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Patients with left breast cancer who undergo radiotherapy have a non-negligible risk of developing radiation-induced cardiovascular disease (CVD). Cardioprotection can be achieved through better treatment planning protocols and through respiratory gating techniques, including deep inspiration breath hold (DIBH). Several dosimetric studies have shown that DIBH reduces the cardiac dose, but clinical data confirming this effect is limited. The aim of the study was to compare the mean heart dose (MHD) in patients with left breast cancer who underwent radiotherapy at our institution as we transitioned from non-gated free-breathing (FB) radiotherapy to gated radiotherapy (FB-GRT), and finally to DIBH.

Abstract The NOD2 gene has been associated with susceptibility to Crohn's disease and individuals with Crohn's disease are at increased risk for cancer at a number of organ sites. We studied the association between the 3020insC allele of the NOD2 gene and cancer among 2604 cancer patients and 1910 controls from Poland. Patients were diagnosed with one of twelve types of cancer in the Szczecin region between 1994 and 2004. Significant associations were found for colon cancer (OR = 1.8; 95% CI 1.2 to 2.6), for lung cancer (OR = 1.7; 95% CI = 1.1 to 2.5) and for ovarian cancer (OR = 1.6; 95% CI 1.1 to 2.3). In addition, a significant association was found for early-onset laryngeal cancer (OR = 2.9; 95% CI 1.4 to 6.2) and for breast cancer in the presence of DCIS (OR = 2.1 95% CI = 1.2 to 3.6). The NOD2 3020insC allele is relatively common (in Poland 7.3% of individuals) and may be responsible for an important fraction of cancer cases. We estimate that the lifetime cancer risk among carriers of this allele is 30% higher than that of individuals with two wild-type alleles.

W roku 2015 w Polsce na raka prostaty zachorowało około 14 000 mężczyzn. Wskaźnik całkowitych przeżyć 5-letnich w tym nowotworze w polskiej populacji wynosi około 76%, aczkolwiek charakteryzuje się zróżnicowaniem pomiędzy województwami. Czynniki wpływające na przeżycie w raku prostaty to przede wszystkim czynniki kliniczne (stopień lokoregionalnego zaawansowania choroby, stopień histologicznej złośliwości w skali Gleasona, przerzuty odległe, wyjściowy poziom PSA). Ponadto z badań wynika, że również czynniki genetyczne mogą mieć związek ze złym rokowaniem i tzw. agresywną postacią raka prostaty. Zaobserwowano, że pacjenci chorzy na raka prostaty, u których w wywiadzie u ojca wystąpił rak prostaty o agresywnym przebiegu, mieli dwukrotnie większe prawdopodobieństwo zgonu z tego powodu w porównaniu do pacjentów bez takiego wywiadu. Do tej pory zidentyfikowano geny mające wpływ na złe rokowanie w raku prostaty, m.in. geny związane z naprawą DNA - BRCA2, NBS1. Szacuje się, że ok. 2% przypadków raka prostaty w ogólnej populacji dotyczy nosicieli mutacji w BRCA2, a mediana przeżyć u tych chorych wynosi około 50 miesięcy. Częstość mutacji 657del5 w NBS1 w rakach prostaty w polskiej populacji to około 1,4%, a jej obecność jest związana z około 1,8 raza większym ryzykiem zgonu (mediana przeżyć około 57 miesięcy) w porównaniu do osób bez mutacji. Ponadto do tej pory zidentyfikowano inne geny (kandydujące) (LEPR, RNASEL, IL4, CRY1, ARVCF), jak i polimorfizmy pojedynczego nukleotydu (rs4880, rs4054823) mogące mieć wpływ na rokowanie w raku prostaty. Ich użyteczność kliniczna powinna być potwierdzona dalszych badaniach. [ABSTRACT FROM AUTHOR]

Abstract During the past decade many new molecular methods for DNA and RNA analysis have emerged. The most popular thus far have been SSCP, HET, CMC, DGGE, RFLP or ASA, which have now been replaced by methods that are more cost effective and less time consuming. Real-time amplification techniques and particularly those with the capacity of multiplexing have become commonly used in laboratory practice. Novel screening methods enable the very rapid examination of large patients series. Use of liquid handling robotics applied to the isolation of DNA or RNA, the normalisation of sample concentration, and standardization of target amplification by PCR have also contributed to a reduced risk of sample contamination and have resulted in laboratory analysis being easier and faster. The aim of this study is the introduction of a few modern techniques, most commonly used in detection of genetic predisposition to cancer.

Abstract Background CYP1B1 is a P450 enzyme which is involved in the activation of pro-carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs), it represents an attractive candidate gene for studies into colorectal cancer susceptibility. Methods We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls. Results The three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect. Conclusion Genetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk; one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations.

The diagnosis rate of pancreatic cancer is steadily increasing. The average age of onset is close to 70 years. In most cases, the disease is diagnosed at an advanced stage. The indications for and techniques of radiotherapy are changing over time. The aim of this thesis is to present the role and possibilities of radiotherapy from the perspective of radiation oncologist. The most common cause of treatment failure in pancreatic cancer remains generalisation. The implementation of new systemic treatment regimens contributes to improved treatment outcomes regardless of the stage of the disease. With improved treatment outcomes in terms of the incidence of distant metastases, the impact of local curability on the length and quality of life of patients increases. Modern radiotherapy offers the opportunity to achieve high local cure rates. Postoperative radiotherapy in combination with chemotherapy seems justified in the group of postoperative pancreatic cancer patients with pT3 and pN+ features. In the group of patients with borderline resectable pancreatic cancer, the impact of radiotherapy in combination with the latest chemotherapy regimens is difficult to define clearly. In the setting of a diagnosis of advanced pancreatic cancer, radiotherapy, especially stereotactic radiotherapy, in combination with chemotherapy, contributes to improved local curability and allows to achieve a significantly reduced level of pain.

