Mammography screening in three Finnish residential areas: comprehensive population-based study of breast cancer incidence and incidence-based mortality 1976-2009.

BACKGROUND: The aim of this study was to evaluate the effectiveness of a large-scale screening programme for breast cancer (BC) in Turku, Finland. Incidence and incidence-based mortality (IBM) figures were compared with the areas applying different screening policies. METHODS: Deaths and person-time of women aged 40-84 were assessed for the period 1976-1986 (prescreening era) and the periods 1987-1997 and 1998-2009 (screening periods) using incidence and IBM by age at diagnosis and at death. There was a total of 40.7 million women-years, 83 497 invasive BCs obtained from the Finnish Cancer Registry; 17 508 BC deaths were linked with the data from Statistics Finland. RESULTS: In Turku, a significant (> 20%) reduction in IBM occurred during 1987-2009 among women aged 60-74 years at diagnosis compared with Helsinki (IBMRR: 0.75, 95% CI: 0.57-1.00), and in women aged 75-84 years at death compared with the rest of Finland (IBMRR: 0.72, 95% CI: 0.53-0.96). CONCLUSIONS: The wide mammography screening programme in Turku was effective in decreasing BC mortality in the elderly age groups. These results support the implementation of BC screening from age 50 up to 74 years.

Basic linguistic composition recruits the left anterior temporal lobe and left angular gyrus during both listening and reading.

Language is experienced primarily through one of two mediums--spoken words and written text. Although substantially different in form, these two linguistic vehicles possess similar powers of expression. Consequently, one goal for the cognitive neuroscience of language is to determine where, if anywhere, along the neural path from sensory stimulation to ultimate comprehension these two processing streams converge. In the present study, we investigate the relationship between basic combinatorial operations in both reading and listening. Using magnetoencephalography, we measured neural activity elicited by the comprehension of simple adjective-noun phrases (red boat) using the same linguistic materials and tasks in both modalities. The present paradigm deviates from previous cross-modality studies by investigating only basic combinatorial mechanisms--specifically, those evoked by the construction of simple adjective-noun phrases. Our results indicate that both modalities rely upon shared neural mechanisms localized to the left anterior temporal lobe (lATL) and left angular gyrus (lAG) during such processing. Furthermore, we found that combinatorial mechanisms subserved by these regions are deployed in the same temporal order within each modality, with lATL activity preceding lAG activity. Modality-specific combinatorial effects were identified during initial perceptual processing, suggesting top-down modulation of low-level mechanisms even during basic composition.

Effects of annual vs triennial mammography interval on breast cancer incidence and mortality in ages 40-49 in Finland.

BACKGROUND: The aim of this study was to evaluate the effects of mammography screening invitation interval on breast cancer mortality in women aged 40-49 years. METHODS: Since 1987 in Turku, Finland, women aged 40-49 years and born in even calendar years were invited for mammography screening annually and those born in odd years triennially. The female cohorts born during 1945-1955 were followed for up to 10 years for incident breast cancers and thereafter for an additional 3 years for mortality. RESULTS: Among 14,765 women free of breast cancer at age 40, there were 207 incident primary invasive breast cancers diagnosed before the age of 50. Of these, 36 women died of breast cancer. The mean follow-up time for cancer incidence was 9.8 years and for mortality 12.8 years. The incidence of breast cancer was similar in the annual and triennial invitation groups (RR: 0.98, 95% confidence interval (CI): 0.75-1.29). Further, there were no significant differences in overall mortality (RR: 1.20, 95% CI: 0.99-1.46) or in incidence-based breast cancer mortality (RR: 1.14, 95% CI: 0.59-1.27) between the annual and triennial invitation groups. CONCLUSIONS: There were no differences in the incidence of breast cancer or incidence-based breast cancer mortality between the women who were invited for screening annually or triennially.

The effect of hospital volume on the outcome of breast cancer surgery.

