The Role of Salivary Vascular Endothelial Growth Factor A, Cytokines, and Amino Acids in Immunomodulation and Angiogenesis in Breast Cancer.

In this work, we focused on the analysis of VEGF content in saliva and its relationship with pro-inflammatory cytokines and amino acids involved in immunomodulation and angiogenesis in breast cancer. The study included 230 breast cancer patients, 92 patients with benign breast disease, and 59 healthy controls. Before treatment, saliva samples were obtained from all participants, and the content of VEGF and cytokines in saliva was determined by an enzyme-linked immunosorbent assay, as well as the content of amino acids by high-performance liquid chromatography. It was found that VEGF was positively correlated with the level of pro-inflammatory cytokines IL-1ß (r = 0.6367), IL-6 (r = 0.3813), IL-8 (r = 0.4370), and IL-18 (r = 0.4184). Weak correlations were shown for MCP-1 (r = 0.2663) and TNF-α (r = 0.2817). For the first time, we demonstrated changes in the concentration of VEGF and related cytokines in saliva in different molecular biological subtypes of breast cancer depending on the stage of the disease, differentiation, proliferation, and metastasis to the lymph nodes. A correlation was established between the expression of VEGF and the content of aspartic acid (r = -0.3050), citrulline (r = -0.2914), and tryptophan (r = 0.3382) in saliva. It has been suggested that aspartic acid and citrulline influence the expression of VEGF via the synthesis of the signaling molecule NO, and then tryptophan ensures tolerance of the immune system to tumor cells.

Free Salivary Amino Acid Profile in Breast Cancer: Clinicopathological and Molecular Biological Features.

The study of salivary amino acid profiles has attracted the attention of researchers, since amino acids are actively involved in most metabolic processes, including breast cancer. In this study, we analyzed the amino acid profile of saliva in a sample including all molecular biological subtypes of breast cancer to obtain a more complete picture and evaluate the potential utility of individual amino acids or their combinations for diagnostic purposes. This study included 116 patients with breast cancer, 24 patients with benign breast disease, and 25 healthy controls. From all patients, strictly before the start of treatment, saliva samples were collected, and the quantitative content of 26 amino acids was determined. Statistically significant differences between the three groups are shown in the content of Asp, Gly, Leu + Ile, Orn, Phe, Pro, Thr, and Tyr. To differentiate the three groups from each other, a decision tree was built. To construct it, we selected those amino acids for which the change in concentrations in the subgroups was multidirectional (GABA, Hyl, Arg, His, Pro, and Car). For the first time, it is shown that the amino acid profile of saliva depends on the molecular biological subtype of breast cancer. The most significant differences are shown for the luminal B HER2-positive and TNBC subgroups. In our opinion, it is critically important to consider the molecular biological subtype of breast cancer when searching for potential diagnostic markers.

Oxidative Stress in Breast Cancer: A Biochemical Map of Reactive Oxygen Species Production.

This review systematizes information about the metabolic features of breast cancer directly related to oxidative stress. It has been shown those redox changes occur at all levels and affect many regulatory systems in the human body. The features of the biochemical processes occurring in breast cancer are described, ranging from nonspecific, at first glance, and strictly biochemical to hormone-induced reactions, genetic and epigenetic regulation, which allows for a broader and deeper understanding of the principles of oncogenesis, as well as maintaining the viability of cancer cells in the mammary gland. Specific pathways of the activation of oxidative stress have been studied as a response to the overproduction of stress hormones and estrogens, and specific ways to reduce its negative impact have been described. The diversity of participants that trigger redox reactions from different sides is considered more fully: glycolytic activity in breast cancer, and the nature of consumption of amino acids and metals. The role of metals in oxidative stress is discussed in detail. They can act as both co-factors and direct participants in oxidative stress, since they are either a trigger mechanism for lipid peroxidation or capable of activating signaling pathways that affect tumorigenesis. Special attention has been paid to the genetic and epigenetic regulation of breast tumors. A complex cascade of mechanisms of epigenetic regulation is explained, which made it possible to reconsider the existing opinion about the triggers and pathways for launching the oncological process, the survival of cancer cells and their ability to localize.

Salivary Tryptophan as a Metabolic Marker of HER2-Negative Molecular Subtypes of Breast Cancer.