Organ-sparing combined-modality treatment for muscle-invasive bladder cancer remains underutilized despite high-quality evidence regarding its efficacy, safety, and preservation of quality of life. It may be offered to patients unwilling to undergo radical cystectomy, as well as those unfit for neoadjuvant chemotherapy and surgery. The treatment plan should be tailored to each patient's characteristics, with more intensive protocols offered to patients who are fit for surgery but opt for organ-sparing. After a thorough, debulking transurethral resection of the tumor and neoadjuvant chemotherapy, the response evaluation should trigger further management with either chemoradiation or early cystectomy in non-responders. A hypofractionated, continuous radiotherapy regimen of 55 Gy in 20 fractions with concurrent radiosensitizing chemotherapy with gemcitabine, cisplatin, or 5-fluorouracil and mitomycin C is currently preferred based on clinical trials. The response should be evaluated with repeated transurethral resections of the tumor bed and abdominopelvic-computed tomography after chemoradiation, with quarterly assessments during the first year. Salvage cystectomy should be offered to patients fit for surgery who failed to respond to treatment or developed a muscle-invasive recurrence. Non-muscle-invasive bladder recurrences and upper tract tumors should be treated in line with guidelines for respective primary tumors. Multiparametric magnetic resonance can be used for tumor staging and response monitoring, as it may distinguish disease recurrence from treatment-induced inflammation and fibrosis.

Adjuvant whole breast irradiation (AWBI) improves local control and survival in breast cancer patients after breast-conserving surgery. Between 2010 and 2017, 823 patients ≥ 60 years with ER-positive, Her-2 negative, clinically N0 breast cancer underwent breast-conserving surgery (BCS) at the West Pomeranian Oncology Center. Intraoperative radiotherapy (IORT) with kV photons was applied to 199 (24.2%) patients according to the IORT protocol, and AWBI only was applied to 624 (75.8%). IORT patients in cases with lymph node metastasis, lobular type presence, extensive in situ components, lymphatic vessel invasion, or resection margin < 2 mm, additionally underwent AWBI. Median follow-up was 74 months. There were two (1%) breast relapses in the IORT protocol group and one (0.2%) in the AWBI-only group. In each group, one axillary lymph node relapse was diagnosed (0.5% and 0.2%, respectively). There were two local relapses in the IORT-only group, and they were treated further with BCS and AWBI. Although locoregional relapse-free survival differed between the AWBI-only and IORT protocol groups (98.5% vs. 99.7%, p = 0.048), the local control, distant metastasis-free survival, and breast cancer-specific survival were similar. IORT is a reasonable option to avoid AWBI in ER-positive, Her-2 negative, cN0 women with breast cancer aged ≥ 60 years.

Background: Breast cancer patients with positive sentinel lymph node biopsy (SLNB) may be spared axillary lymph node dissection (ALND) in favour of irradiation. The aim of the study was to estimate local control probability in the axilla (axLCP)., Materials and Methods: We identified 1832 invasive breast cancer patients who had undergone SLNB at our centre. We measured maximal metastasis diameter (SLDmax) in the sentinel lymph nodes and lymph node metastasis volume (VALN) from ALND in 246 patients with one or two positive SLNs. We calculated axLCP after irradiation and systemic treatment for different molecular types., Results: VALN values are higher for high grade tumours and larger metastases in SLNs (> 5 mm). It is smaller in luminal A tumours. axLCP is high, nearly 100%, in all molecular types in radiation sensitive tumours (SF2 Gy = 0.45), except luminal B. Expected axLCP is relatively low (67%) in luminal B radiation sensitive tumours with no chemotherapy and nearly 100% with chemotherapy., Conclusion: VALN values differ among molecular tumour types. They depend on SLNDmax and tumour grade. New prognostic factors are needed for selected luminal B breast cancer patients (i.e. high grade tumours, large metastases in SLNs) after positive SLNB intended to be spared ALND and chemotherapy., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest., (© 2021 Greater Poland Cancer Centre.)

Melanoma is one of the most aggressive human malignancies. The determination of prognostic biomarkers is important for the early detection of recurrence and for the enrollment of the patients into different treatment regimens. Herein, we report the 10-year survival of 375 melanoma patients depending on their serum selenium levels. The study group was followed up from the date of melanoma diagnosis until death or 2020. Patients were assigned to one of four categories, in accordance with the increasing selenium level (I-IV quartiles). The subgroup with low selenium levels had a significant lower survival rate in relation to patients with high selenium levels, HR = 8.42; p = 0.005 and HR = 5.83; p = 0.02, for uni- and multivariable models, respectively. In the univariable analysis, we also confirmed the association between Breslow thickness, Clark classification and age at melanoma prognosis. In conclusion, a low serum selenium level was associated with an increased mortality rate in the 10 years following melanoma diagnosis. Future studies in other geographic regions with low soil selenium levels should be conducted to confirm our findings.

The effects of heavy metals on cancer risk have been widely studied in recent decades, but there is limited data on the effects of these elements on cancer survival. In this research, we examined whether blood concentrations of the heavy metals arsenic, cadmium, mercury and lead were associated with the overall survival of lung cancer patients. The study group consisted of 336 patients with lung cancer who were prospectively observed. Blood concentrations of heavy metals were measured to study the relationship between their levels and overall survival using Cox proportional hazards analysis. The hazard ratio of death from all causes was 0.99 ( p = 0.94) for arsenic, 1.37 ( p = 0.15) for cadmium, 1.55 ( p = 0.04) for mercury, and 1.18 ( p = 0.47) for lead in patients from the lowest concentration quartile, compared with those in the highest quartile. Among the patients with stage IA disease, this relationship was statistically significant (HR = 7.36; p < 0.01) for cadmium levels in the highest quartile (>1.97-7.77 µg/L) compared to quartile I (0.23-0.57 µg/L, reference). This study revealed that low blood cadmium levels <1.47 µg/L are probably associated with improved overall survival in treated patients with stage IA disease.