BACKGROUND: This study was conducted to investigate whether annual surgical unit caseload affects extent of breast cancer surgery, breast cancer recurrence or breast cancer-specific survival. METHODS: In a population-based cohort study, 12,604 women diagnosed with breast cancer in Finland during the years 1998-2001 were followed up until the end of year 2008. Surgical units were divided into subgroups: >200, 100-200, 50-99 or <50 breast cancer operations per year. Information on patients, treatment, and follow-up was obtained from two national registries. The analyses were adjusted for age and disease stage. The reliability of the registry information was validated by comparison with information from one hospital area. Cox proportional hazard and logistic regression models were employed in the analyses. RESULTS: Validation of the registry data showed that date of diagnosis, age, stage, extent of surgery, and date and cause of death were reliably recorded in the registers. Information on radiotherapy was obtained by combining different registry data. Data on local and distant recurrences were not reliable enough to allow analyses. Patients in hospitals with smaller caseloads underwent mastectomy more often than those operated in hospitals with higher caseloads (P < 0.001). Higher caseloads were also related to improved survival (P = 0.031). CONCLUSIONS: National registries should include information on both local and distant recurrences in order to provide reliable population-based data for evaluation of treatment results. Centralization of surgery to high-volume centers is supported by a higher incidence of conservative surgery and better survival.

Genetic mapping of a locus predisposing to human colorectal cancer.

Genetic linkage analysis was used to determine whether a specific chromosomal locus could be implicated in families with a history of early onset cancer but with no other unique features. Close linkage of disease to anonymous microsatellite markers on chromosome 2 was demonstrated in two large kindreds. The pairwise lod scores for linkage to marker D2S123 in these kindreds were 6.39 and 1.45 at zero recombination, and multipoint linkage with flanking markers resulted in lod scores of 6.47 and 6.01. These results prove the existence of a genetically determined predisposition to colorectal cancer that has important ramifications for understanding and preventing this disease.

Clues to the pathogenesis of familial colorectal cancer.

A predisposition to colorectal cancer is shown to be linked to markers on chromosome 2 in some families. Molecular features of "familial" cancers were compared with those of sporadic colon cancers. Neither the familial nor sporadic cancers showed loss of heterozygosity for chromosome 2 markers, and the incidence of mutations in KRAS, P53, and APC was similar in the two groups of tumors. Most of the familial cancers, however, had widespread alterations in short repeated DNA sequences, suggesting that numerous replication errors had occurred during tumor development. Thirteen percent of sporadic cancers had identical abnormalities and these cancers shared biologic properties with the familial cases. These data suggest a mechanism for familial tumorigenesis different from that mediated by classic tumor suppressor genes.

Internet as a source of medicines information (MI) among frequent internet users.

BACKGROUND: The internet is widely and increasingly used to search for health information. Previous studies have focused mainly on health information on the internet and not specifically on medicines information (MI). OBJECTIVES: The aim of this study was to explore the internet as a source of MI compared to other sources of MI; to identify those who use the internet as a source of MI; and to describe patterns of use of the internet as a source of MI. METHODS: A cross-sectional design employed a web-based questionnaire posted by patients' and other organizations as well as pharmacies on their websites during six weeks in the beginning of 2014. Logistic regression analysis was used to assess associations of background variables to the use of different MI sources. RESULTS: The most frequently used MI sources among respondents (n = 2489) were package leaflets (90%), pharmacists (83%), physicians (72%), and the internet (68%). According to a multivariate analysis, internet use for MI was associated with female gender, age <65 years, higher education, daily use of the internet, and continuous use of vitamins or herbals. MI was most commonly searched from a Finnish health portal (56%) and websites of pharmacies (41%). Of the respondents, nearly half (43%) used search engines to find information from the internet. The names of the medicinal product, symptom or disease were the most commonly used search terms. CONCLUSIONS: Well-educated, young women tend to search MI on the internet. Health care professionals should discuss reliable MI websites and tools that can help patients evaluate the reliability of information.

Service screening mammography reduces breast cancer mortality among elderly women in Turku.

