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Ratios of selected chemical element contents in prostatic tissue as markers of malignancy

Vladimir Zaichick

Radionuclide Diagnostics Department, Medical Radiological Research Centre, Koroleva Str-4, Obninsk-249036, Kaluga Region, Russia

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Sofia Zaichick

Department of Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA

DOI: 10.15761/HMO.1000109

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Abstract

The aim of the study was the development of new highly precise testing methods for early diagnosis of prostate cancer.  For this purpose, the values of Ca/Al, Ca/B, Ca/Ba, Ca/Mn, Mg/Al, Mg/B, Mg/Ba, Mg/Mn, S/Al, S/B, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios in normal (n=37), benign hypertrophic (n=32) and cancerous (n=60) human prostate gland were investigated using a combination of non-destructive and destructive methods: instrumental neutron activation analysis and inductively coupled plasma atomic emission spectrometry, respectively. Mean values ± standard error of mean (M ± SΕΜ) for mass fraction ratios in the normal tissue were as follows Ca/Al 103 ± 21, Ca/B 4320 ± 805, Ca/Ba 2957 ± 577, Ca/Mn 2061 ± 325, Mg/Al 36.1 ± 4.1, Mg/B 1599 ± 239, Mg/Ba 1086 ± 227, Mg/Mn 776 ± 70, S/Al 319 ± 31, S/B 14749 ± 2166, S/Ba 9640 ± 1968, S/Mn 6991 ± 379, Zn/Al 41.3 ± 9.7, Zn/B 1974 ± 559, Zn/Ba 1003 ± 195, and Zn/Mn 875 ± 214, respectively. It was observed that in benign hypertrophic tissues the Ca/B, Mg/B, and S/B mass fraction ratios are lower than normal levels while the Mg/Al and Mg/Mn ratio are significantly higher. In cancerous tissue the values of all ratios investigated were significantly lower than in normal and benign hypertrophic prostate. It was shown that the Ca/Ba, Ca/Mn, Mg/Al, Mg/Ba, Zn/Al, Zn/B, and Zn/Ba mass fraction ratios are the most informative for a differential diagnosis among all investigated mass fraction ratios. Finally, we propose to use the (Ca/Ba)∙(Mg/Al)∙(Zn/Mn) and (Ca/Ba)∙(Mg/Al)∙(S/B)∙(Zn/Mn) multiplications of mass fraction ratios in a needle-biopsy core as the most informative indicators for distinguishing malignant from benign prostate. Sensitivity, specificity, and accuracy of these tests were 100-9%, 100-2%, and 100-2%, respectively. Further studies on larger number of samples are required to confirm our findings, to study the impact of the chemical element contents on prostate cancer etiology and to examine the long-term pathological outcome.

Key words

chemical elements; chemical elemental mass fraction ratios; prostate; benign prostatic hypertrophy; prostatic carcinoma; neutron activation analysis; inductively coupled plasma atomic emission spectrometry

Introduction

The prostate gland may be a source of many health problems in men past middle age, the most common being benign prostatic hyperplasia (BPH), and prostatic carcinoma (PCa). BPH is a noncancerous enlargement of the prostate gland leading to obstruction of the urethra and can significantly impair quality of life [1]. The prevalence of histological BPH is found in approximately 50-60% of males age 40-50, in over 70% at 60 years old and in greater than 90% of men over 70 [2,3]. In many Western industrialized countries, including North America, PCa is the most frequently diagnosed form of noncutaneous malignancy in males and, except for lung cancer, is the leading cause of death from cancer [4-9]. Although the etiology of BPH and PCa is unknown, some electrolytes and trace elements have been highlighted in the literature in relation to the development of these prostate diseases [10-29].

Electrolytes and trace elements have essential physiological functions such as maintenance and regulation of cell function and signalling, gene regulation, activation or inhibition of enzymatic reactions, neurotransmission, and regulation of membrane function. Essential or toxic (mutagenic, carcinogenic) properties of chemical elements depend on tissue-specific need or tolerance, respectively [30]. Excessive accumulation, deficiency or an imbalance of the chemical elements may disturb the cell functions and may result in cellular degeneration, death, and malignant transformation [31].

In reported studies, significant changes of chemical element contents in hyperplastic and cancerous prostate in comparison with those in the normal prostatic tissue were observed [31-66]. Moreover, a significant informative value of Zn content as a tumor marker for PCa diagnostics was shown by us [67,68]. Hence it is possible that besides Zn, some other chemical elements also can be used as tumor markers for distinguish between benign and malignant prostate.

Current methods applied for measurement of chemical element contents in samples of human tissue include a number of methods. Among these methods the instrumental neutron activation analysis with high resolution spectrometry of short-lived radionuclides (INAA-SLR) is a non-destructive and one of the most sensitive techniques. It allows measure the chemical element contents in a few milligrams tissue without any treatment of sample that avoids the possibility of changing the content of chemical elements during a sample preparation [69-72]. However the INAA-SLR allow only determine the mean mass fractions of 6-7 chemical elements in the tissue samples of normal and cancerous prostate glands [15,21,28,65,66]. The inductively coupled plasma atomic emission spectrometry (ICP-AES) is a more power analytical tool than INAA-SLR [18,22,47] but sample digestion is a critical step in elemental analysis by this method. In our previous studies a combination of both analytical methods were offered for using when the results obtained for some chemical elements by ICP-AES were under the control of INAA-SLR data [47].