Purpose: Sentinel lymph node biopsy is routinely used in breast cancer patients with clinically negative axillary lymph nodes. Locoregional relapses after negative sentinel lymph node biopsy are infrequent, occurring in up to 3% of patients., Methods: Six thousand and eight patients underwent breast cancer surgery in our center between 2006 and 2015. We analyzed 1466 patients with negative sentinel lymph node biopsy and no prior systemic treatment. Mastectomy without irradiation was used in 25.4% of these patients and breast-conserving surgery with adjuvant radiotherapy in 74.6%. Forty-seven (3.21%) locoregional relapses were identified within a median of 51 months (10-138 months). The molecular type was analyzed as a risk factor for locoregional relapses and distant metastases. The locoregional relapse location was then analyzed as a risk factor for distant metastases., Results: Triple-negative breast cancer (P = .003), age <40 year (P = .007), multifocality (P = .011), and mastectomy (P < .0001) were risk factors for locoregional relapses. Patients who developed locoregional relapses more frequently developed distant metastases (P < .0001). The distribution of molecular types did not differ significantly in patients with locoregional relapses and distant metastases, concentrating in triple-negative and Luminal B tumor cases with distant metastases in almost 58% of cases, while not occurring in Luminal A patients. The locoregional-to-distant metastasis interval was shorter in cases of chest wall and lymph nodes relapse compared with breast-only relapse locations(P = .028)., Conclusion: Molecular type, especially triple-negative, young age, mastectomy without adjuvant irradiation, and multifocality are risk factors for locoregional relapse in sentinel lymph node biopsy negative breast cancer patients. Locoregional relapse is an important risk factor for developing distant metastasis, except in Luminal A breast cancer patients and those who suffer from breast-only relapse., (© 2020 Wiley Periodicals LLC.)

Evaluation of the prevalence of POT1, ACD, and TERF2IP mutations among Polish melanoma patients. A cohort of 60 patients from melanoma-prone families, 1500 unselected cases and 1500 controls were genotyped. Methodology included Sanger sequencing, in-silico software predilection, and TaqMan assays. We identified three nonsynonymous variants: POT1 c.903 G>T; TERF2IP c.970 A>G; and ACD c.1544 T>C and a splice site variant ACD c.645 G>A. The c.903 G>T was predicted to be pathogenic according to PolyPhen-2, benign according to Mutation Taster, PROVEAN, AGVGD, and SIFT. The c.645 G>A was defined as disease caused by Mutation Taster and Human Splicing Finder and as variant of unknown significance by ClinVar. The other detected variants were described as benign. The c.903 G>T variant was present in two unselected cases and one control [P = 0.57, odds ratio (OR) = 2.00]; the c.645 G>A variant was not detected among the unselected cases and the controls; the c.970 A>G variant was present in 110 cases and 133 controls (P = 0.14, OR = 0.81); the c.1544 T>C variant was present in 687 cases and 642 controls (P = 0.11, OR = 1.07). We found no loss of heterozygosity of the c.903 G>T, c.970 A>G, and c.645 G>A variants. C.645 G>A variant had no effect on splicing or expression. The changes in POT1 c.903 G>T and ACD c.645 G>A can be classified as rare variants of unknown significance, the other variants appear to be polymorphisms. Germline mutations in POT1, ACD, and TERF2IP are infrequent among Polish melanoma patients.

Introduction: Intraoperative radiotherapy (IORT) based on low-kV photons may be an option for early breast cancer patients. Following Targit trial results some of those patients should undergo whole breast irradiation (WBRT) additionally., Material and Methods: Since April 2010, IORT has been applied to early breast cancer patients. One hundred and fifty patients were prospectively followed up and examined to evaluate the side effects (pain, fibrosis, breast edema, telangiectasias). We present the results 3 years post-treatment. WBRT was given to 82 (54.7%) patients., Results: Tumor cavity fibrosis grade II and more was observed in 18 (12%) patients, as grade III only in 2 (1.33%) patients. Breast tissue fibrosis outside tumor cavity grade II was observed only in 2 (1.33%) patients. Breast edema was present in 10 (6.66%) patients. WBRT administration led to increased frequency of higher grade tumor cavity fibrosis (P < .0001), breast fibrosis (P < .0001), breast edema (P = .003), and occurrence of telangiectasias (P = .03), with no influence on pain reported by patients. In case of WBRT, tumor location (P = .026) and size of the irradiated breast (P = .015) were independent risk factors for higher degree of breast fibrosis, as seroma evacuation 6 months post-WBRT (P = .036) was the only independent risk factor for higher level of tumor cavity fibrosis in multiple regression., Conclusions: The cosmetic result after IORT is good and comparable to other accelerated partial breast irradiation techniques. Administration of WBRT post-IORT in breast cancer patients increases the level of fibrotic changes, breast edema and telangiectasias 3 years post-treatment, but with no influence on pain., (© 2020 Wiley Periodicals, Inc.)