Changes in the concentration of tryptophan (Trp) indicate a serious metabolic restructuring, which is both a cause and a consequence of many diseases. This work examines the upward change in salivary Trp concentrations among patients with breast cancer. This study involved volunteers divided into three groups: breast cancer (n = 104), non-malignant breast pathologies (n = 30) and healthy controls (n = 20). In all participants, before treatment, the quantitative content of Trp in saliva was determined by capillary electrophoresis. In 20 patients with breast cancer, Trp was re-tested four weeks after surgical removal of the tumor. An increase in the Trp content in saliva in breast cancer has been shown, which statistically significantly decreases after surgical removal of the tumor. A direct correlation was found between increased Trp levels with the degree of malignancy and aggressive molecular subtypes of breast cancer, namely triple negative and luminal B-like HER2-negative. These conclusions were based on an increase in Ki-67 and an increase in Trp in HER2-negative and progesterone-negative subtypes. Factors under which an increase in Trp concentration in saliva was observed were identified: advanced stage of breast cancer, the presence of regional metastasis, low tumor differentiation, a lack of expression of HER2, estrogen and progesterone receptors and the high proliferative activity of the tumor. Thus, the determination of salivary Trp may be a valuable tool in the study of metabolic changes associated with cancer, particularly breast cancer.

The Role of Amino Acids in the Diagnosis, Risk Assessment, and Treatment of Breast Cancer: A Review.

This review summarizes the role of amino acids in the diagnosis, risk assessment, imaging, and treatment of breast cancer. It was shown that the content of individual amino acids changes in breast cancer by an average of 10-15% compared with healthy controls. For some amino acids (Thr, Arg, Met, and Ser), an increase in concentration is more often observed in breast cancer, and for others, a decrease is observed (Asp, Pro, Trp, and His). The accuracy of diagnostics using individual amino acids is low and increases when a number of amino acids are combined with each other or with other metabolites. Gln/Glu, Asp, Arg, Leu/Ile, Lys, and Orn have the greatest significance in assessing the risk of breast cancer. The variability in the amino acid composition of biological fluids was shown to depend on the breast cancer phenotype, as well as the age, race, and menopausal status of patients. In general, the analysis of changes in the amino acid metabolism in breast cancer is a promising strategy not only for diagnosis, but also for developing new therapeutic agents, monitoring the treatment process, correcting complications after treatment, and evaluating survival rates.

Diagnostic Value of Salivary Amino Acid Levels in Cancer.

This review analyzed 21 scientific papers on the determination of amino acids in various types of cancer in saliva. Most of the studies are on oral cancer (8/21), breast cancer (4/21), gastric cancer (3/21), lung cancer (2/21), glioblastoma (2/21) and one study on colorectal, pancreatic, thyroid and liver cancer. The amino acids alanine, valine, phenylalanine, leucine and isoleucine play a leading role in the diagnosis of cancer via the saliva. In an independent version, amino acids are rarely used; the authors combine either amino acids with each other or with other metabolites, which makes it possible to obtain high values of sensitivity and specificity. Nevertheless, a logical and complete substantiation of the changes in saliva occurring in cancer, including changes in salivary amino acid levels, has not yet been formed, which makes it important to continue research in this direction.

Potential Diagnostic Value of Salivary Tumor Markers in Breast, Lung and Ovarian Cancer: A Preliminary Study.

The aim of the study was to determine the content of tumor markers for breast, lung and ovarian cancer in saliva, as well as for benign diseases of the corresponding organs and in the control group, and to evaluate their diagnostic significance. Strictly before the start of treatment, saliva samples were obtained and the concentrations of tumor markers (AFP, NSE, HE4, CA15-3, CA72-4, CA125 and CEA) were determined using an enzyme immunoassay (ELISA). CA125 and HE4 were simultaneously determined to be in the blood serum of patients with ovarian cancer. The concentrations of salivary CEA, NSE, CA15-3, CA72-4 and CA125 of the control group were significantly lower than in oncological diseases; however, these tumor markers also increased in saliva with benign diseases. The content of tumor markers depends on the stage of cancer, and the presence of lymph node metastasis; however, the identified patterns are statistically unreliable. The determination of HE4 and AFP in saliva was not informative. In general, the area of potential use of tumor markers in saliva is extremely narrow. Thus, CEA may be diagnostic for breast and lung cancer, but not for ovarian cancer. CA72-4 is most informative for ovarian mucinous carcinoma. None of the markers showed significant differences between malignant and non-malignant pathologies.

