Evidence for a cluster of rare birth defects in the Ain department (France).

BACKGROUND: REMERA (REgistre des Malformations En Rhône-Alpes) is a registry of congenital malformations that covers 58,000 births annually in Central-East France. In 2010, the registry raised an alarm to the health authorities (Santé publique France, SpF) about three cases of a unilateral isolated transverse upper limb reduction defect (UITULRD) in a small subarea; the general prevalence of this defect is one case in 10,000 births. In the following years, more infants were born with the same malformation in the same territory of the Ain department. Public health authorities, supported by an expert committee, rejected the existence of a cluster, but we aim here at providing evidence for this cluster. METHODS: Geocoded data for all UITULRD cases (ICD-10 codes Q71.2 and Q71.3) were extracted from the REMERA database. We conducted a Kulldorff cluster analysis of these data, using the spatial SaTScanTM algorithm. RESULTS: The analysis found a cluster of eight cases of UITULRD among the 8,204 births occurring between 2009 and 2014 within a circle of 16.24 km radius centered on a village of the Ain department, whereas 0.82 cases were expected under a uniform probability of such a birth throughout the registry territory. This represents an almost 10fold excess over the expected number of cases (p = .0057). CONCLUSIONS: The arguments used to deny the cluster are disputed and we present the evidence supporting its reality. The controversy that has followed the alarm has compromised the search for the cause(s) of this excess of rare malformations.

Trends in short-term survival from distant-stage cutaneous melanoma in the United States, 2001-2013 (CONCORD-3).

BACKGROUND: Survival from metastatic cutaneous melanoma is substantially lower than for localized disease. Treatments for metastatic melanoma have been limited, but remarkable clinical improvements have been reported in clinical trials in the last decade. We described the characteristics of US patients diagnosed with cutaneous melanoma during 2001-2013 and assessed trends in short-term survival for distant-stage disease. METHODS: Trends in 1-year net survival were estimated using the Pohar Perme estimator, controlling for background mortality with life tables of all-cause mortality rates by county of residence, single year of age, sex, and race for each year 2001-2013. We fitted a flexible parametric survival model on the log-hazard scale to estimate the effect of race on the hazard of death because of melanoma and estimated 1-year net survival by race. RESULTS: Only 4.4% of the 425 915 melanomas were diagnosed at a distant stage, cases diagnosed at a distant stage are more commonly men, older patients, and African Americans. Age-standardized, 1-year net survival for distant-stage disease was stable at approximately 43% during 2001-2010. From 2010 onward, survival improved rapidly, reaching 58.9% (95% confidence interval = 56.6% to 61.2%) for patients diagnosed in 2013. Younger patients experienced the largest improvement. Survival for distant-stage disease increased in both Blacks and Whites but was consistently lower in Blacks. CONCLUSIONS: One-year survival for distant-stage melanoma improved during 2001-2013, particularly in younger patients and those diagnosed since 2010. This improvement may be a consequence of the introduction of immune-checkpoint-inhibitors and other targeted treatments for metastatic and unresectable disease. Persistent survival inequalities exist between Blacks and Whites, suggesting differential access to treatment.

Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries.

BACKGROUND: In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. METHODS: CONCORD-3 includes individual records for 37·5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89·5% in Australia and 90·2% in the USA, but international differences remain very wide, with levels as low as 66·1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68·9%), colon (71·8%), and rectum (71·1%); in Japan for oesophageal cancer (36·0%); and in Taiwan for liver cancer (27·9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59·9% in South Korea, 52·1% in Taiwan, and 49·6% in China), and for both lymphoid malignancies (52·5%, 50·5%, and 38·3%) and myeloid malignancies (45·9%, 33·4%, and 24·8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49·8% in Ecuador to 95·2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28·9% in Brazil to nearly 80% in Sweden and Denmark). INTERPRETATION: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer. FUNDING: American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation.

Analysing population-based cancer survival - settling the controversies.

