Causes of death in women with breast cancer: a risks and rates study on a population-based cohort.

Introduction: The increasing survival of patients with breast cancer has prompted the assessment of mortality due to all causes of death in these patients. We estimated the absolute risks of death from different causes, useful for health-care planning and clinical prediction, as well as cause-specific hazards, useful for hypothesis generation on etiology and risk factors. Materials and methods: Using data from population-based cancer registries we performed a retrospective study on a cohort of women diagnosed with primary breast cancer. We carried out a competing-cause analysis computing cumulative incidence functions (CIFs) and cause-specific hazards (CSHs) in the whole cohort, separately by age, stage and registry area. Results: The study cohort comprised 12,742 women followed up for six years. Breast cancer showed the highest CIF, 13.71%, and cardiovascular disease was the second leading cause of death with a CIF of 3.60%. The contribution of breast cancer deaths to the CIF for all causes varied widely by age class: 89.25% in women diagnosed at age <50 years, 72.94% in women diagnosed at age 50-69 and 48.25% in women diagnosed at age ≥70. Greater CIF variations were observed according to stage: the contribution of causes other than breast cancer to CIF for all causes was 73.4% in women with stage I disease, 42.9% in stage II-III and only 13.2% in stage IV. CSH computation revealed temporal variations: in women diagnosed at age ≥70 the CSH for breast cancer was equaled by that for cardiovascular disease and "other diseases" in the sixth year following diagnosis, and an early peak for breast cancer was identified in the first year following diagnosis. Among women aged 50-69 we identified an early peak for breast cancer followed by a further peak near the second year of follow-up. Comparison by geographic area highlighted conspicuous variations: the highest CIF for cardiovascular disease was more than 70% higher than the lowest, while for breast cancer the highest CIF doubled the lowest. Conclusion: The integrated interpretation of absolute risks and hazards suggests the need for multidisciplinary surveillance and prevention using community-based, holistic and well-coordinated survivorship care models.

Comparison between two cancer registry quality check systems: functional features and differences in an Italian network of cancer registries dataset.

Purpose: The aim of this study was to compare the functional characteristics of two computer-based systems for quality control of cancer registry data through analysis of their output differences. Methods: The study used cancer incidence data from 22 of the 49 registries of the Italian Network of Cancer Registries registered between 1986 and 2017. Two different data checking systems developed by the WHO International Agency for Research on Cancer (IARC) and the Joint Research Center (JRC) with the European Network of Cancer Registries (ENCR) and routinely used by registrars were used to check the quality of the data. The outputs generated by the two systems on the same dataset of each registry were analyzed and compared. Results: The study included a total of 1,305,689 cancer cases. The overall quality of the dataset was high, with 86% (81.7-94.1) microscopically verified cases and only 1.3% (0.03-3.06) cases with a diagnosis by death certificate only. The two check systems identified a low percentage of errors (JRC-ENCR 0.17% and IARC 0.003%) and about the same proportion of warnings (JRC-ENCR 2.79% and IARC 2.42%) in the dataset. Forty-two cases (2% of errors) and 7067 cases (11.5% of warnings) were identified by both systems in equivalent categories. 11.7% of warnings related to TNM staging were identified by the JRC-ENCR system only. The IARC system identified mainly incorrect combination of tumor grade and morphology (72.5% of warnings). Conclusion: Both systems apply checks on a common set of variables, but some variables are checked by only one of the systems (for example, checks on patient follow-up and tumor stage at diagnosis are included by the JRC-ENCR system only). Most errors and warnings were categorized differently by the two systems, but usually described the same issues, with warnings related to "morphology" (JRC-ENCR) and "histology" (IARC) being the most frequent. It is important to find the right balance between the need to maintain high standards of data quality and the workability of such systems in the daily routine of the cancer registry.

Influence of Sex and Age on Site of Onset, Morphology, and Site of Metastasis in Colorectal Cancer: A Population-Based Study on Data from Four Italian Cancer Registries.

