Enhancing the BOADICEA cancer risk prediction model to incorporate new data on RAD51C, RAD51D, BARD1 updates to tumour pathology and cancer incidence.

BACKGROUND: BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) for breast cancer and the epithelial tubo-ovarian cancer (EOC) models included in the CanRisk tool (www.canrisk.org) provide future cancer risks based on pathogenic variants in cancer-susceptibility genes, polygenic risk scores, breast density, questionnaire-based risk factors and family history. Here, we extend the models to include the effects of pathogenic variants in recently established breast cancer and EOC susceptibility genes, up-to-date age-specific pathology distributions and continuous risk factors. METHODS: BOADICEA was extended to further incorporate the associations of pathogenic variants in BARD1, RAD51C and RAD51D with breast cancer risk. The EOC model was extended to include the association of PALB2 pathogenic variants with EOC risk. Age-specific distributions of oestrogen-receptor-negative and triple-negative breast cancer status for pathogenic variant carriers in these genes and CHEK2 and ATM were also incorporated. A novel method to include continuous risk factors was developed, exemplified by including adult height as continuous. RESULTS: BARD1, RAD51C and RAD51D explain 0.31% of the breast cancer polygenic variance. When incorporated into the multifactorial model, 34%-44% of these carriers would be reclassified to the near-population and 15%-22% to the high-risk categories based on the UK National Institute for Health and Care Excellence guidelines. Under the EOC multifactorial model, 62%, 35% and 3% of PALB2 carriers have lifetime EOC risks of <5%, 5%-10% and >10%, respectively. Including height as continuous, increased the breast cancer relative risk variance from 0.002 to 0.010. CONCLUSIONS: These extensions will allow for better personalised risks for BARD1, RAD51C, RAD51D and PALB2 pathogenic variant carriers and more informed choices on screening, prevention, risk factor modification or other risk-reducing options.

Colorectal cancer incidence, mortality, and stage distribution in European countries in the colorectal cancer screening era: an international population-based study.

BACKGROUND: Colorectal cancer screening programmes and uptake vary substantially across Europe. We aimed to compare changes over time in colorectal cancer incidence, mortality, and stage distribution in relation to colorectal cancer screening implementation in European countries. METHODS: Data from nearly 3·1 million patients with colorectal cancer diagnosed from 2000 onwards (up to 2016 for most countries) were obtained from 21 European countries, and were used to analyse changes over time in age-standardised colorectal cancer incidence and stage distribution. The WHO mortality database was used to analyse changes over time in age-standardised colorectal cancer mortality over the same period for the 16 countries with nationwide data. Incidence rates were calculated for all sites of the colon and rectum combined, as well as the subsites proximal colon, distal colon, and rectum. Average annual percentage changes (AAPCs) in incidence and mortality were estimated and relevant patterns were descriptively analysed. FINDINGS: In countries with long-standing programmes of screening colonoscopy and faecal tests (ie, Austria, the Czech Republic, and Germany), colorectal cancer incidence decreased substantially over time, with AAPCs ranging from -2·5% (95% CI -2·8 to -2·2) to -1·6% (-2·0 to -1·2) in men and from -2·4% (-2·7 to -2·1) to -1·3% (-1·7 to -0·9) in women. In countries where screening programmes were implemented during the study period, age-standardised colorectal cancer incidence either remained stable or increased up to the year screening was implemented. AAPCs for these countries ranged from -0·2% (95% CI -1·4 to 1·0) to 1·5% (1·1 to 1·8) in men and from -0·5% (-1·7 to 0·6) to 1·2% (0·8 to 1·5) in women. Where high screening coverage and uptake were rapidly achieved (ie, Denmark, the Netherlands, and Slovenia), age-standardised incidence rates initially increased but then subsequently decreased. Conversely, colorectal cancer incidence increased in most countries where no large-scale screening programmes were available (eg, Bulgaria, Estonia, Norway, and Ukraine), with AAPCs ranging from 0·3% (95% CI 0·1 to 0·5) to 1·9% (1·2 to 2·6) in men and from 0·6% (0·4 to 0·8) to 1·1% (0·8 to 1·4) in women. The largest decreases in colorectal cancer mortality were seen in countries with long-standing screening programmes. INTERPRETATION: We observed divergent trends in colorectal cancer incidence, mortality, and stage distribution across European countries, which appear to be largely explained by different levels of colorectal cancer screening implementation. FUNDING: German Cancer Aid (Deutsche Krebshilfe) and the German Federal Ministry of Education and Research.