BACKGROUND: The relative survival field has seen a lot of development in the last decade, resulting in many different and even opposing suggestions on how to approach the analysis. METHODS: We carefully define and explain the differences between the various measures of survival (overall survival, crude mortality, net survival and relative survival ratio) and study their differences using colon and prostate cancer data extracted from the national population-based cancer registry of Slovenia as well as simulated data. RESULTS: The colon and prostate cancer data demonstrate clearly that when analysing population-based data, it is useful to split the overall mortality in crude probabilities of dying from cancer and from other causes. Complemented by net survival, it provides a complete picture of cancer survival in a given population. But when comparisons of different populations as defined for example by place or time are of interest, our simulated data demonstrate that net survival is the only measure to be used. CONCLUSIONS: The choice of the method should be done in two steps: first, one should determine the measure of interest and second, one should choose among the methods that estimate that measure consistently.

Cancer incidence, survival and mortality: explaining the concepts.

Cancer incidence, survival and mortality are essential population-based indicators for public health and cancer control. Confusion and misunderstanding still surround the estimation and interpretation of these indicators. Recurring controversies over the use and misuse of population-based cancer statistics in health policy suggests the need for further clarification. In our article, we describe the concepts that underlie the measures of incidence, survival and mortality, and illustrate the synergy between these measures of the cancer burden. We demonstrate the relationships between trends in incidence, survival and mortality, using real data for cancers of the lung and breast from England and Sweden. Finally, we discuss the importance of using all three measures in combination when interpreting overall progress in cancer control, and we offer some recommendations for their use.

Comparison of direct digital mammography, computed radiography, and film-screen in the French national breast cancer screening program.

OBJECTIVE: The purpose of this article was to compare the performance of digital mammography using hardcopy image reading against film-screen mammography in a French national routine population-based screening program with a decentralized organization. The French context offered the opportunity to examine separately computed radiography and direct digital mammography performances in a large cohort. MATERIALS AND METHODS: The study includes 23,423 direct digital mammography, 73,320 computed radiography, and 65,514 film-screen mammography examinations performed by 123 facilities in Bouches du Rhône, France, for women 50-74 years old between 2008 and 2010. We compared abnormal mammography findings rate, cancer detection rate, and tumor characteristics among the technologies. RESULTS: Abnormal finding rates were higher for direct digital mammography (7.78% vs 6.11% for film-screen mammography and 5.34% for computed radiography), particularly in younger women and in denser breasts. Cancer detection rates were also higher for direct digital mammography (0.71% vs 0.66% for film-screen mammography and 0.55% for computed radiography). The contrast between detection rates was stronger for ductal carcinoma in situ. Breast density was the main factor explaining the differences in detection rates. For direct digital mammography only, the detection rate was clearly higher in dense breasts whatever the age (odds ratio, 2.20). Except for grade, no differences were recorded concerning tumor characteristics in which the proportion of high-grade tumors was larger for direct digital mammography for invasive and in situ tumors. CONCLUSION: Direct digital mammography has a higher detection rate than film-screen mammography in dense breasts and for tumors of high grade. This latter association warrants further study to measure the impact of technology on efficacy of screening. The data indicate that computed radiography detects fewer tumors than film-screen mammography in most instances.

On estimation in relative survival.

Estimation of relative survival has become the first and the most basic step when reporting cancer survival statistics. Standard estimators are in routine use by all cancer registries. However, it has been recently noted that these estimators do not provide information on cancer mortality that is independent of the national general population mortality. Thus they are not suitable for comparison between countries. Furthermore, the commonly used interpretation of the relative survival curve is vague and misleading. The present article attempts to remedy these basic problems. The population quantities of the traditional estimators are carefully described and their interpretation discussed. We then propose a new estimator of net survival probability that enables the desired comparability between countries. The new estimator requires no modeling and is accompanied with a straightforward variance estimate. The methods are described on real as well as simulated data.

Reliability of recording uterine cancer in death certification in France and age-specific proportions of deaths from cervix and corpus uteri.