Analytical studies of the Al, B, Ba, Br, Ca, Cu, Fe, K, Li, Mg, Mn, Na, P, S, Si, Sr, and Zn contents in normal, BPH and PCa tissue were done by us using the combination of INAA-SLR and ICP-AES methods, which allowed for the first time to obtain reliable results [22]. In particular, it was shown that in PCa the mean values of Al, B, Ba, and Mn are higher while those of Ca Mg, S, and Zn are lower than in healthy and hyperplastic prostates [22,73-78]. Obtained results formed the basis for a new method for differential diagnosis of BPH and PCa, the essence of which was to determine the ratios of chemical element contents in the material of needle biopsy of prostate indurated site, because, in comparison with the absolute values of chemical element contents, using their content ratios is more suitable for diagnostics [79].  

The present study had three aims. The main objective was to obtain reliable results about the chemical element contents and calculate the values of Ca/Al, Ca/B, Ca/Ba, Ca/Mn, Mg/Al, Mg/B, Mg/Ba, Mg/Mn, S/Al, S/B, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios  in intact prostate of healthy men aged over 40 years and in the prostate gland of age-matched patients, who had either BPH or PCa combining in consecutive order non-destructive INAA-SLR with destructive ICP-AES. The second aim was to compare the levels of chemical element ratios in normal, hyperplastic, and cancerous prostate, and the third aim was to evaluate the levels of chemical element ratios for diagnosis of prostate cancer.

All studies were approved by the Ethical Committees of the Medical Radiological Research Centre, Obninsk.

Material and methods

Samples

The patients studied (n=92) were hospitalized in the Urological Department of the Medical Radiological Research Centre. All of them were European-Caucasian, citizens of Moscow and Obninsk (a small city in a non-industrial region 105 km south-west of Moscow). Transrectal puncture biopsy of suspicious indurated regions of the prostate was performed for every patient, to permit morphological study of prostatic tissue at these sites and to estimate their chemical element contents. In all cases the diagnosis has been confirmed by clinical and morphological results obtained during studies of biopsy and resected materials. The age of 32 patients with BPH ranged from 56 to 78 years, the mean being 66 ± 6 (M ± SD) years. The 60 patients aged 40-79 suffered from PCa (stage T1-T4). Their mean age was 65 ± 10 (M ± SD) years.

Intact (Norm) prostates were removed at necropsy from 37 men aged 41-87 who had died suddenly. All deceased were European-Caucasian, citizens of Moscow. Their mean age was 55 ± 11 (M ± SD) years. The majority of deaths were due to trauma. Tissue samples were collected from the peripheral zone of dorsal and lateral lobes of their prostates, within 2 days of death and then the samples were divided into two portions. One was used for morphological study while the other was intended for chemical element analysis. A histological examination was used to control the age norm conformity, as well as to confirm the absence of microadenomatosis and latent cancer [15,21,28].

Sample preparation

All tissue samples were divided into two portions. One was used for morphological study while the other was intended for chemical element analysis. After the samples intended for chemical element analysis were weighed, they were freeze-dried and homogenized. The sample weighing about 10 mg (for biopsy materials) and 50-100 mg (for resected materials) was used for chemical element measurement by INAA-SLR. The samples for INAA-SLR were sealed separately in thin polyethylene films washed beforehand with acetone and rectified alcohol. The sealed samples were placed in labelled polyethylene ampoules.

After NAA-SLR investigation the prostate samples were taken out from the polyethylene ampoules and used for ICP-AES. The samples were decomposed in autoclaves; 1.5 mL of concentrated HNO3 (nitric acid at 65%, maximum (max) of 0.0000005% Hg; GR, ISO, Merck) and 0.3 mL of H2O2 (pure for analysis) were added to prostate tissue samples, placed in one-chamber autoclaves (Ancon-AT2, Ltd., Russia) and then heated for 3 h at 160–200°C. After autoclaving, they were cooled to room temperature and solutions from the decomposed samples were diluted with deionized water (up to 20 mL) and transferred to plastic measuring bottles. Simultaneously, the same procedure was performed in autoclaves without tissue samples (only HNO3+H2O2+ deionized water), and the resultant solutions were used as control samples.

Instrumentation and methods

Information detailing with the NAA-SLR and ICP-AES methods used and other details of the analysis was presented in our previous publication [15,18,21,22,28,47,65,66].

Certified reference materials

For quality control, ten subsamples of the certified reference materials IAEA H-4 Animal muscle from the International Atomic Energy Agency (IAEA), and also five sub-samples INCT-SBF-4 Soya Bean Flour, INCT-TL-1 Tea Leaves and INCT-MPH-2 Mixed Polish Herbs from the Institute of Nuclear Chemistry and Technology (INCT, Warszawa, Poland) were analyzed simultaneously with the investigated prostate tissue samples. All samples of CRM were treated in the same way as the prostate tissue samples. Detailed results of this quality assurance program were presented in earlier publications [18,22,47].

