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).

Impact of early integrated rehabilitation on fatigue in 600 patients with breast cancer - a prospective study.

BACKGROUND: Fatigue after breast cancer treatment is a common burden that is challenging to treat. The aim of this study was to explore if such integrated rehabilitation program reduces the prevalence of chronic fatigue compared to simple, non-integrated rehabilitation. PATIENTS AND METHODS: The subjects of our prospective study were 600 female breast cancer patients (29-65 [mean 52 years] of age), who participated in the pilot study on the individualized integrated rehabilitation of breast cancer patients in 2019-2021 and were monitored for one year. The control group included 301 patients and the intervention group numbered 299 patients. The patients completed three questionnaires (EORTC QLQ-C30, -BR23 and NCCN): before cancer treatment, and then six and twelve months after the beginning of cancer treatment. The control group obtained the standard rehabilitation program, while the intervention group was part of the early, individualized multidisciplinary and integrated approach of rehabilitation. The rehabilitation coordinator referred patients for additional interventions (e.g., psychologist, gynecologist, pain management team, physiotherapy, clinical nutrition team, kinesiologist-guided online training, vocational rehabilitation, general practitioner). Data on the patients' demographics, disease extent, cancer treatment and complaints reported in questionnaires were collected and analyzed. RESULTS: There were no differences between the control and the intervention group of patients in terms of age, education, disease extent, surgical procedures, systemic cancer treatment, or radiotherapy, and also no differences in the fatigue before the beginning of treatment. However, patients from the control group had a greater level of constant fatigue than patients from the intervention group half a year (p = 0.018) and a year (p = 0.001) after the beginning of treatment. Furthermore, a greater proportion of patients from the control group experienced significant interference with their usual activities from fatigue than from the intervention group, half a year (p = 0.042) and a year (p = 0.001) after the beginning of treatment. A multivariate logistic regression showed that one year after the beginning of treatment, the only independent factor correlated to fatigue was inclusion into the intervention group (p = 0.044). Inclusion in the intervention group was beneficial-patients from the control group were 1.5 times more likely to be fatigued. CONCLUSIONS: Early individualized integrated rehabilitation is associated with a lower prevalence of chronic fatigue or fatigue interfering with usual activities in breast cancer patients in comparison to the control group of patients.

A Population-Based Study of Patients With Small Cell Carcinoma of the Ovary, Hypercalcemic Type, Encompassing a 30-Year Period.

CONTEXT.­: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and lethal tumor, characterized by hypercalcemia and early onset and associated with germline and somatic SMARCA4 variants. OBJECTIVE.­: To identify all known cases of SCCOHT in the Slovenian population from 1991 to 2021 and present genetic testing results, histopathologic findings, and clinical data for these patients. We also estimate the incidence of SCCOHT. DESIGN.­: We conducted a retrospective analysis of hospital medical records and data from the Slovenian Cancer Registry in order to identify cases of SCCOHT and obtain relevant clinical data. Histopathologic review of tumor samples with assessment of immunohistochemical staining for SMARCA4/BRG1 was undertaken to confirm the diagnosis of SCCOHT. Germline and somatic genetic analyses were performed using targeted next-generation sequencing. RESULTS.­: Between 1991 and 2021, we identified 7 cases of SCCOHT in a population of 2 million. Genetic causes were determined in all cases. Two novel germline loss-of-function variants in SMARCA4 LRG_878t1:c.1423_1429delTACCTCA p.(Tyr475Ilefs*24) and LRG_878t1:c.3216-1G>T were identified. At diagnosis, patients were ages 21 to 41 and had International Federation of Gynecology and Obstetrics, or FIGO, stage IA-III disease. Outcomes were poor, with 6 of 7 patients dying of disease-related complications within 27 months from diagnosis. One patient had stable disease for 12 months while receiving immunotherapy. CONCLUSIONS.­: We present genetic, histopathologic, and clinical characteristics for all cases of SCCOHT identified in the Slovenian population during a 30-year period. We report 2 novel germline SMARCA4 variants, possibly associated with high penetrance. We estimate the minimal incidence of SCCOHT to be 0.12 per 1 million per year.

