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The Open Lung Cancer Journal, 2008, 1, 1-12                                               1

                                                                                                                            Open Access
Early Detection and Diagnosis of Lung Cancer and Immune Circuit

Oleg Kshivets*

Thoracic Surgery Department, Klaipeda University Hospital, Klaipeda, Lithuania

            Abstract: Purpose: Significance of immune cell and humoral circuit in terms of early detection and diagnosis of lung
            cancer (LC) was investigated.
            Methods: In retrospective trial (1987-2008) consecutive cases after surgery, monitored 533 LCP (males - 472, females -
            61; pneumonectomies - 181, upper lobectomies - 138, lower lobectomies - 67, upper/lower bilobectomies - 24, middle
            lobectomies - 6, segmentectomies - 76, exploratory thoracotomies and biopsies - 41) with pathologic stage I-IV (stage I -
            48, stage II - 47, stage III - 321; stage IV - 117; squamous cell LC - 294, adenocarcinoma - 171, large cell LC - 48, small
            cell LC - 20; T1 - 116, T2 - 168, T3 - 125, T4 - 124; N0 - 148, N1 - 144, N2 - 159; N3 - 82; G1 - 88, G2 - 166, G3 - 279;
            M0 - 438; M1 - 95) and 282 patients with lung non-malignant pathology (NMP) (males - 188, females - 94; pneumonec-
            tomies - 5, upper lobectomies - 96, lower lobectomies - 81, middle lobectomies - 2, segmentectomies and wedge resec-
            tions - 98; non-malignant tumors - 100; abscess - 112; tuberculoma - 70) were reviewed. Variables selected for study were
            input levels of immunity blood parameters, sex, age, TNMG. Thawed aliquoted samples were evaluated for IgG, IgM,
            IgA, natural antibodies, circulating immune complexes. The percentage, absolute count and total population number (per
            human organism) of T-lymphocytes (CD3), B-lymphocytes (CD19), helper T-lymphocytes (CD4), suppressor/cytotoxic
            T-lymphocytes (CD8), killer cells (O-cells, K-cells or CD16), precursor T-cells (CD1), activated T-cells (CDw26), mono-
            cytes (CD64, CD13), helper/inducer T-lymphocytes (CD4+2H), contrsuppressor T-lymphocytes (CD8+VV), CD4/CD8,
            leukocytes, lymphocytes, polymorphonuclear and stabnuclear leukocytes were estimated. The laboratory blood studies
            also included input levels of NST (tests of oxygen dependent metabolism of neutrophils spontaneous and stimulated by
            Staphylococcus aureus or by Streptococcus pyogenes), index of stimulation of leukocytes by Staphylococcus aureus or
            Streptococcus pyogenes, index of thymus function, phagocytic number, phagocyte index, index of complete phagocytosis.
            Differences between groups were evaluated using multi-factor clustering, nonlinear estimation (logistic regression), struc-
            tural equation modeling and Monte Carlo simulation.
            Results: It was revealed that early detection of LC (stage I-II; tumor size=2.5±0.1 cm; T1-2N0M0; n=95) from NMP
            (n=282) significantly (P=0.000000) depended on: 1) level of immune cell circuit ( 2=38749.1; Df=989); 2) value of
            monocyte and macrophage circuit ( 2=662.8; Df=20); 3) level of humoral immunity ( 2=585.9; Df=9); 4) neutrophils cir-
            cuit ( 2=5214.4; Df=77). It was also founded that diagnosis of LC (stage I-IV; tumor size=5.4±0.1 cm; T1-4N0-3M0-1;
            n=533) from NMP significantly (P=0.000000) depended on: 1) value of immune cell subpopulations ( 2=80569.9;
            Df=989); 2) macrophage circuit ( 2=312.1; Df=20); 3) humoral factors ( 2=243.1; Df=9); 4) neutrophils circuit
            ( 2=10772.3; Df=77).
Keywords: Lung cancer, immunity, early detection, diagnosis.

INTRODUCTION                                                                  fluorescence techniques, computerized molecular analysis of
                                                                              airway cell markers, etc. [1,2].
    Theoretically the early detection (ED) of lung cancer
(LC) allows increasing the 5-year survival rate of the LC                         Differential diagnosis (DS) of LC from non-malignant
patients (LCP) by several times while the combined and                        pathology (NMP) is another very complicated branch of
complex treatment - only by 5-30% with incomparable fi-                       clinical oncology. In this sphere there are more illusions,
nancial expenses [1]. That is why screening programs domi-                    disappointments and failures than real results. That is why
nate in the long-term strategic anti-cancer programs in the                   the great number of LCP is treated in the hospitals for so-
USA, Japan and Europe, that is why hundred million dollars                    matic pathology and is observed by different physicians for
are assigned on these programs, and that is why the super                     many years. It means that the fate of the patient depends on
modern high technologies are tested here: spiral CT scans                     the first visit to a doctor and if the last is not vigilant enough,
screening, automated computerized microscopy screening,                       the future of the person is tragic [1]. At the same time LCP
monoclonal antibody staining techniques, fluorodeoxyglu-                      have been reported to have immune dysfunctions of the cell-
cose-Positron Emission Tomography, bronchoscopic auto-                        mediated and humoral response [3,4]. However, little is
                                                                              known about value of immune system data in terms of early
                                                                              detection and differential diagnosis of LC. Therefore, we
*Address correspondence to this author at the Thoracic Surgery Department,    examined immune system data in LCP and in patients with
Klaipeda University Hospital, Brozynu: 5-54, Klaipeda, LT95214, Lithua-       NMP (PNMP).
nia; Tel: 37060878390; E-mail: kshivets003@yahoo.com


                                                            1876-8199/08      2008 Bentham Open
2   The Open Lung Cancer Journal, 2008, Volume 1                                                                     Oleg Kshivets

PATIENTS AND METHODS                                               mononuclears and neutrophils were isolated from a freshly
                                                                   drawn heparinized tube of blood. Mononuclear cells and
    Venous blood samples from 815 consecutive operated
                                                                   neutrophils were isolated after discontinuous density gradi-
and monitored in 1987-2008 LCP and PNMP (control group)
                                                                   ents separation on Ficoll-Hypaque (3 ml of 1 solution: 10
were obtained prior to any treatment. All patients in both
                                                                   portions of 33.9% Hypaque and 24 portions of 9% Ficoll + 3
groups were Europeans. 533 LCP with pathologic stage I-IV          ml of 2 solution: 10 portions of 50% Hypaque and 20 por-
LCP (males - 472, females - 61; age=57.4±0.4 years)
                                                                   tions of 9% Ficoll), washed in Hank’s balanced salt solution
(mean±standard error) and 282 PNMP (males - 188, females
                                                                   with 10% AB group serum, resuspended and cultured with
- 94; age=50.3±0.7 years) entered this trial. All patients from
                                                                   ram erythrocytes by incubation at +37°C 15 minutes without
the control group were checked and operated in the clinic for
                                                                   or with immunoglobulins IgG, IgM and IgA antiserum. The
suspicion of LC. Patients were not considered eligible if they
                                                                   rosette methods were used to evaluate immune cell subpopu-
had previous treatment with chemotherapy, immunotherapy            lations counts. The obtained results were converted to mod-
or radiotherapy, if there were two primary tumors of the time
                                                                   ern defined clusters of human leukocytes [8]. Clotted blood
of diagnosis or if patients did not leave the clinic or died
                                                                   was clarified and sera collected, aliquoted, and stored at -
after surgery. Staging procedures included medical history,
                                                                   80°C. Thawed aliquoted samples were evaluated for IgG,
physical examination, complete blood count with differen-
                                                                   IgM, IgA, natural antibodies, circulating immune complexes
tials, biochemistry and electrolyte panel, chest X-ray (PA
                                                                   (CIC). Traditionally the percentage, absolute count and total
and laterals), abdominal ultrasound, fibrobronchoscopy,            population number (per human organism) of T-lymphocytes
electrocardiogram, spirometry, bronchial or transthoracic
                                                                   (CD3), B-lymphocytes (CD19), helper T-lymphocytes
biopsy. Computed tomography scan of chest, upper abdomen
                                                                   (CD4), suppressor/cytotoxic T-lymphocytes (CD8), killer
and brain, liver and bone radionucle scan were performed
                                                                   cells (O-cells, K-cells or CD16), precursor T-cells (CD1),
whenever needed. Midiastinoscopy was not used. All LCP
                                                                   activated T-cells (CDw26), monocytes (CD64, CD13),
were diagnosed with histologically confirmed non-small cell
                                                                   helper/inducer T-lymphocytes (CD4+2H), contrsuppressor
lung cancer. All had measurable tumor and ECOG perform-            T-lymphocytes (CD8+VV), CD4/CD8, leukocytes, lympho-
ance status 0 or 1. Before any treatment each patient was
                                                                   cytes, polymorphonuclear and stabnuclear leukocytes were
carefully examined by medical panel composed of thoracic
                                                                   estimated. The laboratory blood studies also included input
surgeon, chemotherapeutist, radiation oncologist and pneu-
                                                                   levels of NST (tests of oxygen dependent metabolism of
mologist to confirm the stage of disease. All patients signed
                                                                   neutrophils spontaneous and stimulated by Staphylococcus
a written informed consent form approved by the local Insti-
                                                                   aureus or by Streptococcus pyogenes), index of stimulation
tutional Review Board.                                             of leukocytes by Staphylococcus aureus or Streptococcus
    Among 533 LCP 181 underwent pneumonectomy, 138 -               pyogenes, index of thymus function, phagocytic number,
upper lobectomy, 67 - lower lobectomy, 24 - upper/lower            phagocyte index, index of complete phagocytosis, immune
bilolobectomy, 6 - middle lobectomy, 76 - segmentectomy,           cell ratio factors (ratio between total immune cell subpopula-
41 - exploratory thoracotomy and biopsy. All LCP under-            tion number in patient organism and general number of can-
went routine systematic mediastinal nodal dissection.              cer cell population).
Among all LCP, 55 LCP underwent combined and extensive
                                                                      Multi-factor clustering, structural equation modeling
radical procedures with the resection of pericardium, atrium,
                                                                   (SEPATH) and Monte Carlo simulation were used to deter-
part of aorta, part of vena cava superior, vena azygos, carina,
                                                                   mine any significant dependence [9,10,11,12]. System, bio-
diaphragm, chest wall, ribs, etc.
                                                                   metric and statistical analyses were conducted using
   Of the 282 PNMP, surgical procedures consisted of               CLASS-MASTER (Stat Dialog, Inc., Moscow, Russia),
pneumonectomy in 5, upper lobectomy - in 96, lower lobec-          SANI (Stat Dialog, Inc., Moscow, Russia) and STATIS-
tomy - in 81, middle lobectomy - in 2, segmentectomy or            TICA (Stat Soft, Inc., Tulsa, OK, the USA). All tests were
wedge resection - in 98.                                           considered significant when the resulting P value was less
                                                                   than 0.05.
    The histological diagnosis of LC was based on the crite-
ria of the World Health Organization [5,6]. Histological ex-
amination showed squamous cell LC in 294, adenocarci-              RESULTS
noma - in 171, large cell LC - in 48 and small LC - in 20              The immunological characteristics of the cohort studied
patients. The pathological TNM stage I was in 48, II - in 47,      are summarized in Tables 1-8. These Tables show descrip-
III - in 321, IV - in 117 patients; the pathological T stage was   tive statistics of important pre-treatment variables such as
T1 in 116, T2 - in 168, T3 - in 125, T4 - in 124 cases; the        factors of T-, B-, K-cell and monocyte/macrophage circuit
pathological N stage was N0 in 148, N1 - in 144, N2 - in           (Tables 1-4). Reported also is date of humoral immunity and
159, N3 - in 82 patients; the M0 was in 438, M1 - in 95            neutrophil circuit (Tables 5-8). In terms of ED no statistical
cases. The tumor differentiation was graded as G1 in 88, G2        difference was found in T-cells, K-cells, CD1, CDw26,
- in 166, G3 - in 279 cases.                                       CD4+2H, CD8+VV, CD4, CD8, CD4/CD8, lymphocytes,
   Among 282 PNMP the histological analysis displayed              index thymus function, phagocyte index, phagocyte number,
benign tumors in 100, chronical abscess - in 112, tubercu-         index complete phagocytosis, titters of IgG, IgA, natural
loma - in 70 patients.                                             antibodies, circulating immune complexes, NST spontaneous
                                                                   and NST stimulated Staphylococcus aureus and Streptococ-
   Baseline venous blood samples for immunology studies            cus pyogenes, index stimulation by Staphylococcus aureus,
were taken on the first morning prior to any treatment. All        leucocytes, stab neutrophils between groups. The input level
immunologic parameters measured using traditional well-            of B-cells (P=0.024-0.001), monocytes (P=0.048-0.001),
regulated immunodiagnostic methods [7]. Venous blood
Early Detection and Diagnosis of Lung Cancer and Immune Circuit                          The Open Lung Cancer Journal, 2008, Volume 1 3