Computer programs and statistic

A dedicated computer program for INAA mode optimization was used [80]. All prostate samples for INAA-SLR were prepared in duplicate and mean values of chemical element contents were used in final calculation. For elements investigated by INAA-SLR and ICP-AES the mean of all results was used. Using the Microsoft Office Excel software, the summary of statistics, arithmetic mean, standard deviation, standard error of mean, minimum and maximum values, median, percentiles with 0.025 and 0.975 levels was calculated for Ca/Al, Ca/B, Ca/Ba, Ca/Mn, Mg/Al, Mg/B, Mg/Ba, Mg/Mn, S/Al, S/B, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios in normal, benign hyperplastic and cancerous prostate tissue. The difference in the results between BPH and Norm, PCa and Norm, and PCA and BPH was evaluated by parametric Student’s t-test and nonparametric Wilcoxon-Mann-Whitney U-test. For the construction of “individual data sets for ratios of chemical element mass fraction or multiplications of selected ratios in normal, benign hypertrophic and cancerous prostate” diagrams the Microsoft Office Excel software was also used.

Results

Table 1 depicts certain statistical parameters (arithmetic mean, standard deviation, standard error of mean, minimal and maximal values, median, percentiles with 0.025 and 0.975 levels) of the Ca/Al, Ca/B, Ca/Ba, Ca/Mn, Mg/Al, Mg/B, Mg/Ba, Mg/Mn, S/Al, S/B, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios in normal, benign hypertrophic and cancerous prostate.

The ratios of means and the difference between mean values of Ca/Al, Ca/B, Ca/Ba, Ca/Mn, Mg/Al, Mg/B, Mg/Ba, Mg/Mn, S/Al, S/B, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios in normal, benign hypertrophic and cancerous prostate are presented in Table 2.

Table 3 contains parameters of the importance (sensitivity, specificity and accuracy) of Al, B, Ba, Ca, Mg, Mn, S, and Zn mass fraction for the diagnosis of PCa calculated in this work.

Figures 1-4 and 5 depict individual data sets for Ca/Al, Ca/B, Ca/Ba, Ca/Mn, Mg/Al, Mg/B, Mg/Ba, Mg/Mn, S/Al, S/B, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios as well as for (Ca/Ba)∙(Mg/Al)∙(Zn/Mn) and (Ca/Ba)∙(Mg/Al)∙(S/B)∙(Zn/Mn) multiplications of mass fraction ratios in all samples of normal, benign hypertrophic and cancerous prostate, respectively.

Discussion

As was shown by us [18,22,47] the use of CRM IAEA H-4, INCT-SBF-4 Soya Bean Flour, INCT-TL-1 Tea Leaves, and INCT-MPH-2 Mixed Polish Herbs as certified reference materials for the analysis of samples of prostate tissue can be seen as quite acceptable. Good agreement of the Al, B, Ba, Ca, Mg, Mn, S, and Zn contents analyzed by INAA-SLR and ICP-AES with the certified data of reference materials indicated an acceptable accuracy of the results obtained in the study and presented in Tables 1and 2.

The mean values and all selected statistical parameters were calculated for sixteen mass fraction ratios: Ca/Al, Ca/B, Ca/Ba, Ca/Mn, Mg/Al, Mg/B, Mg/Ba, Mg/Mn, S/Al, S/B, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn (Table 1). The mass fraction of these chemical elements were measured in all, or a major portion of normal prostate samples. The masses of BPH and PCa samples varied very strong from a few milligrams (sample from needle biopsy material) to 100 mg (sample from resected material). Therefore, in BPH and PCa prostates mass fractions of Zn were measured in all samples, while mass fractions of other chemical elements were determined in 22 samples (11 BPH and 11 PCa samples, respectively). Thus, the Ca/Al, Ca/B, Ca/Ba, Ca/Mn, Mg/Al, Mg/B, Mg/Ba, Mg/Mn, S/Al, S/B, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios were calculated in all, or a major portion of normal prostates, and only in 22 hyperplastic and  cancerous prostates.

The results presented in Table 1 showed substantial differences between the arithmetic means and the medians, which impeached a normal distribution of the investigated elemental content ratios. These findings were a motive for us to compare the means of mass fraction ratios in normal, BPH and PCa prostate using parametric Student’s t-test and nonparametric Wilcoxon-Mann-Whitney U-test. No published data referring to mass fraction ratios of chemical elements in the human prostate was found.

Table 1. Some statistical parameters of Ca/Al, Ca/B, Ca/Ba, Ca/Mn, Mg/Al, Mg/B, Mg/Ba, Mg/Mn, S/Al, S/B, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios in normal, benign hyperplastic (BPH), and cancerous (PCa) prostate. M-arithmetic mean; SD-standard deviation; SEM–standard error of mean; Min-minimum value; Max–maximum value; Per. 0.025–percentile with 0.025 level; Per. 0.975–percentile with 0.975 level.