Evaluation of an Early Individualized Integrated Rehabilitation Program versus Standard Rehabilitation Program for Smoking Cessation in 115 Smokers Among 467 Female Breast Cancer Patients 2019-2021 in Slovenia.

BACKGROUND Cigarette smoking affects cancer risk and cardiovascular risk. Smoking cessation is very beneficial for health. This study aimed to evaluate an early individualized integrated rehabilitation program and standard rehabilitation program for smoking cessation in breast cancer patients. MATERIAL AND METHODS This prospective study included 467 breast cancer patients (29-65 (mean 52) years of age) treated at the Institute of Oncology Ljubljana from 2019 to 2021 and were followed longer than 1 year. The control group and intervention group included 282 and 185 patients, respectively. Three questionnaires were completed by patients before and 1 year after the beginning of oncological treatment. The intervention group received interventions according to the patient's needs, while the control group underwent standard rehabilitation. The data obtained from the survey were analyzed using the chi-square test and analysis of variance. RESULTS In total, 115 patients were tobacco smokers before the beginning of cancer treatment. There were no differences between the intervention and control group in the prevalence of smoking before the treatment. Before the cancer treatment, smoking was present in the intervention group in 22% and in control group in 27% (P=0.27). One year after the beginning of cancer treatment, smoking was present in the intervention group in only 10% of cases, while it was present in control group in 20% of cases. Smoking was significantly less common in the intervention group than in the control group (P=0.004). CONCLUSIONS Smoking cessation was more common after early integrated rehabilitation than after standard rehabilitation.

Estimating exposure to extremely low frequency magnetic fields near high-voltage power lines and assessment of possible increased cancer risk among Slovenian children and adolescents.

BACKGROUND: Some previous research showed that average daily exposure to extremely low frequency (ELF) magnetic fields (MF) of more than 0.3 or 0.4 µT could potentially increase risk of childhood leukaemia. MATERIALS AND METHODS: To allow calculations of ELF MF around high voltage (HV) power lines (PL) for the whole Slovenia, a new three-dimensional method including precision terrain elevation data was developed to calculate the long-term average ELF MF. Data on population of Slovenian children and adolescents and on cancer patients with leukaemia's aged 0-19 years, brain tumours at age 0-29, and cancer in general at age 0-14 for a 12-year period 2005-2016 was obtained from the Slovenian Cancer Registry. RESULTS: According to the large-scale calculation for the whole country, only 0.5% of children and adolescents under the age of 19 in Slovenia lived in an area near HV PL with ELF MF density greater than 0.1 µT. The risk of cancer for children and adolescents living in areas with higher ELF MF was not significantly different from the risk of their peers. CONCLUSIONS: The new method enables relatively fast calculation of the value of low-frequency magnetic fields for arbitrary loads of the power distribution network, as the value of each source for arbitrary load is calculated by scaling the value for nominal load, which also enables significantly faster adjustment of calculated estimates in the power distribution network.

Impact of the COVID-19 epidemic on cancer burden and cancer care in Slovenia: a follow-up study.

