randomised study assessed the safety and efficacy of the multikinase inhibitor regorafenib for treatment of renal-cell carcinoma. METHODS: Patients were recruited from 18 academic oncology centres across Europe and USA. Patients with previously untreated metastatic or unresectable clear-cell renal-cell carcinoma received oral regorafenib (160 mg per day) in repeating cycles of 3 weeks on, 1 week off until disease progression or until patients met the criteria for removal from study. The primary efficacy endpoint was the proportion of patients who achieved an objective overall response, assessed in all patients who were evaluable for response. The trial has finished. This trial is registered with ClinicalTrials.gov, number NCT00664326. FINDINGS: The study was done between April 30, 2008, and June 1, 2011. We screened 64 patients, of whom 49 received regorafenib. Median duration of treatment was 7·1 months (range 0·7-34·4, IQR 2·5-18·0) and at the time of data cutoff, six patients (12%) were still receiving treatment. 48 patients were assessable for tumour response. 19 patients (39·6%, 90% CI 27·7-52·5) had an objective response, all of which were partial responses. Drug-related adverse events occurred in 48 patients (98%) and drug-related serious adverse events in 17 (35%). Grade 3 drug-related adverse events were common, most frequently hand and foot skin reaction (16 patients, 33%), diarrhoea (five patients, 10%), renal failure (five patients, 10%), fatigue (four patients, 8%), and hypertension (three patients, 6%). Two patients had grade 4 treatment-related adverse events: two cardiac ischaemia or infarction, one hypomagnesaemia, and one pain in the chest or thorax. Four patients died during study treatment or within 30 days of last dose, of which two were deemed likely to be related to the study drug. INTERPRETATION: Regorafenib has antitumour activity as first-line treatment for metastatic or unresectable renal-cell carcinoma. The drug's safety profile requires close monitoring.

Ozonation of Whole Blood Results in an Increased Release of Microparticles from Blood Cells.

Autohemotherapy with ozonated blood is used in the treatment of a broad spectrum of clinical disorders. Ozone demonstrates strong oxidizing properties and causes damage to cell membranes. The impact of whole-blood ozonation on the release of microparticles from blood and endothelial cells and the concentration of selected markers in the hemostatic system (APTT, PT, D-dimer, fibrinogen) were investigated. Venous blood, obtained from 19 healthy men, was split into four equal parts and treated with air, 15 µg/mL ozone, or 30 µg/mL ozone, or left untreated. The number and types of microparticles released were determined using flow cytometry on the basis of surface antigen expression: erythrocyte-derived microparticles (CD235+), platelet-derived microparticles (CD42+), leukocyte-derived microparticles (CD45+), and endothelial-derived microparticles (CD144+). The study is the first to demonstrate that ozone induces a statistically significant increase in the number of microparticles derived from blood and endothelial cells. Although statistically significant, the changes in some coagulation factors were somewhat mild and did not exceed normal values.

Is depression the missing link between inflammatory mediators and cancer?

Patients with cancer are at greater risk of developing depression in comparison to the general population and this is associated with serious adverse effects, such as poorer quality of life, worse prognosis and higher mortality. Although the relationship between depression and cancer is now well established, a common underlying pathophysiological mechanism between the two conditions is yet to be elucidated. Existing theories of depression, based on monoamine neurotransmitter system dysfunction, are insufficient as explanations of the disorder. Recent advances have implicated neuroinflammatory mechanisms in the etiology of depression and it has been demonstrated that inflammation at a peripheral level may be mirrored centrally in astrocytes and microglia serving to promote chronic levels of inflammation in the brain. Three major routes to depression in cancer in which proinflammatory mediators are implicated, seem likely. Activation of the kynurenine pathway involving cytokines, increases tryptophan catabolism, resulting in diminished levels of serotonin which is widely acknowledged as being the hallmark of depression. It also results in neurotoxic effects on brain regions thought to be involved in the evolution of major depression. Proinflammatory mediators also play a crucial role in impairing regulatory glucocorticoid mediated feedback of the hypothalamic-pituitary-adrenal axis, which is activated by stress and considered to be involved in both depression and cancer. The third route is via the glutamatergic pathway, whereby glutamate excitotoxicity may lead to depression associated with cancer. A better understanding of the mechanisms underlying these dysregulated and other newly emerging pathways may provide a rationale for therapeutic targeting, serving to improve the care of cancer patients.