Infrared Spectroscopy to Analyze Sexual Dimorphism of Hard Dental Tissue Maturation at Eruption in Patients with Connective Tissue Dysplasia.

The aim of this study was to research the biochemical changes in the hard tissues of the lower "wisdom" teeth, which are at the stage of eruption, with connective tissue dysplasia, depending on sex. The study involved 38 patients aged 17-25 years, who had the extraction of the lower third molars on the left and right for medical reasons. Twenty-one participants in the experiment (16 females, five males) were diagnosed with connective tissue dysplasia; the remaining 17 were healthy and made up the control group (11 females, six males). Samples of enamel, dentin, and enamel-dentin junction were dried to constant weight and examined in tablets pressed in a mixture with potassium bromide on an FT-801 Fourier transform infrared (FT-IR) spectrometer (NPF Simex, Russia) in the range of 500-4000 cm-1. In the IR spectra of the enamel, enamel-dentin junction, and dentin, the absorbance ratio of amide I and II changed significantly and the absorbance of the absorption band of phosphate ions decreased from enamel to dentin. Differences between groups with and without connective tissue dysplasia increased in the following series: dentin, enamel-dentin junction, and enamel. With connective tissue dysplasia, a change in the ratio of the intensities of the absorption bands of amide I and phosphate ions was observed. Normally, the content of organic substances in the enamel of the teeth in the males group is lower than in the females group. Against the background of connective tissue dysplasia, the content of organic substances in the enamel in women decreased while in men it increased, which confirmed the presence of sexual dimorphism during the maturation of hard dental tissues at the eruption stage. The study confirms the opinion of many researchers about the significant role of collagen proteins, which, together with non-collagen proteins, are involved in the development and maturation of dental hard tissues, which are characterized by pronounced heterogeneity and sexual dimorphism in the group with connective tissue dysplasia.

The Role of Amino Acids in Non-Enzymatic Antioxidant Mechanisms in Cancer: A Review.

Currently, the antioxidant properties of amino acids and their role in the physicochemical processes accompanying oxidative stress in cancer remain unclear. Cancer cells are known to extensively uptake amino acids, which are used as an energy source, antioxidant precursors that reduce oxidative stress in cancer, and as regulators of inhibiting or inducing tumor cell-associated gene expression. This review examines nine amino acids (Cys, His, Phe, Met, Trp, Tyr, Pro, Arg, Lys), which play a key role in the non-enzymatic oxidative process in various cancers. Conventionally, these amino acids can be divided into two groups, in one of which the activity increases (Cys, Phe, Met, Pro, Arg, Lys) in cancer, and in the other, it decreases (His, Trp, Tyr). The review examines changes in the metabolism of nine amino acids in eleven types of oncology. We have identified the main nonspecific mechanisms of changes in the metabolic activity of amino acids, and described direct and indirect effects on the redox homeostasis of cells. In the future, this will help to understand better the nature of life of a cancer cell and identify therapeutic targets more effectively.

Pro-Inflammatory and Anti-Inflammatory Salivary Cytokines in Breast Cancer: Relationship with Clinicopathological Characteristics of the Tumor.

The aim of the work was to compare the salivary cytokine profile of breast cancer patients with the clinicopathological characteristics of the tumor. The study included 113 patients with breast cancer (main group, mean age 54.1 years) and 111 patients with breast fibroadenomas (control group, mean age 56.7 years). Before treatment, saliva samples were collected from all patients and the content of cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, MCP-1, and TNF-α) was determined. The content of cytokines in saliva correlates well with the clinicopathological characteristics of breast cancer. The level of all salivary cytokines increases at advanced stages of breast cancer and at a low degree of tumor differentiation. The exception is MCP-1, for which there is an extremely high content for well-differentiated breast cancer. A statistically significant increase in the content of MCP-1, IL-1ß, IL-2, IL-4, and IL-10 was found in triple-negative breast cancer. For the first time, the correlation of salivary levels of TNF-α, IL-1ß, and IL-6 with HER2 status, MCP-1, IL-1ß, IL-2, and IL-4 with the hormonal status of the tumor was shown. The relationship between the level of IL-2, IL-10, and IL-18 in saliva with the level of Ki-67 expression has been established.

«Salivaomics¼ of Different Molecular Biological Subtypes of Breast Cancer.