OBJECTIVES: The aim of this study was to assess the effects of service screening mammography on breast carcinoma incidence and refined mortality among women aged 55-69 at entry in three cities employing different screening policies. METHODS: Since 1987, the city of Turku, Finland, has provided service screening mammography for women aged 55-69 at entry (in 1987), and Tampere provided screening for women aged 55-59 at entry, whereas Helsinki did not screen any of these age groups. The incidence of breast carcinoma during the screening period 1987-97 in women born in 1918-32 (1918-22, 1923-27, 1928-32) was compared with incidence during the pre-screening period 1976-86 in women born in 1907-21 (1907-11, 1912-16, 1917-21) in each city. The follow-up for mortality was four years longer. RESULTS: Breast carcinoma incidence was 31-38% higher in the screening period in all three cities irrespective of screening. In breast carcinoma mortality, no significant changes were seen in Helsinki or Tampere. In Turku, a 36% mortality reduction (relative risk [RR] 0.64; 95% confidence interval [CI] 0.47-0.88; P=0.007) in the whole study population and a 47% reduction in women aged 65-69 at entry (RR 0.53; 95% CI 0.28-0.99; P=0.047) were seen. CONCLUSIONS: The incidence of breast carcinoma increased in all study cities irrespective of screening. The comprehensive screening programme in Turku including women aged 55-69 at entry was associated with a significant reduction in breast carcinoma mortality. The pronounced decrease in mortality in the oldest age group (65-69 years at entry) also indicated that women of this age group greatly benefit from mammography screening.

Evidence supporting exclusion of the DCC gene and a portion of chromosome 18q as the locus for susceptibility to hereditary nonpolyposis colorectal carcinoma in five kindreds.

Hereditary non-polyposis colorectal carcinoma (HNPCC) syndrome is characterized by early onset and multiple cancers of predominantly the proximal colon and occasionally other organs. The mode of transmission is compatible with autosomal dominant inheritance but the location and characteristics of the putative susceptibility gene are unknown. We performed linkage analyses with the aim of proving or excluding the existence of a susceptibility locus on 18q. This hypothesis was based on the frequent involvement of the DCC gene in colorectal carcinoma and on the previously reported linkage between HNPCC and the Kidd blood group locus (JK) also on 18q. Seven HNPCC families were tested with eight polymorphisms, including three from within DCC. The DCC locus could be excluded as the HNPCC susceptibility locus in five families in which the two point logarithm-of-odds scores were -3.66, -3.63, -4.12, -7.90, and -3.74 at the recombination fraction of 0.00. In the remaining two families linkage could be neither excluded nor confirmed. The added pairwise logarithm-of-odds score for all seven families was -22.65 at the recombination fraction of 0.00. Multipoint analyses of linkage in the seven families suggested exclusion of some 60 cM in the region DCC-D18S18-D18S22-D18S7 as the site for HNPCC susceptibility locus. In addition to DCC, the excluded portion comprises JK.

Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history.

Recent reports have suggested that one or more genes may cause replication errors (RER) during colorectal tumorigenesis. Additional alleles are seen in the tumors when analyzing random microsatellite loci. We have studied seven dinucleotide repeat loci, located on seven different chromosomes, by use of polymerase chain reaction amplification and denaturing polyacrylamide gel electrophoresis. We found that 16.5% (40 of 243) colorectal cancers showed RER at one or several loci (RER+). This includes 31% (4 of 13) among cases with a strong positive family history according to previously published criteria and 17% (35 of 207) among cases with no history of familial cancer. Interestingly, no significant association was found between RER+ tumors and a general familial clustering of cancer. Microsatellite instability was significantly associated with DNA diploid status of the tumor (P < 0.001), with the location of the tumor in the proximal colon (P < 0.001), and with poorly differentiated tumor phenotype (P < 0.001). Patients with RER+ at > or = 2 loci tumors had an increased survival (P = 0.05). We further analyzed 84 breast cancers and 86 male germ cell cancers using the same seven markers. None of the tumors were RER+, indicating that this phenomenon may be specific to certain types of tumors.

Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome.

Microsatellite instability implying multiple replication errors (RER+ phenotype) characterizes a proportion of colorectal carcinomas, particularly those from patients with the hereditary non-polyposis colorectal carcinoma syndrome. We studied the incidence of microsatellite instability in more than 500 sporadic tumors representing 6 different types of cancer. Apart from colorectal carcinoma [see the paper by Lothe et al. (Cancer Res., 53:5849-5852, 1993)] the RER+ phenotype was found in 18% (6 of 33) of gastric carcinomas and 22% (4 of 18) of endometrial carcinomas. In contrast, no evidence of this abnormality was detected in cancers of the lung (N = 85), breast (N = 84), and testis (N = 86). Importantly, the first three cancers, as opposed to the latter three, are characteristic of the hereditary non-polyposis colorectal carcinoma syndrome. These findings suggest that the cancers belonging to the hereditary non-polyposis colorectal carcinoma tumor spectrum may have essential pathogenetic steps in common, including a tendency to multiple replication errors.