Tissue

Ratio

Mean

SD

SEM

Min

Max

Median

Per.0.025

Per.0.975

Normal n = 25

Ca/Al

103

101

21

18.0

507

69.2

19.9

329

Ca/B

4320

3778

805

421

16360

3127

447

12941

Ca/Ba

2957

2705

577

503

10895

2119

620

9324

Ca/Mn

2061

1557

325

787

7659

1669

808

6380

Mg/Al

36.1

20.3

4.1

9.00

83.2

32.9

9.14

75.3

Mg/B

1599

1147

239

262

3777

1340

293

3762

Mg/Ba

1086

1090

227

213

4355

712

290

4213

Mg/Mn

776

344

70

405

1638

681

417

1615

S/Al

319

157

31

110

806

302

111

676

S/B

14749

10389

2166

2882

31840

11739

2903

31608

S/Ba

9640

9438

1968

2065

46175

6967

2694

33980

S/Mn

6991

1857

379

3298

10203

7047

4164

10178

Zn/Al

41.3

48.4

9.7

3.84

234

30.9

6.18

169

Zn/B

1974

2682

559

220

12225

1174

258

8801

Zn/Ba

1003

933

195

117

3918

581

191

3393

Zn/Mn

875

1050

214

177

5335

585

203

3347

BPH n = 11

Ca/Al

101

57

18

46.2

221

73.3

46.5

208

Ca/B

1550

572

191

365

2302

1696

487

2221

Ca/Ba

2034

832

251

796

3111

1915

823

3040

Ca/Mn

1789

616

186

973

2982

1691

987

2829

Mg/Al

58.8

28.4

9.0

27.2

127

51.2

29.3

117

Mg/B

928

413

138

215

1453

971

282

1436

Mg/Ba

1258

657

198

403

2421

1034

4792

2377

Mg/Mn

1077

377

114

520

1710

1148

533

1665

S/Al

431

214

68

227

939

345

237

854

S/B

6694

3038

1013

2638

12977

6908

2820

12004

S/Ba

9418

5273

1590

3487

21629

8361

3710

19680

S/Mn

7735

1965

592

4507

11355

7276

4732

10913

Zn/Al

59.0

31.0

9.8

12.9

109

53.4

16.3

107

Zn/B

1360

1250

417

102

4432

1130

216

3902

Zn/Ba

1373

674

203

534

2266

1251

534

2234

Zn/Mn

1261

615

185

272

2462

1479

383

2292

PCa n = 11

Ca/Al

5.24

6.51

1.96

0.982

19.3

1.63

1.03

17.7

Ca/B

119

183

58

17.4

635

62.3

22.1

515

Ca/Ba

102

157

47

8.27

422

38.6

8.80

420

Ca/Mn

181

218

66

44.9

772

91.0

46.7

670

Mg/Al

2.78

3.33

1.05

0.277

8.75

0.852

0.313

8.47

Mg/B

70.1

132

44.2

8.35

421

31.6

9.08

346

Mg/Ba

67.5

105

33.4

5.99

275

12.4

6.02

269

Mg/Mn

107

133

42

9.07

458

74.1

10.2

389

S/Al

37.0

39.9

12.0

7.52

119

15.2

7.66

112

S/B

903

1298

410

167

4519

457

184

3752

S/Ba

850

1324

399

84.3

3957

190

85.7

3704

S/Mn

1476

1966

593

264

7241

1116

301

5834

Zn/Al

1.16

1.73

0.52

0.119

4.53

0.231

0.126

4.48

Zn/B

28.8

66.5

21.0

2.73

218

9.16

3.13

172

Zn/Ba

29.5

56.5

17.0

1.26

145

3.51

1.28

144

Zn/Mn

42.8

76.9

23.2

4.87

265

13.9

5.37

218

From Table 2, it is observed that in benign hypertrophic tissues the Ca/Al, Ca/Ba, Ca/Mn, Mg/Ba, S/Al, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios do not differ from normal levels while the Mg/Al and Mg/Mn ratios are higher and Ca/B, Mg/B, and S/B ratios are lower. In cancerous tissue all ratios of chemical element mass fractions investigated were significantly lower than in normal parenchyma of the prostate. All these mass fraction ratios show similar variations in cancerous tissues when compared with benign hypertrophic tissues of the prostate.

Table 2. Ratio of means and the difference between mean values of Ca/Al, Ca/B, Ca/Ba, Ca/Mn, Mg/Al, Mg/B, Mg/Ba, Mg/Mn, S/Al, S/B, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios in normal, benign hypertrophic and cancerous prostate. t-test-Student’s t-test, U-test-Wilcoxon-Mann-Whitney U-test, Bold significant differences.

Mass fraction

ratio

BPH and Normal (N)

PCa and Normal (N)