French uterine cancer recordings in death certificates include 60% of "uterine cancer, Not Otherwise Specified (NOS)"; this hampers the estimation of mortalities from cervix and corpus uteri cancers. The aims of this work were to study the reliability of uterine cancer recordings in death certificates using a case matching with cancer registries and estimate age-specific proportions of deaths from cervix and corpus uteri cancers among all uterine cancer deaths by a statistical approach that uses incidence and survival data. Deaths from uterine cancer between 1989 and 2001 were extracted from the French National database of causes of death and case-to-case matched to women diagnosed with uterine cancer between 1989 and 1997 in 8 cancer registries. Registry data were considered as "gold-standard". Among the 1825 matched deaths, cancer registries recorded 830 cervix and 995 corpus uteri cancers. In death certificates, 5% and 40% of "true" cervix cancers were respectively coded "corpus" and "uterus, NOS" and 5% and 59% of "true" corpus cancers respectively coded "cervix" and "uterus, NOS". Miscoding cervix cancers was more frequent at advanced ages at death and in deaths at home or in small urban areas. Miscoding corpus cancers was more frequent in deaths at home or in small urban areas. From the statistical method, the estimated proportion of deaths from cervix cancer among all uterine cancer deaths was higher than 95% in women aged 30-40 years old but declined to 35% in women older than 70 years. The study clarifies the reason for poor encoding of uterus cancer mortality and refines the estimation of mortalities from cervix and corpus uteri cancers allowing future studies on the efficacy of cervical cancer screening.

What reasons lie behind long-term survival differences for gastric cancer within Europe?

BACKGROUND: Wide geographic variations in survival for gastric cancer in Europe have been reported. The aim of this study was to analyse the effect of stage at diagnosis, treatment and cancer characteristics on long-term survival for gastric cancer in populations covered by cancer registries. METHODS: We analysed survival in 4620 cases of gastric cancer from 17 European population-based cancer registries from 8 countries. Univariate and multivariate regression of relative survival were performed. RESULTS: Five-year relative survival varied between 10.6% and 24.0%, while 10-year survival ranged from 7.7% to 23.0%. After adjustment for age and sex, the regional excess hazard ratio (EHR) of death was significantly higher in Ragusa, Granada, Yorkshire, Slovakia, Slovenia and Poland than in France, Northern Italy, The Netherlands and the Basque Country. After further adjustment for surgical resection versus no resection (a proxy of stage), the EHR of death remained significantly higher only in Granada and Yorkshire than in the reference country (France). After adjustment for stage, the EHR was significantly higher only in Yorkshire (EHR: 1.51; 95% confidence interval (CI): 1.29-1.77). The EHR in this area was limited to the first year following diagnosis. CONCLUSION: Differences across Europe in gastric cancer survival depend to a large extent on differences in stage at diagnosis. However they do not explain all variations. Quality of management and treatment can explain some differences.

Conditional relative survival of cancer patients and conditional probability of death: a French National Database analysis.

BACKGROUND: Little information is available on the conditional probabilities of death among patients who survive for >5 years after a diagnosis with cancer. The objective of this study was to estimate the conditional probabilities of death for breast cancer, prostate cancer, colorectal cancer, and lung cancer in France. METHODS: The study included data from the French Network of Cancer Registries from 205,562 patients aged <75 years who were diagnosed with cancer between 1989 and 1997. The conditional probabilities of death were calculated by using a relative survival regression model in which age was included as a covariate. RESULTS: After the first year and until 10 years after diagnosis, the annual probability of death decreased dramatically for colorectal cancer: It was the same in all age groups after 3 years, and it was approximately 1% at 10 years. For prostate cancer, the decrease was not as great, and the conditional probability of death remained higher among younger patients at >4% at 10 years. During the 3 years after diagnosis, the probability of death was greater for older patients with breast cancer; then, it decreased less for younger patients compared with older patients, leading to a greater conditional probability of death among younger patients at 4 years and up to 10 years. The annual probability of death in patients with lung cancer decreased for both sexes but remained substantially higher for men than for women, reaching approximately 8% and 5%, respectively, at 10 years. CONCLUSIONS: Further studies would facilitate a better understanding of the observed differences in relative survival within European countries.