Skin melanoma deaths within 1 or 3 years from diagnosis in Europe.

The steep increase in incidence of cutaneous malignant melanoma in white populations mainly applies to thin lesions with good survival suggesting overdiagnosis. Based on population-based cancer registries (CRs), we have investigated changes in aggressive melanoma, selecting only cases who died within 1 or 3 years after diagnosis in 11 European countries between 1995 and 2012. Trends in fatal cases were analysed by period of diagnosis, sex, tumour thickness, histologic subtype of the lesion, tumour site and CR with a multivariate generalised linear mixed effects model, where geographical area was considered as a random effect. We collected data on 123 360 invasive melanomas, with 5133 fatal cases at 1 year (4%) and 12 330 (10%) at 3 years. The number of fatal cases showed a 16% decrease at 1 year and 8% at 3 years between the first (1995-2000) and the last (2007-2012) period. The highest proportion of fatal cases was seen for men, older age (≥65 years), thick lesions (>1 mm), nodular melanoma, melanoma on the trunk and for poorly documented cases, lacking information about thickness and histologic subtype. The mixed-effects model showed a remarkable variability among European countries. The majority of registries showed a decreasing trend in fatal cases, but a few registries showed an opposite pattern. Trends in fatal melanoma cases, highlighting real changes in risk not related to overdiagnosis, showed a decrease in most European countries, with a few exceptions. Stronger efforts for early detection could lead to a more efficient treatment of melanoma in general.

Endocrine treatment and incidence of relapse in women with oestrogen receptor-positive breast cancer in Europe: a population-based study.

PURPOSE: Endocrine therapy (ET) is the mainstream adjuvant treatment for ER-positive breast cancer (BC). We analysed 9293 ER-positive BC patients diagnosed in nine European countries in 2009-2013 to investigate how comorbidities at diagnosis, age, stage and subtype affected ET use over time, and relapse. METHODS: Adjusted odds ratios (ORs) and 95% confidence intervals (95%CIs) of receiving ET were estimated according to Charlson comorbidity, age, stage and subtype using logistic regression. The 2-year cumulative incidence and adjusted sub-hazard ratios (SHRs) of relapse were estimated using competing risk analysis, with all-cause death as the competing event. The z-test was used to assess differences in the proportion of patients receiving ET in 1996-1998 and 2009-2013. RESULTS: Ninety percent of the patients started adjuvant ET, range 96% (Belgium, Estonia, Slovenia, Spain)-75% (Switzerland). ORs of starting ET were lower for women aged > 75 years, with severe comorbidities, or luminal B HER2-positive cancer. The factors independently increasing the risk of relapse were: not receiving ET (SHR 2.26, 95%CI 1.02-5.03); severe comorbidity (SHR 1.94, 95%CI 1.06-3.55); luminal B, either HER2 negative (SHR 3.06, 95%CI 1.61-5.79) or positive (SHR 3.10, 95%CI 1.36-7.07); stage II (SHR 3.20, 95%CI 1.56-6.57) or stage III (SHR 7.41, 95%CI 3.48-15.73). ET use increased significantly but differently across countries from 51-85% in 1996-1998 to 86-96% in 2009-2013. CONCLUSIONS: ER-positive BC patients in Europe are increasingly prescribed ET but between-country disparities persist. Older women and women with severe comorbidity less frequently receive ET. ET omission and severe comorbidity independently predict early disease relapse.

Reasons for low cervical cancer survival in new accession European Union countries: a EUROCARE-5 study.

PURPOSE: With better access to early diagnosis and appropriate treatment, cervical cancer (CC) burden decreased in several European countries. In Eastern European (EE) countries, which accessed European Union in 2004, CC survival was worse than in the rest of Europe. The present study investigates CC survival differences across five European regions, considering stage at diagnosis (local, regional and metastatic), morphology (mainly squamous versus glandular tumours) and patients' age. METHODS: We analysed 101,714 CC women diagnosed in 2000-2007 and followed-up to December 2008. Age-standardised 5-year relative survival (RS) and the excess risks of cancer death in the 5 years after diagnosis were computed. RESULTS: EE women were older and less commonly diagnosed with glandular tumours. Proportions of local stage cancers were similar across Europe, while morphology- and stage-specific RS (especially for non-metastatic disease) were lower in Eastern Europe. Adjusting for age and morphology, excess risk of local stage CC death for EE patients remained higher than that for other European women. CONCLUSION: Stage, age and morphology alone do not explain worse survival in Eastern Europe: less effective care may play a role, probably partly due to fewer or inadequate resources being allocated to health care in this area, compared to the rest of Europe.

Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years.

OBJECTIVE: The incidence of colorectal cancer (CRC) declines among subjects aged 50 years and above. An opposite trend appears among younger adults. In Europe, data on CRC incidence among younger adults are lacking. We therefore aimed to analyse European trends in CRC incidence and mortality in subjects younger than 50 years. DESIGN: Data on age-related CRC incidence and mortality between 1990 and 2016 were retrieved from national and regional cancer registries. Trends were analysed by Joinpoint regression and expressed as annual percent change. RESULTS: We retrieved data on 143.7 million people aged 20-49 years from 20 European countries. Of them, 187 918 (0.13%) were diagnosed with CRC. On average, CRC incidence increased with 7.9% per year among subjects aged 20-29 years from 2004 to 2016. The increase in the age group of 30-39 years was 4.9% per year from 2005 to 2016, the increase in the age group of 40-49 years was 1.6% per year from 2004 to 2016. This increase started earliest in subjects aged 20-29 years, and 10-20 years later in those aged 30-39 and 40-49 years. This is consistent with an age-cohort phenomenon. Although in most European countries the CRC incidence had risen, some heterogeneity was found between countries. CRC mortality did not significantly change among the youngest adults, but decreased with 1.1%per year between 1990 and 2016 and 2.4% per year between 1990 and 2009 among those aged 30-39 years and 40-49 years, respectively. CONCLUSION: CRC incidence rises among young adults in Europe. The cause for this trend needs to be elucidated. Clinicians should be aware of this trend. If the trend continues, screening guidelines may need to be reconsidered.

Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations.

OBJECTIVE: Resection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation. DESIGN: Data from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003-2016 were analysed. Age-standardised resection rates for overall and stage I-II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models. RESULTS: A total of 153 698 records were analysed. In population-based registries in 2012-2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I-II tumours, with great international variations. During 2003-2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I-II tumours: 0.05-0.18 and 0.01-0.06 across countries) and increasing age (ORs for patients 70-79 and ≥80 versus those <60 years: 0.37-0.63 and 0.03-0.16 across countries). Patients with advanced-stage tumours (stage III-IV: 63.8%-81.2%) and at older ages (≥70 years: 52.6%-59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application. CONCLUSION: Rates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations.

Explaining variation in quality of breast cancer care and its impact: a nationwide population-based study from Slovenia.

PURPOSE: To assess and explain variation in quality of care in breast cancer patients and estimate its impact on disease outcome. METHODS: The Slovenian National Cancer Registry database and clinical records of 1053 women with unilateral primarily non-metastatic invasive breast cancer diagnosed in 2013 were reviewed in this retrospective analysis. Quality care was defined as care fully compliant with quality indicators (QI) defined by European Society of Breast Cancer Specialists (EUSOMA). Multivariate logistic regression was used to determine the predictors of receiving quality care. Differences in overall survival (OS) and event-free survival (EFS, relapse, or progression of disease or death considered an event) based on adherence to QI were analyzed using Kaplan-Meier method and Cox models. RESULTS: Younger age, no comorbidities, and HER2-negative tumor were associated with increased odds ratios for receiving quality care, whereas tumor stage and type of hospital had no significant association. Median follow-up was 54.5 months. Not receiving quality care resulted in an increased risk of dying [hazard ratio (HR) 1.68; 95% confidence interval (CI) 1.06-2.66; p = 0.026]. Difference in EFS between two groups was significant after adjusting for case mix and type of hospital (HR 1.80; 95% CI 1.29-2.52; p = 0.001) but disappeared when type of treatment was added into the model (HR 1.30; 95% CI 0.89-1.90; p = 0.178). CONCLUSION: Observed comorbidity and age bias in delivering quality breast cancer care could be medically justifiable, whereas observed deviations dependent on HER2 status are puzzling. Complete adherence of treatment to quality indicators resulted in better OS.

Development and validation of a prognostic model to predict the prognosis of patients who underwent chemotherapy and resection of pancreatic adenocarcinoma: a large international population-based cohort study.