PCa and BPH

Ratio

BPH/N 

p

t-test

p

U-test

Ratio

PCa/N

p

t-test

p

U-test

Ratio

PCa/BPH

p

t-test

p

U-test

Ca/Al

0.98

 = 0.94

 > 0.05

0.051

 < 0.00047

0.01

0.052

 < 0.00009

0.01

Ca/B

0.36

 < 0.003

0.01

0.028

 < 0.00004

0.01

0.077

 < 0.00004

0.01

Ca/Ba

0.69

 = 0.15

 > 0.05

0.034

 < 0.00002

0.01

0.050

 < 0.00007

0.01

Ca/Mn

0.87

 = 0.47

 > 0.05

0.088

 < 0.00001

0.01

0.101

 < 0.00001

0.01

Mg/Al

1.63

 = 0.039

 > 0.05

0.077

 < 0.00015

0.01

0.047

 < 0.00001

0.01

Mg/B

0.58

 = 0.021

0.05

0.044

 < 0.00017

0.01

0.076

 < 0.00001

0.01

Mg/Ba

1.16

 = 0.57

 > 0.05

0.062

 < 0.00012

0.01

0.054

 < 0.00019

0.01

Mg/Mn

1.39

 = 0.037

 > 0.05

0.138

 < 0.00001

0.01

0.099

 < 0.00001

0.01

S/Al

1.35

 = 0.15

 > 0.05

0.116

 < 0.00023

0.01

0.086

 < 0.00001

0.01

S/B

0.45

 < 0.003

0.01

0.061

 < 0.00029

0.01

0.135

 < 0.00001

0.01

S/Ba

0.98

 = 0.93

 > 0.05

0.088

 < 0.00026

0.01

0.090

 < 0.00021

0.01

S/Mn

1.11

 = 0.30

 > 0.05

0.211

 < 0.00001

0.01

0.191

 < 0.00001

0.01

Zn/Al

1.43

 = 0.21

 > 0.05

0.028

 < 0.00023

0.01

0.020

 < 0.00037

0.01

Zn/B

0.69

 = 0.39

 > 0.05

0.015

 < 0.013

0.01

0.021

 < 0.0022

0.01

Zn/Ba

1.37

 = 0.20

 > 0.05

0.029

 < 0.00006

0.01

0.021

 < 0.00006

0.01

Zn/Mn

1.44

 = 0.18

 > 0.05

0.049

 < 0.00006

0.01

0.034

 < 0.00077

0.01

Analysis of elemental content ratios in prostate tissue could become a powerful diagnostic tool. To a large extent, the resumption of the search for new methods for early diagnosis of PCa was due to experience gained in a critical assessment of the limited capacity of the prostate specific antigen (PSA) serum test [81,82]. In addition to the PSA serum test and morphological study of needle-biopsy cores of the prostate, the development of other highly precise testing methods seems to be very useful. Experimental conditions of the present study were approximated to the hospital conditions as closely as possible. In all cases we analyzed a part of the material obtained from a biopsy of the indurated site in the prostate. Therefore, our data allow us to evaluate adequately the importance of elemental content ratios for the diagnosis of PCa. As is evident from individual data sets (Figures 1-4) and Table 3, the values of all mass fraction ratios are very informative for a differential diagnosis. For example, if 450 is the value of Ca/Ba mass fraction ratio assumed to be the upper limit for PCa (Figure 1 and Table 3) and an estimation is made for “PCa or intact and BPH tissue”, the following values was obtained:

Sensitivity = {True Positives (TP)/ [TP + False Negatives (FN)]}·100% = (100-9)%;

Specificity = {True Negatives (TN)/ [TN + False Positives (FP)]}·100% = (100-3)%;

Accuracy = [(TP+TN)/(TP+FP+TN+FN)] ·100% = (100-2)%.

Figure 1. Individual data sets for Ca/Al, Ca/B, Ca/Ba, and Ca/Mn mass fraction ratios in samples of normal (1) benign hypertrophic (2) and cancerous (3) prostate.

Figure 2. . Individual data sets for Mg/Al, Mg/B, Mg/Ba, and Mg/Mn mass fraction ratios in samples of normal (1) benign hypertrophic (2) and cancerous (3) prostate.

Figure 3. Individual data sets for S/Al, S/B, S/Ba, and S/Mn mass fraction ratios in samples of normal (1) benign hypertrophic (2) and cancerous (3) prostate.

Figure 4. Individual data sets for Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios in samples of normal (1) benign hypertrophic (2) and cancerous (3) prostate.

The number of prostates investigated was taken into account for calculation of confidence intervals [83].  In other words, if Ca/Ba mass fraction ratio in a prostate biopsy sample does not higher 450, one could diagnose a malignant tumor with an accuracy of (100-2)%. Thus, using the (Ca/Ba)-test makes it possible to diagnose cancer in (100-9)% cases (sensitivity).

It should be noted, that all ratios of chemical element mass fraction investigated in the study are very informative for the diagnosis of PCa and these tests have good levels of sensitivity, specificity and accuracy varied in ranges 89%-100%, 86%-100%, and 89%-100%, respectively (Table 3). However, it is possible to increase a separation distance between the value of “Upper limit” for PCa and the lowest values among normal and BPH results if use a combination of the selected ratios. For example, for this purpose a multiplication of (Ca/Ba)∙(Mg/Al)∙(Zn/Mn) or (Ca/Ba)∙(Mg/Al)∙(S/B)∙(Zn/Mn) can be used. If the level 130000 was accepted as the “Upper limit” of (Ca/Ba)∙(Mg/Al)∙(S/B)∙(Zn/Mn) test for the diagnosis of PCa (Figure 5), the sensitivity, specificity and accuracy of this test are 100-9%, 100-3%, and 100-2%, respectively and the lowest value in normal and BPH prostate  is almost 30 time higher the highest value in cancerous prostate.

Figure 5. Individual data sets for (Ca/Ba)∙(Mg/Al)∙(Zn/Mn) and (Ca/Ba)∙(Mg/Al)∙(S/B)∙(Zn/Mn) test in samples of normal (1) benign hypertrophic (2) and cancerous (3) prostate.

