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Selected features of breast and peritoneal cancers diagnosed in BRCA1 carriers after risk-reducing salpingo-oophorectomy

  • Janusz Menkiszak
  • Anita Chudecka-Głaz
  • Aneta Cymbaluk-Płoska
  • Aleksander Celewicz
  • Zbigniew Kojs
  • Mariusz Szajda
  • Maria Świniarska
  • Ryszard Bedner
  • Anna Jurczak
  • Marta Celewicz
  • Monika Cieszyńska
  • Jan Lubiński
  • Jacek GronwaldEmail author
Open Access
Research
  • 75 Downloads

Abstract

Background

Since more than two decades Risk-reducing salpingo-oophorectomy (RRSO) is recommended and widely accepted by BRCA1/2 carriers as a method reducing ovarian cancer risk and improving survival rate. After RRSO, there remains a risk of breast cancer and peritoneal cancer. The characteristics of these neoplasms are not well known. In this study, we determined the selected parameters such as age at cancer diagnosis, time from RRSO to the diagnosis of cancer, and significance of BRCA1 mutation type in patients diagnosed with breast or peritoneal cancer during postoperative follow-up.

Methods

The material comprised of 195 BRCA1 carriers who performed RRSO between years 1999–2012. In this period, 16 patients developed cancer (6-primary breast cancer, 3-contralateral breast cancer, 5-relapse of breast cancer, 2-peritoneal cancer). They were subject of the further analysis.

Results

During the follow-up period mean age of patients after RRSO at the time of cancer diagnosis was 53.19. The mean age of patients diagnosed with primary breast cancer was 50, contralateral breast cancer – 58.67, recurrence of breast cancer - 51 and peritoneal cancer 60. The mean time periods from RRSO to the diagnosis of primary, contralateral, recurrence breast cancer were 53, 58.67 and 25,4 months respectively and of peritoneal cancer 46 months. BRCA1 c.5266dupC mutation carriers demonstrated significantly shorter time of cancer development compared to patients carrying c.181T > G and c.4035delA mutations. Peritoneal cancer was only observed in two c.181T > G BRCA1 mutation carriers.

Conclusions

The mean age of cancer diagnosis and the mean time periods from RRSO to the diagnosis of cancer are similar to those observed by other researchers. The carriers of c.181T > G and c.5266dupC BRCA1 mutation should be the subject further studies in context of breast and peritoneal cancer risk or time of cancer development after RRSO, respectively.

Keywords

BRCA1 mutation Cancer Prophylactic surgery 

Abbreviations

CI

Confidence interval

CPBC

Contralateral primary breast cancer

OR

Odds ratio

PBC

Primary breast cancer

RBC

Relapse of breast cancer

RRSO

Risk-reducing salpingo-oophorectomy

Introduction

It was shown that diagnostic methods for ovarian cancer early-stage detection are ineffective [1]. Intensive screening tests in groups with the highest risk of ovarian cancer, such as carriers of the BRCA1 and BRCA2 mutations, have also low efficacy [1, 2, 3, 4, 5, 6]. For these reasons, patients who are carriers of the BRCA1/2 mutation are offered risk-reducing salpingo-oophorectomies (RRSO), which is widely accepted by BRCA1/2 carriers and have been performed for decades in hospitals and gynecological clinics all around the world. At the moment, such management is considered the best possible option for reducing ovarian cancer risk and improving the survival rate [1, 7, 8]. However, after this surgery, there remains a risk of breast cancer and risk of peritoneal cancer. Data about characteristics of these cancers developing after RRSO are pure. In this study, we analyzed characteristics of breast or peritoneal cancer after RRSO. Follow-up was conducted over the course of 12 years. The analysis included: age at cancer diagnosis, time from RRSO to the diagnosis of cancer, significance of BRCA1 mutation type in patients diagnosed with breast or peritoneal cancer during postoperative follow-up.