BACKGROUND: Pancreatic cancer (PaC) remains extremely lethal worldwide even after resection. PaC resection rates are low, making prognostic studies in resected PaC difficult. This large international population-based study aimed at exploring factors associated with survival in patients with resected TNM stage I-II PaC receiving chemotherapy and at developing and internationally validating a survival-predicting model. METHODS: Data of stage I-II PaC patients resected and receiving chemotherapy in 2003-2014 were obtained from the national cancer registries of Belgium, the Netherlands, Slovenia, and Norway, and the US Surveillance, Epidemiology, and End Results (SEER)-18 Program. Multivariable Cox proportional hazards models were constructed to investigate the associations of patient and tumor characteristics with overall survival, and analysis was performed in each country respectively without pooling. Prognostic factors remaining after backward selection in SEER-18 were used to build a nomogram, which was subjected to bootstrap internal validation and external validation using the European datasets. RESULTS: A total of 11,837 resected PaC patients were analyzed, with median survival time of 18-23 months and 3-year survival rates of 21-31%. In the main analysis, patient age, tumor T stage, N stage, and differentiation were associated with survival across most countries, with country-specific association patterns and strengths. However, tumor location was mostly not significantly associated with survival. Resection margin, hospital type, tumor size, positive and harvested lymph node number, lymph node ratio, and comorbidity number were associated with survival in certain countries where the information was available. A median survival time- and 1-, 2-, 3-, and 5-year survival probability-predictive nomogram incorporating the backward-selected variables in the main analysis was established. It fits each European national cohort similarly well. Calibration curves showed very good agreement between nomogram-prediction and actual observation. The concordance index of the nomogram (0.60) was significantly higher than that of the T and N stage-based model (0.56) for predicting survival. CONCLUSIONS: In these large international population-based cohorts, patients with resected PaC receiving chemotherapy have distinct characteristics independently associated with survival, with country-specific patterns and strengths. A robust benchmark population-based survival-predicting model is established and internationally validated. Like previous models predicting survival in resected PaC, our nomogram performs modestly.

Nonsurgical therapies for resected and unresected pancreatic cancer in Europe and USA in 2003-2014: a large international population-based study.

The role of chemotherapy in the treatment of pancreatic cancer (PaC) has been well-established, while radiation plays ambiguous roles. This international large-scale population-based study aimed to investigate the real-world application of chemotherapy and radiotherapy for resected and unresected PaC in Europe and USA. Population-based data from multiple European national cancer registries and the US Surveillance, Epidemiology and End Results (SEER)-18 database during 2003-2014 were analyzed. Temporal trends and geographical variations in the application rates of chemotherapy and radiotherapy were quantified using age standardization. Associations of treatment with demographic and clinical characteristics were assessed using multivariable logistic regression. A total of 141,533 PaC patients were analyzed. From 2003-2005 to 2012-2014, chemotherapy administration rates increased in most countries and more strongly among resected patients, while radiation rates were generally low with a slight decline or no obvious trend. In 2012-2014, 12.5% (Estonia) to 61.7% (Belgium) of resected and 17.1% (Slovenia) to 56.9% (Belgium) of unresected patients received chemotherapy. Radiation was administered in 2.6% (Netherlands) to 32.6% (USA) of resected and 1.0% (USA) to 6.0% (Belgium) of unresected patients. Strong temporal and geographical variations were observed. Patterns and strengths of associations of treatment administration with various demographic and clinical factors differed substantially between resected and unresected cancers and varied greatly across countries. Conclusively, administration of chemotherapy but not radiotherapy for PaC increased during the last decade in Europe and USA. Treatment rates were low and the uptake strongly varied across countries, highlighting the need for standardization in PaC treatment to improve patient care.

Stratified survival of resected and overall pancreatic cancer patients in Europe and the USA in the early twenty-first century: a large, international population-based study.