The prognosis of colorectal cancer is affected by factors such as site of origin, tumor morphology, and metastasis at diagnosis, but also age and sex seem to play a role. This study aimed to investigate within the Italian population how sex and age interact in influencing certain aspects of the disease and how they affect patient survival, particularly in the metastatic cohort. Data from four cancer registries were collected, and patients were classified by sex and age (<50, 50-69, and >69 years). Two separate analyses were conducted: one for patients having right or left colon cancer with adenocarcinoma or mucinous morphology, and one for patients having metastases at diagnosis. Women showed significant differences in right colon cases from the youngest to oldest age group (36% vs. 45% vs. 60%). Men <50 years had a significantly higher mucinous carcinoma percentage than their female counterparts (22% vs. 11%), while in the oldest age group women had the highest percentage (15% vs. 11%). The metastatic pattern differed between men and women and by age. The three-year relative survival in the <50 age group was better for women than men, but this survival advantage was reversed in the oldest group. In conclusion, sex and age are factors that influence the biological and clinical characteristics of colorectal cancer, affecting the metastatic pattern as well as patient survival.

Clinical features of type 1 and 2 refractory celiac disease: Results from a large cohort over a decade.

OBJECTIVES: Refractory celiac disease (RCeD) is a rare complication of celiac disease (CeD) with a severe prognosis. We describe a cohort of patients with RCeD, their clinical and histological features at diagnosis, after therapy and at lymphoma onset, and the rate and causes of death over a 17-year follow-up. METHODS: We retrospectively enrolled RCeD-I and RCeD-II patients attending our center between January 2002 and October 2019. Medical data were collected at diagnosis and during monitoring. Response to therapy, changes in RCeD molecular markers, number of hospitalizations, discharge diagnosis, and cause and date of death were evaluated. The control cohort consisted of 1015 responsive CeD patients. RESULTS: Compared with RCeD-I, RCeD-II more frequently exhibits diarrhea (83 vs 64%), anemia (61 vs 50%), hypoalbuminemia (70 vs 21%), parenteral nutrition need (48 vs 7%), ulcerative jejuno-ileitis (7 vs 39%), and extended small intestinal atrophy (62 vs 21%). One RCeD-I and six RCeD-II patients developed lymphoma. Ten RCeD-II patients died, four from lymphoma progression. Among RCeD-II patients, atrophy extension was the only parameter correlated with hypoalbuminemia and mortality. CONCLUSIONS: Clinical severity, response to therapy, and mortality differ between RCeD-I and RCeD-II. Atrophy extension, evaluated at capsule endoscopy, was associated with disease severity and mortality.

Effectiveness of Capsule Endoscopy and Double-Balloon Enteroscopy in Suspected Complicated Celiac Disease.

BACKGROUND & AIMS: Complicated celiac disease (CCD) is a rare but severe condition with a poor prognosis. Guidelines recommend use of capsule endoscopy (CE) to explore the small bowel (SB), followed by a double-balloon enteroscopy (DBE) in selected cases with suspected CCD. Our study aimed to evaluate the diagnostic yield (DY) of CE and DBE in identifying and monitoring CCD. METHODS: Consecutive suspected CCD patients were enrolled prospectively to undergo CE and/or DBE in the presence of: persistent symptoms despite a correct gluten-free diet (GFD), increased anti-transglutaminase antibodies titer, lack of adherence to the GFD, and CCD monitoring. The DY of CE and DBE were calculated. The incidence of neoplastic complications and mortality were assessed. RESULTS: In total, 130 patients (97 women; age, 49 ± 16 y) underwent 151 CEs and 23 DBEs. The DY of CE was 46%. Patients older than age 50 years (at CE examination or at CD diagnosis) with a CD duration shorter than 5 years were at higher risk of positive CE (relative risk, 1.6 and 1.7 in case of enrollement or CD diagnosis after 50 years of age, and 1.5 in case of short CD duration; P < .05) than their counterparts. Up to 40% of SB lesions were unreachable by upper endoscopy. At the end of the diagnostic work-up, 25 patients with premalignant/malignant lesions were identified: 12 type 1 refractory CD (RCD-1), 7 type 2 RCD (RCD-2), and 6 enteropathy-associated T-cell lymphoma (EATL). Six patients died: 2 patients with RCD-2 and 4 patients with EATL. CONCLUSIONS: In case of suspected CCD, CE should be the first-line approach to detect complications and to identify patients deserving DBE. Older and symptomatic patients with suspected CCD deserve a careful evaluation of the SB, especially during the first years after diagnosis.

Molecular Subtypes, Metastatic Pattern and Patient Age in Breast Cancer: An Analysis of Italian Network of Cancer Registries (AIRTUM) Data.

