**6. Fibrinogen in gastric cancer evaluation**

The association between malignant solid tumours and disturbances of blood clotting is wellknown. In addition, fibrinogen is an acute phase reactant glycoprotein [110]. Consequently, the presence of hyperfibrinogenaemia in gastric cancer patients can be almost expected. Indeed, increased levels of fibrinogen have been identified and explored regarding the prognostic value or the association with tumour parameters. The studies range from historical to up-to-dated and cover aspects of patient's survival, tumour progression, diagnostic value, estimates of tumour burden and insights into novel treatment options.

Elevated concentration of fibrinogen in the serum of gastric carcinoma patients has negative prognostic value regarding several aspects of survival—overall and cancer-free survival. The independent prognostic value of increased fibrinogen level has been demonstrated in 351 surgically treated gastric cancer patients. The hazard ratio was 2.61 (95% CI = 1.18–5.76) as reported by Suzuki et al. [111]. The independent prognostic role was confirmed in another large surgically treated cohort of 1196 gastric cancer patients [112]. Applying ROC-identified cut-off (3.9 g/L), high fibrinogen level was significantly associated with overall survival in multivariate analysis [113]. In patients who underwent curative gastrectomy, hyperfibrinogenaemia (reaching or exceeding 350 mg/dL) was associated not only with overall but also cancer-free survival. By multivariate analysis, fibrinogen level again was an independent prognostic factor along with pTN [33].

Classic studies have explored the diagnostic meaning of hyperfibrinogenaemia resulting in conclusion that fibrinogen level is significantly elevated in gastric cancer patients but not in individuals having gastric or duodenal peptic ulcer. Such reports stem back as far as to 1975 [114]. Later, it was repeatedly confirmed that fibrinogen levels in gastric cancer are higher than in controls, even if the tumour was non-metastatic. The mean levels in cancer patients vs. control individuals were 505 vs. 336 mg/dL [115]. Nowadays, the ongoing research has identified fibrinogen fragments that could potentially serve as serum markers of gastric cancer. Fibrinogen fragments, e.g., carboxyl terminal fraction of fibrinogen alpha, have been tested as a serum marker of gastric cancer in comparison with healthy controls and individuals affected by chronic gastritis [116, 117].

A 15-amino acid peptide of the fibrinogen alpha chain, fibrinostatin, has anti-angiogenic properties; thus therapeutic applications have been hypothesised [118].

Regarding the local events within the tumour, fibrinogen has been identified in tumour stroma as early as 1984 [119, 120] while fibrin and D-dimers are found in the invasive front [120].

Fibrinogen level parallels the tumour burden, correlates with advanced TNM stage [112] and is associated with adjacent organ involvement [121]. In a recent considerable cohort of 1090 gastric cancer patients treated by gastrectomy, high fibrinogen level (exceeding the ROCidentified cut-off at 3.9 g/L) was significantly associated with tumour size, T, N and TNM stage [113]. Fibrinogen shows statistically significant associations with the invasion depth of gastric cancer confirmed by several other studies focusing on T [122–124]. Several studies have identified meaningful association with presence of metastasis in lymph nodes [122–124]. The association with tumour spread has also been confirmed, regarding the presence of distant metastases [122].

The logical next step is incorporation of fibrinogen measurements into combined scores that could be used to assess the prognosis or tumour spread. A complex score comprising evaluation of hyperfibrinogenemia (exceeding 400 mg/dL) and elevated NLR (exceeding 3.0) was associated with shorter survival. The combined score showed significantly different results in patients developing progressive disease despite chemotherapy or chemoradiotherapy [103]. Similar score comprising evaluation of hyperfibrinogenemia (reaching or exceeding 305 mg/dL) and elevated NLR (reaching or exceeding 2.34) was significantly associated with invasion depth, lymph node metastasis, lymphovascular invasion and stage [110]. Coagulation score based on the assessment of fibrinogen and D-dimer levels, was significantly associated with overall and cancer-free survival as well as with recurrence and development of liver metastases [125].

Other blood clotting parameters show similar associations with patient's prognosis and tumour burden. Thus, D-dimers [126, 127] and thrombocytosis [128] have prognostic role in gastric cancer. In turn, D-dimers and prothrombin time are associated with lymph node involvement [129].