The aim of the study was to determine the metabolic characteristics of saliva depending on the molecular biological subtype of breast cancer, as well as depending on the expression levels of HER2, estrogen receptors (ER), and progesterone receptors (PR). The study included 487 patients with morphologically verified breast cancer and 298 volunteers without breast pathologies. Saliva samples were obtained from all patients strictly before the start of treatment and the values of 42 biochemical indicators were determined. It has been established that the saliva of healthy volunteers and patients with various molecular biological subtypes of breast cancer differs in 12 biochemical indicators: concentrations of protein, urea, nitric oxide, malondialdehyde, total amino acid content, and activity of lactate dehydrogenase, alkaline phosphatase, gamma-glutamyltransferase, catalase, amylase, superoxide dismutase, and peroxidases. The saliva composition of patients with basal-like breast cancer differs from other subtypes in terms of the maximum number of indicators. Changes in biochemical indicators indicated an increase in the processes of lipid peroxidation and endogenous intoxication and a weakening of antioxidant protection, which correlates with the severity of the disease and the least favorable prognosis for this subtype of breast cancer. An analysis was made of the individual contribution of the expression level of HER2, estrogen, and progesterone receptors to changes in the biochemical composition of saliva. The HER2 (-)/HER2 (+) group, which should be considered as a single group, as well as ER-positive breast cancer, differ statistically significantly from the control group. For ER/PR-positive breast cancer, a more favorable ratio of saliva biochemical indicators was also noted compared to ER/PR-negative breast cancer.

Prognostic Value of Salivary Biochemical Indicators in Primary Resectable Breast Cancer.

Despite the fact that breast cancer was detected in the early stages, the prognosis was not always favorable. In this paper, we examined the impact of clinical and pathological characteristics of patients and the composition of saliva before treatment on overall survival and the risk of recurrence of primary resectable breast cancer. The study included 355 patients of the Omsk Clinical Oncology Center with a diagnosis of primary resectable breast cancer (T1-3N0-1M0). Saliva was analyzed for 42 biochemical indicators before the start of treatment. We have identified two biochemical indicators of saliva that can act as prognostic markers: alkaline phosphatase (ALP) and diene conjugates (DC). Favorable prognostic factors were ALP activity above 71.7 U/L and DC level above 3.93 c.u. Additional accounting for aspartate aminotransferase (AST) activity allows for forming a group with a favorable prognosis, for which the relative risk is reduced by more than 11 times (HR = 11.49, 95% CI 1.43-88.99, p = 0.01591). Salivary AST activity has no independent prognostic value. Multivariate analysis showed that tumor size, lymph nodes metastasis status, malignancy grade, tumor HER2 status, and salivary ALP activity were independent predictors. It was shown that the risk of recurrence decreased with menopause and increased with an increase in the size of the primary tumor and lymph node involvement. Significant risk factors for recurrence were salivary ALP activity below 71.7 U/L and DC levels below 3.93 c.u. before treatment. Thus, the assessment of biochemical indicators of saliva before treatment can provide prognostic information comparable in importance to the clinicopathological characteristics of the tumor and can be used to identify a risk group for recurrence in primary resectable breast cancer.

Metabolic Features of Saliva in Breast Cancer Patients.

The aim of the work was to study the metabolic characteristics of saliva in breast cancer and the subsequent assessment of the potential information content of its individual biochemical indicators. The study included 487 patients of the Omsk Clinical Oncology Center with morphologically verified breast cancer and 298 volunteers without breast pathologies. Saliva samples were obtained from all patients before the start of treatment, and the values of 34 biochemical indicators were determined. It has been shown that concentration of total protein, urea, uric acid (UA), the total content of α-amino acids and lipid peroxidation products, and the activity of metabolic and antioxidant enzymes (in particular catalase-CAT) of saliva changed significantly in breast cancer. Biochemical indicators characterizing early breast cancer have been identified, which can be used for timely diagnosis in addition to existing methods. The coefficients UA/Urea and UA·CAT/Urea are proposed, for which the maximum deviation from the norm was observed in the early stages of the disease. It was shown that for ductal breast cancer, changes in the activity of metabolic enzymes of saliva were more pronounced, while, for lobular breast cancer, the indicators of enzymatic and non-enzymatic components of antioxidant protection changed. The results confirmed the potential importance of saliva in the diagnosis of breast cancer.

Potential Diagnostic Significance of Salivary Copper Determination in Breast Cancer Patients: A Pilot Study.