Table 3. Parameters of the importance (sensitivity, specificity and accuracy) of Ca/Al, Ca/B, Ca/Ba, Ca/Mn, Mg/Al, Mg/B, Mg/Ba, Mg/Mn, S/Al, S/B, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios for the diagnosis of PCa (an estimation is made for “PCa or normal and BPH prostate”). M-arithmetic mean, SD-standard deviation.

Mass fraction ratio

or their multiplication

Upper limit for PCa

 

Sensitivity

%

Specificity

%

Accuracy 

%

Ca/Al

17

91 ± 9

97 ± 3

96 ± 3

Ca/B

300

90 ± 10

91 ± 5

90 ± 5

Ca/Ba

450

100-9

100-3

100-2

Ca/Mn

780

100-9

100-3

100-2

Mg/Al

8.8

100-10

100-3

100-2

Mg/B

200

89 ± 11

86 ± 6

89 ± 5

Mg/Ba

280

100-10

97 ± 3

98 ± 2

Mg/Mn

370

90 ± 10

100-3

100-2

S/Al

100

91 ± 9

100-3

98 ± 2

S/B

2500

89 ± 11

100-3

98 ± 2

S/Ba

2950

91 ± 9

97 ± 3

96 ± 3

S/Mn

3200

91 ± 9

100-3

98 ± 2

Zn/Al

4.6

100-9

97 ± 3

98 ± 2

Zn/B

220

100-10

97 ± 3

98 ± 2

Zn/Ba

150

100-9

97 ± 3

98 ± 2

Zn/Mn

170

91 ± 9

100-3

98 ± 2

(Ca/Ba)∙(Mg/Al)∙(Zn/Mn)

100000

100-9

100-3

100-2

(Ca/Ba)∙(Mg/Al)∙(S/B)∙(Zn/Mn)

130000

100-9

100-3

100-2

Mass fraction ratios of Ca/Al, Ca/Ba, Ca/Mn, Mg/Ba, S/Al, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba,  and Zn/Mn in the needle-biopsy cores could be used as a tool to diagnose PCa and are comparable with characteristics of the Zn mass fraction-test [67,68]. However, it is our opinion that application of the elemental content ratios is more suitable for PCa diagnosis. Elemental mass fraction depends on the sample mass, which decreases with loss of its moisture. The needle-biopsy core is a small piece of tissue with a relatively high "surface/volume" ratio. After sampling, it begins to lose mass very fast. Weight loss of samples depends on the humidity of operating and store rooms [69]. Thus, it is very difficult to determine the fresh mass of needle-biopsy cores and to calculate the precise mass fraction of chemical elements. Sample freeze-dry, storage in air-tight vials until weighing, and then calculating mass fraction on dry mass basis is the only possible method that eliminates the variation in sample mass. Conversely, accuracy of elemental content ratios does not depend on sample mass and changes in moisture content. Therefore, this method does not require dry samples. Moreover, the use of the relations between mass fractions of chemical elements is particularly promising for the development of in vivo diagnostic methods, including the diagnosis of PCa.

Conclusion

The combination of nondestructive INAA-SLR and destructive ICP-AES methods is satisfactory analytical tool for the precise determination of chemical element mass fractions and their ratios in the tissue samples of normal, BPH and carcinomatous prostate glands. In this work, mean values of Ca/Al, Ca/Ba, Ca/Mn, Mg/Ba, S/Al, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios in normal, benign hyperplastic and cancerous prostate were calculated using data of INAA-SLR and ICP-AES. It was observed that in benign hyperplastic prostate the Ca/Al, Ca/Ba, Ca/Mn, Mg/Ba, S/Al, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios do not differ from normal levels while the Mg/Al and Mg/Mn ratios are higher and Ca/B, Mg/B, and S/B ratios are lower. In cancerous prostate the Ca/Al, Ca/Ba, Ca/Mn, Mg/Ba, S/Al, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios are significantly lower than in normal and benign hyperplastic prostate. It was shown that all ratios of chemical element mass fractions investigated in the study are informative for the prostate cancer diagnosis. Finally, we propose to use the estimation of selected elemental mass fraction ratios and some theirs multiplications in a needle-biopsy core as an accurate tool to diagnose prostate cancer. Further studies on larger number of samples are required to confirm our findings, to study the impact of the elemental mass fraction ratios in gland tissue on prostate cancer etiology and to examine the long-term pathological outcome.

Acknowledgements

We are grateful to Dr. Tatyana Sviridova, Medical Radiological Research Center, Obninsk, and to the late Prof. A.A. Zhavoronkov, Institute of Human Morphology, Russian Academy of Medical Sciences, Moscow, for supplying prostate samples. We are also grateful to Dr. Karandaschev V., Dr. Nosenko S., and Moskvina I., Institute of Microelectronics Technology and High Purity Materials, Chernogolovka, Russia, for their help in ICP-AES analysis.

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Editorial Information

Editor-in-Chief

Ciro Rinaldi
University Federico II Naples

Article Type

Research Article

Publication history

Received date: October 13, 2016
Accepted date: November 23, 2016
Published date: November 26, 2016

Copyright

© 2016 Zaichick V. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Zaichick V, Zaichick S (2016). Ratios of selected chemical element contents in prostatic tissue as markers of malignancy. Hematol Med Oncol 1: DOI: 10.15761/HMO.1000109.