titters of IgM (P=0.021), index stimulation by Streptococcus              In terms of DS the baseline number of T-cells, K-cells,
pyogenes (P=0.024) and the number of total segmented neu-             CD1, CDw26, CD8+VV, CD4/CD8, index thymus function,
trophils (P=0.040) differed significantly in their capability to      phagocyte index, phagocyte number, index complete phago-
recognize the small LC with stage I-II (T1-2N0M0; n=95;               cytosis, titter of IgG, natural antibodies, circulating immune
tumor size=2.5±0.1 cm) (Tables 1, 3, 5 and 7). Accordingly,           complexes, NST-tests, indexes of stimulation of leukocytes
we revealed the direct significant correlations between ED            did not differ significantly between the two groups of pa-
and 9 lab tests. The obvious correlation with ED was signifi-         tients (Tables 2, 4, 6 and 8).
cantly related to the count of B-cells (r=-0.12-0.17; P=0.024-
                                                                         In group of LCP with stage I-IV (T1-4N0-3M0-1; n=533;
0.001), monocytes (r=-0.10-0.17; P=0.048-0.001), titter of
                                                                      tumor size=5.4±0.1 cm) the percent of B-cells (P=0.009), the
IgM (r=0.12; P=0.021), index stimulation by Streptococcus
                                                                      count of monocytes (P=0.045-0.000), leucocytes (P=0.000)
pyogenes (r=0.12; P=0.024) and the number of total seg-               and neutrophils (P=0.010-0.000) were remarkably increased
mented neutrophils (r=-0.11; P=0.040) (Tables 9 and 10, Fig.
                                                                      but the CD4+2H (P=0.034-0.027), CD4 (P=0.030), CD8
1).
                                                                      count (P=0.015-0.012) and the percent of lymphocytes

Table 1.    Factors of T-, B- and K-Cell Circuit Between LCP and NMP in Terms of Early Detection

                                                    LCP st I-II    n=95           NMP             n=282
  NN                   Factors                                                                                           P
                                                      Mean          SD           Mean              SD

   1                 T-cells (%)                      53.62        12.82         52.84            11.97                0.590
                                       9
   2              T-cells (abs)*10 /l                  0.94        0.49           0.93             0.46                0.942
   3               T-cells (tot)*109                   4.63        2.45           4.50             2.56                0.680
   4                 B-cells (%)                      18.34        8.32          16.46             6.46               0.024*
   5              B-cells (abs)*109/l                  0.39        0.44           0.29             0.14               0.001*
   6               B-cells (tot)*109                   1.94        2.21           1.44             0.76               0.001*
   7                 K-cells (%)                      26.86        11.49         29.25            10.84                0.068
   8              K-cells (abs)*109/l                  0.55        0.65           0.55             0.30                0.910
   9               K-cells (tot)*109                   2.65        3.15           2.71             1.66                0.805
  10                  CD1 (%)                          9.17        9.90           8.11             8.96                0.333
                                   9
  11               CD1 (abs)*10 /l                     0.17        0.23           0.15             0.20                0.372
  12                CD1 (tot)*109                      0.84        1.16           0.71             0.88                0.243
  13                 CDw26 (%)                         6.32        8.70           6.20             6.50                0.893
                                        9
  14              CDw26 (abs)*10 /l                    0.10        0.16           0.10             0.11                0.792
                                        9
  15              CDw26 (tot)*10                       0.49        0.77           0.48             0.60                0.890
  16                CD4+2H (%)                        34.37        13.74         33.78            14.59                0.729
  17             CD4+2H (abs)*109/l                    0.61        0.42           0.59             0.38                0.713
                                            9
  18              CD4+2H (tot) *10                     2.96        1.94           2.87             1.94                0.681
  19                CD8+VV (%)                        32.34        16.55         30.32            16.98                0.315
                                            9
  20             CD8+VV (abs)*10 /l                    0.58        0.46           0.55             0.46                0.534
                                            9
  21             CD8+VV (tot) *10                      2.89        2.30           2.63             2.13                0.324
  22                  CD4 (%)                         44.00        16.28         44.01            15.95                0.997
  23               CD4 (abs)*109/l                     0.76        0.47           0.78             0.46                0.760
                                    9
  24                CD4 (tot) *10                      3.76        2.33           3.78             2.38                0.944
  25                  CD8 (%)                         14.80        8.87          13.46             7.79                0.163
                                   9
  26               CD8 (abs)*10 /l                     0.25        0.20           0.25             0.20                0.968
  27                CD8 (tot) *109                     1.24        0.99           1.22             0.98                0.814
  28              Lymphocytes (%)                     30.98        11.23         33.07            11.43                0.121
                                                9
  29           Lymphocytes (abs)*10 /l                 1.82        1.31           1.77             0.81                0.725
                                                9
  30            Lymphocytes (tot) *10                  8.95        6.48           8.66             4.37                0.623
  31                  CD4/CD8                          6.50        10.85          6.90            10.73                0.751
  32           Index Thymus Function                   1.08        0.59           0.99             0.40                0.090
4   The Open Lung Cancer Journal, 2008, Volume 1                                                                           Oleg Kshivets

Table 2.    Factors of T-, B- and K-Cell Circuit Between LCP and NMP in Terms of Diagnosis

                                                       LCP st I-IV   n=533          NMP          n=282
    NN                 Factors                                                                                         P
                                                         Mean         SD           Mean            SD

    1                T-cells (%)                          52.26      13.35          52.84         11.97              0.544
                                       9
    2             T-cells (abs)*10 /l                     0.87       0.46           0.93          0.46               0.088
                                       9
    3              T-cells (tot)*10                       4.18       2.35           4.50          2.56               0.071
    4                B-cells (%)                          17.89      7.74           16.46         6.46               0.009*
    5             B-cells (abs)*109/l                     0.32       0.25           0.29          0.14               0.064
                                        9
    6              B-cells (tot)*10                       1.55       1.25           1.44          0.76               0.179
    7                K-cells (%)                          30.84      29.49          29.25         10.84              0.382
                                       9
    8             K-cells (abs)*10 /l                     0.52       0.45           0.55          0.30               0.285
                                        9
    9              K-cells (tot)*10                       2.49       2.28           2.71          1.66               0.157
    10                CD1 (%)                             8.74       9.72           8.11          8.96               0.368
                                   9
    11             CD1 (abs)*10 /l                        0.15       0.20           0.15          0.20               0.954
                                   9
    12              CD1 (tot)*10                          0.73       1.01           0.71          0.88               0.814
    13               CDw26 (%)                            6.05       6.94           6.20          6.50               0.762
                                        9
    14            CDw26 (abs)*10 /l                       0.10       0.13           0.10          0.11               0.970
    15            CDw26 (tot)*109                         0.47       0.67           0.48          0.60               0.844
    16              CD4+2H (%)                            31.79      14.72          33.78         14.59              0.089
                                           9
    17           CD4+2H (abs)*10 /l                       0.53       0.36           0.59          0.38               0.034*
                                            9
    18            CD4+2H (tot) *10                        2.56       1.82           2.87          1.94               0.027*
    19              CD8+VV (%)                            30.60      17.44          30.32         16.98              0.827
    20           CD8+VV (abs)*109/l                       0.52       0.42           0.55          0.46               0.387
                                               9
    21           CD8+VV (tot) *10                         2.51       2.09           2.63          2.13               0.429
    22                CD4 (%)                             42.31      16.32          44.01         15.95              0.156
                                   9
    23             CD4 (abs)*10 /l                        0.71       0.44           0.78          0.46               0.055
    24              CD4 (tot) *109                        3.41       2.25           3.78          2.38               0.030*
    25                CD8 (%)                             12.93      7.93           13.46         7.79               0.356
                                   9
    26             CD8 (abs)*10 /l                        0.22       0.17           0.25          0.20               0.015*
                                    9
    27              CD8 (tot) *10                         1.05       0.81           1.22          0.98               0.012*
    28            Lymphocytes (%)                         28.04      11.12          33.07         11.43              0.000*
    29         Lymphocytes (abs)*109/l                    1.70       0.91           1.77          0.81               0.234
                                                   9
    30          Lymphocytes (tot) *10                     8.16       4.74           8.66          4.37               0.140
    31                CD4/CD8                             6.50       9.80           6.90          10.73              0.591
    32          Index Thymus Function                     1.01       0.48           0.99          0.40               0.090