Determination of the copper content in the saliva of breast cancer patients was carried out to assess the potential diagnostic and prognostic value. The malignant group included 75 breast cancer patients; the benign group included 87 patients with fibroadenomas; and the control group included 20 volunteers without breast pathology. All participants had 1 ml of saliva collected prior to treatment. The determination of copper in saliva was carried out by the stripping voltammetric method. Overall survival was assessed using the Kaplan-Meier method with the presentation of survival curves and the calculation of the significance of differences by Log-rank. The average copper content in the saliva of breast cancer patients is 49.3% higher than in patients with fibroadenomas and 60.4% higher than in volunteers without breast pathologies. Within the group of breast cancer patients, the content of copper in saliva is heterogeneous, which limits the possibilities of using this indicator for diagnostic purposes. The copper content increases when comparing the initial stages and locally widespread (+ 22.4%) and then sharply increases by 3.5 times at the T3-4N0-2M0 stage. For HER2-positive breast cancer, the copper content in saliva is 51.9% higher than for HER2-negative, a similar pattern was observed for luminal A and B breast cancer subtypes. The content of copper in saliva less than 1.14 mg/l is a prognostically unfavorable sign, while the relative risk of dying from breast cancer more than doubles. Thus, the content of copper in saliva can be used in clinical practice for planning treatment tactics.

Application of FTIR Spectroscopy for Quantitative Analysis of Blood Serum: A Preliminary Study.

The aim of this study was to analyze the possibility of simultaneous determination of the concentration of components from the characteristics of FTIR spectra using the example of a model blood serum. To prepare model solutions, a set of freeze-dried control sera based on bovine blood serum was used, certified for approximately 38 parameters. Based on the values of the absorbance and areas of absorption bands in the FTIR spectra of model solutions, a regression equation was constructed by solving a nonlinear problem using the generalized reduced gradient method. By using the absorbance of the absorption bands at 1717 and 3903 cm-1 and the areas of the absorption bands at 616, 3750, and 3903 cm-1, it is possible to simultaneously determine the concentrations of 38 components with an error of less than 0.1%. The results obtained confirm the potential clinical use of FTIR spectroscopy as a reagent-free express method for the analysis of blood serum. However, its practical implementation requires additional research, in particular, analysis of real blood serum samples and validation of the method.

Analysis of Saliva Lipids in Breast and Prostate Cancer by IR Spectroscopy.

We have developed a method for studying the lipid profile of saliva, combining preliminary extraction and IR spectroscopic detection. The case-control study involved patients with a histologically verified diagnosis of breast and prostate cancer and healthy volunteers. The comparison group included patients with non-malignant pathologies of the breast (fibroadenomas) and prostate gland (prostatic intraepithelial neoplasia). Saliva was used as a material for biochemical studies. It has been shown that the lipid profile of saliva depends on gender, and for males it also depends on the age group. In cancer pathologies, the lipid profile changes significantly and also depends on gender and age characteristics. The ratio of 1458/1396 cm-1 for both breast and prostate cancer has a potential diagnostic value. In both cases, this ratio decreases compared to healthy controls. For prostate cancer, the ratio of 2923/2957 cm-1 is also potentially informative, which grows against the background of prostate pathologies. It is noted that, in all cases, changes in the proposed ratios are more pronounced in the early stages of diseases, which increases the relevance of their study in biomedical applications.

Survival Rates of Patients with Non-Small Cell Lung Cancer Depending on Lymph Node Metastasis: A Focus on Saliva.

The aim of this study was to compare overall survival (OS) rates at different pN stages of NSCLC depending on tumor characteristics and to assess the applicability of saliva biochemical markers as prognostic signs. The study included 239 patients with NSCLC (pN0-120, pN1-51, pN2-68). Saliva was analyzed for 34 biochemical indicators before the start of treatment. For pN0, the tumor size does not have a prognostic effect, but the histological type should be taken into account. For pN1 and pN2, long-term results are significantly worse in squamous cell cancer with a large tumor size. A larger volume of surgical treatment reduces the differences between OS. The statistically significant factors of an unfavorable prognosis at pN0 are the lactate dehydrogenase activity <1294 U/L and the level of diene conjugates >3.97 c.u. (HR = 3.48, 95% CI 1.21-9.85, p = 0.01541); at pN1, the content of imidazole compounds >0.296 mmol/L (HR = 6.75, 95% CI 1.28-34.57, p = 0.00822); at pN2 levels of protein <0.583 g/L and Schiff bases >0.602 c.u., as well as protein >0.583 g/L and Schiff bases <0.602 c.u. (HR = 2.07, 95% CI 1.47-8.93, p = 0.04351). Using salivary biochemical indicators, it is possible to carry out stratification into prognostic groups depending on the lymph node metastasis.