Material and methods

The material comprised of 195 BRCA1 carriers from the West Pomeranian Voivodship in Poland who performed RRSO between 15.09.1999–31.12.2012 at the Department of Gynecological Surgery and Oncology of Adults and Adolescents of the Pomeranian Medical University in Szczecin. No malignancy was found in the histopathological examination of the excised material. 80 of 195 (41.03%) patients were treated for breast cancer before risk-reducing surgery. All patients carried one of three BRCA1 mutations most commonly occurring in the Polish population (c.5266dupC – 128 patients, c.4035delA – 19 patients and c.181T > G – 48 patients) [9]. Median follow-up time for the group of 195 patients amounted to 80 months.

At the time of observation 16 out of 195 patients were diagnosed with cancer. 6 (3.1%) cases with primary breast cancer (PBC); 3 (1.5%) cases contralateral primary breast cancer (CPBC); 5 (2.56%) cases with cancer cells diagnosed in a scar after mastectomy defined as relapse of breast cancer (RBC); 2 (1.03%) cases with peritoneal cancer. The detailed characteristics of 16 patients from the study group are shown in Table 1. Ten (62.5%) of these patients had been treated for breast cancer also before the RRSO. The median age of affected patients (n = 16) at the time of RRSO was 46.5 years (36–63 years), which did not deviate from median age for the whole group (n = 195) – 47 years (31–78 years).
Table 1

Characteristics of 16 patients who developed cancer after risk-reducing salpingo-oophorectomy

Patient number

BRCA1 mutation type

Cancer diagnosed before prophylactic surgery (yes/no) location

Date of prophylactic surgery (month/year)

Date of cancer diagnosis after prophylactic surgery (month/year)

Cancer diagnosed after prophylactic surgery (location)

Time from risk-reducing surgery to cancer diagnosis (months)

1.

c.5266dupC

Yes breast

02/2008

06/2008

breast - second primary

4

2.

c.5266dupC

Yes breast

06/2006

04/2008

breast -recurrence

22

3.

c.181T > G

Yes breast

09/1999

11/2004

peritoneum

62

4.

c.5266dupC

Yes breast

11/2002

05/2004

breast -recurrence

18

5.

c.181T > G

Yes breast

02/2001

08/2003

peritoneum

30

6.

c.5266dupC

Yes breast

01/2002

04/2008

breast -recurrence

75

7.

c.181T > G

no

08/2003

06/2008

breast - primary

58

8.

c.5266dupC

no

06/2002

10/2006

breast - primary

52

9.

c.5266dupC

Yes breast

09/2001

01/2002

breast -recurrence

4

10.

c.5266dupC

no

11/2001

01/2008

breast - primary

74

11.

c.5266dupC

no

04/2006

03/2008

breast - primary

23

12.

c.5266dupC

Yes breast

06/2004

06/2006

breast - second primary

24

13.

c.4035delA

no

11/2002

07/2009

breast primary

80

14.

c.181T > G

Yes breast

05/2000

09/2012

breast - second primary

148

15.

c.5266dupC

Yes breast

07/2002

03/2003

breast -recurrence

8

16.

c.5266dupC

no

11/2000

06/2003

breast - primary

31

Histopathological examination of tissues excised during RRSO was performed with extraordinary caution in order to rule out the presence of cancerous foci in the ovary or the salpinx, which have been described in the literature and could have been missed in the primary histopathological assessment [10, 11]. Repeated histopathological examination of excised material failed to reveal micro-invasive foci in both of our patients diagnosed with primary peritoneal cancer during the follow-up period.

The patient analysis included: age at cancer diagnosis, time from RRSO to the diagnosis of cancer, significance of BRCA1 mutation type in patients diagnosed with breast or peritoneal cancer during postoperative follow-up. The data has been subjected to statistical analysis.

Statistical analysis

All variables were checked for normal distribution using the Shapiro-Wilk test. They were described as means, standard deviations, medians, quartiles, as well as minimal and maximal values. We checked for statistically significant differences in quantitative variables using Student’s t-test or Mann-Whitney test and Fisher’s exact test were used in order to calculate differences in proportions. For all tests, the differences were considered statistically significant at p-value < 0.05. Statistical analyses were performed using STATA 11 software (license no. 30110532736).