(P=0.000) were decreased significantly in comparison with              of IgM (r=0.09; P=0.012) and IgA (r=-0.13; P=0.000) (Ta-
PNMP (n=282) (Tables 2, 4, 6 and 8). The Table 6 also                  bles 9 and 10, Fig. 2).
shows that LCP with stage I-IV had strong evidence of de-                 The relationships between gender, age, weight, height
creasing of IgM (P=0.012) and increasing of IgA (P=0.000).
                                                                       and ED/DS of the groups are summarized in Table 9.
In addition, we found direct significant correlations between
DS and 20 lab tests: the percent of B-cells (r=-0.09;                      All significant variables were also evaluated in a tradi-
P=0.008) and lymphocytes (r=0.21; P=0.000), the count of               tional multivariate logistic regression analysis. All parame-
CD4+2H (r=0.07-0.08; P=0.034-0.27), CD4 (r=0.08;                       ters were analyzed in a logistic regression model in accor-
P=0.030), CD8 (r=0.08-0.09; P=0.015-0.012), monocytes                  dance with Tables 1-10. In terms of ED it was revealed that
(r=-0.07-0.14; P=0.045-0.000), leucocytes (r=-0.13-0.17;               logistic regression model based on 9 lab tests (the percent,
P=0.000), neutrophils (r=-0.09-0.22; P=0.010-0.000), titters           absolute and total count of B-cells, monocytes, titter of IgM,
Early Detection and Diagnosis of Lung Cancer and Immune Circuit                      The Open Lung Cancer Journal, 2008, Volume 1 5



Table 3.    Factors of Monocyte and Macrophage Circuit Between LCP and NMP in Terms of Early Detection


                                                   LCP st I-II    n=95       NMP              n=282
  NN                   Factors                                                                                       P
                                                     Mean          SD       Mean               SD

   1               Monocytes (%)                      3.45        2.92       2.87              2.29               0.048*
                                     9
   2            Monocytes (abs)*10 /l                 0.22        0.22       0.16              0.14               0.003*
   3             Monocytes (tot) *109                 1.08        1.10       0.76              0.70               0.001*
   4               Phagocyte Index                   21.84        14.64      23.05            15.89                0.512
   5              Phagocyte Number                    3.96        2.27       4.17              2.62                0.477
   6         Index Complete Phagocytosis              1.09        0.59       1.01              0.50                0.187


Table 4.    Factors of Monocyte and Macrophage Circuit Between LCP and NMP in Terms of Diagnosis

                                                  LCP st I-IV     n=533      NMP              n=282
  NN                   Factors                                                                                       P
                                                     Mean          SD       Mean               SD

   1               Monocytes (%)                      3.24        2.57       2.87              2.29               0.045*
   2            Monocytes (abs)*109/l                 0.21        0.21       0.16              0.14               0.000*
                                       9
   3             Monocytes (tot) *10                  1.01        1.06       0.76              0.70               0.000*
   4               Phagocyte Index                   22.29        15.15      23.05            15.89                0.501
   5              Phagocyte Number                    4.14        2.46       4.17              2.62                0.860
   6         Index Complete Phagocytosis              1.02        0.49       1.01              0.50                0.653




Table 5.    Factors of Humoral Immunity Between LCP and NMP in Terms of Early Detection

                                                   LCP st I-II    n=95       NMP              n=282
  NN                   Factors                                                                                       P
                                                     Mean          SD       Mean               SD

   1                  IgG (g/l)                      10.57        2.93       10.52             2.23                0.880
   2                  IgM (g/l)                       1.56        0.51       1.72              0.62                0.021*
   3                  IgA (g/l)                       2.38        0.94       2.26              0.85                0.206
   4              Natural Antibodies                 25.01        26.13      23.82            20.35                0.648
   5        Circulating Immune Complexes             25.33        20.60      25.80            23.51                0.862




Table 6.    Factors of Humoral Immunity Between LCP and NMP in Terms of Diagnosis

                                                  LCP st I-IV     n=533      NMP              n=282
  NN                   Factors                                                                                       P
                                                     Mean          SD        Mean               SD

   1                  IgG (g/l)                      10.70        2.84       10.52             2.23                0.372
   2                  IgM (g/l)                       1.61        0.58       1.72              0.62                0.012*
   3                  IgA (g/l)                       2.52        1.02       2.26              0.85                0.000*
   4              Natural Antibodies                 27.31        26.54      23.82             20.35               0.055
   5        Circulating Immune Complexes             24.47        19.36      25.80             23.51               0.388
6   The Open Lung Cancer Journal, 2008, Volume 1                                                                          Oleg Kshivets



Table 7.    Factors of Neutrophil Circuit Between LCP and NMP in Terms of Early Detection


                                                          LCP st I-II      n=95        NMP        n=282
    NN                        Factors                                                                                 P
                                                            Mean            SD         Mean         SD

                         NST spontaneous
    1                                                        7.64           6.60       7.93        6.93             0.727
               NST stimulated Staphylococcus aureus
    2                                                        8.49           9.34       8.55        8.60             0.955
                   NST stimulated Streptococcus
    3                                                        10.49          9.65       10.58       9.05             0.939
                             Pyogenes
    4       Index Stimulation by Staphylococcus aureus       1.02           0.72       1.45        2.09             0.052
    5       Index Stimulation by Streptococcus pyogenes      1.37           0.94       1.89        2.13             0.024*
                                           9
    6                 Leukocytes (abs)*10 /l                 5.88           2.47       5.47        1.85             0.086
    7                  Leukocytes (tot)*109                  29.17         13.09       26.73       10.19            0.061
    8                  Stab Neutrophils (%)                  1.06           1.31       0.97        1.58             0.598
                                                 9
    9               Stab Neutrophils (abs)*10 /l             0.07           0.13       0.06        0.12             0.404
                                                 9
    10               Stab Neutrophils (tot)*10               0.35           0.65       0.28        0.57             0.300
    11              Segmented Neutrophils (%)                61.53         11.58       59.47       11.75            0.139
                                                     9
    12           Segmented Neutrophils (abs)*10 /l           3.61           1.58       3.29        1.41             0.064
                                                     9
    13            Segmented Neutrophils (tot)*10             17.92          8.46       16.06       7.28             0.040*


Table 8.    Factors of Neutrophil Circuit Between LCP and NMP in Terms of Diagnosis

                                                          LCP st I-IV      n=533       NMP        n=282
    NN                        Factors                                                                                 P
                                                            Mean            SD         Mean         SD

                         NST spontaneous
    1                                                        8.65           8.49       7.93        6.93             0.217
               NST stimulated Staphylococcus aureus
    2                                                        9.36           9.98       8.55        8.60             0.248
                   NST stimulated Streptococcus
    3                                                        11.13          9.46       10.58       9.05             0.425
                             Pyogenes
    4       Index Stimulation by Staphylococcus aureus       1.35           1.51       1.45        2.09             0.441
    5       Index Stimulation by Streptococcus pyogenes      1.76           1.72       1.89        2.13             0.365
                                           9
    6                 Leukocytes (abs)*10 /l                 6.31           2.48       5.47        1.85             0.000*
                                             9
    7                  Leukocytes (tot)*10                   30.09         12.52       26.73       10.19            0.000*
    8                  Stab Neutrophils (%)                  1.27           1.57       0.97        1.58             0.010*
                                                 9
    9               Stab Neutrophils (abs)*10 /l             0.09           0.18       0.06        0.12             0.003*
                                                 9
    10               Stab Neutrophils (tot)*10               0.44           0.78       0.28        0.57             0.003*
    11              Segmented Neutrophils (%)                64.23         11.48       59.47       11.75            0.000*
    12           Segmented Neutrophils (abs)*109/l           4.10           1.88       3.29        1.41             0.000*
                                                     9
    13            Segmented Neutrophils (tot)*10             19.49          9.06       16.06       7.28             0.000*

index stimulation by Streptococcus pyogenes and the total               and IgA) was significantly capable to diagnose LC with
count of segmented neutrophils) significantly recognized                stage T1-4N0-3M0-1 from NMP ( 2=108.075; Df=20;
small LC with stage T1-2N0M0 from NMP ( 2=27.543;                       P=0.00000001; n=815) (Table 12).
Df=9; P=0.001; n=377) (Table 11). Accordingly, the logistic
                                                                            All of these differences and discrepancies were further
regression model based on 20 lab tests (the percent of B-cells          investigated by SEPATH analysis (structural equation mod-
and lymphocytes, the absolute and total count of CD4+2H,
                                                                        eling) and multi-factor clustering. The values are shown in
CD8 and leukocytes, the total count of CD4, the percent,
                                                                        Tables 13 and 14. It was revealed that ED of LC with stage
absolute and total count of monocytes, stab and segmented
                                                                        I-II (tumor size=2.5±0.1 cm; T1-2N0M0; n=95) from NMP
neutrophils, (r=-0.09-0.22; P=0.010-0.000), the titters of IgM
                                                                        (n=282) significantly (P=0.000000) depended on: 1) level of
Early Detection and Diagnosis of Lung Cancer and Immune Circuit                              The Open Lung Cancer Journal, 2008, Volume 1 7

Table 9.    Correlations Between Early Detection (n=377) and Diagnosis of LC (n=815) and Factors (LCP---NMP)

                                                                  ED                n=377                  DS                 n=815
  NN                         Factors
                                                                   r                  P                     r                   P

   1                         Gender                               0.18              0.000*                0.27                0.000*
   2                       Age (years)                            -0.33             0.000*                -0.34               0.000*
   3                       Weight (kg)                            -0.05              0.358                0.05                0.140
   4                       Height (cm)                            -0.13             0.010*                -0.11               0.001*
   5                       T-cells (%)                            -0.03              0.590                0.02                0.544
                                          9
   6                    T-cells (abs)*10 /l                       -0.00              0.942                0.06                0.080
                                             9
   7                     T-cells (tot)*10                         -0.02              0.660                0.06                0.071
   8                       B-cells (%)                            -0.12             0.024*                -0.09               0.008*
                                             9
   9                    B-cells (abs)*10 /l                       -0.16             0.001*                -0.06               0.064
  10                     B-cells (tot)*109                        -0.17             0.001*                -0.05               0.179
  11                       K-cells (%)                            0.09               0.068                -0.03               0.382
                                             9
  12                    K-cells (abs)*10 /l                       0.01               0.909                0.04                0.285
                                              9
  13                     K-cells (tot)*10                         0.01               0.803                0.05                0.157
  14                        CD1 (%)                               -0.05              0.333                -0.01               0.814
  15                     CD1 (abs)*109/l                          -0.05              0.372                -0.03               0.368
                                         9
  16                      CD1 (tot)*10                            -0.06              0.243                0.00                0.954
  17                       CDw26 (%)                              -0.01              0.893                0.01                0.762
                                              9
  18                    CDw26 (abs)*10 /l                         -0.01              0.792                -0.00               0.970
  19                     CDw26 (tot)*109                          -0.01              0.890                0.01                0.844