Background: Although the results of studies in populations with low selenium status indicate an inverse correlation between body selenium levels and the risk of the lung cancer, the effect of this microelement on survival has not been studied., Materials and Methods: We performed a prospective study of 302 patients diagnosed with lung cancer in Szczecin, Poland. Selenium concentration in serum was measured at the time of diagnosis and before treatment. All patients were followed for a maximum of 80 months or until death. Vital status was obtained from the Polish National Death Registry., Results: Using Cox proportional hazard analysis, performed for all individuals with lung cancer, the hazard ratio (HR) for death from all causes was 1.25 (95% CI: 0.86-1.83, P = 0.99) for patients in the lowest tertile compared to those in the highest tertile of serum selenium levels. Among the patients with stage I disease this relationship was significant (HR-2.73; P = 0.01) for selenium level in tertile 1 (<57 μg/L) compared to tertile 3 (>69 μg/L, reference). The 80 months crude survival after diagnosis was 79.5% (95% CI: 68.5-92.4%) for individuals in the highest tertile and 58.1% (95% CI: 45.1-74.9%) for individuals in the lowest tertile with stage I lung cancer., Conclusion: These results suggest that in patients undergoing treatment for stage I lung cancer, serum selenium levels at the time of diagnosis (>69 μg/L) may be associated with improved overall survival., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Purpose: To establish the contribution of four founder alleles of NBN to prostate cancer risk and cancer survival., Materials and Methods: Five thousand one hundred eighty-nine men with prostate cancer and 6,152 controls were genotyped for four recurrent variants of NBN (657del5, R215W, I171V, and E185Q)., Results: The NBN 657del5 mutation was detected in 74 of 5,189 unselected cases and in 35 of 6,152 controls (odds ratio [OR], 2.5; p < 0.001). In carriers of 657del5 deletion, the cancer risk was restricted to men with the GG genotype of the E185Q variant of the same gene. Among men with the GG genotype, the OR associated with 657del5 was 4.4 (95% confidence interval [CI], 2.4 to 8.0). Among men with other E185Q genotypes, the OR associated with 657del5 was 1.4 (95% CI, 0.8 to 2.4) and the interaction was significant (homogeneity p=0.006). After a median follow-up of 109 months, mortality was worse for 657del5 mutation carriers than for non-carriers (hazard ratio [HR], 1.6; p=0.001). The adverse effect of 657del5 on survival was only seen on the background of the GG genotype of E185Q (HR, 1.9; p=0.0004)., Conclusion: The NBN 657del5 mutation predisposes to poor prognosis prostate cancer. The pathogenicity of this mutation, with regards to both prostate cancer risk and survival, is modified by a missense variant of the same gene (E185Q).

Introduction: Omission of axillary lymph node dissection (ALND) after positive sentinel lymph biopsy (SLNB) has become a standard procedure for breast cancer patients with one or two metastatic lymph nodes. Here the aim was model development for selection for ALND., Material and Methods: We analyzed 323 positive SLNB breast cancer patients, who afterwards underwent ALND. In 126 (39%), there were positive additional axillary lymph nodes. Specimens of resected lymph nodes were scanned and the volumes of tumors (expressed as diameter in mm) were calculated. The maximal diameter of metastasis in the sentinel lymph nodes (SLN Dmax ) and axillary lymph nodes (ALN Dsum ) indicated tumor load in the resected lymph nodes. ALN Dsum higher or equal to 5 mm was defined as high and present in 62 patients (21%)., Results: Risk factors for high ALN Dsum were primary tumor diameter (P = 0.0092), histopathological type (P = 0.0173), number of positive SLNs (P = 0.0012), type of metastasis (P = 0.0025), molecular type (P = 0.0037), SLN Dmax (P = 0.0001), and Her-2 status (P = 0.0093). Independent variables for high ALN Dsum were SLN Dmax (P < 0.0001), number of positive SLNs (P = 0.0237) and primary tumor diameter (P = 0.0296)., Conclusions: Twenty-one percent patients with positive SLNB are at risk of high ALN Dsum . SLN Dmax is the strong predictive factor for high ALN Dsum after positive ALND., (© 2019 John Wiley & Sons Australia, Ltd.)

Purpose: Germline mutations within melanoma susceptibility genes are present only in minority of melanoma patients and it is expected that additional genes will be discovered with next generation sequence technology and whole-exome sequencing (WES)., Materials and Methods: Herein we performed WES on a cohort of 96 unrelated Polish patients with melanoma diagnosed under the age of 40 years who all screened negative for the presence of CDKN2Avariants. A replication study using a set of 1,200 melanoma patient DNA samples and similarly large series of healthy controls was undertaken., Results: We selected 21 potentially deleterious variants in 20 genes (VRK1, MYCT1, DNAH14, CASC3, MS4A12, PRC1, WWOX, CARD6, EXO5, CASC3, CASP8AP2, STK33, SAMD11, CNDP2, CPNE1, EFCAB6, CABLES1, LEKR1, NUDT17, and RRP15), which were identified by WES and confirmed by Sanger sequencing for an association study. Evaluation of the allele distribution among carriers and their relatives in available family trios revealed that these variants were unlikely to account for many familial cases of melanoma. Replication study revealed no statistically significant differences between cases and controls., Conclusion: Although most of the changes seemed to be neutral we could not exclude an association between variants in VRK1, CREB3L3, EXO5, and STK33 with melanoma risk.

The association of BRCA1/2 mutations with melanoma is not completely determined; the interpretation of variants of unknown significance is also problematic. To evaluate these issues we explored the molecular basis of melanoma risk by performing whole-exome sequencing on a cohort of 96 unrelated Polish early-onset melanoma patients and targeted sequencing of BRCA1/2 genes on additional 30 melanoma patients with familial aggregation of breast and other cancers. Sequencing was performed on peripheral blood. We evaluated MutationTaster, Polyphen2, SIFT, PROVEAN algorithms, analyzed segregation with cancer disease (in both families with identified BRCA2 variants) and in one family performed LOH (based on 2 primary tumors). We found neither pathogenic mutations nor variants of unknown significance within BRCA1. We identified two BRCA2 variants of unknown significance: c.9334G>A and c.4534 C>T. Disease allele frequency was evaluated by genotyping of 1230 consecutive melanoma cases, 5000 breast cancer patients, 3500 prostate cancers and 9900 controls. Both variants were found to be absent among unselected cancer patients and healthy controls. The MutationTaster, Polyphen2 and SIFT algorithms indicate that c.9334G>A is a damaging variant. Due to lack of tumour tissue LOH analysis could not be performed for this variant. The variant segregated with the disease. The c.4534 C>T variant did not segregate with disease, there was no LOH of the variant. The c.9334G>A variant, classified as a rare variant of unknown significance, on current evidence may predisposes to cancers of the breast, prostate and melanoma. Functional studies to describe how the DNA change affects the protein function and a large multi-center study to evaluate its penetrance are required., Competing Interests: The authors have declared that no competing interests exist.