BACKGROUND: In Slovenia, cancer care services were exempt from government decrees for COVID-19 containment. Nevertheless, cancer control can be impacted also by access to other health services and changes in health-seeking behaviour. In this follow up study, we explored changes in cancer burden and cancer care beyond the first months after the onset of the COVID-19 epidemic. MATERIALS AND METHODS: We analysed routinely collected data for the period January 2019 through July 2022 from three sources: (1) pathohistological and clinical practice cancer notifications from two major cancer centres in Ljubljana and Maribor (source: Slovenian Cancer Registry); (2) referrals issued for oncological services (source: e-referral system); and (3) outpatient appointments and diagnostic imaging performed (source: administrative data of the Institute of Oncology Ljubljana - IOL). Additionally, changes in certain clinical and demographic characteristics in patients diagnosed and treated during the epidemic were analysed using the Hospital-Based Cancer Registry of the IOL (period 2015-2021). RESULTS: After a drop in referrals to follow-up cancer appointments in April 2020, in June-August 2020, there was an increase in referrals, but it did not make-up for the drop in the first wave; the numbers in 2021 and 2022 were even lower than 2020. Referrals to first cancer care appointments and genetic testing and counselling increased in 2021 compared to 2019 and in 2022 increased further by more than a quarter. First and follow-up outpatient appointments and cancer diagnostic imaging at the IOL dropped after the onset of the epidemic in March 2020 but were as high as expected according to 2019 baseline already in 2021. Some deficits remain for follow-up outpatients' appointments in surgical and radiotherapy departments. There were more CT, MRI and PET scans performed during the COVID-19 period than before. New cancer diagnoses dropped in all observed years 2020, 2021 and until July 2022 by 6%, 3% and 8%, respectively, varying substantially by cancer type. The largest drop was seen in the 50-64 age group (almost 14% in 2020 and 16% in 2021), while for patients older than 80 years, the numbers were above expected according to the 2015-2019 average (4% in 2020, 8% in 2021). CONCLUSIONS: Our results show a varying effect of COVID-19 epidemic in Slovenia for different types of cancers and at different stages on the patient care pathway - it is probably a mixture of changes in health-seeking behaviour and systemic changes due to modifications in healthcare organisation on account of COVID-19. A general drop in new cancer cases reflects disruptions in the pre-diagnostic phase and could have profound long-term consequences on cancer burden indicators.

Prognostic factors and outcomes in women with breast cancer in Slovenia in relation to step-wise implementation of organized screening.

INTRODUCTION: The aim of organized breast cancer screening is early detection and reduction in mortality. Organized screening should promote equal access and reduce socio-economic inequalities. In Slovenia, organized breast cancer screening achieved complete coverage in 11-years' time. We explored whether step-wise implementation reflects in prognostic factors (earlier diagnosis and treatment) and survival of breast cancer patients in our population. METHODS: Using population-based cancer registry and screening registry data on breast cancer cases from 2008-2018, we compared stage distribution and mean time to surgical treatment in (A) women who underwent at least one mammography in the organized screening programme, women who received at least one invitation but did not undergo mammography and women who did not receive any screening invitation, and in (B) women who were invited to organized screening and those who were not. We also compared net survival by stage in different groups of women according to their screening programme status. RESULTS: Women who underwent at least one mammography in organized screening had lower disease stage at diagnosis. Time-to-treatment analysis showed mean time to surgery was shortest in women not included in organized screening (all stages = 36.0 days vs. 40.3 days in women included in organized screening). This could be due to quality assurance protocols with an obligatory multidisciplinary approach within the organized screening vs. standard treatment pathways which can vary in different (smaller) hospitals. Higher standard of care in screening is reflected in better survival in women included in organized screening (5-years net survival for regional stage: at least one mammography in the screening programme- 96%; invitation, but no mammography- 87.4%; no invitation or mammography in the screening programme- 82.6%). CONCLUSION: Our study, which is one of the first in central European countries, shows that introduction of organized screening has temporary effects on population cancer burden indicators already during roll-out period, which should therefore be as short as possible.

Current Concepts of Vitiligo Immunopathogenesis.