  20                      CD4+2H (%)                              -0.02              0.681                0.06                0.067
                                                 9
  21                   CD4+2H (abs)*10 /l                         -0.02              0.729                0.07                0.034*
  22                    CD4+2H (tot)*109                          -0.02              0.713                0.08                0.027*
  23                      CD8+VV (%)                              -0.05              0.315                -0.01               0.826
                                                  9
  24                   CD8+VV (abs)*10 /l                         -0.03              0.534                0.03                0.367
  25                    CD8+VV (tot)*109                          -0.05              0.324                0.03                0.429
  26                        CD4 (%)                               0.00               0.944                0.05                0.156
                                         9
  27                     CD4 (abs) *10 /l                         0.00               0.997                0.07                0.055
                                          9
  28                      CD4 (tot) *10                           0.02               0.760                0.08                0.030*
  29                        CD8 (%)                               -0.07              0.163                0.03                0.356
  30                     CD8 (abs) *109/l                         -0.00              0.968                0.08                0.015*
  31                      CD8 (tot) *109                          -0.01              0.814                0.09                0.012*
  32                    Lymphocytes (%)                           0.08               0.121                0.21                0.000*
                                                      9
  33                 Lymphocytes (abs)*10 /l                      -0.02              0.725                0.04                0.234
                                                      9
  34                  Lymphocytes (tot) *10                       -0.03              0.623                0.05                0.140
  35                        CD4/CD8                               0.02               0.751                0.02                0.591
  36                 Index Thymus Function                        -0.09              0.090                -0.02               0.594

immune cell circuit ( 2=38749.1; Df=989); 2) value of                     Df=989); 2) macrophage circuit ( 2=312.1; Df=20); 3) hu-
monocyte and macrophage circuit ( 2=662.8; Df=20); 3)                     moral factors ( 2=243.1; Df=9); 4) neutrophils circuit
level of humoral immunity ( 2=585.9; Df=9); 4) neutrophils                ( 2=10772.3; Df=77). Monte Carlo simulation confirmed
circuit ( 2=5214.4; Df=77). It was also founded that DS of                significant (P=0.000000) overall networks between ED and
LC with stage I-IV (tumor size=5.4±0.1 cm; T1-4N0-3M0-1;                  DS of LC and the cell immunity circuit, the humoral immu-
n=533) from NMP significantly (P=0.000000) depended on:                   nity data, macrophage and neutrophil circuit (Fig. 3).
1) value of immune cell subpopulations ( 2=80569.9;
8    The Open Lung Cancer Journal, 2008, Volume 1                                                                       Oleg Kshivets



Table 10. Correlations Between Early Detection (n=377) and Diagnosis of LC (n=815) and Factors (LCP---NMP)


                                                              ED                 n=377               DS                n=815
     NN                        Factors
                                                                  r                P                  r                  P

     37                    Monocytes (%)                     -0.10               0.048*             -0.07              0.045*
                                             9
     38                 Monocytes (abs)*10 /l                -0.15               0.003*             -0.14              0.000*
     39                  Monocytes (tot)*109                 -0.17               0.001*             -0.13              0.000*
     40                    Phagocyte Index                   0.03                 0.512              0.02               0.501
     41                  Phagocytic Number                   0.04                 0.477              0.01               0.860
     42              Index Complete Phagocytosis             -0.07                0.187             -0.02               0.653
     43                       IgG (g/l)                      -0.01                0.880             -0.03               0.372
     44                       IgM (g/l)                      0.12                0.021*              0.09              0.012*
     45                       IgA (g/l)                      -0.07                0.206             -0.13              0.000*
     46                   Natural Antibodies                 -0.02                0.648             -0.07               0.055
     47          Circulating Immune Complexes (CIC)          0.01                 0.862              0.03               0.388
     48                   NST spontaneous                    0.02                 0.727             -0.04               0.217
     49         NST stimulated Staphylococcus aureus         0.00                 0.955             -0.04               0.248
     50         NST stimulated Streptococcus pyogenes        0.00                 0.939             -0.03               0.425
     51        Index Stimulation Staphylococcus aureus       0.10                 0.052              0.03               0.447
     52        Index Stimulation Streptococcus pyogenes      0.12                0.024*              0.03               0.365
                                             9
     53                 Leukocytes (abs)*10 /l               -0.09                0.086             -0.17              0.000*
                                               9
     54                  Leukocytes (tot)*10                 -0.10                0.062             -0.13              0.000*
     55                  Stab Neutrophils (%)                -0.03                0.598             -0.09              0.010*
     56              Stab Neutrophils (abs)*109/l            -0.04                0.404             -0.10              0.003*
                                                   9
     57               Stab Neutrophils (tot)*10              -0.05                0.300             -0.10              0.003*
     58               Segmented Neutrophils (%)              -0.08                0.139             -0.19              0.000*
                                                       9
     59           Segmented Neutrophils (abs)*10 /l          -0.10                0.064             -0.22              0.000*
     60            Segmented Neutrophils (tot)*109           -0.11               0.040*             -0.19              0.000*

DISCUSSION                                                            2.     The clinical utility of some immune cell and humoral
                                                                             markers are feasible in ED and DS of LC and may be
    This study aimed to assess, in the large populations of
                                                                             defined, in general, moderate.
LCP, the real diagnostic value of immune cell and humoral
markers in comparison with the large population of PNMP.              3.     At ED and DS of LC the complex of recognized im-
The importance must be stressed of using complex system                      mune markers is better than any single factor.
analysis, statistical and biometrical methods in combination,         4.     Immune cell subpopulations and humoral factors
because the different approaches yield complementary pieces                  communicate knotty with each other.
of diagnostic information [1].
                                                                          To explain such results we entertained the hypothesis that
     Its main findings can be summarized as follows:                  immune cell and humoral circuit regulate cancer dynamics
1.        LCP even with the first and second stages had certain       and participate in host defense mechanism against tumor.
          changes of immunological parameters and their rela-         Disbalance and deficiency of immune cells and humoral fac-
          tionships, while these changes were detected even at        tors as well as deregulation of their networks can lead to
          early LC when the effectiveness of the treatment            tumor appearance and tumor progression. It is clear that
          process (5-year survival after complete resections)         these relationships discrepancies in immune cell and hu-
          tends to be 80-100%. The data of immunological ho-          moral circuit are remarkable tests for recognition LC. As
          meostasis of patients with an early LC significantly        shown in our results, the number of immune markers tends
          differed from non-malignant pathology, that is ho-          to be more frequently abnormal when the disease is ad-
          meostasis of a patient with the non-malignant pathol-       vanced and this effect is enough for reaching a statistically
          ogy principally distinguished from the homeostasis of       significant conclusion. In agreement with our findings, re-
          a patient with early LC.                                    cent studies have demonstrated some defects and impaired
Early Detection and Diagnosis of Lung Cancer and Immune Circuit                        The Open Lung Cancer Journal, 2008, Volume 1 9




Fig. (1). Significant networks between factors of immune cell and humoral circuit and early detection of LC (LCP with stage T1-2N0M0,
n=95---PNMP, n=282).




Fig. (2). Significant networks between factors of immune cell and humoral circuit and diagnosis of LC (LCP with stage T1-4N0-3M0-1,
n=533---PNMP, n=282).

effector function of T-cell subpopulations, K-cells, lym-            from patients with various malignancies including LCP
phokin-activated killer cells and monocytes/macrophages              [1,13-18].
10 The Open Lung Cancer Journal, 2008, Volume 1                                                                                             Oleg Kshivets



Table 11. Results of Logistic Regression Modeling in Early Detection of LC (n=95) from NMP (n=282)

                                                            2
 NN                      Significant Immune Factors:            =27.543; Df=9; P=0.0011407;                                     Estimate

                                                    Const.B0                                                                     1.34429
  1                                                B-cells (%)                                                                   -0.01543
  2                                          B-cells (abs)*109/l                                                                 -3.80134
                                                                        9
  3                                           B-cells (tot)*10                                                                   0.45341
  4                                            Monocytes (%)                                                                     0.00167
                                                                            9
  5                                        Monocytes (abs)*10 /l                                                                 2.36224
  6                                         Monocytes (tot) *109                                                                 -0.70182
  7                                                 IgM (g/l)                                                                    0.44811
  8                              Index Stimulation by Streptococcus pyogenes                                                     0.18113
                                                                                    9
  9                                    Segmented Neutrophils (tot)*10                                                            -0.01816




Table 12. Results of Logistic Regression Modeling in Diagnosis of LC (n=533) from NMP (n=282)

                                                        2
 NN                     Significant Immune Factors:      =108.075; Df=20; P=0.0000000;                                          Estimate

                                                    Const.B0                                                                     4.67194
  1                                                B-cells (%)                                                                   -0.02946
  2                                         CD4+2H (abs)*109/l                                                                   3.17501
                                                                            9
  3                                          CD4+2H (tot) *10                                                                    -0.57679
                                                                    9
  4                                               CD4 (tot) *10                                                                  0.09542
                                                                    9
  5                                           CD8 (abs)*10 /l                                                                    3.60816
  6                                               CD8 (tot) *109                                                                 -0.41372
  7                                           Lymphocytes (%)                                                                    -0.03025
  8                                            Monocytes (%)                                                                     0.07468
                                                                            9
  9                                        Monocytes (abs)*10 /l                                                                 -0.39635
  10                                        Monocytes (tot) *109                                                                 -0.53516
  11                                                IgM (g/l)                                                                    0.43660
  12                                                IgA (g/l)                                                                    -0.37333
                                                                            9
  13                                       Leukocytes (abs)*10 /l                                                                -1.40877
  14                                        Leukocytes (tot)*109                                                                 0.22663
  15                                        Stab Neutrophils (%)                                                                 -0.08793
                                                                                9
  16                                     Stab Neutrophils (abs)*10 /l                                                            3.97775
                                                                                9
  17                                      Stab Neutrophils (tot)*10                                                              -0.64340
  18                                     Segmented Neutrophils (%)                                                               -0.05288
                                                                                    9
  19                                  Segmented Neutrophils (abs)*10 /l                                                          1.09895
                                                                                    9
  20                                   Segmented Neutrophils (tot)*10                                                            -0.18262

    The main conclusion that can be drown from the present                              immunity networks differed significantly in their capability
results is that there were 4 basic hidden clusters of immunity                          to recognize early LC as well as advanced LC from NMP.
networks between system “immune homeostasis—lung can-
                                                                                            The rational for the investigation was that immunodiag-
cer”: 1) the level of T-, B- and K-cell subpopulations circuit;
                                                                                        nosis is likely to be reliable for separation of LCP including
2) the value of monocyte/macrophage circuit; 3) the level of
                                                                                        stage I-II from NMP for surgery, and because these patients
humoral immunity; 4) the value of neutrophil circuit. These
                                                                                        would be expected to have the better outcome.
Early Detection and Diagnosis of Lung Cancer and Immune Circuit                           The Open Lung Cancer Journal, 2008, Volume 1 11



Table 13. Results of Structural Equation Modeling and Monte Carlo Simulation in Early Detection of LC Stage I-II (n=95) from
          NMP (n=282)

                                                                                            2
   NN                                       Networks                                                          Df               P