Evidence that the MCC-APC gene region in 5q21 is not the site for susceptibility to hereditary nonpolyposis colorectal carcinoma.

Hereditary nonpolyposis colorectal carcinoma (HNPCC) is the most common form of hereditary colon cancer. Autosomal dominant inheritance is evident from pedigrees but the genetic basis of the disorder is otherwise unknown. Recently, two genes in 5q21 involved in colon carcinogenesis, APC and MCC, were identified, and APC was shown to be the gene predisposing to familial adenomatous polyposis. To determine if these genes also confer susceptibility to HNPCC we performed linkage analyses in nine affected families. The MCC-APC region could be formally excluded as the locus for HNPCC in seven families. In one family the results were suggestive of exclusion, although they were not conclusive. The remaining family was uninformative. We used two alternative definitions of affected status. Based on haplotypes for MCC and APC the added pairwise logarithm-of-odds score for all nine families was -22.57 at the recombination fraction of 0.00 using more stringent criteria for the HNPCC phenotype and -22.67 for less stringent criteria. In addition to blood DNA samples from living family members, DNA from formaldehyde-fixed archival pathology specimens from decreased individuals contributed to these linkage results.

Psycho-oncological support for breast cancer patients: A brief overview of breast cancer services certification schemes and national health policies in Europe.

Psycho-oncology addresses the psychological, social, behavioural, and ethical aspects of cancer. Identification and proper management of the patients' psychosocial needs, as well as the needs of their caregivers and family are essential for a person-centred concept of breast cancer care. The aim of this overview is to describe how psychosocial support in breast cancer is incorporated in cancer-related policy documents, such as national cancer plans and breast cancer care certification schemes.

Omission of histologic grading from clinical decision making may result in overuse of adjuvant therapies in breast cancer: results from a nationwide study.

PURPOSE: To investigate the influence of routinely performed histologic grading on breast cancer outcome prediction and patient selection for adjuvant therapy. PATIENTS AND METHODS: The analysis is based on a cohort of 2,842 women diagnosed with breast cancer and comprising 91% of all breast cancers diagnosed in five defined geographical regions in Finland in 1991 through 1992. Data on clinicopathologic factors and follow-up were collected from hospital case records and national registries. Histologic grade assessed at diagnosis and other clinicopathologic data were available for 1,554 operable unilateral invasive carcinomas. The relative value of grade with respect to competing prognostic factors was estimated with the Cox proportional hazards model and logistic regression. Interactions and nonlinearity of factors were accounted for by using an artificial neural network. RESULTS: Histologic grade was correlated strongly with survival in the entire series and in all subgroups studied. Women with well-differentiated node-negative cancer had a 97% 5-year distant disease-free survival rate as compared with 78% for women with poorly differentiated cancer. Grade was an independent prognostic factor in multivariate models and increased the predictive accuracy of a neural network model. Inclusion of grade data in a Cox multivariate model based on tumor size and hormone receptor status in node-negative cancer increased the proportion of patients with 5% or less risk for distant recurrence at 5 years from 15% to 54%. CONCLUSION: Even when assessed by pathologists who have no special training in breast cancer pathology, histologic grade has substantial and independent prognostic value in breast cancer. Omission of grading from clinical decision making may result in considerable overuse of adjuvant therapies.

Effectiveness of screening for colorectal cancer with a faecal occult-blood test, in Finland.