New tools to measure discrepancy between prescribing practices and guideline recommendations.

OBJECTIVE: To study the performance of a new method designed to measure discrepancy between real prescriptions and evidence-based reference treatments. METHODS: Two different indices (additive and multiplicative) are proposed to summarize deviation between prescription and reference. Deviations thought to be observed in a population of prescribers are simulated in diverse hypothetical situations in the presence or absence of evidence-based references. The performances of both indices are compared and their sensitivities to change are explored. RESULTS: Both indices are sensitive to variation in prescriber behaviour. The additive index allows a more accurate analysis of deviation while the multiplicative index is simpler to implement and interpret but more sensitive to change. CONCLUSION: The two deviation indices may be used as new tools in surveys or trials dealing with prescribing practices.

Importance of data structure in comparing two dimension reduction methods for classification of microarray gene expression data.

BACKGROUND: With the advance of microarray technology, several methods for gene classification and prognosis have been already designed. However, under various denominations, some of these methods have similar approaches. This study evaluates the influence of gene expression variance structure on the performance of methods that describe the relationship between gene expression levels and a given phenotype through projection of data onto discriminant axes. RESULTS: We compared Between-Group Analysis and Discriminant Analysis (with prior dimension reduction through Partial Least Squares or Principal Components Analysis). A geometric approach showed that these two methods are strongly related, but differ in the way they handle data structure. Yet, data structure helps understanding the predictive efficiency of these methods. Three main structure situations may be identified. When the clusters of points are clearly split, both methods perform equally well. When the clusters superpose, both methods fail to give interesting predictions. In intermediate situations, the configuration of the clusters of points has to be handled by the projection to improve prediction. For this, we recommend Discriminant Analysis. Besides, an innovative way of simulation generated the three main structures by modelling different partitions of the whole variance into within-group and between-group variances. These simulated datasets were used in complement to some well-known public datasets to investigate the methods behaviour in a large diversity of structure situations. To examine the structure of a dataset before analysis and preselect an a priori appropriate method for its analysis, we proposed a two-graph preliminary visualization tool: plotting patients on the Between-Group Analysis discriminant axis (x-axis) and on the first and the second within-group Principal Components Analysis component (y-axis), respectively. CONCLUSION: Discriminant Analysis outperformed Between-Group Analysis because it allows for the dataset structure. An a priori knowledge of that structure may guide the choice of the analysis method. Simulated datasets with known properties are valuable to assess and compare the performance of analysis methods, then implementation on real datasets checks and validates the results. Thus, we warn against the use of unchallenging datasets for method comparison, such as the Golub dataset, because their structure is such that any method would be efficient.

[Incidence of breast cancer in France and other industrialized countries]. / Incidence du cancer du sein en France et dans les pays développés.

The incidence of breast cancer increased over the last 20 years of the 20(th) century in all industrialized countries. The shape of the trend varied according to country. The increase in the prevalence of risk factors associated with a "western" lifestyle has had a major influence on this increase in countries where incidence was low at the start of the study period. Generalized screening practices, on the other hand, has played a key role in countries where incidence was already elevated in the 1970s. This evolution over time, together with the cohort effect (associated with year of birth), makes analysis and interpretation of the available international data too complex to allow us to quantify the respective contributions of screening, treatments and risk factors to mortality trends, which are beginning to decrease substantially in most countries with elevated incidence rates.

Differences in oxidative stress dependence between gastric adenocarcinoma subtypes.