Results

Summary of selected features of BRCA1 carriers diagnosed with cancer during the follow-up period is shown in Table 2. The mean age of cancer diagnosis in 16 patients who were subject of the study, was 53.19. Peritoneal cancer observed in two patients was diagnosed significantly later at a mean age of 60. Both patients were previously treated (before RRSO) due to breast cancer. With regards to breast cancer, the PBC was diagnosed in 6, CPBC in 3 and RBC in 5 out of 16 cases. The peritoneal cancer was diagnosed almost 7 months earlier than PBC (46 months vs. 53 months), but this difference was not statistically significant. Breast cancer recurrence was diagnosed almost twice as fast as primary breast cancer and peritoneal cancer (25.4 vs. 53 months), but this difference was also not statistically significant.
Table 2

Summary of selected features of BRCA1 carriers diagnosed with cancer during the follow-up period

Type and number

Peritoneal cancer

n = 2

Primary breast cancer

n = 6

Contralateral breast cancer

n = 3

Breast cancer recurrence

n = 5

Total for the whole group diagnosed with cancers

n = 16

Feature and type of mutation

Patient age at the time of cancer diagnosis (mean; years old)

60

50.00

58.67

51.00

53.19

Time from RRSO to cancer diagnosis (mean; months)

46

53

58.67

25.4

44,56

Type of BRCA1 mutation in patients who developed cancer during follow-up period

2x c.181T > G

4x c.5266dupC 1x c.181T > G 1x c.4035delA

2x c.5266dupC 1x c.181T > G

5x c.5266dupC

11x c.5266dupC 4x c.181T > G 1x c.4035delA

Peritoneal cancers diagnosed during the follow-up period were observed only in two c.181T > G BRCA1 mutation carriers. We performed a statistical analysis of the frequency of peritoneal cancer in c.181T > G BRCA1 mutation carriers in comparison to other mutation carriers. Statistical significant differences were observed for this characteristic (p = 0.0392; OR = 29.00; 95% CI: 1.048–802.64).

The time to any cancer diagnosis after RRSO was significantly shorter for c.5266dupC mutation carriers compared to c.181T > G and c.4035delA mutation carriers (30.45 vs. 75.6 months; p = 0.021).

The c.5266dupC BRCA1 mutation was most frequent among patients who developed any cancer – 68.75% (11/16), followed by c.181T > G mutation – 25% (4/16), and c.4035delA observed in 6,25% (1/16) of patients. This reflects the frequency of these mutations in the Polish population.

Discussion

In our material, we observed relatively advanced age of cancer diagnosis among BRCA1 carriers after RRSO. It is most likely associated with particularly late age of undergoing this surgery. In our study, the average age of undergoing such an operation is 46–49 years [12, 13, 14]. The reason for delayed RRSO was that, in a significant number of breast cancer patients, BRCA1 mutation was diagnosed after diagnosis of breast cancer. In our study group, 62.5% of patients had been previously treated due to breast cancer. As indicated in our previous studies, patients treated for breast cancer undergo RRSO at a later age compared to patients without the diagnosis of breast cancer (50 vs. 46 years; p = 0.0003) [13].

In our study, we found that the mean age at diagnosis of any breast cancer was similar to those observed by Ramon et al. and equaled 52.2 vs. 51.8 years of age. The mean time from RRSO to diagnosis of breast cancer was also similar and amounted to 44,35 vs. 40.8 months [15]. Fakkert et al. reported breast cancer diagnosis among BRCA1 patients after RRSO at a significantly younger age – 45.25 years, and somewhat longer time from RRSO to the diagnosis of breast cancer – 52.8 months [16]. Kauff et al. indicated significantly shorter time to diagnosis of breast and peritoneal cancer among patients after RRSO – 10.3 and 16.3 months, respectively [17].