BACKGROUND: Screening for colorectal cancer (CRC) with guaiac-based faecal occult-blood test (FOBT) has been reported to reduce CRC mortality in randomised trials in the 1990s, but not in routine screening, so far. In Finland, a large randomised study on biennial FOB screening for CRC was gradually nested as part of the routine health services from 2004. We evaluate the effectiveness of screening as a public health policy in the largest population so far reported. METHODS: We randomly allocated (1:1) men and women aged 60-69 years to those invited for screening and those not invited (controls), between 2004 and 2012. This resulted in 180 210 subjects in the screening arm and 180 282 in the control arm. In 2012, the programme covered 43% of the target age population in Finland. RESULTS: The median follow-up time was 4.5 years (maximum 8.3 years), with a total of 1.6 million person-years. The CRC incidence rate ratio between the screening and control arm was 1.11 (95% CI 1.01 to 1.23). The mortality rate ratio from CRC between the screening and control arm was 1.04 (0.84 to 1.28), respectively. The CRC mortality risk ratio was 0.88 (0.66 to 1.16) and 1.33 (0.94 to 1.87) in males and females, respectively. CONCLUSIONS: We did not find any effect in a randomised health services study of FOBT screening on CRC mortality. The substantial effect difference between males and females is inconsistent with the evidence from randomised clinical trials and with the recommendations of several international organisations. Even if our findings are still inconclusive, they highlight the importance of randomised evaluation when new health policies are implemented. TRIAL REGISTRATION: 002_2010_august.

Timing of food intake has a marked effect on the bioavailability of clodronate.

Because of the low and variable bioavailability of bisphosphonates and the huge effect of food on their gastrointestinal absorption, it is of utmost importance to know the optimal timing of drug intake in relation to food intake. We investigated the effect of time on the bioavailability of clodronate when the drug was administered 2, 1, or 0.5 h before breakfast, with breakfast, or 2 h after breakfast (in the middle of a 4-h fast). The study was conducted as a single-center, open, balanced, randomized, crossover pharmacokinetic study in 31 healthy subjects aged 21 to 34 years. The volunteers participated in five different sessions with 800 mg of oral clodronate, and these sessions were separated by washout phases, each for at least 1 week. The primary pharmacokinetic variables were the area under the serum concentration time curve in 24 h (AUC(0-24)) for clodronate and the maximal concentration of clodronate in serum (C(max)). Clodronate was absorbed rather similarly when taken in the morning on an empty stomach 2, 1, or 0.5 h before breakfast, but because the best absorption occurred (as expected) when the drug was taken 2 h before breakfast, this scheme served as the reference treatment. As evaluated by area under the serum concentration time curves, the dose-breakfast interval of 1 h scarcely reduced absorption from the reference treatment level (relative absorption 91%, p = 1.0). Compared with the reference treatment, clodronate was absorbed with 69% efficacy (p = 0.65) when breakfast followed only 0.5 h later. The dose-breakfast intervals of 0.5 and 1 h did not differ significantly from each other (p = 0.85). Absorption was, however, only 34% (p < 0.0001) of the optimum when the drug was taken 2 h after breakfast, and only 10% of optimal when clodronate was taken with breakfast (p < 0.0001). In conclusion, it can be recommended to take Bonefos capsules in the morning on an empty stomach at least 0.5 h before breakfast.

The absolute bioavailability of clodronate from two different oral doses.

Clodronate (disodium clodronate tetrahydrate) is a bisphosphonate used in the treatment of hypercalcemia and osteolysis due to malignancy. Like all bisphosphonates, clodronate has low and variable oral bioavailability. The purpose of this study was to examine the absolute bioavailability of clodronate from two different oral doses. Thirty-one healthy young volunteers participated in this open, randomized, three-period, single-dose, cross-over study. The absolute bioavailability was calculated from the area under the serum clodronate-time curve in 48 h (AUC(0-48 h)) after administration of 800 or 1600 mg (Bonefos 400 mg capsules) of oral clodronate, or 30 mg (Bonefos 60 mg/mL infusion concentrate) of intravenous clodronate. The maximum concentration of clodronate in serum (C(max)), the time to maximum concentration (t(max)), the elimination half-life (t(1/2)), and the cumulative amount of clodronate excreted into urine in 48 h (Ae(0-48 h)) were also determined. The geometric mean of the absolute bioavailability of 800 mg of clodronate was 1.9% and that of 1600 mg 2.1%. The difference in the absolute bioavailability of these two doses was statistically nonsignificant. All treatments were well tolerated, and the AE profiles were similar in the different treatment groups. There were no serious adverse events during the study.

No evidence of microsatellite instability but frequent loss of heterozygosity in primary resected lung cancer.