    1                         T-, B-, K-cells Circuit/Early Detection                    38749.1              989          0.000000*
    2                     Monocyte-Macrophage Circuit/Early Detection                     662.8               20           0.000000*
    3                          Humoral Immunity/Early Detection                           585.9                   9        0.000000*
    4                          Neutrophils Circuit/Early Detection                       5214.4               77           0.000000*
    5                  T-, B-, K-cells Circuit/Monocyte-Macrophage Circuit               39424.6             1125          0.000000*
    6                       T-, B-, K-cells Circuit/Humoral Immunity                     39080.3             1224          0.000000*
    7                       T-, B-, K-cells Circuit/Neutrophils Circuit                  38381.3             1216          0.000000*
    8                   Monocyte-Macrophage Circuit/Humoral Immunity                      160.9               54           0.000000*
    9                   Monocyte-Macrophage Circuit/Neutrophils Circuit                  5831.0               170          0.000000*
   10                        Humoral Immunity/ Neutrophils Circuit                       5161.8               134          0.000000*


Table 14. Results of Structural Equation Modeling and Monte Carlo Simulation in Diagnosis of LC Stage I-IV (n=533) from NMP
          (n=282)

                                                                                            2
   NN                                       Networks                                                          Df               P

    1                            T-, B-, K-cells Circuit/Diagnosis                       80569.9              989          0.000000*
    2                        Monocyte-Macrophage Circuit/Diagnosis                        312.1               20           0.000000*
    3                             Humoral Immunity/Diagnosis                              243.1                   9        0.000000*
    4                             Neutrophils Circuit/Diagnosis                          10772.3              77           0.000000*
    5                  T-, B-, K-cells Circuit/Monocyte-Macrophage Circuit               82709.1             1125          0.000000*
    6                       T-, B-, K-cells Circuit/Humoral Immunity                     81232.2             1224          0.000000*
    7                       T-, B-, K-cells Circuit/Neutrophils Circuit                  78126.0             1216          0.000000*
    8                   Monocyte-Macrophage Circuit/Humoral Immunity                      227.5               54           0.000000*
    9                   Monocyte-Macrophage Circuit/Neutrophils Circuit                  2506.1               170          0.000000*
   10                        Humoral Immunity/ Neutrophils Circuit                       10876.6              134          0.000000*




Fig. (3). Significant networks between immune cell and humoral circuit and early detection and diagnosis of LC.
12 The Open Lung Cancer Journal, 2008, Volume 1                                                                                                Oleg Kshivets

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[2]     Henschke C. Meeting report: The First International Conference on        [13]    Klotz M., Blaes F., Funke D., et al. Shift in the IgG subclass distri-
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Received: October 20, 2008                                        Revised: November 7, 2008                                     Accepted: November 7, 2008


© Oleg Kshivets; Licensee Bentham Open.
This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http: //creativecommons.org/licenses/by-
nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

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Kshivets O. Lung Cancer: Early Detection and Diagnosis