Vitiligo is an acquired immune-mediated disorder of pigmentation clinically characterized by well-defined depigmented or chalk-white macules and patches on the skin. The prevalence of vitiligo varies by geographical area, affecting 0.5% to 2% of the population. The disease imposes a significant psychological burden due to its major impact on patients' social and emotional aspects of life. Given its autoimmune background, vitiligo is frequently associated with other autoimmune diseases or immune-mediated diseases. Vitiligo is a multifaceted disorder that involves both genetic predisposition and environmental triggers. In recent years, major predisposing genetic loci for the development of vitiligo have been discovered. The current findings emphasize the critical role of immune cells and their mediators in the immunopathogenesis of vitiligo. Oxidative-stress-mediated activation of innate immunity cells such as dendritic cells, natural killer, and ILC-1 cells is thought to be a key event in the early onset of vitiligo. Innate immunity cells serve as a bridge to adaptive immunity cells including T helper 1 cells, cytotoxic T cells and resident memory T cells. IFN-γ is the primary cytokine mediator that activates the JAK/STAT pathway, causing keratinocytes to produce the key chemokines CXCL9 and CXCL10. Complex interactions between immune and non-immune cells finally result in apoptosis of melanocytes. This paper summarizes current knowledge on the etiological and genetic factors that contribute to vitiligo, with a focus on immunopathogenesis and the key cellular and cytokine players in the disease's inflammatory pathways.

Overall and stage-specific survival of patients with screen-detected colorectal cancer in European countries: A population-based study in 9 countries.

Background: An increasing proportion of colorectal cancers (CRCs) are detected through screening due to the availability of organised population-based programmes. We aimed to analyse survival probabilities of patients with screen-detected CRC in European countries. Methods: Data from CRC patients were obtained from 16 population-based cancer registries in nine European countries. We included patients with cancer diagnosed from the year organised CRC screening programmes were introduced until the most recent year with available data at the time of analysis, whose ages at diagnosis fell into the age groups targeted by screening. Patients were followed up with regards to vital status until 2016-2020 across the various countries. Overall and CRC-specific survival were analysed by mode of detection and stage at diagnosis for all countries combined and for each country separately using the Kaplan-Meier method. Findings: We included data from 228 134 patients, of whom 134 597 (aged 60-69 years at diagnosis targeted by screening in all countries) were considered in analyses for all countries combined. 22·3% (38 080/134 597) of patients had cancer detected through screening. Most screen-detected cancers were found at stages I-II (65·6% [12 772/19 469 included in stage-specific analyses]), while the majority of non-screen-detected cancers were found at stages III-IV (56·4% [31 882/56 543 included in stage-specific analyses]). Five-year overall and CRC-specific survival rates for patients with screen-detected cancer were 83·4% (95% CI 82·9-83·9) and 89·2% (88·8-89·7), respectively; for patients with non-screen-detected cancer, they were much lower (57·5% [57·2-57·8] and 65·7% [65·4-66·1], respectively). The favourable survival of patients with screen-detected cancer was also seen within each stage - five-year overall survival rates for patients with screen-detected stage I, II, III, and IV cancers were 92.4% (95% CI 91·6-93·1), 87·9% (86·6-89·1), 80·7% (79·3-82·0), and 32·3 (29·4-35·2), respectively. These patterns were also consistently seen for each individual country. Interpretation: Patients with cancer diagnosed at screening have a very favourable prognosis. In the rare case of detection of advanced stage cancer, survival probabilities are still much higher than those commonly reported for all patients regardless of mode of detection. Although these results cannot be taken to quantify screening effects, they provide useful and encouraging information for patients with screen-detected CRC and their physicians. Funding: This study was supported in part by grants from the German Federal Ministry of Education and Research and the German Cancer Aid.

Survival trends of patients with non-metastatic gastric adenocarcinoma in the US and European countries: the impact of decreasing resection rates.