We examined microsatellite instability and loss of heterozygosity (LOH) in primary lung tumors from 93 cancer patients, using 16 microsatellite markers. The cases studied included 87 non-small-cell lung cancers (NSCLC) and six small-cell lung cancers (SCLC). All the patients except two were current or former smokers. The microsatellite markers were all dinucleotide repeat sequences from chromosomal locations 1p, 3p, 5q, 8p, 9p, 10p, 11p, 13q, and 17q. None of the tumors showed microsatellite instability (0/93). In NSCLC, 28% (24/87) of the cases showed LOH in at least one locus, whereas, in SCLC, 67% (4/6) had allelic losses. The frequency of LOH differed between the various cell types of NSCLC. The highest frequency was seen in large cell carcinoma (3/6, 50%) followed by squamous cell carcinoma (16/43, 37%) and adenocarcinoma (5/35, 14%). The most common site of LOH was 3p, where markers D3S1284, D3S659, D3S1289, D3S966, D3S647, and D3S1038 were studied. LOH, studied with 9p markers (D9S126, D9S171, D9S162), was less common. The present results, together with earlier reports, suggest that smoking-related primary lung cancers seldom show microsatellite instability but are characterized by frequent LOH.

Treatment results of osteogenic sarcoma. An evaluation of 36 patients treated during 30-year period in south-western Finland.

Histological re-evaluation revealed 36 osteogenic sarcoma (OS) patients for analysis in South-Western Finland treated between 1958 and 1987. In 21 cases (58%) the tumour was located in the knee region. The mean age at diagnosis was 28 years (range: 5-62 years) and the follow-up time of the patients was at least 5 years or until death. In 29 patients without metastases at the time of diagnosis, the extent of the primary tumour was T2 in 37% and T3 in 63% of the patients. There were no differences regarding the extent of the primary tumour, delay of the diagnosis, mean age of the patients, or duration of the symptoms while comparing the three decades of the study. Before the 1970s the treatment consisted of surgery with or without radiotherapy in most cases. Since the 1970s the combination of surgical treatment (amputation or wide excision) and adjuvant chemotherapy was the most common treatment modality. Since the late 1970s limb-salvage surgery has been applied in selected cases, and it seems to be justified. None of the patients treated before 1970 survived for 5 years. The 5- and 10-year survival of all 36 patients was 44.4% and 33.6%, respectively. In non-metastatic patients both the 5- and 10-year disease-free survival was 46.7%. A certain group exhibiting a good prognosis was found; the 10-year survival of the 10 patients with OS in extremities, treated with combined chemotherapy and surgery, was 70%. The median survival time was significantly longer for the patients with an intracompartmental tumour extent of T2 (112 months) compared with an extracompartmental extent of T3 (23 months), and for the patients with the primary tumour in the knee region (112 months) compared with other locations (18 months). The long-term survival of the OS patients has improved concomitantly with the multimodality of the treatment.

Testicular toxicity and mutagenicity of steroidal and non-steroidal estrogens in the male mouse.

The mutagenicity and toxicity of diethylstilbestrol (DES), 17 beta-estradiol and zeranol on the male mouse germ cells were investigated with meiotic micronucleus assays in vivo and in vitro, sperm-head abnormality test and morphometry. Further, the developmental effects of DES on testicular morphology were explored. Micronucleus induction was observed at 10(-7) M concentration of DES and 17 beta-estradiol in vitro, but other treatments yielded negative results. The micronucleus assay in vivo revealed a small number of micronuclei in early haploid spermatids 17 days after a single subcutaneous injection of DES 50 mg/kg, whereas estradiol and zeranol gave negative results. The sperm-head abnormality rates were significantly elevated 5 weeks after treatments with high doses of DES, 17 beta-estradiol and zeranol, and testicular morphometry revealed transient changes in the volume densities of testicular tissue components. Prenatal and neonatal estrogen administration resulted in permanent alterations in seminiferous epithelium and dilatation of the rete testis, but did not affect micronucleus or sperm-head abnormality rates. The mutagenicity and toxicity of hormones in the mouse testis paralleled the hormonal activity of these compounds. Early estrogenization was the most sensitive toxicity test, followed by in vitro meiotic micronucleus induction, whereas the sperm-head abnormality assay and morphological analysis did not reveal subtle changes.