Background: Accelerated partial breast irradiation (APBI) is a promising method of adjuvant radiotherapy for select patients. Intraoperative radiotherapy (IORT) is a form of APBI, and appropriate patient selection is important., Aim: The aim of our study was to analyse the influence of our protocol on the frequency of WBRT after IORT and our protocol's correlation with the reported use of WBRT according to TARGIT guidelines. We also aimed to verify how changes in our protocol influenced the frequency of WBRT., Material and Methods: Between April 20, 2010 and May 10, 2017, we identified 207 patients irradiated with IORT for APBI., Results: Ninety-one patients (44%) met the criteria for APBI only, while 116 (56%) should have been offered additional WBRT. Retrospective analysis showed that WBRT was applied statistically significantly less frequently compared with strict protocol indications: 99 patients (47.8%) received APBI only and 108 (51.2%) underwent adjuvant WBRT ( p  < 0.0001). Applying the TARGIT trial guidelines, 69 patients (33.4%) should have been offered WBRT ( p  < 0.0001), which is twice the number of patients treated with WBRT in our study. Changing the protocol to less restrictive criteria would have statistically significantly decreased the number of patients (95, 46%) offered WBRT ( p  < 0.0001)., Conclusions: Following international guidelines, 46% of patients should receive WBRT after IORT, which is 1.5-2 times more than for the TARGIT criteria. In our analysis, a high percentage of patients (19%) did not receive WBRT after IORT despite the protocol recommendations. The chosen protocol strongly influences the frequency of adjuvant WBRT.

This work describes the use of 3D printing technology to create individualized boluses for patients treated with electron beam therapy for skin lesions of the eye canthi. It aimed to demonstrate the effectiveness of 3D-printed over manually fabricated paraffin boluses. The study involved 11 patients for whom the construction of individual boluses were required. CT scans of the fabricated 3D-printed boluses and paraffin boluses were acquired and superimposed onto patient CT scans to compare their fitting, bolus homogeneity, and underlying dose distribution. To quantify the level of matching, multiple metrics were utilized. Matching Level Index (ML) values ranged from 0 to 100%, where 100% indicated a perfect fit between the reference bolus (planned in treatment planning system) and 3D-printed and paraffin bolus. The average ML (± 1 SD) of the 3D-printed boluses was 95.1 ± 2.1%, compared to 46.0 ± 10.1% for the manually fabricated paraffin bolus. Correspondingly, mean doses were closer to the prescribed doses, and dose spreads were less for the dose distributions from the 3D-printed boluses, as compared to those for the manually fabricated paraffin boluses. It was concluded that 3D-printing technology is a viable method for fabricating boluses for small eye lesions and provides boluses superior to our boluses manually fabricated from paraffin sheets., (© 2016 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Background: Novel techniques in oncology provide new treatment opportunities but also introduce different patterns of side effects. Intraoperative radiotherapy (IORT) allows a shortened overall treatment time for early breast cancer either combined with whole breast radiotherapy (WBRT), or alone. Although the early side effects of IORT are well known, data on clinically important late side effects, which require medical intervention, are scarce., Aim: In this study, we analyze risk factors for seroma evacuation more than 6 months after IORT., Materials and Methods: We evaluated 120 patients with a mean follow-up of 27.8 months (range: 7-52 months). Fifty-one patients received IORT only and 69 were additionally treated with WBRT., Results: Seroma evacuation was performed 6-38 months after IORT. Two (3.9%) events were observed in the IORT group and 14 (20%) in the IORT + WBRT group. Univariate (Kaplan-Meier) analysis showed that addition of WBRT to IORT increased the risk of seroma evacuation [hazard ratio = 5.5, 95% confidence interval: 2.0-14.7, P = 0.011]. In a multivariate analysis (Cox proportional hazards regression), WBRT and axillary lymph node dissection were significant risk factors for seroma evacuation (model P value = 0.0025)., Conclusions: WBRT applied after IORT is associated with increased risk of seroma evacuation, which might be considered as a late side effect.

Several moderate- and high-risk breast cancer susceptibility genes have been discovered, but more are likely to exist. To discover new breast cancer susceptibility genes, we used 2 populations (from Poland and Quebec, Canada) and applied whole-exome sequencing in a discovery phase (n = 195), followed by validation. We identified rare recurrent RECQL mutations in each population. In Quebec, 7 of 1,013 higher-risk breast cancer cases and 1 of 7,136 newborns carried the c.634C>T (p.Arg215*) variant (P = 0.00004). In Poland, 30 of 13,136 unselected breast cancer cases and 2 of 4,702 controls carried the c.1667&#95;1667+3delAGTA (p.K555delinsMYKLIHYSFR) variant (P = 0.008). RECQL is implicated in resolving stalled DNA replication forks to prevent double-stranded DNA (dsDNA) breaks. This function is related to that of other known breast cancer susceptibility genes, many of which are involved in repairing dsDNA breaks. We conclude that RECQL is a breast cancer susceptibility gene.

