Radiotherapy in Pancreatic Cancer: To Whom, When, and How?

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.

Combined Modality Bladder-Sparing Therapy for Muscle-Invasive Bladder Cancer: How (Should) We Do It? A Narrative Review.

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.

Accelerated Partial Breast Irradiation with Intraoperative Radiotherapy Is Effective in Luminal Breast Cancer Patients Aged 60 Years and Older.

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.

Molecular type and maximal metastasis diameter influence risk of axillary recurrence in breast cancer patients after positive sentinel lymph node biopsy.

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.

Influence of the Levels of Arsenic, Cadmium, Mercury and Lead on Overall Survival in Lung Cancer.

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.

Serum Selenium Level and 10-Year Survival after Melanoma.

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.

Deep inspiration breath hold reduces the mean heart dose in left breast cancer radiotherapy.

BACKGROUND: 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. PATIENTS AND METHODS: Retrospective study involving 2022 breast cancer patients who underwent radiotherapy at West Pomeranian Oncology Center in Szczecin from January 1, 2014 through December 31, 2017. We compared the MHD in these patients according to year of treatment and technique. RESULTS: Overall, the MHD for patients with left breast cancer in our cohort was 3.37 Gy. MHD values in the patients treated with DIBH were significantly lower than in patients treated with non-gated FB (2.1 vs. 3.48 Gy, p < 0.0001) and gated FB (3.28 Gy, p < 0.0001). The lowest MHD values over the four-year period were observed in 2017, when nearly 85% of left breast cancer patients were treated with DIBH. The proportion of patients exposed to high (> 4 Gy) MHD values decreased every year, from 40% in 2014 to 7.9% in 2017, while the percentage of patients receiving DIBH increased. CONCLUSIONS: Compared to free-breathing techniques (both gated and non-gated), DIBH reduces the mean radiation dose to the heart in patients with left breast cancer. These findings support the use of DIBH in patients with left breast cancer treated with radiotherapy.

Locoregional relapse is a strong prognostic indicator of distant metastatic progression in breast cancer patients after negative sentinel lymph node biopsy.

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.

Constitutional variants in POT1, TERF2IP, and ACD genes in patients with melanoma in the Polish population.

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.

Analysis of breast cosmetic effects 3 years after breast-conserving surgery and intraoperative radiotherapy with and without adjuvant whole breast irradiation.

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.

Influence of the selenium level on overall survival in lung cancer.

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.

The diameter of metastasis in positive sentinel lymph node biopsy affects axillary tumor load in early breast cancer.

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 (SLNDmax ) and axillary lymph nodes (ALNDsum ) indicated tumor load in the resected lymph nodes. ALNDsum higher or equal to 5 mm was defined as high and present in 62 patients (21%). RESULTS: Risk factors for high ALNDsum 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), SLNDmax (P = 0.0001), and Her-2 status (P = 0.0093). Independent variables for high ALNDsum were SLNDmax (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 ALNDsum . SLNDmax is the strong predictive factor for high ALNDsum after positive ALND.

Founder Mutations for Early Onset Melanoma as Revealed by Whole Exome Sequencing Suggests That This is Not Associated with the Increasing Incidence of Melanoma in Poland.

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.

Inherited NBN Mutations and Prostate Cancer Risk and Survival.

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).

BRCA1/2 mutations are not a common cause of malignant melanoma in the Polish population.

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.

Frequency of whole breast irradiation (WBRT) after intraoperative radiotherapy (IORT) is strongly influenced by institutional protocol qualification criteria.

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.

Utilization of a 3D printer to fabricate boluses used for electron therapy of skin lesions of the eye canthi.

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.

Risk factors for seroma evacuation in breast cancer patients treated with intraoperative radiotherapy.

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.

Germline RECQL mutations are associated with breast cancer susceptibility.

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_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.