BACKGROUND: The prognosis of pancreatic cancer (PaC) strongly varies across different stages and age groups, which has unfortunately not been well recorded in the literature. This international population-based study aimed to provide tumor-node-metastasis (TNM) stage- and age-specific survival estimates and trends in resected and overall (resected and unresected) PaC in the early twenty-first century. METHODS: Using data from the US Surveillance, Epidemiology, and End Results-18 Program and the national cancer registries of the Netherlands, Belgium, Norway, and Slovenia, short-term and long-term overall survival results stratified by TNM stage and age in resected and overall primary PaC, irrespective of being microscopically confirmed or not, in 2003-2014 were computed using the Kaplan-Meier method. The temporal survival trends over three predefined periods (2003-2005, 2006-2008, and 2009-2011) were further examined using the log-rank test. RESULTS: In total, data for 125,183 patients were analyzed. Overall, age-stratified 3-year survival was 20-34% (< 60 years), 14-25% (60-69 years), and 9-13% (≥ 70 years) in stages I-II PaC; and 2-5% (< 60 years), 1-2% (60-69 years), and < 1-1% (≥ 70 years) in stages III-IV cancer. Patients who underwent operation had higher 3-year survival in each stage and age group (stages I-II: 23-39% (< 60 years), 16-31% (60-69 years), and 17-30% (≥ 70 years); stages III-IV: 5-19% (< 70 years) and 2-14% (≥ 70 years)). Perioperative survival also decreased with advancing stage and older age (stages I-II: 98-100% (< 60 years), 97-99% (60-69 years), and 94-99% (≥ 70 years); stages III-IV: 94-99% (< 70 years) and 81-96% (≥ 70 years)). Between 2003 and 2005 and 2009-2011, for overall PaC, both short-term and long-term survival improvements were observed in all countries except Belgium; for resected disease, short-term improvements were present only in the USA and Slovenia, but long-term improvements were observed in all countries except Slovenia, with stage-specific variations. CONCLUSIONS: Our large international study provides TNM stage- and age-specific population-based survival in overall and resected PaC that will facilitate clinical counseling. While the survival expectations for patients with resected PaC are substantially higher than the widely available and known dismal survival predictions for overall patients, conclusions on the benefits of resection cannot be made from this observational study. Patients with advanced-stage disease and/or older age should undergo careful risk assessment before treatment. Limited but inspiring improvement in survival is observed.

CD56 Expression Is an Important Prognostic Factor in Multiple Myeloma Even with Bortezomib Induction.

OBJECTIVES: In this retrospective study, we evaluated the impact of CD56, CD117, and CD28 expression on clinical characteristics and survival in newly diagnosed myeloma patients treated with bortezomib-based induction therapy. METHODS: We analyzed 110 myeloma patients. Immunophenotype was determined using panels consisting of CD19/CD38/CD45/CD56/CD138 and CD20, CD28, and CD117 were used additionally. All samples were tested for recurrent chromosomal aberrations. RESULTS: CD56, CD117, and CD28 expression rates were 71, 6, and 68%, respectively. The lack of CD56 expression was associated with light chain myeloma. The lack of CD117 expression was associated with elevated creatinine levels (p = 0.037). We discovered the correlation between CD 28 expression and female gender. The median progression-free survival (PFS) for patients with revised International Staging System stage 2 disease with CD56 expression or the lack of CD56 expression was 20.5 vs. 13.8 months (p = 0.03). In patients undergoing autologous hematopoietic stem cell transplantation (aHSCT), we found no difference in PFS and overall survival regarding the CD56 expression. We found no impact of CD117 and CD28 expression on PFS in patients regarding aHSCT. CONCLUSIONS: Induction treatment incorporating bortezomib diminishes the negative impact of the lack of CD117 expression and aberrancy of CD28 but does not overcome the negative impact of the lack of CD56 expression.

Risk of cancer after primary total hip replacement: The influence of bearings, cementation and the material of the stem.

Background and purpose - Despite the increasing number of total hip replacements (THRs), their systemic influence is still not known. We have studied the influence of specific features of THRs-the bearing surface, the use of bone cement and the material of the stem-on the cancer incidence. Patients and methods - In a retrospective cohort study we identified 8,343 patients with THRs performed at Valdoltra Hospital from September 1, 1997 to December 31, 2009. Patient data were linked to national cancer and population registries. The standardized incidence ratios (SIR) and Poisson regression relative risks (RR) were calculated for all and specific cancers. Results - General cancer risk in our cohort was comparable to the population risk. Comparing with population, the risk of prostate cancer was statistically significantly higher in patients with metal-on-metal bearings (SIR =1.35); with metal-on-polyethylene bearings (SIR =1.30), with non-cemented THRs (SIR =1.40), and with titanium alloy THRs (SIR =1.41). In these last 3 groups there was a lower risk of hematopoietic tumors (SIR =0.69; 0.66 and 0.66 respectively). Risk of kidney cancer was significantly higher in the non-metal-on-metal, non-cemented, and titanium alloy groups (SIR =1.30; 1.46 and 1.41 respectively). Risk of colorectal and lung cancer was significantly lower in the investigated cohort (SIR =0.82 and 0.83, respectively). Risk for all cancers combined as well as for prostate and skin cancer, shown by Poisson analysis, was higher in the metal-on-metal group compared with non-metal-on-metal group (RR =1.56; 2.02 and 1.92, respectively). Interpretation - Some associations were found between the THRs' features, especially a positive association between metal-on-metal bearings, and specific cancers.