BACKGROUND: We previously observed decreasing resection rates of non-metastatic gastric adenocarcinoma (GaC) in the US and some European countries. If and to what extent these trends affect the trends in overall survival (OS) of patients with non-metastatic GaC at the population level remain unclear. This large international population-based cohort study aimed to assess the impact of the previously observed decreasing resection rates on multivariable-adjusted trends in the long-term OS of patients with non-metastatic GaC. METHODS: Individual-level data of patients with non-metastatic GaC were obtained from the national cancer registries of the Netherlands, Belgium, Sweden, Norway, and Slovenia, and the US Surveillance, Epidemiology, and End Results database. We analyzed data for each country separately. Associations between year of diagnosis and OS were assessed using Cox proportional hazards regression model with adjustment for multiple prognostic variables, with and without including resection and chemotherapy as potential explanatory variables. RESULTS: A total of 66,398 non-metastatic GaC patients diagnosed in 2003-2016 were analyzed, with an accumulated follow-up of 172,357 person-years. Without adjustment for resection, OS was improved only slightly in the US [hazard ratio (HR)per year = 0.99; HR≥vs.<2010 = 0.96], and no improvement was observed in the investigated European countries, with OS even worsening in Sweden (HRper year = 1.03; HR≥vs.<2010 = 1.17). After adjusting for resection, the increasing OS trend became stronger in the US (HRper year = 0.98; HR≥vs.<2010 = 0.88), and the temporal trend became insignificant in Sweden. In Slovenia (HRper year = 0.99; HR≥vs.<2010 = 0.92) and Norway (HRper year = 0.97; HR≥vs.<2010 = 0.86), improved OS over time emerged after resection adjustment. Improved OS in patients undergoing resection was observed in the US, the Netherlands, and Norway. Adjustment for chemotherapy did not alter the observed associations. Stratified analyses by tumor location showed mostly similar results with the findings in all patients with non-metastatic GaCs regarding the associations between year of diagnosis and survival. CONCLUSIONS: OS of patients with non-metastatic GaC mostly did not improve in selected European countries and was even worsened in Sweden, while it was slightly increased in the US in the early 21st century. Progress in OS of patients with non-metastatic GaC seems to have been impeded to a large extent by decreasing rates of resection.

Proportion and stage distribution of screen-detected and non-screen-detected colorectal cancer in nine European countries: an international, population-based study.

BACKGROUND: The effects of recently implemented colorectal cancer screening programmes in Europe on colorectal cancer mortality will take several years to be fully known. We aimed to analyse the characteristics and parameters of screening programmes, proportions of colorectal cancers detected through screening, and stage distribution in screen-detected and non-screen-detected colorectal cancers to provide a timely assessment of the potential effects of screening programmes in several European countries. METHODS: We conducted this population-based study in nine European countries for which data on mode of detection were available (Belgium, Denmark, England, France, Italy, Ireland, the Netherlands, Slovenia, and Spain). Data from 16 population-based cancer registries were included. Patients were included if they were diagnosed with colorectal cancer from the year that organised colorectal cancer screening programmes were implemented in each country until the latest year with available data at the time of analysis, and if their age at diagnosis fell within the age groups targeted by the programmes. Data collected included sex, age at diagnosis, date of diagnosis, topography, morphology, clinical and pathological TNM information based on the edition in place at time of diagnosis, and mode of detection (ie, screen detected or non-screen detected). If stage information was not available, patients were not included in stage-specific analyses. The primary outcome was proportion and stage distribution of screen-detected versus non-screen detected colorectal cancers. FINDINGS: 228 667 colorectal cancer cases were included in the analyses. Proportions of screen-detected cancers varied widely across countries and regions. The highest proportions (40-60%) were found in Slovenia and the Basque Country in Spain, where FIT-based programmes were fully rolled out, and participation rates were higher than 50%. A similar proportion of screen-detected cancers was also found for the Netherlands in 2015, where participation was over 70%, even though the programme had not yet been fully rolled out to all age groups. In most other countries and regions, proportions of screen-detected cancers were below 30%. Compared with non-screen-detected cancers, screen-detected cancers were much more often found in the distal colon (range 34·5-51·1% screen detected vs 26·4-35·7% non-screen detected) and less often in the proximal colon (19·5-29·9% screen detected vs 24·9-32·8% non-screen detected) p≤0·02 for each country, more often at stage I (35·7-52·7% screen detected vs 13·2-24·9% non-screen detected), and less often at stage IV (5·8-12·5% screen detected vs 22·5-31·9% non-screen detected) p<0·0001 for each country. INTERPRETATION: The proportion of colorectal cancer cases detected by screening varied widely between countries. However, in all countries, screen-detected cancers had a more favourable stage distribution than cancers detected otherwise. There is still much need and scope for improving early detection of cancer across all segments of the colorectum, and particularly in the proximal colon and rectum. FUNDING: Deutsche Krebshilfe.