A number of single nucleotide polymorphisms (SNPs) in the human genome have been associated with increased risk of prostate cancer. Recently, a single SNP in the region of chromosome 8q24 (rs188140481) has been associated with a three-fold increased risk of prostate cancer in Europe and North America. To establish whether rs188140481 is associated with the risk of prostate cancer in Poland, we genotyped 3467 men with prostate cancer and 1958 controls. The A allele of rs188140481 was detected in 44 of 3467 (1.3%) men with prostate cancer and in seven of 1958 (0.4%) controls (odds ratio=3.6; 95% confidence interval 1.6-7.9; P=0.0006). The allele was present in eight of 390 (2.1%) men with familial prostate cancer (odds ratio=5.8; 95% confidence interval 2.1-16.2; P=0.001). A positive family history of cancers at sites other than the prostate was observed in 27% of men who carried the rs188140481 risk allele and in 44% of noncarriers (P=0.04). No cancer at a site other than the prostate was more common in first-degree or second-degree relatives of carriers of the rs188140481 risk allele than relatives of noncarriers. The rs188140481 polymorphism in the 8q24 region confers a moderate increase in the risk of prostate cancer in Polish men. The SNP does not appear to be associated with susceptibility to cancers of other types.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. Genetic polymorphisms in XP genes may be associated with a change in DNA repair capacity, which could be associated with colorectal cancer development. We assessed the association between 94 single nucleotide polymorphisms (SNPs) within seven XP genes (XPA-XPG) and the colorectal cancer risk in the Polish population. We genotyped 758 unselected patients with colorectal cancer and 1,841 healthy adults. We found that a significantly decreased risk of colorectal cancer was associated with XPC polymorphism rs2228000&#95;CT genotype (OR 0.59; p < 0.0001) and the rs2228000&#95;TT genotype (OR 0.29; p < 0.0001) compared to the reference genotype (CC). And an increased disease risk was associated with the XPD SNP, rs1799793&#95;AG genotype (OR 1.44, p = 0.018) and rs1799793&#95;AA genotype (OR 3.31, p < 0.0001) compared to the reference genotype. Haplotype analysis within XPC, XPD and XPG revealed haplotypes associated with an altered colorectal cancer risk. Stratified analysis by gender showed differences between the association of three SNPs: XPC rs2228000, XPD rs1799793 and XPD rs238406 in females and males. Association analysis between age of disease onset and polymorphisms in XPD (rs1799793) and XPC (rs2228000) revealed differences in the prevalence of these variants in patients under and over 50 years of age. Our results confirmed that polymorphisms in XPC and XPD may be associated with the risk of colorectal cancer.

The E318K mutation in the MITF gene has been associated with a high risk of melanoma, renal cell carcinoma, and pancreatic cancer; the risk of other cancers has not been evaluated so far. Herein, we examined the possible association of E318K and a novel variant of the MITF gene, V320I, with the risk of cancers of different sites of origin in a Polish population. We assayed for the presence of the E318K and V320I missense mutations in 4,226 patients with one of six various cancers (melanoma or cancer of the kidney, lung, prostate, colon, or breast) and 2,114 controls from Poland. The E318K mutation was detected in 4 of 2,114 participants (0.19%) in the Polish control population, the V320I in 3 of 2,114 participants (0.14%) in the control group. We found no statistically significant differences in the prevalence of the E318K and V320I variants among cases and controls. We found two carriers of the E318K variant among melanoma patients (P = 0.95), one carrier among breast cancer patients (P = 0.77), one carrier among colorectal cancer patients (P = 0.82), and one carrier among kidney cancer patients (P = 0.64). Our study demonstrates a lack of strong association of E318K and V320I with increased risk of melanoma or cancers of the kidney, breast, prostate, lung, or colon., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Several single nucleotide polymorphisms (SNPs) have been associated with an elevated risk of prostate cancer risk. It is not established if they are useful in predicting the presence of prostate cancer at biopsy or if they can be used to define a low-risk group of men. In this study, 4,548 men underwent a prostate biopsy because of an elevated prostate specific antigen (PSA; ≥4 ng/mL) or an abnormal digital rectal examination (DRE). All men were genotyped for 11 selected SNPs. The effect of each SNP, alone and in combination, on prostate cancer prevalence was studied. Of 4,548 men: 1,834 (40.3%) were found to have cancer. A positive association with prostate cancer was seen for 5 of 11 SNPs studied (rs1800629, rs1859962, rs1447295, rs4430796, rs11228565). The cancer detection rate rose with the number of SNP risk alleles from 29% for men with no variant to 63% for men who carried seven or more risk alleles (OR = 4.2; p = 0.002). The SNP data did not improve the predictive power of clinical factors (age, PSA and DRE) for detecting prostate cancer (AUC: 0.726 vs. 0.735; p = 0.4). We were unable to define a group of men with a sufficiently low prevalence of prostate cancer that a biopsy might have been avoided. In conclusion, our data do not support the routine use of SNP polymorphisms as an adjunct test to be used on the context of prostate biopsy for Polish men with an abnormal screening test., (© 2013 UICC.)

Background: Germline mutations of BRCA2 and NBS1 genes cause inherited recessive chromosomal instability syndromes and predispose to prostate cancer of poor prognosis. Mutations of the BLM gene cause another chromosomal instability clinical syndrome, called Bloom syndrome. Recently, a recurrent truncating mutation of BLM (Q548X) has been associated with a 6-fold increased risk of breast cancer in Russia, Belarus and Ukraine, but its role in prostate cancer etiology and survival has not been investigated yet., Methods: To establish whether the Q548X allele of the BLM gene is present in Poland, and whether this allele predisposes to poor prognosis prostate cancer, we genotyped 3337 men with prostate cancer and 2604 controls., Results: Q548X was detected in 13 of 3337 (0.4%) men with prostate cancer compared to 15 of 2604 (0.6%) controls (OR=0.7; 95% CI 0.3-1.4). A positive family history of any cancer in a first- or second-degree relative was seen only in 4 of the 13 (30%) mutation positive families, compared to 49% (1485/3001) of the non-carrier families (p=0.3). The mean follow-up was 49months. Survival was similar among carriers of Q548X and non-carriers (HR=1.1; p=0.9). The 5-year survival for men with a BLM mutation was 83%, compared to 72% for mutation-negative cases., Conclusions: BLM Q548X is a common founder mutation in Poland. We found no evidence that this mutation predisposes one to prostate cancer or affect prostate cancer survival. However, based on the observed 0.6% population frequency of the Q548X allele, we estimate that one in 100,000 children should be affected by Bloom syndrome in Poland., (© 2013 Elsevier B.V. All rights reserved.)

