This study draws attention to the final analysis of the association between systemic-immune inflammation index (SII) and both survival prediction and response to treatment with platinum-based regimes in a first-line setting in a Caucasian population of patients with metastatic urothelial carcinoma. High baseline SII levels were associated with poor survival in terms of PFS and OS, as well as poor response to treatment. Compared to baseline values, a level of systemic inflammation determined by SII was generally lower at week 6, which was equivalent to the application of two courses of chemotherapy. High SII at week 6 was associated with poor survival in terms of PFS and OS. The improvement of SII value at week 6 was associated with a better prognosis possibly as an effect of chemotherapy on the counts of peripheral blood cells secondary to a reduction of inflammation processes. A clinically significant difference was noted in PFS and OS between the subgroup of patients with a low level of SII both at baseline and at week 6 compared to a subgroup with a high level of SII at baseline and at week 6. While SII showed prognostic value in anti-PD-L1-treated patients with MUC after progression on first-line therapy , to the best of our knowledge, this is the first trial to demonstrate the significance of changes in SII during platinum-based chemotherapy in a Caucasian population.
Inflammation both systemic and in the local tumor microenvironment plays a critical role in tumorigenesis.  The number and distribution of immune cell types, including neutrophils, macrophages, dendritic cells, natural killer (NK) cells, T cells and B cells, and proinflammatory cytokines produced by malignant and inflammatory cells in the tumor microenvironment are involved in the initiation, development, and metastatic spread.  Therefore, changes in the balance between immune cells and cytokines can result in different responses of the immune system, as well as in the amount and ratio of cells detectable in peripheral blood.
Some types of cancers may accelerate the process of myelopoiesis, resulting in leukocytosis, characterized by increased numbers of immature myeloid cells in the bone marrow and blood.  In this setting, accelerated myelopoiesis appears to result from the production of bone marrow-stimulating growth factors by tumor cells, most notably the cytokines granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF).  Human-neutrophil proteins 1, 2, and 3 help release cytokines, stimulate monocytes and inhibit the fibrinolytic system and, together with proinflammatory mediators, promote cell proliferation, survival, migration, angiogenesis, and metastasis. [7, 20] Increases in numbers of neutrophils negatively impacts the T-cell mediated adaptive immunity.  CD4 + T cells play key roles in tumor immunity through three different mechanisms.  Firstly, the provision of help for anti-tumor CD8 + cytotoxic T lymphocytes (CTLs) through direct and indirect mechanisms. Secondly, the production of effector cytokines such as interferon γ (IFNγ) and tumor necrosis factor-α (TNFα), both of which have direct anti-tumor activity. In addition, CD4 + T cells can mediate direct cytotoxicity against tumor cells. Finally, the induction of humoral responses against tumor antigens provides help to B cells in driving their differentiation and maturation into affinity-matured, class-switched plasma cells.
Among the causes of thrombocytosis is the capability of some tumor cells to produce thrombopoietin and an up-regulation of the platelet activation markers such as P-selectin, β-thromboglobulin or CD40 ligand contributing to the increase of platelets.  Thrombocytes also display a pro-metastatic effect by producing platelet-derived transforming growth factor β (TGF-β), which down-regulates NK group 2, member D (NKG2D) and results in protection of tumor cells from NK cells while promoting epithelial to mesenchymal transition by activation of TGF-β/smad and NF-қb signaling pathways inducing epithelial-mesenchymal transition7 and promoting tumor cell extravasation.  TGF-β is partially responsible for the transformation of the neutrophils toward a pro-tumorigenic phenotype.  Preoperative and postoperative thrombocytosis was associated with worse outcomes in subjects with both bladder carcinoma and upper tract urothelial carcinoma. [16, 10]
Several models [6, 11, 27–29] have been established in the effort to identify in advance a subpopulation of patients with inoperable locally-advanced and/or metastatic urothelial carcinoma, that has worse outcomes. Probably the most often used prognostic score is the Bajorin model  based on performance status and visceral metastasis sites of the disease. The Galsky model  consists of a number of visceral metastases, the site of the primary tumor, performance status by Eastern Cooperative Oncology Group (ECOG), the presence or absence of lymph node metastases, and leukocyte count. The Glasgow prognostic score  incorporates an inflammation factor (C-reactive protein). Later, neutrophil to lymphocyte ratio as a prognostic index was confirmed in the different stages of urothelial carcinoma including in the metastatic setting.  In 2017, Su et al.  published a paper on the novel inflammation-based prognostic score incorporating absolute neutrophil count and the absolute lymphocyte count to predict survival in patients with metastatic urothelial carcinoma in Taiwan. A systemic immune-inflammation index (SII) combining neutrophil to lymphocyte ratio with the platelet counts [13, 14] seems to be more objective in reflecting the balance between host inflammatory and immune response status than the previously mentioned neutrophil to lymphocyte ratio.
As was shown in this study, SII determined the prognosis of subjects with metastatic urothelial carcinoma and their response to treatment. SII at baseline and its changes over time could be used for improved patient stratification. Early identification of subjects not responding to first-line platinum-based chemotherapy can spare them unnecessary toxicity while providing justification for the use of different therapeutic approaches within clinical trials and in clinical practice.
Among the limitations of this trial are its non-randomized single-center retrospective design, the relatively low number of enrolled patients, and the lack of detailed analysis of chemotherapy toxicity. On the other hand, this study reflects a real-world population of subjects with metastatic urothelial carcinoma and its treatment over the first 15 years of this millennium. However, validation with a larger prospective data set is necessary.
In previous studies of the inoperable advanced setting, urothelial carcinoma patients have been selected for treatment based on various criteria. In the JAVELIN study , subjects were randomized to avelumab maintenance or best supportive care considering their response to 4–6 courses of platinum-based chemotherapy with significantly better results in favor of immunotherapy. In the mono-immunotherapy arms of the phase 3 trial IMvigor130  with atezolizumab and phase 3 study KEYNOTE-361  with pembrolizumab, only patients with programmed cell death ligand 1 (PD-L1) positive tumors were enrolled. However, none of the studies referred to above has included data on SII at baseline and during treatment and so no conclusions can be drawn as to whether SII can act as a predictor for outcomes for these newer therapies in terms of survival and response to treatment.
One of the earliest immunotherapies for muscle-non-invasive urothelial bladder cancer is Bacille Calmette Guerin (BCG). Despite being used since 1970s, the exact mechanism of action had not been clarified for a long time. In 2019, Joseph and Enting published a review,  in which they summarize an immunological cascade in BCG treatment with the key role of neutrophils, macrophages, and dendritic cells. Newer immunotherapies based on check-point inhibition have proved to offer some success in urothelial carcinoma over the last decade with response rates ranging from 10–50%. This limited efficacy may be explained by adaptations of the tumor and by their sole targeting of the CD8 + T lymphocytes that represent only the culmination of the activation of successive immune populations.  Among the probable future directions in the urothelial carcinoma landscape are combinations of effective strategies, such as check-point inhibitors and BCG with some hypothetic treatment suppressing immunosuppressing tumor microenvironment and/or increasing the actions of innate immune cell subpopulations. New findings in urothelial carcinoma pathogenesis and novel therapeutics could also result from an increasing interest in urine microbiome research.