Corresponding author

Vladimir Zaichick

Radionuclide Diagnostics Department, Medical Radiological Research Centre, Koroleva Str-4, Obninsk-249036, Kaluga Region, Russia

Figure 1. Individual data sets for Ca/Al, Ca/B, Ca/Ba, and Ca/Mn mass fraction ratios in samples of normal (1) benign hypertrophic (2) and cancerous (3) prostate.

Figure 2. . Individual data sets for Mg/Al, Mg/B, Mg/Ba, and Mg/Mn mass fraction ratios in samples of normal (1) benign hypertrophic (2) and cancerous (3) prostate.

Figure 3. Individual data sets for S/Al, S/B, S/Ba, and S/Mn mass fraction ratios in samples of normal (1) benign hypertrophic (2) and cancerous (3) prostate.

Figure 4. Individual data sets for Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios in samples of normal (1) benign hypertrophic (2) and cancerous (3) prostate.

Figure 5. Individual data sets for (Ca/Ba)∙(Mg/Al)∙(Zn/Mn) and (Ca/Ba)∙(Mg/Al)∙(S/B)∙(Zn/Mn) test in samples of normal (1) benign hypertrophic (2) and cancerous (3) prostate.

Table 1. Some statistical parameters of Ca/Al, Ca/B, Ca/Ba, Ca/Mn, Mg/Al, Mg/B, Mg/Ba, Mg/Mn, S/Al, S/B, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios in normal, benign hyperplastic (BPH), and cancerous (PCa) prostate. M-arithmetic mean; SD-standard deviation; SEM–standard error of mean; Min-minimum value; Max–maximum value; Per. 0.025–percentile with 0.025 level; Per. 0.975–percentile with 0.975 level.

Tissue

Ratio

Mean

SD

SEM

Min

Max

Median

Per.0.025

Per.0.975

Normal n = 25

Ca/Al

103

101

21

18.0

507

69.2

19.9

329

Ca/B

4320

3778

805

421

16360

3127

447

12941

Ca/Ba

2957

2705

577

503

10895

2119

620

9324

Ca/Mn

2061

1557

325

787

7659

1669

808

6380

Mg/Al

36.1

20.3

4.1

9.00

83.2

32.9

9.14

75.3

Mg/B

1599

1147

239

262

3777

1340

293

3762

Mg/Ba

1086

1090

227

213

4355

712

290

4213

Mg/Mn

776

344

70

405

1638

681

417

1615

S/Al

319

157

31

110

806

302

111

676

S/B

14749

10389

2166

2882

31840

11739

2903

31608

S/Ba

9640

9438

1968

2065

46175

6967

2694

33980

S/Mn

6991

1857

379

3298

10203

7047

4164

10178

Zn/Al

41.3

48.4

9.7

3.84

234

30.9

6.18

169

Zn/B

1974

2682

559

220

12225

1174

258

8801

Zn/Ba

1003

933

195

117

3918

581

191

3393

Zn/Mn

875

1050

214

177

5335

585

203

3347

BPH n = 11

Ca/Al

101

57

18

46.2

221

73.3

46.5

208

Ca/B

1550

572

191

365

2302

1696

487

2221

Ca/Ba

2034

832

251

796

3111

1915

823

3040

Ca/Mn

1789

616

186

973

2982

1691

987

2829

Mg/Al

58.8

28.4

9.0

27.2

127

51.2

29.3

117

Mg/B

928

413

138

215

1453

971

282

1436

Mg/Ba

1258

657

198

403

2421

1034

4792

2377

Mg/Mn

1077

377

114

520

1710

1148

533

1665

S/Al

431

214

68

227

939

345

237

854

S/B

6694

3038

1013

2638

12977

6908

2820

12004

S/Ba

9418

5273

1590

3487

21629

8361

3710

19680

S/Mn

7735

1965

592

4507

11355

7276

4732

10913

Zn/Al

59.0

31.0

9.8

12.9

109

53.4

16.3

107

Zn/B

1360

1250

417

102

4432

1130

216

3902

Zn/Ba

1373

674

203

534

2266

1251

534

2234

Zn/Mn

1261

615

185

272

2462

1479

383

2292

PCa n = 11

Ca/Al

5.24

6.51

1.96

0.982

19.3

1.63

1.03

17.7

Ca/B

119

183

58

17.4

635

62.3

22.1

515

Ca/Ba

102

157

47

8.27

422

38.6

8.80

420

Ca/Mn

181

218

66

44.9

772

91.0

46.7

670

Mg/Al

2.78

3.33

1.05

0.277

8.75

0.852

0.313

8.47

Mg/B

70.1

132

44.2

8.35

421

31.6

9.08

346

Mg/Ba

67.5

105

33.4

5.99

275

12.4

6.02

269

Mg/Mn

107

133

42

9.07

458

74.1

10.2

389

S/Al

37.0

39.9

12.0

7.52

119

15.2

7.66

112

S/B

903

1298

410

167

4519

457

184

3752

S/Ba

850

1324

399

84.3

3957

190

85.7

3704

S/Mn

1476

1966

593

264

7241

1116

301

5834

Zn/Al

1.16

1.73

0.52

0.119

4.53

0.231

0.126

4.48

Zn/B

28.8

66.5

21.0

2.73

218

9.16

3.13

172

Zn/Ba

29.5

56.5

17.0

1.26

145

3.51

1.28

144

Zn/Mn

42.8

76.9

23.2

4.87

265

13.9

5.37

218

Table 2. Ratio of means and the difference between mean values of Ca/Al, Ca/B, Ca/Ba, Ca/Mn, Mg/Al, Mg/B, Mg/Ba, Mg/Mn, S/Al, S/B, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios in normal, benign hypertrophic and cancerous prostate. t-test-Student’s t-test, U-test-Wilcoxon-Mann-Whitney U-test, Bold significant differences.