Background: To evaluate whether genotyping for 18 prostate cancer founder variants is helpful in identifying high-risk individuals and for determining optimal screening regimens., Methods: A serum PSA level was measured and a digital rectal examination (DRE) was performed on 2907 unaffected men aged 40-90. Three hundred and twenty-three men with an elevated PSA (≥4 ng ml⁻¹) or an abnormal DRE underwent a prostate biopsy. All men were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA and C61G), for four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395 and I157T), for one allele in NBS1 (657del5), for one allele in HOXB13 (G84E), and for nine low-risk single-nucleotide polymorphisms (SNPs)., Results: On the basis of an elevated PSA or an abnormal DRE, prostate cancer was diagnosed in 135 of 2907 men (4.6%). In men with a CHEK2 missense mutation I157T, the cancer detection rate among men with an elevated PSA or an abnormal DRE was much higher (10.2%, P=0.0008). The cancer detection rate rose with the number of SNP risk genotypes observed from 1.2% for men with no variant to 8.6% for men who carried six or more variants (P=0.04). No single variant was helpful on its own in predicting the presence of prostate cancer, however, the combination of all rare mutations and SNPs improved predictive power (area under the curve=0.59; P=0.03)., Conclusion: These results suggest that testing for germline CHEK2 mutations improves the ability to predict the presence of prostate cancer in screened men, however, the clinical utility of incorporating DNA variants in the screening process is marginal.

Multiple genotyping techniques were developed on the basis of real-time PCR. In this article, we present a genotyping technique extending the induced Förster resonance energy transfer (iFRET) mechanism in conjunction with simultaneous mutation scanning. Rapid, asymmetric PCR was performed with SYTO9, polymerase lacking 5 → 3 exonuclease activity, two primers, and a probe labeled with 6-Carboxy-X-rhodamine. Six primers and probe sets were designed to detect germline mutations in BRCA1, a singular polymorphism in CCND1 and somatic mutations in KRAS and BRAF genes. The validation set consisted of 140 archival DNA samples from patients with previously confirmed BRCA1 mutation and 42 archival formalin-fixed and paraffin-embedded tissues from patients with colorectal cancer or malignant melanoma. BRCA1 and CCND1 genotyping by iFRET probe showed 100% agreement with Sanger sequencing and other validated methods. A combination of iFRET and high-resolution melting analysis (HRMA) detected a spectrum of six different mutations in the KRAS gene and three different mutations in the BRAF gene. Due to anallele enrichment effect, the sensitivity of mutation detection of iFRET–HRMA genotyping and sequencing of iFRET–HRMA PCR products was significant, increasing from 1.5% to 6.2%, respectively. The technique presented in this article is a useful and cost-effective method for the detection of both germline and somatic mutations.

Among many alterations within the TP53 gene the rs1042522 (C72G, p.Pro72Arg) has been associated with numerous cancers , however the results differ between populations for opposite Pro or Arg alleles. Similar thus inconclusive results are observed in ovarian cancer, which may suggest that the rs1042522 does not influence ovarian carcinogenesis directly, but might be linked to another pathogenic alteration. WRAP53 which overlaps the TP53 is required to maintain normal levels of p53 upon DNA damage, but also when altered may independently increase the risk of cancer. To evaluate the association between three SNPs located in WRAP53-TP53 region: rs1042522, rs2287497, rs2287498 and ovarian cancer risk in Polish population we genotyped 626 cases and 1,045 healthy controls. Our results provide the evidence for an association between studied SNPs and a risk of invasive ovarian cancer in Poland. We found that CC homozygotes in rs1042522 were more frequent in cancers when compared to controls (OR = 1.46, p = 0.03). Similarly in WRAP53 both TT homozygotes in rs2287497 (OR = 1.95, p = 0.03) and AA homozygotes in rs2287498 (OR = 2.65, p = 0,01) were more frequent among cases than healthy individuals. There is also a suggestive evidence that specific homozygosity of studied SNPs in TP53-WRAP53 region is significantly overrepresented in ovarian cancer patients. In conclusion SNPs in WRAP53 (rs2287497 and rs2287498) have stronger association with an ovarian cancer risk than rs1042522 in TP53.

Purpose: To estimate the risk of breast cancer in a woman who has a CHEK2 mutation depending on her family history of breast cancer., Patients and Methods: Seven thousand four hundred ninety-four BRCA1 mutation-negative patients with breast cancer and 4,346 control women were genotyped for four founder mutations in CHEK2 (del5395, IVS2+1G>A, 1100delC, and I157T)., Results: A truncating mutation (IVS2+1G>A, 1100delC, or del5395) was present in 227 patients (3.0%) and in 37 female controls (0.8%; odds ratio [OR], 3.6; 95% CI, 2.6 to 5.1). The OR was higher for women with a first- or second-degree relative with breast cancer (OR, 5.0; 95% CI, 3.3 to 7.6) than for women with no family history (OR, 3.3; 95% CI, 2.3 to 4.7). If both a first- and second-degree relative were affected with breast cancer, the OR was 7.3 (95% CI, 3.2 to 16.8). Assuming a baseline risk of 6%, we estimate the lifetime risks for carriers of CHEK2 truncating mutations to be 20% for a woman with no affected relative, 28% for a woman with one second-degree relative affected, 34% for a woman with one first-degree relative affected, and 44% for a woman with both a first- and second-degree relative affected., Conclusion: CHEK2 mutation screening detects a clinically meaningful risk of breast cancer and should be considered in all women with a family history of breast cancer. Women with a truncating mutation in CHEK2 and a positive family history of breast cancer have a lifetime risk of breast cancer of greater than 25% and are candidates for magnetic resonance imaging screening and for tamoxifen chemoprevention.