Breast cancer stage at diagnosis, patient age and molecular tumor subtype influence disease progression. The aim of this study was to analyze the relationships between these factors and survival in breast cancer patients among the Italian population using data from the AIRTUM national database. We enrolled women with primary breast cancer from 17 population-based cancer registries. Patients were subdivided into older (>69 years), middle (50-69 years) and younger age groups (<50 years) and their primary tumors categorized into four molecular subtypes based on hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. There were 8831 patients diagnosed between 2010 and 2012 included. The most represented age group was 50-69 years (41.7%). In 5735 cases the molecular subtype was identified: HER2-/HR+ was the most frequent (66.2%) and HER2+/HR- the least (6.2%). Of the 390 women with metastases at diagnosis, 38% had simultaneous involvement of multiple sites, independent of age and molecular profile. In women with a single metastatic site, bone (20% of cases), liver (11%), lung (7%) and brain (3%) were the most frequent. In the studied age groups with different receptor expression profiles, the tumor metastasized to target organs with differing frequencies, affecting survival. Five-year survival was lowest in women with triple-negative (HER2-/HR-) tumors and women with brain metastases at diagnosis.

Analysis of the Consumption of Non-Oncological Medicines: A Methodological Study on Patients of the Ada Cohort.

Cancer patients are identified as fragile patients who are often immunodepressed and subject to secondary diseases. The Ada cohort comprises cancer survivors aged 15-39 years at diagnosis included in 34 Italian cancer registries. This study aimed to analyze the possible excess of non-cancer medicines use on the basis of the medicine database of the Ada cohort. Records of medicines present in the pharmaceutical flows collected by eight Lombardy cancer registries and used by patients with any type of cancer were extracted for the year 2012. Medicine consumption data were processed to assign a defined daily dose value and to evaluate the consumption of medicines belonging to different groups of the ATC (Anatomical Therapeutic Chemical) classification. The values were compared with values in the Lombardy population. Medicine consumption related to 8150 patients was analyzed, for a total of 632,675 records. ATC groups A and C for females and group N for both sexes showed significant increases. Group J for males and group M for females showed intermediate increases, and group H for both sexes showed smaller increases. This method allowed the identification of excess medicine use to reduce cancer therapy side effects and primary disease sequelae in this group of patients.

An application of the Toronto Childhood Cancer Stage Guidelines in three population-based cancer registries: The case of central nervous tumors.

BACKGROUND: Cancer stage is a determinant of survival of childhood central nervous system (CNS) cancers and could help the interpretation of survival variability among countries. Consensus guidelines to stage childhood malignancies in population cancer registries ("Toronto Childhood Cancer Stage Guidelines") have been recently proposed with the goal of data comparability. Indeed, stage is not systematically recorded in all registries and, when it is, different classification systems are used. We applied the Toronto Childhood Cancer Stage Guidelines to CNS cancer cases of three population-based cancer registries with the aim of evaluating the feasibility of staging this type of cancer and the critical points in the classification of CNS tumors. PROCEDURES: The Toronto Childhood Cancer Stage Guidelines were applied to 175 CNS patients, diagnosed from January 1, 2002 to December 31, 2014 in three cancer registries in Italy, and the percentage of cases that could be staged was assessed. RESULTS: One hundred eight of 126 (86%) medulloblastomas and other embryonal CNS cancers and 22 of 49 (45%) ependymomas were staged. Using these guidelines, survival of children with localized tumors could be discriminated from that of children with metastatic disease. CONCLUSIONS: The use of the Toronto Childhood Cancer Stage Guidelines is feasible for staging medulloblastoma in Italian population-based cancer registries, whereas it is more difficult for ependymomas. In Italy, cerebrospinal fluid examination, one of the decisive tests to stage CNS tumors, is not routinely performed as a first-line diagnosis procedure in ependymoma pediatric patients. A similar exercise by a larger number of cancer registries in different countries could suggest improvements in the childhood cancer staging system.

Safety of occasional ingestion of gluten in patients with celiac disease: a real-life study.