AIM: To investigate the extent of oxidative stress in pre-neoplastic and neoplastic gastric mucosa in relation to their pathological criteria and histological subtypes. METHODS: A total of 104 gastric adenocarcinomas from 98 patients (88 infiltrative and 16 intraepithelial tumors) were assessed immunohistochemically for expression of iNOS and occurrence of nitrotyrosine (NTYR)-containing proteins and 8-hydroxy-2'-deoxyguanosine (8-OH-dG)-containing DNA, as markers of NO production and damages to protein and DNA. RESULTS: Tumor cells staining for iNOS, NTYR and 8-OH-dG were detected in 41%, 62% and 50% of infiltrative carcinoma, respectively. The three markers were shown for the first time in intraepithelial carcinoma. The expression of iNOS was significantly more frequent in tubular carcinoma (TC) compared to diffuse carcinoma (DC) (54% vs 18%; P = 0.008) or in polymorphous carcinoma (PolyC) (54% vs 21%; P = 0.04). NTYR staining was obviously more often found in TC than that in PolyC (72% vs 30%; P = 0.03). There was a tendency towards a higher rate of iNOS staining when distant metastasis (pM) was present. In infiltrative TC, the presence of oxidative stress markers was not significantly correlated with histological grade, density of inflammation, the depth of infiltration (pT), lymph nodes dissemination (pN) and pathological stages (pTNM). CONCLUSION: The iNOS-oxidative pathway may play an important role in TC, but moderately in PolyC and DC. DNA oxidation and protein nitration occur in the three subtypes. Based on the significant differences of NTYR levels, TC and PolyC appear as two distinct subtypes.

How to measure non-consistency of medical practices with available evidence in therapeutics: a methodological framework.

Since the early 1980s many studies showed a gap between available evidence and medical practice. They were designed to assess the real impact of randomized clinical trials on the practice of medicine. Their results substantiated a knowledge translation problem. However, they were qualitative findings, i.e. a gap exists or not, although the problem is quantitative (how large is the gap?) and has several components that should be documented according to the objective of the study. In this article, we explored the components and the various contexts in which the measure of the distance between practice and knowledge is considered. All these features should be taken into account for a more accurate and relevant assessment of the distance.

Improvement in colorectal cancer survival: a population-based study.

The aim of this study was to explore the reasons for improvement in colorectal cancer survival. Trends in relative survival among 5874 patients diagnosed with colorectal cancer over a 24-year period in a well-defined French population were analysed. The 5-year relative survival rate, excluding operative mortality, increased from 49.2% to 56.3% between the periods 1976-1987 and 1988-1999. In multivariate analysis, stage at diagnosis and adjuvant chemotherapy were both associated with better survival after surgery with curative intent. Survival trends differed markedly by age. The improvement in overall survival for older patients can be attributed to the increase in the proportion of patients resected for cure. For younger patients, there was an increase in the proportion of patients operated for cure, but also an improvement in stage-specific survival, particularly for stage III tumours, suggesting an impact of adjuvant chemotherapy.

Incidence of gastrointestinal cancers in France.

AIM: Monitoring cancer incidence and time trends is essential for cancer research and health care planning. The aim of the study was to compare the incidence of gastrointestinal cancers in twelve administrative area in France to estimate the national cancer incidence during 2000 compared with the preceding 20 years. METHODS: Incidence data was provided by cancer registries and mortality data by the French national medical research institute (INSERM). The two data sets were modeled separately over the period 1988-1997 using age-cohort models. The incidence/mortality ratio obtained from these models was applied to the mortality rates of an age-cohort model of the entire population. RESULTS: The estimated number of new cases of gastrointestinal cancer was 61,465 in 2000. Colorectal cancer was the leading localization with 36,257 cases. The incidence of gastrointestinal cancers was slightly higher in northern than in southern area. Incidence of esophageal cancer was three times that of liver cancer. Variations in incidence were less marked for other localizations. The incidence of gastric and esophageal cancer in the male population decreased between 1980 and 2000, on average by slightly more than 2% per year. Incidence of other cancers increased. The number of new cases of colorectal cancer increased by 50%. The rise in the incidence of liver cancer was particularly striking, with an increase from 2000 incident cases in 1980 to nearly 6000 in 2000. CONCLUSION: For most localizations, incidence of gastrointestinal cancers displays few geographical differences in France, but there has been a striking change in incidence trends over the past 20 years.