  • 1. The Open Lung Cancer Journal, 2008, 1, 1-12 1 Open Access Early Detection and Diagnosis of Lung Cancer and Immune Circuit Oleg Kshivets* Thoracic Surgery Department, Klaipeda University Hospital, Klaipeda, Lithuania Abstract: Purpose: Significance of immune cell and humoral circuit in terms of early detection and diagnosis of lung cancer (LC) was investigated. Methods: In retrospective trial (1987-2008) consecutive cases after surgery, monitored 533 LCP (males - 472, females - 61; pneumonectomies - 181, upper lobectomies - 138, lower lobectomies - 67, upper/lower bilobectomies - 24, middle lobectomies - 6, segmentectomies - 76, exploratory thoracotomies and biopsies - 41) with pathologic stage I-IV (stage I - 48, stage II - 47, stage III - 321; stage IV - 117; squamous cell LC - 294, adenocarcinoma - 171, large cell LC - 48, small cell LC - 20; T1 - 116, T2 - 168, T3 - 125, T4 - 124; N0 - 148, N1 - 144, N2 - 159; N3 - 82; G1 - 88, G2 - 166, G3 - 279; M0 - 438; M1 - 95) and 282 patients with lung non-malignant pathology (NMP) (males - 188, females - 94; pneumonec- tomies - 5, upper lobectomies - 96, lower lobectomies - 81, middle lobectomies - 2, segmentectomies and wedge resec- tions - 98; non-malignant tumors - 100; abscess - 112; tuberculoma - 70) were reviewed. Variables selected for study were input levels of immunity blood parameters, sex, age, TNMG. Thawed aliquoted samples were evaluated for IgG, IgM, IgA, natural antibodies, circulating immune complexes. The percentage, absolute count and total population number (per human organism) of T-lymphocytes (CD3), B-lymphocytes (CD19), helper T-lymphocytes (CD4), suppressor/cytotoxic T-lymphocytes (CD8), killer cells (O-cells, K-cells or CD16), precursor T-cells (CD1), activated T-cells (CDw26), mono- cytes (CD64, CD13), helper/inducer T-lymphocytes (CD4+2H), contrsuppressor T-lymphocytes (CD8+VV), CD4/CD8, leukocytes, lymphocytes, polymorphonuclear and stabnuclear leukocytes were estimated. The laboratory blood studies also included input levels of NST (tests of oxygen dependent metabolism of neutrophils spontaneous and stimulated by Staphylococcus aureus or by Streptococcus pyogenes), index of stimulation of leukocytes by Staphylococcus aureus or Streptococcus pyogenes, index of thymus function, phagocytic number, phagocyte index, index of complete phagocytosis. Differences between groups were evaluated using multi-factor clustering, nonlinear estimation (logistic regression), struc- tural equation modeling and Monte Carlo simulation. Results: It was revealed that early detection of LC (stage I-II; tumor size=2.5±0.1 cm; T1-2N0M0; n=95) from NMP (n=282) significantly (P=0.000000) depended on: 1) level of immune cell circuit ( 2=38749.1; Df=989); 2) value of monocyte and macrophage circuit ( 2=662.8; Df=20); 3) level of humoral immunity ( 2=585.9; Df=9); 4) neutrophils cir- cuit ( 2=5214.4; Df=77). It was also founded that diagnosis of LC (stage I-IV; tumor size=5.4±0.1 cm; T1-4N0-3M0-1; n=533) from NMP significantly (P=0.000000) depended on: 1) value of immune cell subpopulations ( 2=80569.9; Df=989); 2) macrophage circuit ( 2=312.1; Df=20); 3) humoral factors ( 2=243.1; Df=9); 4) neutrophils circuit ( 2=10772.3; Df=77). Keywords: Lung cancer, immunity, early detection, diagnosis. INTRODUCTION fluorescence techniques, computerized molecular analysis of airway cell markers, etc. [1,2]. Theoretically the early detection (ED) of lung cancer (LC) allows increasing the 5-year survival rate of the LC Differential diagnosis (DS) of LC from non-malignant patients (LCP) by several times while the combined and pathology (NMP) is another very complicated branch of complex treatment - only by 5-30% with incomparable fi- clinical oncology. In this sphere there are more illusions, nancial expenses [1]. That is why screening programs domi- disappointments and failures than real results. That is why nate in the long-term strategic anti-cancer programs in the the great number of LCP is treated in the hospitals for so- USA, Japan and Europe, that is why hundred million dollars matic pathology and is observed by different physicians for are assigned on these programs, and that is why the super many years. It means that the fate of the patient depends on modern high technologies are tested here: spiral CT scans the first visit to a doctor and if the last is not vigilant enough, screening, automated computerized microscopy screening, the future of the person is tragic [1]. At the same time LCP monoclonal antibody staining techniques, fluorodeoxyglu- have been reported to have immune dysfunctions of the cell- cose-Positron Emission Tomography, bronchoscopic auto- mediated and humoral response [3,4]. However, little is known about value of immune system data in terms of early detection and differential diagnosis of LC. Therefore, we *Address correspondence to this author at the Thoracic Surgery Department, examined immune system data in LCP and in patients with Klaipeda University Hospital, Brozynu: 5-54, Klaipeda, LT95214, Lithua- NMP (PNMP). nia; Tel: 37060878390; E-mail: kshivets003@yahoo.com 1876-8199/08 2008 Bentham Open
  • 2. 2 The Open Lung Cancer Journal, 2008, Volume 1 Oleg Kshivets PATIENTS AND METHODS mononuclears and neutrophils were isolated from a freshly drawn heparinized tube of blood. Mononuclear cells and Venous blood samples from 815 consecutive operated neutrophils were isolated after discontinuous density gradi- and monitored in 1987-2008 LCP and PNMP (control group) ents separation on Ficoll-Hypaque (3 ml of 1 solution: 10 were obtained prior to any treatment. All patients in both portions of 33.9% Hypaque and 24 portions of 9% Ficoll + 3 groups were Europeans. 533 LCP with pathologic stage I-IV ml of 2 solution: 10 portions of 50% Hypaque and 20 por- LCP (males - 472, females - 61; age=57.4±0.4 years) tions of 9% Ficoll), washed in Hank’s balanced salt solution (mean±standard error) and 282 PNMP (males - 188, females with 10% AB group serum, resuspended and cultured with - 94; age=50.3±0.7 years) entered this trial. All patients from ram erythrocytes by incubation at +37°C 15 minutes without the control group were checked and operated in the clinic for or with immunoglobulins IgG, IgM and IgA antiserum. The suspicion of LC. Patients were not considered eligible if they rosette methods were used to evaluate immune cell subpopu- had previous treatment with chemotherapy, immunotherapy lations counts. The obtained results were converted to mod- or radiotherapy, if there were two primary tumors of the time ern defined clusters of human leukocytes [8]. Clotted blood of diagnosis or if patients did not leave the clinic or died was clarified and sera collected, aliquoted, and stored at - after surgery. Staging procedures included medical history, 80°C. Thawed aliquoted samples were evaluated for IgG, physical examination, complete blood count with differen- IgM, IgA, natural antibodies, circulating immune complexes tials, biochemistry and electrolyte panel, chest X-ray (PA (CIC). Traditionally the percentage, absolute count and total and laterals), abdominal ultrasound, fibrobronchoscopy, population number (per human organism) of T-lymphocytes electrocardiogram, spirometry, bronchial or transthoracic (CD3), B-lymphocytes (CD19), helper T-lymphocytes biopsy. Computed tomography scan of chest, upper abdomen (CD4), suppressor/cytotoxic T-lymphocytes (CD8), killer and brain, liver and bone radionucle scan were performed cells (O-cells, K-cells or CD16), precursor T-cells (CD1), whenever needed. Midiastinoscopy was not used. All LCP activated T-cells (CDw26), monocytes (CD64, CD13), were diagnosed with histologically confirmed non-small cell helper/inducer T-lymphocytes (CD4+2H), contrsuppressor lung cancer. All had measurable tumor and ECOG perform- T-lymphocytes (CD8+VV), CD4/CD8, leukocytes, lympho- ance status 0 or 1. Before any treatment each patient was cytes, polymorphonuclear and stabnuclear leukocytes were carefully examined by medical panel composed of thoracic estimated. The laboratory blood studies also included input surgeon, chemotherapeutist, radiation oncologist and pneu- levels of NST (tests of oxygen dependent metabolism of mologist to confirm the stage of disease. All patients signed neutrophils spontaneous and stimulated by Staphylococcus a written informed consent form approved by the local Insti- aureus or by Streptococcus pyogenes), index of stimulation tutional Review Board. of leukocytes by Staphylococcus aureus or Streptococcus Among 533 LCP 181 underwent pneumonectomy, 138 - pyogenes, index of thymus function, phagocytic number, upper lobectomy, 67 - lower lobectomy, 24 - upper/lower phagocyte index, index of complete phagocytosis, immune bilolobectomy, 6 - middle lobectomy, 76 - segmentectomy, cell ratio factors (ratio between total immune cell subpopula- 41 - exploratory thoracotomy and biopsy. All LCP under- tion number in patient organism and general number of can- went routine systematic mediastinal nodal dissection. cer cell population). Among all LCP, 55 LCP underwent combined and extensive Multi-factor clustering, structural equation modeling radical procedures with the resection of pericardium, atrium, (SEPATH) and Monte Carlo simulation were used to deter- part of aorta, part of vena cava superior, vena azygos, carina, mine any significant dependence [9,10,11,12]. System, bio- diaphragm, chest wall, ribs, etc. metric and statistical analyses were conducted using Of the 282 PNMP, surgical procedures consisted of CLASS-MASTER (Stat Dialog, Inc., Moscow, Russia), pneumonectomy in 5, upper lobectomy - in 96, lower lobec- SANI (Stat Dialog, Inc., Moscow, Russia) and STATIS- tomy - in 81, middle lobectomy - in 2, segmentectomy or TICA (Stat Soft, Inc., Tulsa, OK, the USA). All tests were wedge resection - in 98. considered significant when the resulting P value was less than 0.05. The histological diagnosis of LC was based on the crite- ria of the World Health Organization [5,6]. Histological ex- amination showed squamous cell LC in 294, adenocarci- RESULTS noma - in 171, large cell LC - in 48 and small LC - in 20 The immunological characteristics of the cohort studied patients. The pathological TNM stage I was in 48, II - in 47, are summarized in Tables 1-8. These Tables show descrip- III - in 321, IV - in 117 patients; the pathological T stage was tive statistics of important pre-treatment variables such as T1 in 116, T2 - in 168, T3 - in 125, T4 - in 124 cases; the factors of T-, B-, K-cell and monocyte/macrophage circuit pathological N stage was N0 in 148, N1 - in 144, N2 - in (Tables 1-4). Reported also is date of humoral immunity and 159, N3 - in 82 patients; the M0 was in 438, M1 - in 95 neutrophil circuit (Tables 5-8). In terms of ED no statistical cases. The tumor differentiation was graded as G1 in 88, G2 difference was found in T-cells, K-cells, CD1, CDw26, - in 166, G3 - in 279 cases. CD4+2H, CD8+VV, CD4, CD8, CD4/CD8, lymphocytes, Among 282 PNMP the histological analysis displayed index thymus function, phagocyte index, phagocyte number, benign tumors in 100, chronical abscess - in 112, tubercu- index complete phagocytosis, titters of IgG, IgA, natural loma - in 70 patients. antibodies, circulating immune complexes, NST spontaneous and NST stimulated Staphylococcus aureus and Streptococ- Baseline venous blood samples for immunology studies cus pyogenes, index stimulation by Staphylococcus aureus, were taken on the first morning prior to any treatment. All leucocytes, stab neutrophils between groups. The input level immunologic parameters measured using traditional well- of B-cells (P=0.024-0.001), monocytes (P=0.048-0.001), regulated immunodiagnostic methods [7]. Venous blood