Health-related Quality of Life Assessed by the EORTC QLQ-C30 Questionnaire in the General Slovenian Population.

BACKGROUND: The aim of our study was to obtain reference data of the EORTC QLQ-C30 quality of life dimensions for the general Slovenian population. We intend to provide the researchers and clinicians in our country with the expected mean health-related quality of life (HRQL) scores for distinctive socio-demographic population groups. METHODS: The EORTC QLQ-C30 questionnaire supplemented by a socio-demographic inquiry was mailed or distributed to 1,685 randomly selected individuals in the Slovenian population aged 18 - 90. Answers from 1,231 subjects representing socio-demographic diversity of the Slovenian population were collected and transformed into EORTC dimensions and symptoms. The impact of socio-demographic features on HRQL scores was assessed by multiple linear regression models. RESULTS: Gender, age and self-rated social class are the important confounders in the quality of life scores in our population. Men reported better quality of life on the majority of the specific scales and, at the same time, reported fewer symptoms. There was no gender-specific difference in cognitive functioning. The mean scores were consistently lower with age in both sexes. CONCLUSIONS: This is the first study to report the normative EORTC QLQ-C30 scores for one of the south-eastern European populations. The reported expected mean scores allow Slovenian oncologists to estimate what the quality of life in cancer patients would be, had they not been ill. As they are derived by common methodology, our results can easily be included in any further international comparisons or in the calculation of European summarized HRQL scores.

Single Nucleotide Polymorphisms in Genes MACC1, RAD18, MMP7 and SDF-1a As Prognostic Factors in Resectable Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) represents one of the most common malignancies worldwide. Research has indicated that functional gene changes such as single nucleotide polymorphism (SNP) influence carcinogenesis and metastasis and might have an influence on disease relapse. The aim of our study was to evaluate the role of SNPs in selected genes as prognostic markers in resectable CRC. PATIENTS AND METHODS: In total, 163 consecutive patients treated surgically for CRC of stages I, II and III at the University Medical Centre in Maribor in 2007 and 2008 were investigated. DNA was isolated from formalin-fixed paraffin-embedded CRC tissue from the Department of Pathology and SNPs in genes SDF-1a, MMP7, RAD18 and MACC1 were genotyped using polymerase chain reaction followed by high resolution melting curve analysis or restriction fragment length polymorphism. RESULTS: We found worse disease-free survival (DFS) for patients with TT genotype of SNP rs1990172 in gene MACC1 (p = 0.029). Next, we found worse DFS for patients with GG genotype for SNP rs373572 in gene RAD18 (p = 0.020). Higher frequency of genotype GG of MMP7 SNP rs11568818 was found in patients with T3/T4 stage (p = 0.014), N1/N2 stage (p = 0.041) and with lymphovascular invasion (p = 0.018). For MACC1 rs1990172 SNP we found higher frequency of genotype TT in patients with T3/T4 staging (p = 0.024). Higher frequency of genotype GG of RAD18 rs373572 was also found in patients with T1/T2 stage with disease relapse (p = 0.041). CONCLUSIONS: Our results indicate the role of SNPs as prognostic factors in resectable CRC.

Cancer burden in slovenia with the time trends analysis.

BACKGROUND: The aim of our study was to describe cancer burden and time trends of all cancers combined, the most frequent as well as the rare cancers in Slovenia. PATIENTS AND METHODS: The principal data source was the population-based Cancer Registry of Republic of Slovenia. The cancer burden is presented by incidence and prevalence for the period 1950-2013 and by mortality for years 1985-2013. The time trends were characterized in terms of an average annual percent change estimated by the log-linear joinpoint regression. The Dyba-Hakulinen method was used for estimation of incidence in 2016 and the projections of cancer incidence for the year 2025 were calculated applying the Globocan projection software. RESULTS: In recent years, near 14,000 Slovenes were diagnosed with cancer per year and just over 6,000 died; more than 94,000 people who were ever diagnosed with cancer are currently living among us. The total burden of cancer is dominated by five most common cancer sites: skin (non-melanoma), colon and rectum, lung, breast and prostate, together representing almost 60% of all new cancer cases. On average the incidence of common cancers in Slovenia is increasing for 3.0% per year in last decade, but the incidence of rare cancers is stable. CONCLUSIONS: Because cancer occurs more among the elderly, and additionally more numerous post-war generation is entering this age group, it is expected that the burden of this disease will be growing further, even if the level of risk factors remains the same as today.