Finch et al. showed that mean time to development of peritoneal cancer among BRCA1 carriers after RRSO amounted to 63.6 months, although they emphasize that in three cases the diagnosis was made before the end of three years. The mean age of those patients at the time of diagnosis equalled 51.5 years [18], which approximates our data. In another study, Finch et al. reported similar mean age at diagnosis of peritoneal cancer - 51.6 years, but the mean time to diagnosis extended to 73.2 months. Possibly, prolonged time to the diagnosis of peritoneal cancer might have been influenced by the inclusion of four patients with BRCA2 mutation into the study group of 32 patients [19]. In case of particularly short time to diagnosis of peritoneal cancer after RRSO, one should very carefully assess the excised material in order to rule out micro-invasive foci, which is described in the literature [10, 11].

Rhiem et al. observed a case of peritoneal cancer in a 57-year-old woman 26.4 months after RRSO [20]. Rebbeck et al. diagnosed peritoneal cancer in patients 45.6 and 103.2 months after RRSO [21]. Kiely et al. showed peritoneal cancer in a 70-year-old patient eight 96 months after RRSO [22]. In another publication, Kauff et al. reported peritoneal cancers among patients after RRSO on average after 41.16 months and breast cancers after 36.36 months [23]. Powell et al. demonstrated equally short time of diagnosis of peritoneal cancer in a patient after RRSO as Kauff [17]. The diagnosis was made as early as a year after the procedure [24]. In our material, the mean age of patients diagnosed with peritoneal cancer was 60 and the mean time from RRSO to the diagnosis of peritoneal cancer amounted to 46 months.

Influence of particular BRCA1 gene mutation on studied characteristics is a very difficult topic to discuss. Although c.5266dupC, the most common mutation in the Polish population, is also often identified in the Ashkenazi Jewish population [25], available literature lacks data for discussion. The frequency of particular BRCA1 mutations observed between carriers who were diagnosed with any cancer reflects the frequency of these mutations in the Polish population. However, we found peritoneal cancer in two BRCA1 carriers with c.181T > G mutation, only. These two patients also developed breast cancer before RRSO. We observed that the time to any cancer diagnosis after RRSO was significantly shorter for c.5266dupC BRCA1 mutation carriers. We think that these are interesting observations important for future analyses on significance of particular BRCA1 gene mutation, however, for more general conclusions studies on larger groups should be performed.

Conclusions

The mean age of cancer diagnosis and the mean time periods from RRSO to the diagnosis of cancer are similar to those observed by other researchers. The carriers of c.181T > G and c.5266dupC BRCA1 mutation should be the subject further studies in context of breast and peritoneal cancer risk or time of cancer development after RRSO, respectively.

Notes

Acknowledgements

Authors thank for support to Breast Cancer Campaign Estée Lauder Companies.

Funding

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

JM the study design, database management, data collection and computing results, writing manuscript; AC-G sample collection, the manuscript review and approval; AC-P data collection, the manuscript review and approval; AC data collection, data collection and computing results, writing manuscript; ZK the study design, the manuscript review and approval; MS computing results, the manuscript review and approval, MŚ sample collection, the manuscript review and approval; RB sample collection, the manuscript review and approval; AJ sample collection, the manuscript review and approval; MC sample collection, the manuscript review and approval; MC sample collection, the manuscript review and approval; JL the study design, the manuscript review and approval; JG: the study design, database management, sample collection and computing results, molecular analysis, writing manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