Genetic factors associated with the risk of smoking related cancers have until recently remained elusive. Since the publication of a genome-wide association study (GWAS) on lung cancer new genetic loci have been identified that appear to be associated with disease risk. In this replication study we genotyped 14 single nucleotide polymorphisms (SNPs) located at the 5p12.3-p15.33, 6p21.3-p22.1, 6q23-q27 and 15q25.1 loci in 874 lung, 450 bladder, 418 laryngeal cancer cases and cancer-free controls, matched by year of birth and sex to the cases. Our results revealed that loci in the chromosome region 15q25.1 (rs16969968[A], rs8034191[G]) and 5p15 (rs402710[T]) are associated with lung cancer risk in the Polish population (smoking status adjusted OR = 1.45, 1.35, 0.77; p ≤ 0.0001, 0.0005, 0.002; 95%CI 1.23-1.72, 1.14-1.59, 0.66-0.91 respectively). None of the other regions analyzed herein were implicated in the risk of lung, bladder or laryngeal cancer. This study supports previous findings on lung cancer but fails to show association of SNPs located in 15q25.1 and 5p15 region with other smoking related cancers like bladder and laryngeal cancer.

Recent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germline-somatic link in carcinogenesis, we evaluated the distribution of somatic gene labels within the ordered results of a breast cancer risk GWAS. This analysis suggested frequent influence on risk of genetic variation in loci encoding for "driver kinases" (i.e., kinases encoded by genes that showed higher somatic mutation rates than expected by chance and, therefore, whose deregulation may contribute to cancer development and/or progression). Assessment of these predictions using a population-based case-control study in Poland replicated the association for rs3732568 in EPHB1 (odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.63-0.98; P(trend) = 0.031). Analyses by early age at diagnosis and by estrogen receptor α (ERα) tumor status indicated potential associations for rs6852678 in CDKL2 (OR = 0.32, 95% CI: 0.10-1.00; P(recessive) = 0.044) and rs10878640 in DYRK2 (OR = 2.39, 95% CI: 1.32-4.30; P(dominant) = 0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERα tumor status P(interaction)<0.05). The identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. Together, these data may lay the foundations for replication in additional populations and could potentially increase our knowledge of the underlying molecular mechanisms of breast carcinogenesis.

Background: The aim of this study was to analyze the occurrence of clinical features characteristic of breast cancer type 1 susceptibility protein (BRCA-1)-dependent tumors in a series of BRCA-1 mutation carriers with laryngeal cancer., Patients and Methods: The clinical features of five laryngeal cancer patients with BRCA-1 mutations registered in our center were analyzed for: sex, age at diagnosis, age at operation, tumor size and localization, histopathological subtype and grading, lymph node and distant metastases, mode of treatment and long term results of the therapy., Results: The five patients were all men, with an average age at diagnosis of 52.4 years. The majority of the patients had clinical features typical of BRCA-1-dependent tumors: four out of the five patients had advanced staging at the time of diagnosis and in three of them the disorder disseminated within one year of follow-up., Conclusion: Since laryngeal carcinomas in men with BRCA-1 mutations show clinical features characteristic of BRCA-1 dependent tumors, it is reasonable to consider treatment modifications appropriate for this sub-group of tumors.

The aim of the study is to verify the hypothesis that genetic polymorphisms are associated with the predisposition to all malignancies. Using as a model breast cancers from the homogenous Polish population (West Pomeranian region) after stratification of 977 patients by age at diagnosis (under 51 years and above 50 years) and by tumour pathology (ductal cancers--low and high grade, lobular cancers, ER-positive/negative) we tested this hypothesis. Altogether 20 different groups of breast cancer cases have been analyzed. The results were compared to a group of unaffected controls that were matched by age, sex, ethnicity and geographical location and originated from families without cancers of any site among relatives. Molecular alterations selected for analyses included those which have been previously recognized as being associated with breast cancer predisposition. Statistically significant differences between the breast cancer cases and controls were observed in 19 of the 20 analyzed groups. Genetic changes were present in more than 90% of the breast cancer patients in 18 of 20 groups. The highest proportion of cases with constitutional changes-99.3% (139/140) was observed for lobular cancers. The number and type of genetic marker and/or the level of their association with the specific cancer predisposition was different between groups. Markers associated with majority of groups included: BRCA1, CHEK2, p53, TNRnTT, FGFRnAA, XPD CC/AA and XPD GG. Some markers appeared to be group specific and included polymorphisms in CDKN2A, CYP1B1, M3K nAA, and RS67.

In this report the contribution of CDKN2A/ARF germline mutations to early-onset cancers of the breast, pancreas and malignant melanoma was examined. We screened 66 women with breast cancer diagnosed at age 30 and below, 72 melanoma patients with the median age at diagnosis < or = 40 years and 51 pancreatic cancer patients diagnosed under the age of 50 years. In the total set of 189 patients we found a novel change Pro48Arg (nt 143 c > g), a novel intronic change IVS1+36 g>c and two common variants A148T and IVS3+29 c>g. The results of this study revealed a paucity of mutations in CDKN2A/ARF suggesting that in the Polish population this gene does not contribute significantly to early-onset breast cancer, pancreatic cancer and malignant melanoma.