  • 3. Early Detection and Diagnosis of Lung Cancer and Immune Circuit The Open Lung Cancer Journal, 2008, Volume 1 3 titters of IgM (P=0.021), index stimulation by Streptococcus In terms of DS the baseline number of T-cells, K-cells, pyogenes (P=0.024) and the number of total segmented neu- CD1, CDw26, CD8+VV, CD4/CD8, index thymus function, trophils (P=0.040) differed significantly in their capability to phagocyte index, phagocyte number, index complete phago- recognize the small LC with stage I-II (T1-2N0M0; n=95; cytosis, titter of IgG, natural antibodies, circulating immune tumor size=2.5±0.1 cm) (Tables 1, 3, 5 and 7). Accordingly, complexes, NST-tests, indexes of stimulation of leukocytes we revealed the direct significant correlations between ED did not differ significantly between the two groups of pa- and 9 lab tests. The obvious correlation with ED was signifi- tients (Tables 2, 4, 6 and 8). cantly related to the count of B-cells (r=-0.12-0.17; P=0.024- In group of LCP with stage I-IV (T1-4N0-3M0-1; n=533; 0.001), monocytes (r=-0.10-0.17; P=0.048-0.001), titter of tumor size=5.4±0.1 cm) the percent of B-cells (P=0.009), the IgM (r=0.12; P=0.021), index stimulation by Streptococcus count of monocytes (P=0.045-0.000), leucocytes (P=0.000) pyogenes (r=0.12; P=0.024) and the number of total seg- and neutrophils (P=0.010-0.000) were remarkably increased mented neutrophils (r=-0.11; P=0.040) (Tables 9 and 10, Fig. but the CD4+2H (P=0.034-0.027), CD4 (P=0.030), CD8 1). count (P=0.015-0.012) and the percent of lymphocytes Table 1. Factors of T-, B- and K-Cell Circuit Between LCP and NMP in Terms of Early Detection LCP st I-II n=95 NMP n=282 NN Factors P Mean SD Mean SD 1 T-cells (%) 53.62 12.82 52.84 11.97 0.590 9 2 T-cells (abs)*10 /l 0.94 0.49 0.93 0.46 0.942 3 T-cells (tot)*109 4.63 2.45 4.50 2.56 0.680 4 B-cells (%) 18.34 8.32 16.46 6.46 0.024* 5 B-cells (abs)*109/l 0.39 0.44 0.29 0.14 0.001* 6 B-cells (tot)*109 1.94 2.21 1.44 0.76 0.001* 7 K-cells (%) 26.86 11.49 29.25 10.84 0.068 8 K-cells (abs)*109/l 0.55 0.65 0.55 0.30 0.910 9 K-cells (tot)*109 2.65 3.15 2.71 1.66 0.805 10 CD1 (%) 9.17 9.90 8.11 8.96 0.333 9 11 CD1 (abs)*10 /l 0.17 0.23 0.15 0.20 0.372 12 CD1 (tot)*109 0.84 1.16 0.71 0.88 0.243 13 CDw26 (%) 6.32 8.70 6.20 6.50 0.893 9 14 CDw26 (abs)*10 /l 0.10 0.16 0.10 0.11 0.792 9 15 CDw26 (tot)*10 0.49 0.77 0.48 0.60 0.890 16 CD4+2H (%) 34.37 13.74 33.78 14.59 0.729 17 CD4+2H (abs)*109/l 0.61 0.42 0.59 0.38 0.713 9 18 CD4+2H (tot) *10 2.96 1.94 2.87 1.94 0.681 19 CD8+VV (%) 32.34 16.55 30.32 16.98 0.315 9 20 CD8+VV (abs)*10 /l 0.58 0.46 0.55 0.46 0.534 9 21 CD8+VV (tot) *10 2.89 2.30 2.63 2.13 0.324 22 CD4 (%) 44.00 16.28 44.01 15.95 0.997 23 CD4 (abs)*109/l 0.76 0.47 0.78 0.46 0.760 9 24 CD4 (tot) *10 3.76 2.33 3.78 2.38 0.944 25 CD8 (%) 14.80 8.87 13.46 7.79 0.163 9 26 CD8 (abs)*10 /l 0.25 0.20 0.25 0.20 0.968 27 CD8 (tot) *109 1.24 0.99 1.22 0.98 0.814 28 Lymphocytes (%) 30.98 11.23 33.07 11.43 0.121 9 29 Lymphocytes (abs)*10 /l 1.82 1.31 1.77 0.81 0.725 9 30 Lymphocytes (tot) *10 8.95 6.48 8.66 4.37 0.623 31 CD4/CD8 6.50 10.85 6.90 10.73 0.751 32 Index Thymus Function 1.08 0.59 0.99 0.40 0.090
  • 4. 4 The Open Lung Cancer Journal, 2008, Volume 1 Oleg Kshivets Table 2. Factors of T-, B- and K-Cell Circuit Between LCP and NMP in Terms of Diagnosis LCP st I-IV n=533 NMP n=282 NN Factors P Mean SD Mean SD 1 T-cells (%) 52.26 13.35 52.84 11.97 0.544 9 2 T-cells (abs)*10 /l 0.87 0.46 0.93 0.46 0.088 9 3 T-cells (tot)*10 4.18 2.35 4.50 2.56 0.071 4 B-cells (%) 17.89 7.74 16.46 6.46 0.009* 5 B-cells (abs)*109/l 0.32 0.25 0.29 0.14 0.064 9 6 B-cells (tot)*10 1.55 1.25 1.44 0.76 0.179 7 K-cells (%) 30.84 29.49 29.25 10.84 0.382 9 8 K-cells (abs)*10 /l 0.52 0.45 0.55 0.30 0.285 9 9 K-cells (tot)*10 2.49 2.28 2.71 1.66 0.157 10 CD1 (%) 8.74 9.72 8.11 8.96 0.368 9 11 CD1 (abs)*10 /l 0.15 0.20 0.15 0.20 0.954 9 12 CD1 (tot)*10 0.73 1.01 0.71 0.88 0.814 13 CDw26 (%) 6.05 6.94 6.20 6.50 0.762 9 14 CDw26 (abs)*10 /l 0.10 0.13 0.10 0.11 0.970 15 CDw26 (tot)*109 0.47 0.67 0.48 0.60 0.844 16 CD4+2H (%) 31.79 14.72 33.78 14.59 0.089 9 17 CD4+2H (abs)*10 /l 0.53 0.36 0.59 0.38 0.034* 9 18 CD4+2H (tot) *10 2.56 1.82 2.87 1.94 0.027* 19 CD8+VV (%) 30.60 17.44 30.32 16.98 0.827 20 CD8+VV (abs)*109/l 0.52 0.42 0.55 0.46 0.387 9 21 CD8+VV (tot) *10 2.51 2.09 2.63 2.13 0.429 22 CD4 (%) 42.31 16.32 44.01 15.95 0.156 9 23 CD4 (abs)*10 /l 0.71 0.44 0.78 0.46 0.055 24 CD4 (tot) *109 3.41 2.25 3.78 2.38 0.030* 25 CD8 (%) 12.93 7.93 13.46 7.79 0.356 9 26 CD8 (abs)*10 /l 0.22 0.17 0.25 0.20 0.015* 9 27 CD8 (tot) *10 1.05 0.81 1.22 0.98 0.012* 28 Lymphocytes (%) 28.04 11.12 33.07 11.43 0.000* 29 Lymphocytes (abs)*109/l 1.70 0.91 1.77 0.81 0.234 9 30 Lymphocytes (tot) *10 8.16 4.74 8.66 4.37 0.140 31 CD4/CD8 6.50 9.80 6.90 10.73 0.591 32 Index Thymus Function 1.01 0.48 0.99 0.40 0.090 (P=0.000) were decreased significantly in comparison with of IgM (r=0.09; P=0.012) and IgA (r=-0.13; P=0.000) (Ta- PNMP (n=282) (Tables 2, 4, 6 and 8). The Table 6 also bles 9 and 10, Fig. 2). shows that LCP with stage I-IV had strong evidence of de- The relationships between gender, age, weight, height creasing of IgM (P=0.012) and increasing of IgA (P=0.000). and ED/DS of the groups are summarized in Table 9. In addition, we found direct significant correlations between DS and 20 lab tests: the percent of B-cells (r=-0.09; All significant variables were also evaluated in a tradi- P=0.008) and lymphocytes (r=0.21; P=0.000), the count of tional multivariate logistic regression analysis. All parame- CD4+2H (r=0.07-0.08; P=0.034-0.27), CD4 (r=0.08; ters were analyzed in a logistic regression model in accor- P=0.030), CD8 (r=0.08-0.09; P=0.015-0.012), monocytes dance with Tables 1-10. In terms of ED it was revealed that (r=-0.07-0.14; P=0.045-0.000), leucocytes (r=-0.13-0.17; logistic regression model based on 9 lab tests (the percent, P=0.000), neutrophils (r=-0.09-0.22; P=0.010-0.000), titters absolute and total count of B-cells, monocytes, titter of IgM,
  • 5. Early Detection and Diagnosis of Lung Cancer and Immune Circuit The Open Lung Cancer Journal, 2008, Volume 1 5 Table 3. Factors of Monocyte and Macrophage Circuit Between LCP and NMP in Terms of Early Detection LCP st I-II n=95 NMP n=282 NN Factors P Mean SD Mean SD 1 Monocytes (%) 3.45 2.92 2.87 2.29 0.048* 9 2 Monocytes (abs)*10 /l 0.22 0.22 0.16 0.14 0.003* 3 Monocytes (tot) *109 1.08 1.10 0.76 0.70 0.001* 4 Phagocyte Index 21.84 14.64 23.05 15.89 0.512 5 Phagocyte Number 3.96 2.27 4.17 2.62 0.477 6 Index Complete Phagocytosis 1.09 0.59 1.01 0.50 0.187 Table 4. Factors of Monocyte and Macrophage Circuit Between LCP and NMP in Terms of Diagnosis LCP st I-IV n=533 NMP n=282 NN Factors P Mean SD Mean SD 1 Monocytes (%) 3.24 2.57 2.87 2.29 0.045* 2 Monocytes (abs)*109/l 0.21 0.21 0.16 0.14 0.000* 9 3 Monocytes (tot) *10 1.01 1.06 0.76 0.70 0.000* 4 Phagocyte Index 22.29 15.15 23.05 15.89 0.501 5 Phagocyte Number 4.14 2.46 4.17 2.62 0.860 6 Index Complete Phagocytosis 1.02 0.49 1.01 0.50 0.653 Table 5. Factors of Humoral Immunity Between LCP and NMP in Terms of Early Detection LCP st I-II n=95 NMP n=282 NN Factors P Mean SD Mean SD 1 IgG (g/l) 10.57 2.93 10.52 2.23 0.880 2 IgM (g/l) 1.56 0.51 1.72 0.62 0.021* 3 IgA (g/l) 2.38 0.94 2.26 0.85 0.206 4 Natural Antibodies 25.01 26.13 23.82 20.35 0.648 5 Circulating Immune Complexes 25.33 20.60 25.80 23.51 0.862 Table 6. Factors of Humoral Immunity Between LCP and NMP in Terms of Diagnosis LCP st I-IV n=533 NMP n=282 NN Factors P Mean SD Mean SD 1 IgG (g/l) 10.70 2.84 10.52 2.23 0.372 2 IgM (g/l) 1.61 0.58 1.72 0.62 0.012* 3 IgA (g/l) 2.52 1.02 2.26 0.85 0.000* 4 Natural Antibodies 27.31 26.54 23.82 20.35 0.055 5 Circulating Immune Complexes 24.47 19.36 25.80 23.51 0.388
  • 6. 6 The Open Lung Cancer Journal, 2008, Volume 1 Oleg Kshivets Table 7. Factors of Neutrophil Circuit Between LCP and NMP in Terms of Early Detection LCP st I-II n=95 NMP n=282 NN Factors P Mean SD Mean SD NST spontaneous 1 7.64 6.60 7.93 6.93 0.727 NST stimulated Staphylococcus aureus 2 8.49 9.34 8.55 8.60 0.955 NST stimulated Streptococcus 3 10.49 9.65 10.58 9.05 0.939 Pyogenes 4 Index Stimulation by Staphylococcus aureus 1.02 0.72 1.45 2.09 0.052 5 Index Stimulation by Streptococcus pyogenes 1.37 0.94 1.89 2.13 0.024* 9 6 Leukocytes (abs)*10 /l 5.88 2.47 5.47 1.85 0.086 7 Leukocytes (tot)*109 29.17 13.09 26.73 10.19 0.061 8 Stab Neutrophils (%) 1.06 1.31 0.97 1.58 0.598 9 9 Stab Neutrophils (abs)*10 /l 0.07 0.13 0.06 0.12 0.404 9 10 Stab Neutrophils (tot)*10 0.35 0.65 0.28 0.57 0.300 11 Segmented Neutrophils (%) 61.53 11.58 59.47 11.75 0.139 9 12 Segmented Neutrophils (abs)*10 /l 3.61 1.58 3.29 1.41 0.064 9 13 Segmented Neutrophils (tot)*10 17.92 8.46 16.06 7.28 0.040* Table 8. Factors of Neutrophil Circuit Between LCP and NMP in Terms of Diagnosis LCP st I-IV n=533 NMP n=282 NN Factors P Mean SD Mean SD NST spontaneous 1 8.65 8.49 7.93 6.93 0.217 NST stimulated Staphylococcus aureus 2 9.36 9.98 8.55 8.60 0.248 NST stimulated Streptococcus 3 11.13 9.46 10.58 9.05 0.425 Pyogenes 4 Index Stimulation by Staphylococcus aureus 1.35 1.51 1.45 2.09 0.441 5 Index Stimulation by Streptococcus pyogenes 1.76 1.72 1.89 2.13 0.365 9 6 Leukocytes (abs)*10 /l 6.31 2.48 5.47 1.85 0.000* 9 7 Leukocytes (tot)*10 30.09 12.52 26.73 10.19 0.000* 8 Stab Neutrophils (%) 1.27 1.57 0.97 1.58 0.010* 9 9 Stab Neutrophils (abs)*10 /l 0.09 0.18 0.06 0.12 0.003* 9 10 Stab Neutrophils (tot)*10 0.44 0.78 0.28 0.57 0.003* 11 Segmented Neutrophils (%) 64.23 11.48 59.47 11.75 0.000* 12 Segmented Neutrophils (abs)*109/l 4.10 1.88 3.29 1.41 0.000* 9 13 Segmented Neutrophils (tot)*10 19.49 9.06 16.06 7.28 0.000* index stimulation by Streptococcus pyogenes and the total and IgA) was significantly capable to diagnose LC with count of segmented neutrophils) significantly recognized stage T1-4N0-3M0-1 from NMP ( 2=108.075; Df=20; small LC with stage T1-2N0M0 from NMP ( 2=27.543; P=0.00000001; n=815) (Table 12). Df=9; P=0.001; n=377) (Table 11). Accordingly, the logistic All of these differences and discrepancies were further regression model based on 20 lab tests (the percent of B-cells investigated by SEPATH analysis (structural equation mod- and lymphocytes, the absolute and total count of CD4+2H, eling) and multi-factor clustering. The values are shown in CD8 and leukocytes, the total count of CD4, the percent, Tables 13 and 14. It was revealed that ED of LC with stage absolute and total count of monocytes, stab and segmented I-II (tumor size=2.5±0.1 cm; T1-2N0M0; n=95) from NMP neutrophils, (r=-0.09-0.22; P=0.010-0.000), the titters of IgM (n=282) significantly (P=0.000000) depended on: 1) level of