Mass fraction

ratio

BPH and Normal (N)

PCa and Normal (N)

PCa and BPH

Ratio

BPH/N 

p

t-test

p

U-test

Ratio

PCa/N

p

t-test

p

U-test

Ratio

PCa/BPH

p

t-test

p

U-test

Ca/Al

0.98

 = 0.94

 > 0.05

0.051

 < 0.00047

0.01

0.052

 < 0.00009

0.01

Ca/B

0.36

 < 0.003

0.01

0.028

 < 0.00004

0.01

0.077

 < 0.00004

0.01

Ca/Ba

0.69

 = 0.15

 > 0.05

0.034

 < 0.00002

0.01

0.050

 < 0.00007

0.01

Ca/Mn

0.87

 = 0.47

 > 0.05

0.088

 < 0.00001

0.01

0.101

 < 0.00001

0.01

Mg/Al

1.63

 = 0.039

 > 0.05

0.077

 < 0.00015

0.01

0.047

 < 0.00001

0.01

Mg/B

0.58

 = 0.021

0.05

0.044

 < 0.00017

0.01

0.076

 < 0.00001

0.01

Mg/Ba

1.16

 = 0.57

 > 0.05

0.062

 < 0.00012

0.01

0.054

 < 0.00019

0.01

Mg/Mn

1.39

 = 0.037

 > 0.05

0.138

 < 0.00001

0.01

0.099

 < 0.00001

0.01

S/Al

1.35

 = 0.15

 > 0.05

0.116

 < 0.00023

0.01

0.086

 < 0.00001

0.01

S/B

0.45

 < 0.003

0.01

0.061

 < 0.00029

0.01

0.135

 < 0.00001

0.01

S/Ba

0.98

 = 0.93

 > 0.05

0.088

 < 0.00026

0.01

0.090

 < 0.00021

0.01

S/Mn

1.11

 = 0.30

 > 0.05

0.211

 < 0.00001

0.01

0.191

 < 0.00001

0.01

Zn/Al

1.43

 = 0.21

 > 0.05

0.028

 < 0.00023

0.01

0.020

 < 0.00037

0.01

Zn/B

0.69

 = 0.39

 > 0.05

0.015

 < 0.013

0.01

0.021

 < 0.0022

0.01

Zn/Ba

1.37

 = 0.20

 > 0.05

0.029

 < 0.00006

0.01

0.021

 < 0.00006

0.01

Zn/Mn

1.44

 = 0.18

 > 0.05

0.049

 < 0.00006

0.01

0.034

 < 0.00077

0.01

Table 3. Parameters of the importance (sensitivity, specificity and accuracy) of Ca/Al, Ca/B, Ca/Ba, Ca/Mn, Mg/Al, Mg/B, Mg/Ba, Mg/Mn, S/Al, S/B, S/Ba, S/Mn, Zn/Al, Zn/B, Zn/Ba, and Zn/Mn mass fraction ratios for the diagnosis of PCa (an estimation is made for “PCa or normal and BPH prostate”). M-arithmetic mean, SD-standard deviation.

Mass fraction ratio

or their multiplication

Upper limit for PCa

 

Sensitivity

%

Specificity

%

Accuracy 

%

Ca/Al

17

91 ± 9

97 ± 3

96 ± 3

Ca/B

300

90 ± 10

91 ± 5

90 ± 5

Ca/Ba

450

100-9

100-3

100-2

Ca/Mn

780

100-9

100-3

100-2

Mg/Al

8.8

100-10

100-3

100-2

Mg/B

200

89 ± 11

86 ± 6

89 ± 5

Mg/Ba

280

100-10

97 ± 3

98 ± 2

Mg/Mn

370

90 ± 10

100-3

100-2

S/Al

100

91 ± 9

100-3

98 ± 2

S/B

2500

89 ± 11

100-3

98 ± 2

S/Ba

2950

91 ± 9

97 ± 3

96 ± 3

S/Mn

3200

91 ± 9

100-3

98 ± 2

Zn/Al

4.6

100-9

97 ± 3

98 ± 2

Zn/B

220

100-10

97 ± 3

98 ± 2

Zn/Ba

150

100-9

97 ± 3

98 ± 2

Zn/Mn

170

91 ± 9

100-3

98 ± 2

(Ca/Ba)∙(Mg/Al)∙(Zn/Mn)

100000

100-9

100-3

100-2

(Ca/Ba)∙(Mg/Al)∙(S/B)∙(Zn/Mn)

130000

100-9

100-3

100-2