BACKGROUND: Gluten-free diet (GFD) decreases the quality of life of celiac disease (CD) patients, who frequently ask to occasionally ingest gluten-containing food. We evaluated CD patients reporting voluntary and occasional transgressions to their GFD. METHODS: From October 2017 to September 2018, the patients reporting occasional and voluntary gluten ingestion (GFD-noncompliant) were prospectively enrolled. These patients underwent clinical examination, blood tests, duodenal biopsy, capsule enteroscopy (CE), and a validated food-frequency questionnaire (FFQ) assessing the frequency and quantity of gluten intake. Mortality was calculated and compared to the general population. A group of patients on strict GFD (GFD-adherent) acted as controls. RESULTS: One thousand three hundred seventy-eight CD patients were evaluated during the study period. One hundred nine (8%) reported occasional (weekly or monthly) voluntary ingestion of gluten. The mean gluten intake was 185.2 ± 336.9 g/year, and the duration of their incorrect GFD was 8.6 ± 6.9 years. Among the noncompliant patients, 57% did not present any histological alteration; furthermore, the Marsh score profile was not different between compliant and noncompliant patients. Seventy percent did not present any alteration at CE. Seventy-five percent of patients reported no gastrointestinal symptoms after gluten ingestion. Twenty-three percent of patients in the GFD-noncompliant group presented positive tTG-IgA. No association was found between gluten intake, clinical symptoms, and biomarkers. Mortality was not different between the groups and the general population. CONCLUSIONS: Our results are that in a real-life scenario, a group of CD patients on long-term gluten intake showed no significant clinical symptoms or small bowel damage, thus suggesting that a degree of tolerance towards gluten consumption can be reached.

Tau Mutations Serve as a Novel Risk Factor for Cancer.

In addition to its well-recognized role in neurodegeneration, tau participates in maintenance of genome stability and chromosome integrity. In particular, peripheral cells from patients affected by frontotemporal lobar degeneration carrying a mutation in tau gene (genetic tauopathies), as well as cells from animal models, show chromosome numerical and structural aberrations, chromatin anomalies, and a propensity toward abnormal recombination. As genome instability is tightly linked to cancer development, we hypothesized that mutated tau may be a susceptibility factor for cancer. Here we conducted a retrospective cohort study comparing cancer incidence in families affected by genetic tauopathies to control families. In addition, we carried out a bioinformatics analysis to highlight pathways associated with the tau protein interactome. We report that the risk of developing cancer is significantly higher in families affected by genetic tauopathies, and a high proportion of tau protein interactors are involved in cellular processes particularly relevant to cancer. These findings disclose a novel role of tau as a risk factor for cancer, providing new insights in the various pathologic roles of mutated tau.Significance: This study reveals a novel role for tau as a risk factor for cancer, providing new insights beyond its role in neurodegeneration. Cancer Res; 78(13); 3731-9. ©2018 AACR.

Atmospheric fine particulate matter and breast cancer mortality: a population-based cohort study.

OBJECTIVES: Atmospheric fine particulate matter (PM2.5) has multiple adverse effects on human health. Global atmospheric levels of PM2.5 increased by 0.55 µg/m3/year (2.1%/year) from 1998 through 2012. There is evidence of a causal relationship between atmospheric PM2.5 and breast cancer (BC) incidence, but few studies have investigated BC mortality and atmospheric PM2.5. We investigated BC mortality in relation to atmospheric PM2.5 levels among patients living in Varese Province, northern Italy. METHODS: We selected female BC cases, archived in the local population-based cancer registry, diagnosed at age 50-69 years, between 2003 and 2009. The geographic coordinates of each woman's place of residence were identified, and individual PM2.5 exposures were assessed from satellite data. Grade, stage, age at diagnosis, period of diagnosis and participation in BC screening were potential confounders. Kaplan-Meir and Nelson-Aalen methods were used to test for mortality differences in relation to PM2.5 quartiles. Multivariable Cox proportional hazards modelling estimated HRs and 95% CIs of BC death in relation to PM2.5 exposure. RESULTS: Of 2021 BC cases, 325 died during follow-up to 31 December 2013, 246 for BC. Risk of BC death was significantly higher for all three upper quartiles of PM2.5 exposure compared to the lowest, with HRs of death: 1.82 (95% CI 1.15 to 2.89), 1.73 (95% CI 1.12 to 2.67) and 1.72 (95% CI 1.08 to 2.75). CONCLUSIONS: Our study indicates that the risk of BC mortality increases with PM2.5 exposure. Although additional research is required to confirm these findings, they are further evidence that PM2.5 exposure is harmful and indicate an urgent need to improve global air quality.

Fasting blood glucose and long-term prognosis of non-metastatic breast cancer: a cohort study.