  • 7. Early Detection and Diagnosis of Lung Cancer and Immune Circuit The Open Lung Cancer Journal, 2008, Volume 1 7 Table 9. Correlations Between Early Detection (n=377) and Diagnosis of LC (n=815) and Factors (LCP---NMP) ED n=377 DS n=815 NN Factors r P r P 1 Gender 0.18 0.000* 0.27 0.000* 2 Age (years) -0.33 0.000* -0.34 0.000* 3 Weight (kg) -0.05 0.358 0.05 0.140 4 Height (cm) -0.13 0.010* -0.11 0.001* 5 T-cells (%) -0.03 0.590 0.02 0.544 9 6 T-cells (abs)*10 /l -0.00 0.942 0.06 0.080 9 7 T-cells (tot)*10 -0.02 0.660 0.06 0.071 8 B-cells (%) -0.12 0.024* -0.09 0.008* 9 9 B-cells (abs)*10 /l -0.16 0.001* -0.06 0.064 10 B-cells (tot)*109 -0.17 0.001* -0.05 0.179 11 K-cells (%) 0.09 0.068 -0.03 0.382 9 12 K-cells (abs)*10 /l 0.01 0.909 0.04 0.285 9 13 K-cells (tot)*10 0.01 0.803 0.05 0.157 14 CD1 (%) -0.05 0.333 -0.01 0.814 15 CD1 (abs)*109/l -0.05 0.372 -0.03 0.368 9 16 CD1 (tot)*10 -0.06 0.243 0.00 0.954 17 CDw26 (%) -0.01 0.893 0.01 0.762 9 18 CDw26 (abs)*10 /l -0.01 0.792 -0.00 0.970 19 CDw26 (tot)*109 -0.01 0.890 0.01 0.844 20 CD4+2H (%) -0.02 0.681 0.06 0.067 9 21 CD4+2H (abs)*10 /l -0.02 0.729 0.07 0.034* 22 CD4+2H (tot)*109 -0.02 0.713 0.08 0.027* 23 CD8+VV (%) -0.05 0.315 -0.01 0.826 9 24 CD8+VV (abs)*10 /l -0.03 0.534 0.03 0.367 25 CD8+VV (tot)*109 -0.05 0.324 0.03 0.429 26 CD4 (%) 0.00 0.944 0.05 0.156 9 27 CD4 (abs) *10 /l 0.00 0.997 0.07 0.055 9 28 CD4 (tot) *10 0.02 0.760 0.08 0.030* 29 CD8 (%) -0.07 0.163 0.03 0.356 30 CD8 (abs) *109/l -0.00 0.968 0.08 0.015* 31 CD8 (tot) *109 -0.01 0.814 0.09 0.012* 32 Lymphocytes (%) 0.08 0.121 0.21 0.000* 9 33 Lymphocytes (abs)*10 /l -0.02 0.725 0.04 0.234 9 34 Lymphocytes (tot) *10 -0.03 0.623 0.05 0.140 35 CD4/CD8 0.02 0.751 0.02 0.591 36 Index Thymus Function -0.09 0.090 -0.02 0.594 immune cell circuit ( 2=38749.1; Df=989); 2) value of Df=989); 2) macrophage circuit ( 2=312.1; Df=20); 3) hu- monocyte and macrophage circuit ( 2=662.8; Df=20); 3) moral factors ( 2=243.1; Df=9); 4) neutrophils circuit level of humoral immunity ( 2=585.9; Df=9); 4) neutrophils ( 2=10772.3; Df=77). Monte Carlo simulation confirmed circuit ( 2=5214.4; Df=77). It was also founded that DS of significant (P=0.000000) overall networks between ED and LC with stage I-IV (tumor size=5.4±0.1 cm; T1-4N0-3M0-1; DS of LC and the cell immunity circuit, the humoral immu- n=533) from NMP significantly (P=0.000000) depended on: nity data, macrophage and neutrophil circuit (Fig. 3). 1) value of immune cell subpopulations ( 2=80569.9;
  • 8. 8 The Open Lung Cancer Journal, 2008, Volume 1 Oleg Kshivets Table 10. Correlations Between Early Detection (n=377) and Diagnosis of LC (n=815) and Factors (LCP---NMP) ED n=377 DS n=815 NN Factors r P r P 37 Monocytes (%) -0.10 0.048* -0.07 0.045* 9 38 Monocytes (abs)*10 /l -0.15 0.003* -0.14 0.000* 39 Monocytes (tot)*109 -0.17 0.001* -0.13 0.000* 40 Phagocyte Index 0.03 0.512 0.02 0.501 41 Phagocytic Number 0.04 0.477 0.01 0.860 42 Index Complete Phagocytosis -0.07 0.187 -0.02 0.653 43 IgG (g/l) -0.01 0.880 -0.03 0.372 44 IgM (g/l) 0.12 0.021* 0.09 0.012* 45 IgA (g/l) -0.07 0.206 -0.13 0.000* 46 Natural Antibodies -0.02 0.648 -0.07 0.055 47 Circulating Immune Complexes (CIC) 0.01 0.862 0.03 0.388 48 NST spontaneous 0.02 0.727 -0.04 0.217 49 NST stimulated Staphylococcus aureus 0.00 0.955 -0.04 0.248 50 NST stimulated Streptococcus pyogenes 0.00 0.939 -0.03 0.425 51 Index Stimulation Staphylococcus aureus 0.10 0.052 0.03 0.447 52 Index Stimulation Streptococcus pyogenes 0.12 0.024* 0.03 0.365 9 53 Leukocytes (abs)*10 /l -0.09 0.086 -0.17 0.000* 9 54 Leukocytes (tot)*10 -0.10 0.062 -0.13 0.000* 55 Stab Neutrophils (%) -0.03 0.598 -0.09 0.010* 56 Stab Neutrophils (abs)*109/l -0.04 0.404 -0.10 0.003* 9 57 Stab Neutrophils (tot)*10 -0.05 0.300 -0.10 0.003* 58 Segmented Neutrophils (%) -0.08 0.139 -0.19 0.000* 9 59 Segmented Neutrophils (abs)*10 /l -0.10 0.064 -0.22 0.000* 60 Segmented Neutrophils (tot)*109 -0.11 0.040* -0.19 0.000* DISCUSSION 2. The clinical utility of some immune cell and humoral markers are feasible in ED and DS of LC and may be This study aimed to assess, in the large populations of defined, in general, moderate. LCP, the real diagnostic value of immune cell and humoral markers in comparison with the large population of PNMP. 3. At ED and DS of LC the complex of recognized im- The importance must be stressed of using complex system mune markers is better than any single factor. analysis, statistical and biometrical methods in combination, 4. Immune cell subpopulations and humoral factors because the different approaches yield complementary pieces communicate knotty with each other. of diagnostic information [1]. To explain such results we entertained the hypothesis that Its main findings can be summarized as follows: immune cell and humoral circuit regulate cancer dynamics 1. LCP even with the first and second stages had certain and participate in host defense mechanism against tumor. changes of immunological parameters and their rela- Disbalance and deficiency of immune cells and humoral fac- tionships, while these changes were detected even at tors as well as deregulation of their networks can lead to early LC when the effectiveness of the treatment tumor appearance and tumor progression. It is clear that process (5-year survival after complete resections) these relationships discrepancies in immune cell and hu- tends to be 80-100%. The data of immunological ho- moral circuit are remarkable tests for recognition LC. As meostasis of patients with an early LC significantly shown in our results, the number of immune markers tends differed from non-malignant pathology, that is ho- to be more frequently abnormal when the disease is ad- meostasis of a patient with the non-malignant pathol- vanced and this effect is enough for reaching a statistically ogy principally distinguished from the homeostasis of significant conclusion. In agreement with our findings, re- a patient with early LC. cent studies have demonstrated some defects and impaired
  • 9. Early Detection and Diagnosis of Lung Cancer and Immune Circuit The Open Lung Cancer Journal, 2008, Volume 1 9 Fig. (1). Significant networks between factors of immune cell and humoral circuit and early detection of LC (LCP with stage T1-2N0M0, n=95---PNMP, n=282). Fig. (2). Significant networks between factors of immune cell and humoral circuit and diagnosis of LC (LCP with stage T1-4N0-3M0-1, n=533---PNMP, n=282). effector function of T-cell subpopulations, K-cells, lym- from patients with various malignancies including LCP phokin-activated killer cells and monocytes/macrophages [1,13-18].
  • 10. 10 The Open Lung Cancer Journal, 2008, Volume 1 Oleg Kshivets Table 11. Results of Logistic Regression Modeling in Early Detection of LC (n=95) from NMP (n=282) 2 NN Significant Immune Factors: =27.543; Df=9; P=0.0011407; Estimate Const.B0 1.34429 1 B-cells (%) -0.01543 2 B-cells (abs)*109/l -3.80134 9 3 B-cells (tot)*10 0.45341 4 Monocytes (%) 0.00167 9 5 Monocytes (abs)*10 /l 2.36224 6 Monocytes (tot) *109 -0.70182 7 IgM (g/l) 0.44811 8 Index Stimulation by Streptococcus pyogenes 0.18113 9 9 Segmented Neutrophils (tot)*10 -0.01816 Table 12. Results of Logistic Regression Modeling in Diagnosis of LC (n=533) from NMP (n=282) 2 NN Significant Immune Factors: =108.075; Df=20; P=0.0000000; Estimate Const.B0 4.67194 1 B-cells (%) -0.02946 2 CD4+2H (abs)*109/l 3.17501 9 3 CD4+2H (tot) *10 -0.57679 9 4 CD4 (tot) *10 0.09542 9 5 CD8 (abs)*10 /l 3.60816 6 CD8 (tot) *109 -0.41372 7 Lymphocytes (%) -0.03025 8 Monocytes (%) 0.07468 9 9 Monocytes (abs)*10 /l -0.39635 10 Monocytes (tot) *109 -0.53516 11 IgM (g/l) 0.43660 12 IgA (g/l) -0.37333 9 13 Leukocytes (abs)*10 /l -1.40877 14 Leukocytes (tot)*109 0.22663 15 Stab Neutrophils (%) -0.08793 9 16 Stab Neutrophils (abs)*10 /l 3.97775 9 17 Stab Neutrophils (tot)*10 -0.64340 18 Segmented Neutrophils (%) -0.05288 9 19 Segmented Neutrophils (abs)*10 /l 1.09895 9 20 Segmented Neutrophils (tot)*10 -0.18262 The main conclusion that can be drown from the present immunity networks differed significantly in their capability results is that there were 4 basic hidden clusters of immunity to recognize early LC as well as advanced LC from NMP. networks between system “immune homeostasis—lung can- The rational for the investigation was that immunodiag- cer”: 1) the level of T-, B- and K-cell subpopulations circuit; nosis is likely to be reliable for separation of LCP including 2) the value of monocyte/macrophage circuit; 3) the level of stage I-II from NMP for surgery, and because these patients humoral immunity; 4) the value of neutrophil circuit. These would be expected to have the better outcome.
  • 11. Early Detection and Diagnosis of Lung Cancer and Immune Circuit The Open Lung Cancer Journal, 2008, Volume 1 11 Table 13. Results of Structural Equation Modeling and Monte Carlo Simulation in Early Detection of LC Stage I-II (n=95) from NMP (n=282) 2 NN Networks Df P 1 T-, B-, K-cells Circuit/Early Detection 38749.1 989 0.000000* 2 Monocyte-Macrophage Circuit/Early Detection 662.8 20 0.000000* 3 Humoral Immunity/Early Detection 585.9 9 0.000000* 4 Neutrophils Circuit/Early Detection 5214.4 77 0.000000* 5 T-, B-, K-cells Circuit/Monocyte-Macrophage Circuit 39424.6 1125 0.000000* 6 T-, B-, K-cells Circuit/Humoral Immunity 39080.3 1224 0.000000* 7 T-, B-, K-cells Circuit/Neutrophils Circuit 38381.3 1216 0.000000* 8 Monocyte-Macrophage Circuit/Humoral Immunity 160.9 54 0.000000* 9 Monocyte-Macrophage Circuit/Neutrophils Circuit 5831.0 170 0.000000* 10 Humoral Immunity/ Neutrophils Circuit 5161.8 134 0.000000* Table 14. Results of Structural Equation Modeling and Monte Carlo Simulation in Diagnosis of LC Stage I-IV (n=533) from NMP (n=282) 2 NN Networks Df P 1 T-, B-, K-cells Circuit/Diagnosis 80569.9 989 0.000000* 2 Monocyte-Macrophage Circuit/Diagnosis 312.1 20 0.000000* 3 Humoral Immunity/Diagnosis 243.1 9 0.000000* 4 Neutrophils Circuit/Diagnosis 10772.3 77 0.000000* 5 T-, B-, K-cells Circuit/Monocyte-Macrophage Circuit 82709.1 1125 0.000000* 6 T-, B-, K-cells Circuit/Humoral Immunity 81232.2 1224 0.000000* 7 T-, B-, K-cells Circuit/Neutrophils Circuit 78126.0 1216 0.000000* 8 Monocyte-Macrophage Circuit/Humoral Immunity 227.5 54 0.000000* 9 Monocyte-Macrophage Circuit/Neutrophils Circuit 2506.1 170 0.000000* 10 Humoral Immunity/ Neutrophils Circuit 10876.6 134 0.000000* Fig. (3). Significant networks between immune cell and humoral circuit and early detection and diagnosis of LC.
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