All participants gave informed written consent prior blood donating. The study was approved by Ethics Committee of the Pomeranian Medical University in Szczecin, Poland (decision No. BN-001/174/05).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.
    Walker JL, Bethan Powell C, Chen L-M, Carter J, Bae Jump VL, et al. Society of Gynecologic Oncology Recommendations for the prevention of ovarian Cancer. Cancer. 2015;121:2108–20.CrossRefGoogle Scholar
  2. 2.
    Goff BA, Lowe KA, Kane JC, Robertson MD, Gaul MA, Andersen MR. Symptom triggered screening for ovarian cancer: a pilot study of feasibility and acceptability. Gynecol Oncol. 2012;24:230–5.CrossRefGoogle Scholar
  3. 3.
    Goff BA. Ovarian cancer: screening and early detection. Obstet Gynecol Clin N Am. 2012;39:183–94.CrossRefGoogle Scholar
  4. 4.
    Goff BA, Matthews B, Andrilla CH, Miller JW, Trivers KF, Berry D, et al. How are symptoms of ovarian cancer managed? A study of primary care physicians. Cancer. 2011;117:4414–23.CrossRefGoogle Scholar
  5. 5.
    Goff B. Symptoms associated with ovarian cancer. Clin Obstet Gynecol. 2012;55:36–42.CrossRefGoogle Scholar
  6. 6.
    Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, et al. Effect of screening on ovarian cancer mortality: the prostate, lung, colorectal and ovarian (PLCO) cancer screening randomized controlled trial. JAMA. 2011;305:2295–303.CrossRefGoogle Scholar
  7. 7.
    Gilbert L, Basso O, Sampalis J, Karp I, Martins C, Feng J, et al. Assessment of symptomatic women for early diagnosis of ovarian cancer: results from the prospective DOvE pilot project. Lancet Oncol. 2012;13:285–91.CrossRefGoogle Scholar
  8. 8.
    Synowiec A, Wcisło G, Bodnar L, Gasowska-Bodnar A, Szczylik C. Screening for ovarian cancer in BRCA1/BRCA2 mutations carriers. Ginekol Pol. 2014;85(5):377–81.CrossRefGoogle Scholar
  9. 9.
    Górski B, Byrski T, Huzarski T, Jakubowska A, Menkiszak J, Gronwald J, et al. Founder mutations in the BRCA1 gene in polish families with breast-ovarian cancer. Am J Hum Genet. 2000;66(6):1963–8.CrossRefGoogle Scholar
  10. 10.
    Rabban JT, Krasik E, Chen LM, Powell CB, Crawford B, Zaloudek CJ. Multistep level sections to detect occult fallopian tube carcinoma in risk-reducing salpingo-oophorectomies from women with BRCA mutations: implications for defining an optimal specimen dissection protocol. Am J Surg Pathol. 2009;33:1878–85.CrossRefGoogle Scholar
  11. 11.
    Reitsma W, de Bock GH, Oosterwijk JC, Bart J, Hollema H, Mourits MJ. Support of the ‘fallopian tube hypothesis’ in a prospective series of risk-reducing salpingo-oophorectomy specimens. Eur J Cancer. 2013;49:132–41.CrossRefGoogle Scholar
  12. 12.
    Menkiszak J, Chudecka-Głaz A, Bedner R, Gronwald J, Wężowska M, Kojs Z, et al. Genital malignant tumors and precancerous conditions in female carriers of constitutional BRCA 1 gene mutations undergoing prophylactic adnexectomy. Curr Gynecol Oncol. 2012;10(4):270–85.Google Scholar
  13. 13.
    Menkiszak J, Chudecka-Głaz A, Gronwald J, Bedner R, Cymbaluk-Płoska A, Wężowska M, et al. Characteristics of selected clinical features in BRCA1 mutation carriers affected with breast cancer undergoing preventive female genital tract surgeries. Ginekol Pol. 2013;84(9):758–64.CrossRefGoogle Scholar
  14. 14.
    Menkiszak J, Chudecka-Głaz A, Gronwald J, Cymbaluk-Płoska A, Celewicz A, Świniarska M, et al. Prophylactic salpingo-oophorectomy in BRCA1 mutation carriers and postoperative incidence of peritoneal and breast cancers. J Ovarian Res. 2016 Feb;29(9):11.  https://doi.org/10.1186/s13048-016-0220-4.CrossRefGoogle Scholar
  15. 15.
    Ramon Y, Cajal T, Torres A, Alonso C, Fisas D, Ojeda B, et al. Risk factors associated with the occurrence of breast cancer after bilateral salpingo-oophorectomy in high-risk women. Cancer Epidemiol. 2011 Feb;35(1):78–82.CrossRefGoogle Scholar
  16. 16.
    Fakkert IE, Mourits MJ, Jansen L, van der Kolk DM, Meijer K, Oosterwijk JC, et al. Breast Cancer incidence after risk-reducing Salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers. Cancer Prev Res (Phila). 2012;5(11):1291–7.CrossRefGoogle Scholar
  17. 17.
    Kauff ND, Satagopan JM, Robson ME, Scheuer L, Hensley M, Hudis CA, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2002;346(21):1609–15.CrossRefGoogle Scholar
  18. 18.
    Finch A, Beiner M, Lubinski J, Lynch HT, Moller P, Rosen B, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 mutation. JAMA. 2006;296(2):185–92.CrossRefGoogle Scholar
  19. 19.
    Finch AP, Lubinski J, Møller P, Singer CF, Karlan B, Senter L, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014;32(15):1547–53.CrossRefGoogle Scholar
  20. 20.
    Rhiem K, Foth D, Wappenschmidt B, Gevensleben H, Büttner R, Ulrich U, et al. Risk-reducing salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers. Arch Gynecol Obstet. 2011;283(3):623–7.CrossRefGoogle Scholar
  21. 21.
    Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, Van't Veer L, Garber JE, et al. Prevention and observation of surgical end points study group. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002;346(21):1616–22.CrossRefGoogle Scholar
  22. 22.
    Kiely BE, Friedlander ML, Milne RL, Stanhope L, Russell P, Jenkins MA, et al. Adequacy of risk-reducing gynaecologic surgery in BRCA1 or BRCA2 mutation carriers and other women at high risk of pelvic serous cancer. Familial Cancer. 2011;10(3):505–14.CrossRefGoogle Scholar
  23. 23.
    Kauff ND, Domchek SM, Friebel TM, Robson ME, Lee J, Garber JE, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol. 2008;26(8):1331–7.CrossRefGoogle Scholar
  24. 24.
    Powell CB, Chen LM, McLennan J, Crawford B, Zaloudek C, Rabban JT, et al. Risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers: experience with a consecutive series of 111 patients using a standardized surgical-pathological protocol. Int J Gynecol Cancer. 2011;21(5):846–51.CrossRefGoogle Scholar
  25. 25.
    Satagopan JM, Boyd J, Kauff ND, Robson M, Scheuer L, Narod S, et al. Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Clin Cancer Res. 2002;8(12):3776–81.PubMedGoogle Scholar