High circulating glucose has been associated with increased risk of breast cancer (BC). There may also be a link between serum glucose and prognosis in women treated for BC. We assessed the effect of peridiagnostic fasting blood glucose and body mass index (BMI) on long-term BC prognosis. We retrospectively investigated 1,261 women diagnosed and treated for stage I-III BC at the National Cancer Institute, Milan, in 1996, 1999 and 2000. Data on blood tests and follow-up were obtained by linking electronic archives, with follow-up to end of 2009. Multivariate Cox modelling estimated hazard ratios (HR) with 95 % confidence intervals (CI) for distant metastasis, recurrence and death (all causes) in relation to categorized peridiagnostic fasting blood glucose and BMI. Mediation analysis investigated whether blood glucose mediated the BMI-breast cancer prognosis association. The risks of distant metastasis were significantly higher for all other quintiles compared to the lowest glucose quintile (reference <87 mg/dL) (respective HRs: 1.99 95 % CI 1.23-3.24, 1.85 95 % CI 1.14-3.0, 1.73 95 % CI 1.07-2.8, and 1.91 95 % CI 1.15-3.17). The risk of recurrence was significantly higher for all other glucose quintiles compared to the first. The risk of death was significantly higher than reference in the second, fourth and fifth quintiles. Women with BMI ≥ 25 kg/m(2) had significantly greater risks of recurrence and distant metastasis than those with BMI < 25 kg/m(2), irrespective of blood glucose. The increased risks remained invariant over a median follow-up of 9.5 years. Mediation analysis indicated that glucose and BMI had independent effects on BC prognosis. Peridiagnostic high fasting glucose and obesity predict worsened short- and long-term outcomes in BC patients. Maintaining healthy blood glucose levels and normal weight may improve prognosis.

Comparison with manual registration reveals satisfactory completeness and efficiency of a computerized cancer registration system.

Automated software for cancer registration, called Open Registry and developed by ourselves was adopted by the Varese (population-based) Cancer Registry starting from 1997. Since the use of automated cancer registration is increasing, it is important to assess the quality and completeness of the automated data being produced. In this study, we assessed the completeness of the automatically generated data by comparison with a gold standard of all cases identified by manual and automatic systems for the year 1997 when the automated system was introduced, and the manual system was still in operation. We also evaluated the efficiency of the automated system. 5027 cases were generated automatically; 2959 (59%) were accepted automatically and 2068 (41%) were flagged for manual checking. Sixty-nine cases (1.3%) were not recorded automatically, the most common reason (0.8%) being that the incidence record was dated 1998, even though the case was incident in 1997. A total of 98.7% of all cases found were picked up by the automated system. A completeness figure of 98.7% indicates that the automatic procedure is a valid alternative to manual methods for routine case generation. The fact that 59% of cases were registered automatically indicates that the system can speed up data production and enhance registry efficiency.

Consistency and accuracy of diagnostic cancer codes generated by automated registration: comparison with manual registration.

BACKGROUND: Automated procedures are increasingly used in cancer registration, and it is important that the data produced are systematically checked for consistency and accuracy. We evaluated an automated procedure for cancer registration adopted by the Lombardy Cancer Registry in 1997, comparing automatically-generated diagnostic codes with those produced manually over one year (1997). METHODS: The automatically generated cancer cases were produced by Open Registry algorithms. For manual registration, trained staff consulted clinical records, pathology reports and death certificates. The social security code, present and checked in both databases in all cases, was used to match the files in the automatic and manual databases. The cancer cases generated by the two methods were compared by manual revision. RESULTS: The automated procedure generated 5027 cases: 2959 (59%) were accepted automatically and 2068 (41%) were flagged for manual checking. Among the cases accepted automatically, discrepancies in data items (surname, first name, sex and date of birth) constituted 8.5% of cases, and discrepancies in the first three digits of the ICD-9 code constituted 1.6%. Among flagged cases, cancers of female genital tract, hematopoietic system, metastatic and ill-defined sites, and oropharynx predominated. The usual reasons were use of specific vs. generic codes, presence of multiple primaries, and use of extranodal vs. nodal codes for lymphomas. The percentage of automatically accepted cases ranged from 83% for breast and thyroid cancers to 13% for metastatic and ill-defined cancer sites. CONCLUSION: Since 59% of cases were accepted automatically and contained relatively few, mostly trivial discrepancies, the automatic procedure is efficient for routine case generation effectively cutting the workload required for routine case checking by this amount. Among cases not accepted automatically, discrepancies were mainly due to variations in coding practice.