Squamous cell carcinoma of unknown primary tumor metastatic to neck nodes: role of elective irradiation.

In patients with squamous cell carcinoma (SCC) metastases to neck lymph nodes and unknown primary tumor, the role of elective irradiation of uninvolved neck and potential mucosal primary sites is yet to be determined. The aim of this study was to review the experience treating SCC of unknown primary metastatic to neck nodes with surgery and postoperative radiotherapy (PORT) in Slovenia between 1995 and 2010 and to determine the importance of the extent of irradiated volume. For this purpose, the nationwide Cancer Registry of Slovenia database was used for identifying patients. 126 patients were identified. Involved-field PORT and extended-field PORT was used in 50 and 76 patients, respectively. At 5 years, locoregional control was 86 %, disease-specific survival 77 %, and overall survival 57 %. In multivariate analysis, the extent of irradiated volume has not been predictive for any outcome under study. Grade ≥3 acute and late radiotherapy-induced toxicities were more frequent in the extended-field PORT group. In conclusion, although not superior, involved-field PORT seems to be a preferred treatment option in SCC of unknown primary metastatic to neck nodes due to significantly reduced toxicity and better prospects for successful salvage.

Incidence trends in head and neck squamous cell carcinoma in Slovenia, 1983-2009: role of human papillomavirus infection.

An increase in the incidence of oropharyngeal squamous cell carcinoma (OPSCC) was observed in several population-based registries and has been attributed to human papillomavirus (HPV) infection. In the present study, we aimed to assess the contribution of HPV infection to the burden of mucosal head and neck squamous cell carcinoma (HNSCC) in Slovenia. For this purpose, data from the nationwide Cancer Registry of Slovenia for cases diagnosed between 1983 and 2009 were analyzed to determine time trends of age-adjusted incidence rates and survival in terms of annual percentage change (APC) for HNSCC in potentially HPV-related and HPV-unrelated sites. In addition, determination of p16 protein, HPV DNA and E6/E7 mRNA was performed in a cohort of OPSCC patients identified from the prospective database for the years 2007-2008. In total, 2,862 cases of HNSCC in potentially HPV-related sites and 7,006 cases in potentially HPV-unrelated sites were identified with decreased incidence observed over the time period in both groups (-0.58; 95 % CI -1.28 to -0.13 and -0.90; 95 % CI -1.23 to -0.57). Regardless of the group, incidence trends for both genders showed a significant decrease in men and increase in women. In a cohort of 99 OPSCC patients diagnosed between 2007 and 2008, 20 (20.2 %) patients had HPV positive tumors and exhibited a superior outcome compared to HPV-negative patients. In conclusion, results of the epidemiologic and histopathologic study confirmed that HPV infection had no major impact on the incidence trends in the Slovenian patients with HNSCC and, specifically, OPSCC during the studied period.

Impact of Indoor Radon Exposure on Lung Cancer Incidence in Slovenia.

Indoor radon is an important risk factor for lung cancer, as 3-14% of lung cancer cases can be attributed to radon. The aim of our study was to estimate the impact of indoor radon exposure on lung cancer incidence over the last 40 years in Slovenia. We analyzed the distribution of lung cancer incidence across 212 municipalities and 6032 settlements in Slovenia. The standardized incidence ratios were smoothed with the Besag-York-Mollie model and fitted with the integrated nested Laplace approximation. A categorical explanatory variable, the risk of indoor radon exposure with low, moderate and high risk values, was added to the models. We also calculated the population attributable fraction. Between 2.8% and 6.5% of the lung cancer cases in Slovenia were attributable to indoor radon exposure, with values varying by time period. The relative risk of developing lung cancer was significantly higher among the residents of areas with a moderate and high risk of radon exposure. Indoor radon exposure is an important risk factor for lung cancer in Slovenia in areas with high natural radon radiation (especially in the southern and south-eastern parts of the country).