Features of the Metabolic Profile of Saliva in Lung Cancer and COPD: The Effect of Smoking Status.

The aim of the study was to compare the metabolic characteristics of the salivary composition in lung cancer, chronic obstructive pulmonary disease (COPD) and their combination, depending on the smoking history. The study group included 392 patients with lung cancer of various histological types. The division into subgroups was carried out in accordance with the severity of COPD and smoking experience. Salivary biochemical composition was determined according to 34 indicators. For data processing, the principal component method was used. Different groups of biochemical saliva markers are informative when separately accounting for the smoking factor and the presence of COPD in lung cancer. For smoking, antioxidant enzymes and electrolyte components of saliva are informative; for COPD metabolic enzymes, lipid peroxidation products, sialic acids and electrolyte components are informative. While taking into account the smoking factor and the presence of COPD, biochemical markers corresponding to the presence/absence and severity of COPD are the priority. Changes occurring in the background of smoking are of a secondary nature, manifesting as much as possible with a smoking history of more than 50 pack-years. Thus, the metabolic changes that occur in lung cancer in combination with COPD, depending on the smoking factor, can be estimated using saliva.

Indicators of L-arginine metabolism in saliva: A focus on breast cancer.

OBJECTIVES: To analyze the arginase activity, the level of nitric oxide (NO) and the cytokine profile of saliva in patients with breast cancer. METHODS: A total of 114 volunteers took part in this case-control study, and were divided into three groups as follows: The main group (breast cancer, n = 43), the comparison group (fibroadenomas, n = 32), and the control group (conditionally healthy, n = 39). All participants underwent biochemical examination of saliva and histological verification of the diagnosis. RESULTS: We found that the arginase activity in the saliva of breast cancer patients was significantly higher, and the level of NO was lower than in the control group. The 'arginase:NO' ratio was 0.22 for the control group, 0.98 for the comparison group (p = 0.0040), and 1.48 for the breast cancer group (p < 0.0001). The maximum increase in the 'arginase:NO' is characteristic of the early stages of the disease, which makes this ratio potentially applicable for the diagnosis of breast cancer with sensitivity and specificity of 81.1% and 81.0%, respectively. It was not possible to establish an unambiguous relationship between the level of cytokines and the metabolic parameters of L-arginine. However, we found an increase in salivary cytokine levels in breast cancer, and thus may represent an independent direction of research. CONCLUSIONS: Saliva can be used as a substrate to determine L-arginine metabolic parameters.

Salivary Metabolic Profile of Patients with Lung Cancer, Chronic Obstructive Pulmonary Disease of Varying Severity and Their Comorbidity: A Preliminary Study.

The aim of the work was to study the features of the salivary biochemical composition in the combined pathology of lung cancer and chronic obstructive pulmonary disease (COPD) of varying severity (COPD I, COPD II). The study group included patients with lung cancer (n = 392), non-malignant lung pathologies (n = 168) and healthy volunteers (n = 500). Before treatment, the salivary biochemical composition was determined according to 34 indicators. Survival analysis performed by the Kaplan-Meier method. Biochemical parameters (catalase, imidazole compounds ICs, sialic acids, lactate dehydrogenase (LDH)) that can be used to monitor patients at risk (COPD I) for timely diagnosis of lung cancer are determined. A complex of salivary biochemical indicators with prognostic value in lung cancer was revealed. For patients with lung cancer without COPD, a group of patients with a favorable prognosis can be distinguished with a combination of ICs < 0.478 mmol/L and LDH >1248 U/L (HR = 1.56, 95% CI 0.40-6.07, p = 0.03891). For COPD I, a level of ICs < 0.182 mmol/L are prognostically favorable (HR = 1.74, 95% CI 0.71-4.21, p = 0.07270). For COPD II, combinations of pH < 6.74 and LDH >1006 U/L are prognostically favorable. In general, for patients with lung cancer in combination with COPD I, the prognosis is more favorable than without COPD.