Cancer Patients' Survival According to Socioeconomic Environment in a High-Income Country with Universal Health Coverage.

Despite having an established systematic approach to population survival estimation in Slovenia, the influence of socioeconomic environment on cancer patients' survival has not yet been evaluated. Thus, the main aim of our study was to quantify the potential impact of socioeconomic environment on cancer patients' survival in our population in the 21st century. The net survival was calculated and stratified into quintiles of Slovenian version of the European Deprivation Index for all adult cancer patients diagnosed between 2004 and 2018 using the national cancer registry data. After accounting for basic demographic variables (age and gender), differences in stage at diagnosis, as well as the impact of the cancer treatment improvements over time, we found that cancer patients in Slovenia with lower socioeconomic status experience worse survival and have higher mortality. In particular, the odds of dying from oral, stomach, colorectal, liver, pancreatic, lung, breast, ovarian, corpus uteri, prostate, and bladder cancers, as well as for melanoma, leukemia, and non-Hodgkin lymphoma, are significantly higher in the socioeconomically most deprived group of patients compared to the most affluent group. The inequalities in cancer burden we found could help decision-makers to better understand the magnitude of this problem.

Improved Survival after Breast-Conserving Therapy Compared with Mastectomy in Stage I-IIA Breast Cancer.

In the current study, we sought to compare survival outcomes after breast-conserving therapy (BCT) or mastectomy alone in patients with stage I-IIA breast cancer, whose tumors are typically suitable for both locoregional treatments. The study cohort consisted of 1360 patients with stage I-IIA (T1-2N0 or T0-1N1) breast cancer diagnosed between 2001 and 2013 and treated with either BCT (n = 1021, 75.1%) or mastectomy alone (n = 339, 24.9%). Median follow-ups for disease-free survival (DFS) and overall survival (OS) were 6.9 years (range, 0.3-15.9) and 7.5 years (range, 0.2-25.9), respectively. Fifteen (1.1%), 14 (1.0%) and 48 (3.5%) patients experienced local, regional, and distant relapse, respectively. For the whole cohort of patients, the estimated 5-year DFS and OS were 96% and 97%, respectively. After stratification based on the type of local treatment, the estimated 5-year DFS for BCT was 97%, while it was 91% (p < 0.001) for mastectomy-only treatment. Inverse probability of treatment weighting matching based on confounding confirmed that mastectomy was associated with worse DFS (HR 2.839, 95% CI 1.760-4.579, p < 0.0001), but not with OS (HR 1.455, 95% CI 0.844-2.511, p = 0.177). In our study, BCT was shown to have improved disease-specific outcomes compared to mastectomy alone, emphasizing the important role of adjuvant treatments, including postoperative radiation therapy, in patients with early-stage breast cancer at diagnosis.

Largely varying patterns and trends of primary cancer-directed resection for gastric carcinoma with synchronous distant metastasis in Europe and the US: a population-based study calling for further standardization of care.