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  • Janusz Menkiszak
    • 1
  • Anita Chudecka-Głaz
    • 1
  • Aneta Cymbaluk-Płoska
    • 1
  • Aleksander Celewicz
    • 1
  • Zbigniew Kojs
    • 2
  • Mariusz Szajda
    • 3
  • Maria Świniarska
    • 4
  • Ryszard Bedner
    • 1
  • Anna Jurczak
    • 5
  • Marta Celewicz
    • 6
  • Monika Cieszyńska
    • 3
  • Jan Lubiński
    • 3
  • Jacek Gronwald
    • 3
    Email author
  1. 1.Department of Gynecological Surgery and Gynecological Oncology of Adults and AdolescentsPomeranian Medical UniversitySzczecinPoland
  2. 2.Department of Gynecologic Oncology, Centre of OncologyMaria Sklodowska-Curie Memorial InstituteCracowPoland
  3. 3.International Hereditary Cancer Center, Department of Genetics and PathologyPomeranian Medical UniversitySzczecinPoland
  4. 4.Department of the Clinical Oncology the West Pomeranian Centre of the Oncology in SzczecinSzczecinPoland
  5. 5.Department of Clinical NursingPomeranian Medical UniversitySzczecinPoland
  6. 6.Department of Obstetrics and GynecologyPomeranian Medical UniversitySzczecinPoland

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