AIMS: The role of resection remains debated in cases of metastatic gastric carcinoma (mGC). Some mGCs are technically resectable. At the population level, the real-world application of resection for mGC remains largely unclear in most Western countries. This large, population-based international investigation aimed to reveal the resection patterns and trends for mGC and the treatment-associated factors in Europe and the US. METHODS: Data on cases with microscopically-confirmed primary invasive stomach carcinoma with distant metastasis were obtained from the nationwide cancer registries of the Netherlands, Belgium, Norway, Sweden, Estonia, and Slovenia and the US Surveillance, Epidemiology, and End Results-18 database. We calculated age-standardized rates of primary cancer-directed resection and assessed resection trends using linear regression. We investigated associations of treatment with patient and cancer factors using multivariable-adjusted log-binomial regression. RESULTS: Among 133,321 patients with gastric cancer, overall, 40,215 cases with mGC diagnosed between 2003-2017 were investigated. Age-standardized resection rates significantly declined over time in the US, Belgium, Sweden, and Norway (by 5-14%). Resection rates greatly differed from 5% to 16% in 2013-2014. Cases with older ages, cardia tumors, or tumors involving adjacent structures were significantly less often operated across most countries. Sex was not significantly associated with resection. Across countries the association patterns and strengths differed largely. With multivariable adjustment, resection rates decreased significantly in all countries except Slovenia and Estonia (prevalence ratio per year = 0.90-0.98), and the decreasing trends were consistently observed in various stratifications by age and location. CONCLUSION: In Europe and the US, resection patterns and trends largely varied across countries for mGCs, which were mostly less often resected in the early 21st century. Various resection-associated factors were shown, with greatly varying association patterns and strengths. Our report could aid to identify discrepancies in clinical practice and highlight the great need for further clarifying the role of resection in mGCs to enhance standardization of care.

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.

Crude annual incidence rate of medullary thyroid cancer and RET mutation frequency.

AIM: To determine the frequency and type of RET mutation in Slovenian medullary thyroid cancer (MTC) patients and estimate the crude annual incidence of MTC in Slovenia. METHODS: This referral-center retrospective analysis involved 186 MTC patients diagnosed between 1995 and 2015 and their relatives who underwent genetic counseling and testing. The crude incidence rate of MTC was estimated with the joinpoint regression analysis. Genomic DNA was isolated, and exons 10, 11, 13, 14, 15, and 16 of the RET proto-oncogene were amplified with polymerase chain reaction. Point mutations of the RET gene were detected by single-strand conformation analysis and DNA sequencing. Detected mutations were confirmed by restriction enzymes. RESULTS: The average crude annual incidence rate of MTC in Slovenia was 0.34/100,000. A germline mutation in the RET proto-oncogene was identified in 25.9% of MTC patients. The most frequently altered codons were codons 634 and 618, followed by codon 790, codon 804, and codon 918. CONCLUSIONS: Annual incidence increase and nation-specific frequency of RET mutations justify the future use of genetic counseling and testing of MTC patients in Slovenia.

Water and Soil Pollution: Ecological Environmental Study Methodologies Useful for Public Health Projects. A Literature Review.

Health risks at population level may be investigated with different types of environmental studies depending on access to data and funds. Options include ecological studies, case-control studies with individual interviews and human sample analysis, risk assessment or cohort studies. Most public health projects use data and methodologies already available due to the cost of ad-hoc data collection. The aim of the article is to perform a literature review of environmental exposure and health outcomes with main focus on methodologies for assessing an association between water and/or soil pollutants and cancer. A systematic literature search was performed in May 2019 using PubMed. Articles were assessed by four independent reviewers. Forty articles were identified and divided into four groups, according to the data and methods they used, i.e.: (1) regression models with data by geographical area; (2) regression models with data at individual level; (3) exposure intensity threshold values for evaluating health outcome trends; (4) analyses of distance between source of pollutant and health outcome clusters. The issue of exposure assessment has been investigated for over 40 years and the most important innovations regard technologies developed to measure pollutants, statistical methodologies to assess exposure, and software development. Thanks to these changes, it has been possible to develop and apply geo-coding and statistical methods to reduce the ecological bias when considering the relationship between humans, geographic areas, pollutants, and health outcomes. The results of the present review may contribute to optimize the use of public health resources.